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Sonstige beteiligte Institutionen
- Johns Hopkins School of Medicine (11)
- IZKF Nachwuchsgruppe Geweberegeneration für muskuloskelettale Erkrankungen (7)
- Clinical Trial Center (CTC) / Zentrale für Klinische Studien Würzburg (ZKSW) (5)
- Wilhelm-Conrad-Röntgen-Forschungszentrum für komplexe Materialsysteme (5)
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- Johns Hopkins University School of Medicine (4)
- Zentraleinheit Klinische Massenspektrometrie (4)
- Center for Interdisciplinary Clinical Research, Würzburg University, Würzburg, Germany (2)
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ResearcherID
- D-1221-2009 (1)
The opportunities genetic engineering has created in the field of adoptive cellular therapy for cancer are accelerating the development of novel treatment strategies using chimeric antigen receptor (CAR) and T cell receptor (TCR) T cells. The great success in the context of hematologic malignancies has made especially CAR T cell therapy a promising approach capable of achieving long-lasting remission. However, the causalities involved in mediating resistance to treatment or relapse are still barely investigated. Research on T cell exhaustion and dysfunction has drawn attention to host-derived factors that define both the immune and tumor microenvironment (TME) crucially influencing efficacy and toxicity of cellular immunotherapy. The microbiome, as one of the most complex host factors, has become a central topic of investigations due to its ability to impact on health and disease. Recent findings support the hypothesis that commensal bacteria and particularly microbiota-derived metabolites educate and modulate host immunity and TME, thereby contributing to the response to cancer immunotherapy. Hence, the composition of microbial strains as well as their soluble messengers are considered to have predictive value regarding CAR T cell efficacy and toxicity. The diversity of mechanisms underlying both beneficial and detrimental effects of microbiota comprise various epigenetic, metabolic and signaling-related pathways that have the potential to be exploited for the improvement of CAR T cell function. In this review, we will discuss the recent findings in the field of microbiome-cancer interaction, especially with respect to new trajectories that commensal factors can offer to advance cellular immunotherapy.
Bullous pemphigoid is the most common autoimmune blistering disease in industrialized countries and particularly affects the elderly. In this patient population, comorbid diseases are frequent and may complicate management and treatment of bullous pemphigoid. A better understanding why distinct diseases are more frequent in bullous pemphigoid patients may lead to new pathophysiological insights and - as a consequence - result in better patient care. The association of bullous pemphigoid with neurological and psychiatric diseases is well known and confirmed by several case-control studies. Association with further diseases such as malignancy and metabolic diseases are still discussed controversially. In recent years new relationships between bullous pemphigoid and autoimmune as well as inflammatory skin diseases have been reported. This review provides a systematic overview on studies addressing comorbidity in bullous pemphigoid patients. Increasing the awareness of both, common and rare comorbid diseases, may enable clinicians to optimize patient support and individualized treatment of bullous pemphigoid.
Sufficient plant-available water is one of the most important requirements for vital, stable, and well-growing forest stands. In the face of climate change, there are various approaches to derive recommendations considering tree species selection based on plant-available water provided by measurements or simulations. Owing to the small-parcel management of Central European forests as well as small-spatial variation of soil and stand properties, in situ data collection for individual forest stands of large areas is not feasible, considering time and cost effort. This problem can be addressed using physically based modeling, aiming to numerically simulate the water balance. In this study, we parameterized, calibrated, and verified the hydrological multidimensional WaSiM-ETH model to assess the water balance at a spatial resolution of 30 m in a German forested catchment area (136.4 km2) for the period 2000–2021 using selected in situ data, remote sensing products, and total runoff. Based on the model output, drought-sensitive parameters, such as the difference between potential and effective stand transpiration (Tdiff) and the water balance, were deduced from the model, analyzed, and evaluated. Results show that the modeled evapotranspiration (ET) correlated significantly (R2 = 0.80) with the estimated ET using MODIS data (MOD16A2GFv006). Compared with observed daily, monthly, and annual runoff data, the model shows a good performance (R2: 0.70|0.77|0.73; Kling–Gupta efficiency: 0.59|0.62|0.83; volumetric efficiency: 0.52|0.60|0.83). The comparison with in situ data from a forest monitoring plot, established at the end of 2020, indicated good agreement between observed and simulated interception and soil water content. According to our results, WaSiM-ETH is a potential supplement for forest management, owing to its multidimensionality and the ability to model soil water balance for large areas at comparable high spatial resolution. The outputs offer, compared to non-distributed models (like LWF-Brook90), spatial differentiability, which is important for small-scale parceled forests, regarding stand structure and soil properties. Due to the spatial component offered, additional verification possibilities are feasible allowing a reliable and profound verification of the model and its parameterization.
In the Amazon basin, particles containing mixed sodium salts are routinely observed and are attributed to marine aerosols transported from the Atlantic Ocean. Using chemical imaging analysis, we show that, during the wet season, fungal spores emitted by the forest biosphere contribute at least 30% (by number) to sodium salt particles in the central Amazon basin. Hydration experiments indicate that sodium content in fungal spores governs their growth factors. Modeling results suggest that fungal spores account for ~69% (31–95%) of the total sodium mass during the wet season and that their fractional contribution increases during nighttime. Contrary to common assumptions that sodium-containing aerosols originate primarily from marine sources, our results suggest that locally-emitted fungal spores contribute substantially to the number and mass of coarse particles containing sodium. Hence, their role in cloud formation and contribution to salt cycles and the terrestrial ecosystem in the Amazon basin warrant further consideration.
Reinforcing hydrogels with micro-fibre scaffolds obtained by a Melt-Electrospinning Writing (MEW) process has demonstrated great promise for developing tissue engineered (TE) constructs with mechanical properties compatible to native tissues. However, the mechanical performance and reinforcement mechanism of the micro-fibre reinforced hydrogels is not yet fully understood. In this study, FE models, implementing material properties measured experimentally, were used to explore the reinforcement mechanism of fibre-hydrogel composites. First, a continuum FE model based on idealized scaffold geometry was used to capture reinforcement effects related to the suppression of lateral gel expansion by the scaffold, while a second micro-FE model based on micro-CT images of the real construct geometry during compaction captured the effects of load transfer through the scaffold interconnections. Results demonstrate that the reinforcement mechanism at higher scaffold volume fractions was dominated by the load carrying-ability of the fibre scaffold interconnections, which was much higher than expected based on testing scaffolds alone because the hydrogel provides resistance against buckling of the scaffold. We propose that the theoretical understanding presented in this work will assist the design of more effective composite constructs with potential applications in a wide range of TE conditions.
While our knowledge about the roles of microbes and viruses in the ocean has increased tremendously due to recent advances in genomics and metagenomics, research on marine microbial eukaryotes and zooplankton has benefited much less from these new technologies because of their larger genomes, their enormous diversity, and largely unexplored physiologies. Here, we use a metatranscriptomics approach to capture expressed genes in open ocean Tara Oceans stations across four organismal size fractions. The individual sequence reads cluster into 116 million unigenes representing the largest reference collection of eukaryotic transcripts from any single biome. The catalog is used to unveil functions expressed by eukaryotic marine plankton, and to assess their functional biogeography. Almost half of the sequences have no similarity with known proteins, and a great number belong to new gene families with a restricted distribution in the ocean. Overall, the resource provides the foundations for exploring the roles of marine eukaryotes in ocean ecology and biogeochemistry.
HyphaTracker: An ImageJ toolbox for time-resolved analysis of spore germination in filamentous fungi
(2018)
The dynamics of early fungal development and its interference with physiological signals and environmental factors is yet poorly understood. Especially computational analysis tools for the evaluation of the process of early spore germination and germ tube formation are still lacking. For the time-resolved analysis of conidia germination of the filamentous ascomycete Fusarium fujikuroi we developed a straightforward toolbox implemented in ImageJ. It allows for processing of microscopic acquisitions (movies) of conidial germination starting with drift correction and data reduction prior to germling analysis. From the image time series germling related region of interests (ROIs) are extracted, which are analysed for their area, circularity, and timing. ROIs originating from germlings crossing other hyphae or the image boundaries are omitted during analysis. Each conidium/hypha is identified and related to its origin, thus allowing subsequent categorization. The efficiency of HyphaTracker was proofed and the accuracy was tested on simulated germlings at different signal-to-noise ratios. Bright-field microscopic images of conidial germination of rhodopsin-deficient F. fujikuroi mutants and their respective control strains were analysed with HyphaTracker. Consistent with our observation in earlier studies the CarO deficient mutant germinated earlier and grew faster than other, CarO expressing strains.
Metabolic conversion of CI-1040 turns a cellular MEK-inhibitor into an antibacterial compound
(2018)
Influenza virus (IV) infections cause severe respiratory illnesses that can be complicated by bacterial super-infections. Previously, we identified the cellular Raf-MEK-ERK cascade as a promising antiviral target. Inhibitors of MEK, such as CI-1040, showed potent antiviral activity. However, it remained unclear if this inhibitor and its active form, ATR-002, might sensitize host cells to either IV or secondary bacterial infections. To address these questions, we studied the anti-pathogen activity of ATR-002 in comparison to CI-1040, particularly, its impact on Staphylococcus aureus (S. aureus), which is a major cause of IV super-infections. We analysed IV and S. aureus titres in vitro during super-infection in the presence and absence of the drugs and characterized the direct impact of ATR-002 on bacterial growth and phenotypic changes. Importantly, neither CI-1040 nor ATR-002 treatment led to increased bacterial titres during super-infection, indicating that the drug does not sensitize cells for bacterial infection. In contrast, we rather observed reduced bacterial titres in presence of ATR-002. Surprisingly, ATR-002 also led to reduced bacterial growth in suspension cultures, reduced stress- and antibiotic tolerance without resistance induction. Our data identified for the first time that a particular MEK-inhibitor metabolite exhibits direct antibacterial activity, which is likely due to interference with the bacterial PknB kinase/Stp phosphatase signalling system.
Coordinated regulation of the lysosomal and autophagic systems ensures basal catabolism and normal cell physiology, and failure of either system causes disease. Here we describe an epigenetic rheostat orchestrated by c-MYC and histone deacetylases that inhibits lysosomal and autophagic biogenesis by concomitantly repressing the expression of the transcription factors MiT/TFE and FOXH1, and that of lysosomal and autophagy genes. Inhibition of histone deacetylases abates c-MYC binding to the promoters of lysosomal and autophagy genes, granting promoter occupancy to the MiT/TFE members, TFEB and TFE3, and/or the autophagy regulator FOXH1. In pluripotent stem cells and cancer, suppression of lysosomal and autophagic function is directly downstream of c-MYC overexpression and may represent a hallmark of malignant transformation. We propose that, by determining the fate of these catabolic systems, this hierarchical switch regulates the adaptive response of cells to pathological and physiological cues that could be exploited therapeutically.
TNF-like weak inducer of apoptosis (TWEAK) and inhibition of protein synthesis with cycloheximide (CHX) sensitize for poly(I:C)-induced cell death. Notably, although CHX preferentially enhanced poly(I:C)-induced apoptosis, TWEAK enhanced primarily poly(I:C)-induced necroptosis. Both sensitizers of poly(I:C)-induced cell death, however, showed no major effect on proinflammatory poly(I:C) signaling. Analysis of a panel of HeLa-RIPK3 variants lacking TRADD, RIPK1, FADD, or caspase-8 expression revealed furthermore similarities and differences in the way how poly(I:C)/TWEAK, TNF, and TRAIL utilize these molecules for signaling. RIPK1 turned out to be essential for poly(I:C)/TWEAK-induced caspase-8-mediated apoptosis but was dispensable for this response in TNF and TRAIL signaling. TRADD-RIPK1-double deficiency differentially affected poly(I:C)-triggered gene induction but abrogated gene induction by TNF completely. FADD deficiency abrogated TRAIL- but not TNF- and poly(I:C)-induced necroptosis, whereas TRADD elicited protective activity against all three death inducers. A general protective activity against poly(I:C)-, TRAIL-, and TNF-induced cell death was also observed in FLIPL and FLIPS transfectrants.
Migration and interactions of immune cells are routinely studied by time-lapse microscopy of in vitro migration and confrontation assays. To objectively quantify the dynamic behavior of cells, software tools for automated cell tracking can be applied. However, many existing tracking algorithms recognize only rather short fragments of a whole cell track and rely on cell staining to enhance cell segmentation. While our previously developed segmentation approach enables tracking of label-free cells, it still suffers from frequently recognizing only short track fragments. In this study, we identify sources of track fragmentation and provide solutions to obtain longer cell tracks. This is achieved by improving the detection of low-contrast cells and by optimizing the value of the gap size parameter, which defines the number of missing cell positions between track fragments that is accepted for still connecting them into one track. We find that the enhanced track recognition increases the average length of cell tracks up to 2.2-fold. Recognizing cell tracks as a whole will enable studying and quantifying more complex patterns of cell behavior, e.g. switches in migration mode or dependence of the phagocytosis efficiency on the number and type of preceding interactions. Such quantitative analyses will improve our understanding of how immune cells interact and function in health and disease.
Introduction
Diagnosis and treatment of insertional tendinopathy of the Achilles tendon (IAT) remains a challenge. The aim of this study was to assess the influence of pre-operative radiological pathologies on the patient-reported outcomes following open debridement of all pathologies for IAT.
Materials and methods
In this IRB-approved retrospective correlation and comparative study, patients with pre-operative imaging were identified from the authors’ retrospective IAT database comprising of 118 patients. All were treated by a standardized surgical treatment strategy utilizing a midline, transachillary approach and debridement of all pathologies. A total of fifteen radiologic parameters were measured on radiographs (RX) and MRI. The patient-reported outcomes were assessed using the Victorian Institute of Sport Assessment-Achilles questionnaire (VISA-A-G) and the general health questionnaire SF-12 at a minimum follow-up of 12 months. The data are presented as mean ± SD (95% CI).
Results
88 patients (74.6%) with an average age of 50 ± 12 (47–52) years were included. Radiographs were available in 68 patients and MRI in 53. The mean follow-up was 3.8 ± 1.9 (3.4–4.3) years. The overall VISA-A-G was 81 ± 22 (77–86), the SF-12 PCS 54 ± 7 (52–55), and the SF-12 MCS 52 ± 9 (50–54) points. None of the assessed radiological parameters had a significant influence on the patient-reported outcome following surgical treatment for IAT.
Conclusion
In this retrospective correlation study, no significant association was found between preoperative radiographic and MRI radiologic parameters for IAT and postoperative patient-reported outcomes (VISA-A-G and SF-12).
Purpose
Over the course of COVID-19 pandemic, evidence has accumulated that SARS-CoV-2 infections may affect multiple organs and have serious clinical sequelae, but on-site clinical examinations with non-hospitalized samples are rare. We, therefore, aimed to systematically assess the long-term health status of samples of hospitalized and non-hospitalized SARS-CoV-2 infected individuals from three regions in Germany.
Methods
The present paper describes the COVIDOM-study within the population-based cohort platform (POP) which has been established under the auspices of the NAPKON infrastructure (German National Pandemic Cohort Network) of the national Network University Medicine (NUM). Comprehensive health assessments among SARS-CoV-2 infected individuals are conducted at least 6 months after the acute infection at the study sites Kiel, Würzburg and Berlin. Potential participants were identified and contacted via the local public health authorities, irrespective of the severity of the initial infection. A harmonized examination protocol has been implemented, consisting of detailed assessments of medical history, physical examinations, and the collection of multiple biosamples (e.g., serum, plasma, saliva, urine) for future analyses. In addition, patient-reported perception of the impact of local pandemic-related measures and infection on quality-of-life are obtained.
Results
As of July 2021, in total 6813 individuals infected in 2020 have been invited into the COVIDOM-study. Of these, about 36% wished to participate and 1295 have already been examined at least once.
Conclusion
NAPKON-POP COVIDOM-study complements other Long COVID studies assessing the long-term consequences of an infection with SARS-CoV-2 by providing detailed health data of population-based samples, including individuals with various degrees of disease severity.
Trial registration
Registered at the German registry for clinical studies (DRKS00023742).
Background
Increasing incidence of invasive infections caused by rare fungi was observed over the recent years.
Case
Here, we describe the first reported case of an infection caused by the thermophilic mold Talaromyces thermophilus. Cultivation and, hence, identification of this fastidious organism is challenging since standard incubation conditions are not sufficient. Retrospective analysis of patient samples and in vitro experiments demonstrated that testing for fungal antigens, i.e., the cell wall components galactomannan and β-1,3-D-glucan, is a promising tool.
Purpose
The ongoing pandemic caused by the novel severe acute respiratory coronavirus 2 (SARS-CoV-2) has stressed health systems worldwide. Patients with chronic kidney disease (CKD) seem to be more prone to a severe course of coronavirus disease (COVID-19) due to comorbidities and an altered immune system. The study’s aim was to identify factors predicting mortality among SARS-CoV-2-infected patients with CKD.
Methods
We analyzed 2817 SARS-CoV-2-infected patients enrolled in the Lean European Open Survey on SARS-CoV-2-infected patients and identified 426 patients with pre-existing CKD. Group comparisons were performed via Chi-squared test. Using univariate and multivariable logistic regression, predictive factors for mortality were identified.
Results
Comparative analyses to patients without CKD revealed a higher mortality (140/426, 32.9% versus 354/2391, 14.8%). Higher age could be confirmed as a demographic predictor for mortality in CKD patients (> 85 years compared to 15–65 years, adjusted odds ratio (aOR) 6.49, 95% CI 1.27–33.20, p = 0.025). We further identified markedly elevated lactate dehydrogenase (> 2 × upper limit of normal, aOR 23.21, 95% CI 3.66–147.11, p < 0.001), thrombocytopenia (< 120,000/µl, aOR 11.66, 95% CI 2.49–54.70, p = 0.002), anemia (Hb < 10 g/dl, aOR 3.21, 95% CI 1.17–8.82, p = 0.024), and C-reactive protein (≥ 30 mg/l, aOR 3.44, 95% CI 1.13–10.45, p = 0.029) as predictors, while renal replacement therapy was not related to mortality (aOR 1.15, 95% CI 0.68–1.93, p = 0.611).
Conclusion
The identified predictors include routinely measured and universally available parameters. Their assessment might facilitate risk stratification in this highly vulnerable cohort as early as at initial medical evaluation for SARS-CoV-2.
Giant cell arteritis (GCA) may affect the brain-supplying arteries, resulting in ischemic stroke, whereby the vertebrobasilar territory is most often involved. Since etiology is unknown in 25% of stroke patients and GCA is hardly considered as a cause, we examined in a pilot study, whether screening for GCA after vertebrobasilar stroke might unmask an otherwise missed disease. Consecutive patients with vertebrobasilar stroke were prospectively screened for GCA using erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), hemoglobin, and halo sign of the temporal and vertebral artery on ultrasound. Furthermore, we conducted a systematic literature review for relevant studies. Sixty-five patients were included, and two patients (3.1%) were diagnosed with GCA. Patients with GCA were older in age (median 85 versus 69 years, p = 0.02). ESR and CRP were significantly increased and hemoglobin was significantly lower in GCA patients compared to non-GCA patients (median, 75 versus 11 mm in 1 h, p = 0.001; 3.84 versus 0.25 mg/dl, p = 0.01, 10.4 versus 14.6 mg/dl, p = 0.003, respectively). Multiple stenoses/occlusions in the vertebrobasilar territory affected our two GCA patients (100%), but only five (7.9%) non-GCA patients (p = 0.01). Our literature review identified 13 articles with 136 stroke patients with concomitant GCA. Those were old in age. Headache, increased inflammatory markers, and anemia were frequently reported. Multiple stenoses/occlusions in the vertebrobasilar territory affected around 70% of stroke patients with GCA. Increased inflammatory markers, older age, anemia, and multiple stenoses/occlusions in the vertebrobasilar territory may be regarded as red flags for GCA among patients with vertebrobasilar stroke.
Species' functional traits set the blueprint for pair-wise interactions in ecological networks. Yet, it is unknown to what extent the functional diversity of plant and animal communities controls network assembly along environmental gradients in real-world ecosystems. Here we address this question with a unique dataset of mutualistic bird-fruit, bird-flower and insect-flower interaction networks and associated functional traits of 200 plant and 282 animal species sampled along broad climate and land-use gradients on Mt. Kilimanjaro. We show that plant functional diversity is mainly limited by precipitation, while animal functional diversity is primarily limited by temperature. Furthermore, shifts in plant and animal functional diversity along the elevational gradient control the niche breadth and partitioning of the respective other trophic level. These findings reveal that climatic constraints on the functional diversity of either plants or animals determine the relative importance of bottom-up and top-down control in plant-animal interaction networks.
Eu\(^{3+}\)-modified carbon dots (C-dots), 3–5 nm in diameter, were prepared, functionalized, and stabilized via a one-pot polyol synthesis. The role of Eu\(^{2+}\)/Eu\(^{3+}\), the influence of O\(_2\) (oxidation) and H\(_2\)O (hydrolysis), as well as the impact of the heating procedure (conventional resistance heating and microwave (MW) heating) were explored. With the reducing conditions of the polyol at the elevated temperature of synthesis (200–230 °C), first of all, Eu\(^{2+}\) was obtained resulting in the blue emission of the C-dots. Subsequent to O\(_2\)-driven oxidation, Eu\(^{3+}\)-modified, red-emitting C-dots were realized. However, the Eu\(^{3+}\) emission is rapidly quenched by water for C-dots prepared via conventional resistance heating. In contrast to the hydroxyl functionalization of conventionally-heated C-dots, MW-heating results in a carboxylate functionalization of the C-dots. Carboxylate-coordinated Eu\(^{3+}\), however, turned out as highly stable even in water. Based on this fundamental understanding of synthesis and material, in sum, a one-pot polyol approach is established that results in H\(_2\)O-dispersable C-dots with intense red Eu\(^{3+}\)-line-type emission.
Alien limb phenomenon is a rare syndrome associated with a feeling of non-belonging and disowning toward one's limb. In contrast, anarchic limb phenomenon leads to involuntary but goal-directed movements. Alien/anarchic limb phenomena are frequent in corticobasal syndrome (CBS), an atypical parkinsonian syndrome characterized by rigidity, akinesia, dystonia, cortical sensory deficit, and apraxia. The structure function relationship of alien/anarchic limb was investigated in multi centric structural magnetic resonance imaging (MRI) data. Whole-group and single subject comparisons were made in 25 CBS and eight CBS-alien/anarchic limb patients versus controls. Support vector machine was used to see if CBS with and without alien/anarchic limb could be distinguished by structural MRI patterns. Whole-group comparison of CBS versus controls revealed asymmetric frontotemporal atrophy. CBS with alien/anarchic limb syndrome versus controls showed frontoparietal atrophy including the supplementary motor area contralateral to the side of the affected limb. Exploratory analysis identified frontotemporal regions encompassing the pre-/and postcentral gyrus as compromised in CBS with alien limb syndrome. Classification of CBS patients yielded accuracies of 79%. CBS-alien/anarchic limb syndrome was differentiated from CBS patients with an accuracy of 81%. Predictive differences were found in the cingulate gyrus spreading to frontomedian cortex, postcentral gyrus, and temporoparietoocipital regions. We present the first MRI-based group analysis on CBS-alien/anarchic limb. Results pave the way for individual clinical syndrome prediction and allow understanding the underlying neurocognitive architecture. (C) 2019 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Highlights
• Dopamine receptor-1 activation induces TrkB cell-surface expression in striatal neurons
• Dopaminergic deficits cause TrkB accumulation and clustering in the ER
• TrkB clusters colocalize with cargo receptor SORCS-2 in direct pathway striatal neurons
• Intracellular TrkB clusters fail to fuse with lysosomes after dopamine depletion
Summary
Disturbed motor control is a hallmark of Parkinson’s disease (PD). Cortico-striatal synapses play a central role in motor learning and adaption, and brain-derived neurotrophic factor (BDNF) from cortico-striatal afferents modulates their plasticity via TrkB in striatal medium spiny projection neurons (SPNs). We studied the role of dopamine in modulating the sensitivity of direct pathway SPNs (dSPNs) to BDNF in cultures of fluorescence-activated cell sorting (FACS)-enriched D1-expressing SPNs and 6-hydroxydopamine (6-OHDA)-treated rats. DRD1 activation causes enhanced TrkB translocation to the cell surface and increased sensitivity for BDNF. In contrast, dopamine depletion in cultured dSPN neurons, 6-OHDA-treated rats, and postmortem brain of patients with PD reduces BDNF responsiveness and causes formation of intracellular TrkB clusters. These clusters associate with sortilin related VPS10 domain containing receptor 2 (SORCS-2) in multivesicular-like structures, which apparently protects them from lysosomal degradation. Thus, impaired TrkB processing might contribute to disturbed motor function in PD.
Neuroinflammation has been suggested as a pathogenetic mechanism contributing to Parkinson’s disease (PD). However, anti-inflammatory treatment strategies have not yet been established as a therapeutic option for PD patients. We have used a human α-synuclein mouse model of progressive PD to examine the anti-inflammatory and neuroprotective effects of inflammasome inhibition on dopaminergic (DA) neurons in the substantia nigra (SN). As the NLRP3 (NOD-, LRR- and pyrin domain-containing 3)-inflammasome is a core interface for both adaptive and innate inflammation and is also highly druggable, we investigated the implications of its inhibition. Repeat administration of MCC950, an inhibitor of NLRP3, in a PD model with ongoing pathology reduced CD4\(^+\) and CD8\(^+\) T cell infiltration into the SN. Furthermore, the anti-inflammasome treatment mitigated microglial activation and modified the aggregation of α-synuclein protein in DA neurons. MCC950-treated mice showed significantly less neurodegeneration of DA neurons and a reduction in PD-related motor behavior. In summary, early inflammasome inhibition can reduce neuroinflammation and prevent DA cell death in an α-synuclein mouse model for progressive PD.
The steadily increasing usage of smart meters generates a valuable amount of high-resolution data about the individual energy consumption and production of local energy systems. Private households install more and more photovoltaic systems, battery storage and big consumers like heat pumps. Thus, our vision is to augment these collected smart meter time series of a complete system (e.g., a city, town or complex institutions like airports) with simulatively added previously named components. We, therefore, propose a novel digital twin of such an energy system based solely on a complete set of smart meter data including additional building data. Based on the additional geospatial data, the twin is intended to represent the addition of the abovementioned components as realistically as possible. Outputs of the twin can be used as a decision support for either system operators where to strengthen the system or for individual households where and how to install photovoltaic systems and batteries. Meanwhile, the first local energy system operators had such smart meter data of almost all residential consumers for several years. We acquire those of an exemplary operator and discuss a case study presenting some features of our digital twin and highlighting the value of the combination of smart meter and geospatial data.
Background
With the emergence of photon-counting CT, ultrahigh-resolution (UHR) imaging can be performed without dose penalty. This study aims to directly compare the image quality of UHR and standard resolution (SR) scan mode in femoral artery angiographies.
Methods
After establishing continuous extracorporeal perfusion in four fresh-frozen cadaveric specimens, photon-counting CT angiographies were performed with a radiation dose of 5 mGy and tube voltage of 120 kV in both SR and UHR mode. Images were reconstructed with dedicated convolution kernels (soft: Body-vascular (Bv)48; sharp: Bv60; ultrasharp: Bv76). Six radiologists evaluated the image quality by means of a pairwise forced-choice comparison tool. Kendall’s concordance coefficient (W) was calculated to quantify interrater agreement. Image quality was further assessed by measuring intraluminal attenuation and image noise as well as by calculating signal-to-noise ratio (SNR) and contrast-to-noise ratios (CNR).
Results
UHR yielded lower noise than SR for identical reconstructions with kernels ≥ Bv60 (p < 0.001). UHR scans exhibited lower intraluminal attenuation compared to SR (Bv60: 406.4 ± 25.1 versus 418.1 ± 30.1 HU; p < 0.001). Irrespective of scan mode, SNR and CNR decreased while noise increased with sharper kernels but UHR scans were objectively superior to SR nonetheless (Bv60: SNR 25.9 ± 6.4 versus 20.9 ± 5.3; CNR 22.7 ± 5.8 versus 18.4 ± 4.8; p < 0.001). Notably, UHR scans were preferred in subjective assessment when images were reconstructed with the ultrasharp Bv76 kernel, whereas SR was rated superior for Bv60. Interrater agreement was high (W = 0.935).
Conclusions
Combinations of UHR scan mode and ultrasharp convolution kernel are able to exploit the full image quality potential in photon-counting CT angiography of the femoral arteries.
Relevance statement
The UHR scan mode offers improved image quality and may increase diagnostic accuracy in CT angiography of the peripheral arterial runoff when optimized reconstruction parameters are chosen.
Key points
• UHR photon-counting CT improves image quality in combination with ultrasharp convolution kernels.
• UHR datasets display lower image noise compared with identically reconstructed standard resolution scans.
• Scans in UHR mode show decreased intraluminal attenuation compared with standard resolution imaging.
With ubiquitous computing, problems can be solved using more strategies than ever, though many strategies feature subpar performance. Here, we explored whether and how simple advice regarding when to use which strategy can improve performance. Specifically, we presented unfamiliar alphanumeric equations (e.g., A + 5 = F) and asked whether counting up the alphabet from the left letter by the indicated number resulted in the right letter. In an initial choice block, participants could engage in one of three cognitive strategies: (a) internal counting, (b) internal retrieval of previously generated solutions, or (c) computer-mediated external retrieval of solutions. Participants belonged to one of two groups: they were either instructed to first try internal retrieval before using external retrieval, or received no specific use instructions. In a subsequent internal block with identical instructions for both groups, external retrieval was made unavailable. The ‘try internal retrieval first’ instruction in the choice block led to pronounced benefits (d = .76) in the internal block. Benefits were due to facilitated creation and retrieval of internal memory traces and possibly also due to improved strategy choice. These results showcase how simple strategy advice can greatly help users navigate cognitive environments. More generally, our results also imply that uninformed use of external tools (i.e., technology) can bear the risk of not developing and using even more superior internal processing strategies.
Background
Exercise intensities are prescribed using specific intensity zones (moderate, heavy, and severe) determined by a ‘lower’ and a ‘higher’ threshold. Typically, ventilatory (VT) or blood lactate thresholds (LT), and critical power/speed concepts (CP/CS) are used. Various heart rate variability-derived thresholds (HRVTs) using different HRV indices may constitute applicable alternatives, but a systematic review of the proximity of HRVTs to established threshold concepts is lacking.
Objective
This systematic review aims to provide an overview of studies that determined HRVTs during endurance exercise in healthy adults in comparison with a reference VT and/or LT concept.
Methods
A systematic literature search for studies determining HRVTs in healthy individuals during endurance exercise and comparing them with VTs or LTs was conducted in Scopus, PubMed and Web of Science (until January 2022). Studies claiming to describe similar physiological boundaries to delineate moderate from heavy (HRVTlow vs. VTlow and/or LTlow), and heavy from severe intensity zone (HRVThigh vs. VThigh and/or LThigh) were grouped and their results synthesized.
Results
Twenty-seven included studies (461 participants) showed a mean difference in relative HR between HRVTlow and VTlow of − 0.6%bpm in weighted means and 0.02%bpm between HRVTlow and LTlow. Bias between HR at HRVTlow and VTlow was 1 bpm (limits of agreement (LoA): − 10.9 to 12.8 bpm) and 2.7 bpm (LoA: − 20.4 to 25.8 bpm) between HRVTlow and LTlow. Mean difference in HR between HRVThigh and VThigh was 0.3%bpm in weighted means and 2.9%bpm between HRVThigh and LThigh while bias between HR at HRVThigh and VThigh was − 4 bpm (LoA: − 17.9 to 9.9 bpm) and 2.5 bpm (LoA: − 12.1 to 17.1 bpm) between HRVThigh and LThigh.
Conclusion
HRVTlow seems to be a promising approach for the determination of a ‘lower’ threshold comparable to VTlow and potentially for HRVThigh compared to VThigh, although the latter needs further empirical evaluation. LoA for both intensity zone boundaries indicates bias of HRVTs on an individual level. Taken together, HRVTs can be a promising alternative for prescribing exercise intensity in healthy, male athletes undertaking endurance activities but due to the heterogeneity of study design, threshold concepts, standardization, and lack of female participants, further research is necessary to draw more robust and nuanced conclusions.
Objectives
We developed a novel human cadaveric perfusion model with continuous extracorporeal femoral perfusion suitable for performing intra-individual comparison studies, training of interventional procedures and preclinical testing of endovascular devices. Objective of this study was to introduce the techniques and evaluate the feasibility for realistic computed tomography angiography (CTA), digital subtraction angiography (DSA) including vascular interventions, and intravascular ultrasound (IVUS).
Methods
The establishment of the extracorporeal perfusion was attempted using one formalin-fixed and five fresh-frozen human cadavers. In all specimens, the common femoral and popliteal arteries were prepared, introducer sheaths inserted, and perfusion established by a peristaltic pump. Subsequently, we performed CTA and bilateral DSA in five cadavers and IVUS on both legs of four donors. Examination time without unintentional interruption was measured both with and without non-contrast planning CT. Percutaneous transluminal angioplasty and stenting was performed by two interventional radiologists on nine extremities (five donors) using a broad spectrum of different intravascular devices.
Results
The perfusion of the upper leg arteries was successfully established in all fresh-frozen but not in the formalin-fixed cadaver. The experimental setup generated a stable circulation in each procedure (ten upper legs) for a period of more than six hours. Images acquired with CT, DSA and IVUS offered a realistic impression and enabled the sufficient visualization of all examined vessel segments. Arterial cannulating, percutaneous transluminal angioplasty as well as stent deployment were feasible in a way that is comparable to a vascular intervention in vivo. The perfusion model allowed for introduction and testing of previously not used devices.
Conclusions
The continuous femoral perfusion model can be established with moderate effort, works stable, and is utilizable for medical imaging of the peripheral arterial system using CTA, DSA and IVUS. Therefore, it appears suitable for research studies, developing skills in interventional procedures and testing of new or unfamiliar vascular devices.
We assessed the relation of creativity and unethical behaviour by manipulating the thinking style of participants (N = 450 adults) and measuring the impact of this manipulation on the prevalence of dishonest behaviour. Participants performed one of three inducer tasks: the alternative uses task to promote divergent thinking, the remote associates task to promote convergent thinking, or a simple classification task for rule-based thinking. Before and after this manipulation, participants conducted the mind game as a straightforward measure of dishonesty. Dishonest behaviour increased from before to after the intervention, but we found no credible evidence that this increase differed between induced mindsets. Exploratory analyses did not support any relation of trait creativity and dishonesty either. We conclude that the influence of creative thinking on unethical behaviour seems to be more ambiguous than assumed in earlier research or might be restricted to specific populations or contexts.
Highlights
• Transcranial ultrasound neuromodulation/stimulation (TUS) is a growing field.
• We conducted a double-blind sham-controlled within-subjects large sample TUS study.
• Right prefrontal cortex TUS inhibits midfrontal theta electroencephalography (MFT).
• TUS MFT inhibition explains greater approach versus withdrawal in a virtual T-maze.
• This distinct TUS-MFT-behavior link merits future basic and applied research.
Abstract
Recent reviews highlighted low-intensity transcranial focused ultrasound (TUS) as a promising new tool for non-invasive neuromodulation in basic and applied sciences. Our preregistered double-blind within-subjects study (N = 152) utilized TUS targeting the right prefrontal cortex, which, in earlier work, was found to positively enhance self-reported global mood, decrease negative states of self-reported emotional conflict (anxiety/worrying), and modulate related midfrontal functional magnetic resonance imaging activity in affect regulation brain networks. To further explore TUS effects on objective physiological and behavioral variables, we used a virtual T-maze task that has been established in prior studies to measure motivational conflicts regarding whether participants execute approach versus withdrawal behavior (with free-choice responses via continuous joystick movements) while allowing to record related electroencephalographic data such as midfrontal theta activity (MFT). MFT, a reliable marker of conflict representation on a neuronal level, was of particular interest to us since it has repeatedly been shown to explain related behavior, with relatively low MFT typically preceding approach-like risky behavior and relatively high MFT typically preceding withdrawal-like risk aversion. Our central hypothesis is that TUS decreases MFT in T-maze conflict situations and thereby increases approach and reduces withdrawal. Results indicate that TUS led to significant MFT decreases, which significantly explained increases in approach behavior and decreases in withdrawal behavior. This study expands TUS evidence on a physiological and behavioral level with a large sample size of human subjects, suggesting the promise of further research based on this distinct TUS-MFT-behavior link to influence conflict monitoring and its behavioral consequences. Ultimately, this can serve as a foundation for future clinical work to establish TUS interventions for emotional and motivational mental health.
Introduction
Commissioning, calibration, and quality control procedures for nuclear medicine imaging systems are typically performed using hollow containers filled with radionuclide solutions. This leads to multiple sources of uncertainty, many of which can be overcome by using traceable, sealed, long-lived surrogate sources containing a radionuclide of comparable energies and emission probabilities. This study presents the results of a quantitative SPECT/CT imaging comparison exercise performed within the MRTDosimetry consortium to assess the feasibility of using 133Ba as a surrogate for 131I imaging.
Materials and methods
Two sets of four traceable 133Ba sources were produced at two National Metrology Institutes and encapsulated in 3D-printed cylinders (volume range 1.68–107.4 mL). Corresponding hollow cylinders to be filled with liquid 131I and a mounting baseplate for repeatable positioning within a Jaszczak phantom were also produced. A quantitative SPECT/CT imaging comparison exercise was conducted between seven members of the consortium (eight SPECT/CT systems from two major vendors) based on a standardised protocol. Each site had to perform three measurements with the two sets of 133Ba sources and liquid 131I.
Results
As anticipated, the 131I pseudo-image calibration factors (cps/MBq) were higher than those for 133Ba for all reconstructions and systems. A site-specific cross-calibration reduced the performance differences between both radionuclides with respect to a cross-calibration based on the ratio of emission probabilities from a median of 12–1.5%. The site-specific cross-calibration method also showed agreement between 133Ba and 131I for all cylinder volumes, which highlights the potential use of 133Ba sources to calculate recovery coefficients for partial volume correction.
Conclusion
This comparison exercise demonstrated that traceable solid 133Ba sources can be used as surrogate for liquid 131I imaging. The use of solid surrogate sources could solve the radiation protection problem inherent in the preparation of phantoms with 131I liquid activity solutions as well as reduce the measurement uncertainties in the activity. This is particularly relevant for stability measurements, which have to be carried out at regular intervals.
Background
Recent data from the randomized SUSTAIN CSX trial could not confirm clinical benefits from perioperative selenium treatment in high-risk cardiac surgery patients. Underlying reasons may involve inadequate biosynthesis of glutathione peroxidase (GPx3), which is a key mediator of selenium's antioxidant effects. This secondary analysis aimed to identify patients with an increase in GPx3 activity following selenium treatment. We hypothesize that these responders might benefit from perioperative selenium treatment.
Methods
Patients were selected based on the availability of selenium biomarker information. Four subgroups were defined according to the patient's baseline status, including those with normal kidney function, reduced kidney function, selenium deficiency, and submaximal GPx3 activity.
Results
Two hundred and forty-four patients were included in this analysis. Overall, higher serum concentrations of selenium, selenoprotein P (SELENOP) and GPx3 were correlated with less organ injury. GPx3 activity at baseline was predictive of 6-month survival (AUC 0.73; p = 0.03). While selenium treatment elevated serum selenium and SELENOP concentrations but not GPx3 activity in the full patient cohort, subgroup analyses revealed that GPx3 activity increased in patients with reduced kidney function, selenium deficiency and low to moderate GPx3 activity. Clinical outcomes did not vary between selenium treatment and placebo in any of these subgroups, though the study was not powered to conclusively detect differences in outcomes.
Conclusions
The identification of GPx3 responders encourages further refined investigations into the treatment effects of selenium in high-risk cardiac surgery patients.
Multiorgan recovery in a cadaver body using mild hypothermic ECMO treatment in a murine model
(2023)
Background
Transplant candidates on the waiting list are increasingly challenged by the lack of organs. Most of the organs can only be kept viable within very limited timeframes (e.g., mere 4–6 h for heart and lungs exposed to refrigeration temperatures ex vivo). Donation after circulatory death (DCD) using extracorporeal membrane oxygenation (ECMO) can significantly enlarge the donor pool, organ yield per donor, and shelf life. Nevertheless, clinical attempts to recover organs for transplantation after uncontrolled DCD are extremely complex and hardly reproducible. Therefore, as a preliminary strategy to fulfill this task, experimental protocols using feasible animal models are highly warranted. The primary aim of the study was to develop a model of ECMO-based cadaver organ recovery in mice. Our model mimics uncontrolled organ donation after an “out-of-hospital” sudden unexpected death with subsequent “in-hospital” cadaver management post-mortem. The secondary aim was to assess blood gas parameters, cardiac activity as well as overall organ state. The study protocol included post-mortem heparin–streptokinase administration 10 min after confirmed death induced by cervical dislocation under full anesthesia. After cannulation, veno-arterial ECMO (V–A ECMO) was started 1 h after death and continued for 2 h under mild hypothermic conditions followed by organ harvest. Pressure- and flow-controlled oxygenated blood-based reperfusion of a cadaver body was accompanied by blood gas analysis (BGA), electrocardiography, and histological evaluation of ischemia–reperfusion injury. For the first time, we designed and implemented, a not yet reported, miniaturized murine hemodialysis circuit for the treatment of severe hyperkalemia and metabolic acidosis post-mortem.
Results
BGA parameters confirmed profound ischemia typical for cadavers and incompatible with normal physiology, including extremely low blood pH, profound negative base excess, and enormously high levels of lactate. Two hours after ECMO implantation, blood pH values of a cadaver body restored from < 6.5 to 7.3 ± 0.05, pCO2 was lowered from > 130 to 41.7 ± 10.5 mmHg, sO2, base excess, and HCO3 were all elevated from below detection thresholds to 99.5 ± 0.6%, − 4 ± 6.2 and 22.0 ± 6.0 mmol/L, respectively (Student T test, p < 0.05). A substantial decrease in hyperlactatemia (from > 20 to 10.5 ± 1.7 mmol/L) and hyperkalemia (from > 9 to 6.9 ± 1.0 mmol/L) was observed when hemodialysis was implemented. On balance, the first signs of regained heart activity appeared on average 10 min after ECMO initiation without cardioplegia or any inotropic and vasopressor support. This was followed by restoration of myocardial contractility with a heart rate of up to 200 beats per minute (bpm) as detected by an electrocardiogram (ECG). Histological examinations revealed no evidence of heart injury 3 h post-mortem, whereas shock-specific morphological changes relevant to acute death and consequent cardiac/circulatory arrest were observed in the lungs, liver, and kidney of both control and ECMO-treated cadaver mice.
Conclusions
Thus, our model represents a promising approach to facilitate studying perspectives of cadaveric multiorgan recovery for transplantation. Moreover, it opens new possibilities for cadaver organ treatment to extend and potentiate donation and, hence, contribute to solving the organ shortage dilemma.
Purpose
Hypertrophic cartilage is an important characteristic of osteoarthritis and can often be found in patients suffering from osteoarthritis. Although the exact pathomechanism remains poorly understood, hypertrophic de-differentiation of chondrocytes also poses a major challenge in the cell-based repair of hyaline cartilage using mesenchymal stromal cells (MSCs). While different members of the transforming growth factor beta (TGF-β) family have been shown to promote chondrogenesis in MSCs, the transition into a hypertrophic phenotype remains a problem. To further examine this topic we compared the effects of the transcription growth and differentiation factor 5 (GDF-5) and the mutant R57A on in vitro chondrogenesis in MSCs.
Methods
Bone marrow-derived MSCs (BMSCs) were placed in pellet culture and in-cubated in chondrogenic differentiation medium containing R57A, GDF-5 and TGF-ß1 for 21 days. Chondrogenesis was examined histologically, immunohistochemically, through biochemical assays and by RT-qPCR regarding the expression of chondrogenic marker genes.
Results
Treatment of BMSCs with R57A led to a dose dependent induction of chondrogenesis in BMSCs. Biochemical assays also showed an elevated glycosaminoglycan (GAG) content and expression of chondrogenic marker genes in corresponding pellets. While treatment with R57A led to superior chondrogenic differentiation compared to treatment with the GDF-5 wild type and similar levels compared to incubation with TGF-ß1, levels of chondrogenic hypertrophy were lower after induction with R57A and the GDF-5 wild type.
Conclusions
R57A is a stronger inducer of chondrogenesis in BMSCs than the GDF-5 wild type while leading to lower levels of chondrogenic hypertrophy in comparison with TGF-ß1.
The AMADEUS score is not a sufficient predictor for functional outcome after high tibial osteotomy
(2023)
Purpose
The Area Measurement And Depth Underlying Structures (AMADEUS) classification system has been proposed as a valuable tool for magnetic resonance (MR)-based grading of preoperatively encountered chondral defects of the knee joint. However, the potential relationship of this novel score with clinical data was yet to determine. It was the primary intention of this study to assess the correlative relationship of the AMADEUS with patient reported outcome scores in patients undergoing medial open-wedge high tibial valgus osteotomy (HTO). Furthermore, the arthroscopic ICRS (International Cartilage Repair Society) grade evaluation was tested for correlation with the AMADEUS classification system.
Methods
This retrospective, monocentric study found a total of 70 individuals that were indicated for HTO due to degenerative chondral defects of the medial compartment between 2008 and 2019. A preoperative MR image as well as a pre-osteotomy diagnostic arthroscopy for ICRS grade evaluation was mandatory for all patients. The Knee Osteoarthritis Outcome Score (KOOS) including its five subscale scores (KOOS-ADL, KOOS-QOL, KOOS-Sports, KOOS-Pain, KOOS-Symptoms) was obtained preoperatively and at a mean follow-up of 41.2 ± 26.3 months. Preoperative chondral defects were evaluated using the AMADEUS classification system and the final AMADEUS scores were correlated with the pre- and postoperative KOOS subscale sores. Furthermore, arthroscopic ICRS defect severity was correlated with the AMADEUS classification system.
Results
There was a statistically significant correlation between the AMADEUS BME (bone marrow edema) subscore and the KOOS Symptoms subscore at the preoperative visit (r = 0.25, p = 0.04). No statistically significant monotonic association between the AMADEUS total score and the AMADEUS grade with pre- and postoperative KOOS subscale scores were found. Intraoperatively obtained ICRS grade did reveal a moderate correlative relation with the AMADEUS total score and the AMADEUS grade (r = 0.28, p = 0.02).
Conclusions
The novel AMADEUS classification system largely lacks correlative capacity with patient reported outcome measures in patients undergoing HTO. The MR tomographic appearance of bone marrow edema is the only parameter predictive of the clinical outcome at the preoperative visit.
Background
Iron deficiency (ID) is the leading cause of anemia worldwide. The prevalence of preoperative ID ranges from 23 to 33%. Preoperative anemia is associated with worse outcomes, making it important to diagnose and treat ID before elective surgery. Several studies indicated the effectiveness of intravenous iron supplementation in iron deficiency with or without anemia (ID(A)). However, it remains challenging to establish reliable evidence due to heterogeneity in utilized study outcomes. The development of a core outcome set (COS) can help to reduce this heterogeneity by proposing a minimal set of meaningful and standardized outcomes. The aim of our systematic review was to identify and assess outcomes reported in randomized controlled trials (RCTs) and observational studies investigating iron supplementation in iron-deficient patients with or without anemia.
Methods
We searched MEDLINE, CENTRAL, and ClinicalTrials.gov systematically from 2000 to April 1, 2022. RCTs and observational studies investigating iron supplementation in patients with a preoperative diagnosis of ID(A), were included. Study characteristics and reported outcomes were extracted. Outcomes were categorized according to an established outcome taxonomy. Quality of outcome reporting was assessed with a pre-specified tool. Reported clinically relevant differences for sample size calculation were extracted.
Results
Out of 2898 records, 346 underwent full-text screening and 13 studies (five RCTs, eight observational studies) with sufficient diagnostic inclusion criteria for iron deficiency with or without anemia (ID(A)) were eligible. It is noteworthy to mention that 49 studies were excluded due to no confirmed diagnosis of ID(A). Overall, 111 outcomes were structured into five core areas including nine domains. Most studies (92%) reported outcomes within the ‘blood and lymphatic system’ domain, followed by “adverse event” (77%) and “need for further resources” (77%). All of the latter reported on the need for blood transfusion. Reported outcomes were heterogeneous in measures and timing. Merely, two (33%) of six prospective studies were registered prospectively of which one (17%) showed no signs of selective outcome reporting.
Conclusion
This systematic review comprehensively depicts the heterogeneity of reported outcomes in studies investigating iron supplementation in ID(A) patients regarding exact definitions and timing. Our analysis provides a systematic base for consenting to a minimal COS.
Systematic review registration
PROSPERO CRD42020214247
Background
Severe acute respiratory syndrome coronavirus 2 is a virus affecting different organs and causing a wide variety and severity of symptoms. Headache as well as loss of smell and taste are the most frequently reported neurological manifestations of coronavirus disease 2019 induced by severe acute respiratory syndrome coronavirus 2. Here we report on a patient with chronic migraine and medication overuse headache, who experienced remarkable mitigation of migraine following coronavirus disease 2019.
Case presentation
For many years prior to the severe acute respiratory syndrome coronavirus 2 infection, a 57-year-old Caucasian male suffered from very frequent migraine attacks and for control of headaches he had been taking triptans almost daily. In the 16-month period before the outbreak of coronavirus disease 2019, triptan was taken 98% of the days with only a 21-day prednisolone-supported triptan holiday, which, however, had no longer-lasting consequences on migraine frequency. Upon severe acute respiratory syndrome coronavirus 2 infection, the patient developed only mild symptoms including fever, fatigue, and headache. Directly following recovery from coronavirus disease 2019, the patient surprisingly experienced a period with largely reduced frequency and severity of migraine attacks. Indeed, during 80 days following coronavirus disease 2019, migraine as well as triptan usage were restricted to only 25% of the days, no longer fulfilling criteria of a chronic migraine and medication overuse headache.
Conclusion
Severe acute respiratory syndrome coronavirus 2 infection might be capable of triggering mitigation of migraine.
Objectives
Open-access cancer imaging datasets have become integral for evaluating novel AI approaches in radiology. However, their use in quantitative analysis with radiomics features presents unique challenges, such as incomplete documentation, low visibility, non-uniform data formats, data inhomogeneity, and complex preprocessing. These issues may cause problems with reproducibility and standardization in radiomics studies.
Methods
We systematically reviewed imaging datasets with public copyright licenses, published up to March 2023 across four large online cancer imaging archives. We included only datasets with tomographic images (CT, MRI, or PET), segmentations, and clinical annotations, specifically identifying those suitable for radiomics research. Reproducible preprocessing and feature extraction were performed for each dataset to enable their easy reuse.
Results
We discovered 29 datasets with corresponding segmentations and labels in the form of health outcomes, tumor pathology, staging, imaging-based scores, genetic markers, or repeated imaging. We compiled a repository encompassing 10,354 patients and 49,515 scans. Of the 29 datasets, 15 were licensed under Creative Commons licenses, allowing both non-commercial and commercial usage and redistribution, while others featured custom or restricted licenses. Studies spanned from the early 1990s to 2021, with the majority concluding after 2013. Seven different formats were used for the imaging data. Preprocessing and feature extraction were successfully performed for each dataset.
Conclusion
RadiomicsHub is a comprehensive public repository with radiomics features derived from a systematic review of public cancer imaging datasets. By converting all datasets to a standardized format and ensuring reproducible and traceable processing, RadiomicsHub addresses key reproducibility and standardization challenges in radiomics.
Critical relevance statement
This study critically addresses the challenges associated with locating, preprocessing, and extracting quantitative features from open-access datasets, to facilitate more robust and reliable evaluations of radiomics models.
Key points
- Through a systematic review, we identified 29 cancer imaging datasets suitable for radiomics research.
- A public repository with collection overview and radiomics features, encompassing 10,354 patients and 49,515 scans, was compiled.
- Most datasets can be shared, used, and built upon freely under a Creative Commons license.
- All 29 identified datasets have been converted into a common format to enable reproducible radiomics feature extraction.
In tumor therapy anti-angiogenic approaches have the potential to increase the efficacy of a wide variety of subsequently or co-administered agents, possibly by improving or normalizing the defective tumor vasculature. Successful implementation of the concept of vascular normalization under anti-angiogenic therapy, however, mandates a detailed understanding of key characteristics and a respective scoring metric that defines an improved vasculature and thus a successful attempt. Here, we show that beyond commonly used parameters such as vessel patency and maturation, anti-angiogenic approaches largely benefit if the complex vascular network with its vessel interconnections is both qualitatively and quantitatively assessed. To gain such deeper insight the organization of vascular networks, we introduce a multi-parametric evaluation of high-resolution angiographic images based on light-sheet fluorescence microscopy images of tumors. We first could pinpoint key correlations between vessel length, straightness and diameter to describe the regular, functional and organized structure observed under physiological conditions. We found that vascular networks from experimental tumors diverted from those in healthy organs, demonstrating the dysfunctionality of the tumor vasculature not only on the level of the individual vessel but also in terms of inadequate organization into larger structures. These parameters proofed effective in scoring the degree of disorganization in different tumor entities, and more importantly in grading a potential reversal under treatment with therapeutic agents. The presented vascular network analysis will support vascular normalization assessment and future optimization of anti-angiogenic therapy.
Variability of gene expression due to stochasticity of transcription or variation of extrinsic signals, termed biological noise, is a potential driving force of cellular differentiation. Utilizing single-cell RNA-sequencing, we develop VarID2 for the quantification of biological noise at single-cell resolution. VarID2 reveals enhanced nuclear versus cytoplasmic noise, and distinct regulatory modes stratified by correlation between noise, expression, and chromatin accessibility. Noise levels are minimal in murine hematopoietic stem cells (HSCs) and increase during differentiation and ageing. Differential noise identifies myeloid-biased Dlk1+ long-term HSCs in aged mice with enhanced quiescence and self-renewal capacity. VarID2 reveals noise dynamics invisible to conventional single-cell transcriptome analysis.
Background
Based on low-quality evidence, current nutrition guidelines recommend the delivery of high-dose protein in critically ill patients. The EFFORT Protein trial showed that higher protein dose is not associated with improved outcomes, whereas the effects in critically ill patients who developed acute kidney injury (AKI) need further evaluation. The overall aim is to evaluate the effects of high-dose protein in critically ill patients who developed different stages of AKI.
Methods
In this post hoc analysis of the EFFORT Protein trial, we investigated the effect of high versus usual protein dose (≥ 2.2 vs. ≤ 1.2 g/kg body weight/day) on time-to-discharge alive from the hospital (TTDA) and 60-day mortality and in different subgroups in critically ill patients with AKI as defined by the Kidney Disease Improving Global Outcomes (KDIGO) criteria within 7 days of ICU admission. The associations of protein dose with incidence and duration of kidney replacement therapy (KRT) were also investigated.
Results
Of the 1329 randomized patients, 312 developed AKI and were included in this analysis (163 in the high and 149 in the usual protein dose group). High protein was associated with a slower time-to-discharge alive from the hospital (TTDA) (hazard ratio 0.5, 95% CI 0.4–0.8) and higher 60-day mortality (relative risk 1.4 (95% CI 1.1–1.8). Effect modification was not statistically significant for any subgroup, and no subgroups suggested a beneficial effect of higher protein, although the harmful effect of higher protein target appeared to disappear in patients who received kidney replacement therapy (KRT). Protein dose was not significantly associated with the incidence of AKI and KRT or duration of KRT.
Conclusions
In critically ill patients with AKI, high protein may be associated with worse outcomes in all AKI stages. Recommendation of higher protein dosing in AKI patients should be carefully re-evaluated to avoid potential harmful effects especially in patients who were not treated with KRT.
Trial registration: This study is registered at ClinicalTrials.gov (NCT03160547) on May 17th 2017.
Repeatedly encountering a stimulus biases the observer’s affective response and evaluation of the stimuli. Here we provide evidence for a causal link between mere exposure to fictitious news reports and subsequent voting behavior. In four pre-registered online experiments, participants browsed through newspaper webpages and were tacitly exposed to names of fictitious politicians. Exposure predicted voting behavior in a subsequent mock election, with a consistent preference for frequent over infrequent names, except when news items were decidedly negative. Follow-up analyses indicated that mere media presence fuels implicit personality theories regarding a candidate’s vigor in political contexts. News outlets should therefore be mindful to cover political candidates as evenly as possible.
Loss of intestinal epithelial barrier function is a hallmark in digestive tract inflammation. The detailed mechanisms remain unclear due to the lack of suitable cell-based models in barrier research. Here we performed a detailed functional characterization of human intestinal organoid cultures under different conditions with the aim to suggest an optimized ex-vivo model to further analyse inflammation-induced intestinal epithelial barrier dysfunction. Differentiated Caco2 cells as a traditional model for intestinal epithelial barrier research displayed mature barrier functions which were reduced after challenge with cytomix (TNFα, IFN-γ, IL-1ß) to mimic inflammatory conditions. Human intestinal organoids grown in culture medium were highly proliferative, displayed high levels of LGR5 with overall low rates of intercellular adhesion and immature barrier function resembling conditions usually found in intestinal crypts. WNT-depletion resulted in the differentiation of intestinal organoids with reduced LGR5 levels and upregulation of markers representing the presence of all cell types present along the crypt-villus axis. This was paralleled by barrier maturation with junctional proteins regularly distributed at the cell borders. Application of cytomix in immature human intestinal organoid cultures resulted in reduced barrier function that was accompanied with cell fragmentation, cell death and overall loss of junctional proteins, demonstrating a high susceptibility of the organoid culture to inflammatory stimuli. In differentiated organoid cultures, cytomix induced a hierarchical sequence of changes beginning with loss of cell adhesion, redistribution of junctional proteins from the cell border, protein degradation which was accompanied by loss of epithelial barrier function. Cell viability was observed to decrease with time but was preserved when initial barrier changes were evident. In summary, differentiated intestinal organoid cultures represent an optimized human ex-vivo model which allows a comprehensive reflection to the situation observed in patients with intestinal inflammation. Our data suggest a hierarchical sequence of inflammation-induced intestinal barrier dysfunction starting with loss of intercellular adhesion, followed by redistribution and loss of junctional proteins resulting in reduced barrier function with consecutive epithelial death.
Pointing gestures can take on different shapes. For example, people often point with a bent wrist at a referent that is occluded by another object. We hypothesized that while the extrapolation of the index finger is the most important visual cue in such bent pointing gestures, arm orientation is affecting interpretations as well. We tested two competing hypotheses. First, the arm could be processed as a less reliable but additional direction cue also indicating the referent. Consequently, the index finger extrapolation would be biased towards the arm direction (assimilation effect). Second, the arm could be perceived as visual context of the index finger, leading to an interpretation that is repulsed from the arm direction (contrast effect). To differentiate between both, we conducted two experiments in which arm and finger orientation of a virtual pointer were independently manipulated. Participants were asked to determine the pointed-at location. As expected, participants based their interpretations on the extrapolation of the index finger. In line with the second hypothesis, the more the arm was oriented upwards, the lower the point was interpreted and vice versa. Thus, interpretation pattern indicated a contrast effect. Unexpectedly, gestures with aligned arm and index finger deviated from the general contrast effect and were interpreted linearly compared to bent gestures. In sum, the experiments show that interpretations of bent pointing gestures are not only based on the direction of the index finger but also depend on the arm orientation and its relationship to the index finger orientation.
Highlights
• Brain connectivity states identified by cofluctuation strength.
• CMEP as new method to robustly predict human traits from brain imaging data.
• Network-identifying connectivity ‘events’ are not predictive of cognitive ability.
• Sixteen temporally independent fMRI time frames allow for significant prediction.
• Neuroimaging-based assessment of cognitive ability requires sufficient scan lengths.
Abstract
Human functional brain connectivity can be temporally decomposed into states of high and low cofluctuation, defined as coactivation of brain regions over time. Rare states of particularly high cofluctuation have been shown to reflect fundamentals of intrinsic functional network architecture and to be highly subject-specific. However, it is unclear whether such network-defining states also contribute to individual variations in cognitive abilities – which strongly rely on the interactions among distributed brain regions. By introducing CMEP, a new eigenvector-based prediction framework, we show that as few as 16 temporally separated time frames (< 1.5% of 10 min resting-state fMRI) can significantly predict individual differences in intelligence (N = 263, p < .001). Against previous expectations, individual's network-defining time frames of particularly high cofluctuation do not predict intelligence. Multiple functional brain networks contribute to the prediction, and all results replicate in an independent sample (N = 831). Our results suggest that although fundamentals of person-specific functional connectomes can be derived from few time frames of highest connectivity, temporally distributed information is necessary to extract information about cognitive abilities. This information is not restricted to specific connectivity states, like network-defining high-cofluctuation states, but rather reflected across the entire length of the brain connectivity time series.
The experience of threat was found to result—mostly—in increased pain, however it is still unclear whether the exact opposite, namely the feeling of safety may lead to a reduction of pain. To test this hypothesis, we conducted two between-subject experiments (N = 94; N = 87), investigating whether learned safety relative to a neutral control condition can reduce pain, while threat should lead to increased pain compared to a neutral condition. Therefore, participants first underwent either threat or safety conditioning, before entering an identical test phase, where the previously conditioned threat or safety cue and a newly introduced visual cue were presented simultaneously with heat pain stimuli. Methodological changes were performed in experiment 2 to prevent safety extinction and to facilitate conditioning in the first place: We included additional verbal instructions, increased the maximum length of the ISI and raised CS-US contingency in the threat group from 50% to 75%. In addition to pain ratings and ratings of the visual cues (threat, safety, arousal, valence, and contingency), in both experiments, we collected heart rate and skin conductance. Analysis of the cue ratings during acquisition indicate successful threat and safety induction, however results of the test phase, when also heat pain was administered, demonstrate rapid safety extinction in both experiments. Results suggest rather small modulation of subjective and physiological pain responses following threat or safety cues relative to the neutral condition. However, exploratory analysis revealed reduced pain ratings in later trials of the experiment in the safety group compared to the threat group in both studies, suggesting different temporal dynamics for threat and safety learning and extinction, respectively.
Perspective: The present results demonstrate the challenge to maintain safety in the presence of acute pain and suggest more research on the interaction of affective learning mechanism and pain processing.
This study investigates the sense of agency (SoA) for saccades with implicit and explicit agency measures. In two eye tracking experiments, participants moved their eyes towards on-screen stimuli that subsequently changed color. Participants then either reproduced the temporal interval between saccade and color-change (Experiment 1) or reported the time points of these events with an auditory Libet clock (Experiment 2) to measure temporal binding effects as implicit indices of SoA. Participants were either made to believe to exert control over the color change or not (agency manipulation). Explicit ratings indicated that the manipulation of causal beliefs and hence agency was successful. However, temporal binding was only evident for caused effects, and only when a sufficiently sensitive procedure was used (auditory Libet clock). This suggests a feebler connection between temporal binding and SoA than previously proposed. The results also provide evidence for a relatively fast acquisition of sense of agency for previously never experienced types of action-effect associations. This indicates that the underlying processes of action control may be rooted in more intricate and adaptable cognitive models than previously thought. Oculomotor SoA as addressed in the present study presumably represents an important cognitive foundation of gaze-based social interaction (social sense of agency) or gaze-based human-machine interaction scenarios.
Public significance statement: In this study, sense of agency for eye movements in the non-social domain is investigated in detail, using both explicit and implicit measures. Therefore, it offers novel and specific insights into comprehending sense of agency concerning effects induced by eye movements, as well as broader insights into agency pertaining to entirely newly acquired types of action-effect associations. Oculomotor sense of agency presumably represents an important cognitive foundation of gaze-based social interaction (social agency) or gaze-based human-machine interaction scenarios. Due to peculiarities of the oculomotor domain such as the varying degree of volitional control, eye movements could provide new information regarding more general theories of sense of agency in future research.
An important cognitive requirement in multitasking is the decision of how multiple tasks should be temporally scheduled (task order control). Specifically, task order switches (vs. repetitions) yield performance costs (i.e., task-order switch costs), suggesting that task order scheduling is a vital part of configuring a task set. Recently, it has been shown that this process takes specific task-related characteristics into account: task order switches were easier when switching to a preferred (vs. non-preferred) task order. Here, we ask whether another determinant of task order control, namely the phenomenon that a task order switch in a previous trial facilitates a task order switch in a current trial (i.e., a sequential modulation of task order switch effect) also takes task-specific characteristics into account. Based on three experiments involving task order switches between a preferred (dominant oculomotor task prior to non-dominant manual/pedal task) and a non-preferred (vice versa) order, we replicated the finding that task order switching (in Trial N) is facilitated after a previous switch (vs. repetition in Trial N - 1) in task order. There was no substantial evidence in favor of a significant difference when switching to the preferred vs. non-preferred order and in the analyses of the dominant oculomotor task and the non-dominant manual task. This indicates different mechanisms underlying the control of immediate task order configuration (indexed by task order switch costs) and the sequential modulation of these costs based on the task order transition type in the previous trial.
The current ARDS guidelines highly recommend lung protective ventilation which include plateau pressure (Pplat < 30 cm H\(_2\)O), positive end expiratory pressure (PEEP > 5 cm H2O) and tidal volume (Vt of 6 ml/kg) of predicted body weight. In contrast, the ELSO guidelines suggest the evaluation of an indication of veno-venous extracorporeal membrane oxygenation (ECMO) due to hypoxemic or hypercapnic respiratory failure or as bridge to lung transplantation. Finally, these recommendations remain a wide range of scope of interpretation. However, particularly patients with moderate-severe to severe ARDS might benefit from strict adherence to lung protective ventilation strategies. Subsequently, we discuss whether extended physiological ventilation parameter analysis might be relevant for indication of ECMO support and can be implemented during the daily routine evaluation of ARDS patients. Particularly, this viewpoint focus on driving pressure and mechanical power.
Emotional dysregulation and its pathways to suicidality in a community-based sample of adolescents
(2024)
Objective
Effective suicide prevention for adolescents is urgently needed but difficult, as suicide models lack a focus on age-specific influencing factors such as emotional dysregulation. Moreover, examined predictors often do not specifically consider the contribution to the severity of suicidality.
To determine which adolescents are at high risk of more severe suicidality, we examined the association between emotional dysregulation and severity of suicidality directly as well as indirectly via depressiveness and nonsuicidal self-injury.
Method
Adolescents from 18 high schools in Bavaria were included in this cross-sectional and questionnaire-based study as part of a larger prevention study. Data were collected between November 2021 and March 2022 and were analyzed from January 2023 to April 2023.
Students in the 6th or 7th grade of high school (11–14 years) were eligible to participate. A total of 2350 adolescents were surveyed and data from 2117 students were used for the analyses after excluding incomplete data sets. Our main outcome variable was severity of suicidality (Paykel Suicide Scale, PSS). Additionally, we assessed emotional dysregulation (Difficulties in Emotion Regulation Scale, DERS-SF), depressiveness (Patient Health Questionnaire, PHQ-9) and nonsuicidal self-injury (Deliberate Self-Harm Inventory, DSHI).
Results
In total, 2117 adolescents (51.6% female; mean age, 12.31 years [standard deviation: 0.67]) were included in the structural equation model (SEM). Due to a clear gender-specific influence, the model was calculated separately for male and female adolescents. For male adolescents, there was a significant indirect association between emotional dysregulation and severity of suicidality, mediated by depressiveness (β = 0.15, SE = .03, p = .008). For female adolescents, there was a significant direct path from emotional dysregulation to severity of suicidality and also indirect paths via depressiveness (β = 0.12, SE = .05, p = 0.02) and NSSI (β = 0.18, SE = .04, p < .001).
Conclusions
Our results suggest that gender-related risk markers in 11–14-year-olds need to be included in future suicide models to increase their predictive power. According to our findings, early detection and prevention interventions based on emotion regulation skills might be enhanced by including gender-specific adjustments for the co-occurrence of emotional dysregulation, depressiveness, and nonsuicidal self-injury in girls and the co-occurrence of emotional dysregulation and depressiveness in boys.
Background
Complex regional pain syndrome (CRPS) develops after injury and is characterized by disproportionate pain, oedema, and functional loss. CRPS has clinical signs of neuropathy as well as neurogenic inflammation. Here, we asked whether skin biopsies could be used to differentiate the contribution of these two systems to ultimately guide therapy. To this end, the cutaneous sensory system including nerve fibres and the recently described nociceptive Schwann cells as well as the cutaneous immune system were analysed.
Methods
We systematically deep-phenotyped CRPS patients and immunolabelled glabrous skin biopsies from the affected ipsilateral and non-affected contralateral finger of 19 acute (< 12 months) and 6 chronic (> 12 months after trauma) CRPS patients as well as 25 sex- and age-matched healthy controls (HC). Murine foot pads harvested one week after sham or chronic constriction injury were immunolabelled to assess intraepidermal Schwann cells.
Results
Intraepidermal Schwann cells were detected in human skin of the finger—but their density was much lower compared to mice. Acute and chronic CRPS patients suffered from moderate to severe CRPS symptoms and corresponding pain. Most patients had CRPS type I in the warm category. Their cutaneous neuroglial complex was completely unaffected despite sensory plus signs, e.g. allodynia and hyperalgesia. Cutaneous innate sentinel immune cells, e.g. mast cells and Langerhans cells, infiltrated or proliferated ipsilaterally independently of each other—but only in acute CRPS. No additional adaptive immune cells, e.g. T cells and plasma cells, infiltrated the skin.
Conclusions
Diagnostic skin punch biopsies could be used to diagnose individual pathophysiology in a very heterogenous disease like acute CRPS to guide tailored treatment in the future. Since numbers of inflammatory cells and pain did not necessarily correlate, more in-depth analysis of individual patients is necessary.
Autophagy is an essential cellular homeostasis pathway initiated by multiple stimuli ranging from nutrient deprivation to viral infection, playing a key role in human health and disease. At present, a growing number of evidence suggests a role of autophagy as a primitive innate immune form of defense for eukaryotic cells, interacting with components of innate immune signaling pathways and regulating thymic selection, antigen presentation, cytokine production and T/NK cell homeostasis. In cancer, autophagy is intimately involved in the immunological control of tumor progression and response to therapy. However, very little is known about the role and impact of autophagy in T and NK cells, the main players in the active fight against infections and tumors. Important questions are emerging: what role does autophagy play on T/NK cells? Could its modulation lead to any advantages? Could specific targeting of autophagy on tumor cells (blocking) and T/NK cells (activation) be a new intervention strategy? In this review, we debate preclinical studies that have identified autophagy as a key regulator of immune responses by modulating the functions of different immune cells and discuss the redundancy or diversity among the subpopulations of both T and NK cells in physiologic context and in cancer.
Background
Research on the needs of people with disability is scarce, which promotes inadequate programs. Community Based Inclusive Development interventions aim to promote rights but demand a high level of community participation. This study aimed to identify prioritized needs as well as lessons learned for successful project implementation in different Latin American communities.
Methods
This study was based on a Community Based Inclusive Development project conducted from 2018 to 2021 led by a Columbian team in Columbia, Brazil and Bolivia. Within a sequential mixed methods design, we first retrospectively analyzed the project baseline data and then conducted Focus Group Discussions, together with ratings of community participation levels. Quantitative descriptive and between group analysis of the baseline survey were used to identify and compare sociodemographic characteristics and prioritized needs of participating communities. We conducted qualitative thematic analysis on Focus Group Discussions, using deductive main categories for triangulation: 1) prioritized needs and 2) lessons learned, with subcategories project impact, facilitators, barriers and community participation. Community participation was assessed via spidergrams. Key findings were compared with triangulation protocols.
Results
A total of 348 people with disability from 6 urban settings participated in the baseline survey, with a mean age of 37.6 years (SD 23.8). Out of these, 18 participated within the four Focus Group Discussions. Less than half of the survey participants were able to read and calculate (42.0%) and reported knowledge on health care routes (46.0%). Unemployment (87.9%) and inadequate housing (57.8%) were other prioritized needs across countries. Focus Group Discussions revealed needs within health, education, livelihood, social and empowerment domains.
Participants highlighted positive project impact in work inclusion, self-esteem and ability for self-advocacy. Facilitators included individual leadership, community networks and previous reputation of participating organizations. Barriers against successful project implementation were inadequate contextualization, lack of resources and on-site support, mostly due to the COVID-19 pandemic. The overall level of community participation was high (mean score 4.0/5) with lower levels in Brazil (3.8/5) and Bolivia (3.2/5).
Conclusion
People with disability still face significant needs. Community Based Inclusive Development can initiate positive changes, but adequate contextualization and on-site support should be assured.
Background
The origin of αSMA-positive myofibroblasts, key players within organ fibrosis, is still not fully elucidated. Pericytes have been discussed as myofibroblast progenitors in several organs including the lung.
Methods
Using tamoxifen-inducible PDGFRβ-tdTomato mice (PDGFRβ-CreERT2; R26tdTomato) lineage of lung pericytes was traced. To induce lung fibrosis, a single orotracheal dose of bleomycin was given. Lung tissue was investigated by immunofluorescence analyses, hydroxyproline collagen assay and RT-qPCR.
Results
Lineage tracing combined with immunofluorescence for nitric oxide-sensitive guanylyl cyclase (NO-GC) as marker for PDGFRβ-positive pericytes allows differentiating two types of αSMA-expressing myofibroblasts in murine pulmonary fibrosis: (1) interstitial myofibroblasts that localize in the alveolar wall, derive from PDGFRβ+ pericytes, express NO-GC and produce collagen 1. (2) intra-alveolar myofibroblasts which do not derive from pericytes (but express PDGFRβ de novo after injury), are negative for NO-GC, have a large multipolar shape and appear to spread over several alveoli within the injured areas. Moreover, NO-GC expression is reduced during fibrosis, i.e., after pericyte-to-myofibroblast transition.
Conclusion
In summary, αSMA/PDGFRβ-positive myofibroblasts should not be addressed as a homogeneous target cell type within pulmonary fibrosis.
Background
Current COVID-19 guidelines recommend the early use of systemic corticoids for COVID-19 acute respiratory distress syndrome (ARDS). It remains unknown if high-dose methylprednisolone pulse therapy (MPT) ameliorates refractory COVID-19 ARDS after many days of mechanical ventilation or rapid deterioration with or without extracorporeal membrane oxygenation (ECMO).
Methods
This is a retrospective observational study. Consecutive patients with COVID-19 ARDS treated with a parenteral high-dose methylprednisolone pulse therapy at the intensive care units (ICU) of two University Hospitals between January 1st 2021 and November 30st 2022 were included. Clinical data collection was at ICU admission, start of MPT, 3-, 10- and 14-days post MPT.
Results
Thirty-seven patients (mean age 55 ± 12 years) were included in the study. MPT started at a mean of 17 ± 12 days after mechanical ventilation. Nineteen patients (54%) received ECMO support when commencing MPT. Mean paO2/FiO2 significantly improved 3- (p = 0.034) and 10 days (p = 0.0313) post MPT. The same applied to the necessary FiO2 10 days after MPT (p = 0.0240). There were no serious infectious complications. Twenty-four patients (65%) survived to ICU discharge, including 13 out of 20 (65%) needing ECMO support.
Conclusions
Late administration of high-dose MPT in a critical subset of refractory COVID-19 ARDS patients improved respiratory function and was associated with a higher-than-expected survival of 65%. These data suggest that high-dose MPT may be a viable salvage therapy in refractory COVID-19 ARDS.
Background
Performance anxiety is the most frequently reported anxiety disorder among professional musicians. Typical symptoms are - on a physical level - the consequences of an increase in sympathetic tone with cardiac stress, such as acceleration of heartbeat, increase in blood pressure, increased respiratory rate and tremor up to nausea or flush reactions. These symptoms can cause emotional distress, a reduced musical and artistical performance up to an impaired functioning. While anxiety disorders are preferably treated using cognitive-behavioral therapy with exposure, this approach is rather difficult for treating music performance anxiety since the presence of a public or professional jury is required and not easily available. The use of virtual reality (VR) could therefore display an alternative. So far, no therapy studies on music performance anxiety applying virtual reality exposure therapy have investigated the therapy outcome including cardiovascular changes as outcome parameters.
Methods
This mono-center, prospective, randomized and controlled clinical trial has a pre-post design with a follow-up period of 6 months. 46 professional and semi-professional musicians will be recruited and allocated randomly to an VR exposure group or a control group receiving progressive muscle relaxation training. Both groups will be treated over 4 single sessions. Music performance anxiety will be diagnosed based on a clinical interview using ICD-10 and DSM-5 criteria for specific phobia or social anxiety. A behavioral assessment test is conducted three times (pre, post, follow-up) in VR through an audition in a concert hall. Primary outcomes are the changes in music performance anxiety measured by the German Bühnenangstfragebogen and the cardiovascular reactivity reflected by heart rate variability (HRV). Secondary outcomes are changes in blood pressure, stress parameters such as cortisol in the blood and saliva, neuropeptides, and DNA-methylation.
Discussion
The trial investigates the effect of VR exposure in musicians with performance anxiety compared to a relaxation technique on anxiety symptoms and corresponding cardiovascular parameters. We expect a reduction of anxiety but also a consecutive improvement of HRV with cardiovascular protective effects.
Trial registration
This study was registered on clinicaltrials.gov. (ClinicalTrials.gov Number: NCT05735860)
Single nucleotide polymorphisms (SNPs) in the ADGRL3 gene have been significantly associated with the development of ADHD, the aetiology of which remains poorly understood. The rs1397547 SNP has additionally been associated with significantly altered ADGRL3 transcription. We therefore generated iPSCs from two wild type ADHD patients, and two ADHD patients heterozygous for the risk SNP. With this resource we aim to facilitate further investigation into the complex and heterogenous pathology of ADHD. Furthermore, we demonstrate the feasibility of using magnetic activated cell sorting to allow the unbiased selection of fully reprogrammed iPSCs.
Background
Hematogenous tumor spread of malignant meningiomas occurs very rarely but is associated with very poor prognosis.
Case presentation
We report an unusual case of a patient with a malignant meningioma who developed multiple metastases in bones, lungs and liver after initial complete resection of the primary tumor. After partial hepatic resection, specimens were histologically analyzed, and a complete loss of E-cadherin adhesion molecules was found. No oncogenic target mutations were found. The patient received a combination of conventional radiotherapy and peptide receptor radionuclide therapy (PRRT). Due to aggressive tumor behavior and rapid spread of metastases, the patient deceased after initiation of treatment.
Conclusions
E-cadherin downregulation is associated with a higher probability of tumor invasion and distant metastasis formation in malignant meningioma. Up to now, the efficacy of systemic therapy, including PRRT, is very limited in malignant meningioma patients.
Background
Colorectal cancer is a leading cause of cancer-related deaths worldwide. The best method to prevent CRC is a colonoscopy. However, not all colon polyps have the risk of becoming cancerous. Therefore, polyps are classified using different classification systems. After the classification, further treatment and procedures are based on the classification of the polyp. Nevertheless, classification is not easy. Therefore, we suggest two novel automated classifications system assisting gastroenterologists in classifying polyps based on the NICE and Paris classification.
Methods
We build two classification systems. One is classifying polyps based on their shape (Paris). The other classifies polyps based on their texture and surface patterns (NICE). A two-step process for the Paris classification is introduced: First, detecting and cropping the polyp on the image, and secondly, classifying the polyp based on the cropped area with a transformer network. For the NICE classification, we design a few-shot learning algorithm based on the Deep Metric Learning approach. The algorithm creates an embedding space for polyps, which allows classification from a few examples to account for the data scarcity of NICE annotated images in our database.
Results
For the Paris classification, we achieve an accuracy of 89.35 %, surpassing all papers in the literature and establishing a new state-of-the-art and baseline accuracy for other publications on a public data set. For the NICE classification, we achieve a competitive accuracy of 81.13 % and demonstrate thereby the viability of the few-shot learning paradigm in polyp classification in data-scarce environments. Additionally, we show different ablations of the algorithms. Finally, we further elaborate on the explainability of the system by showing heat maps of the neural network explaining neural activations.
Conclusion
Overall we introduce two polyp classification systems to assist gastroenterologists. We achieve state-of-the-art performance in the Paris classification and demonstrate the viability of the few-shot learning paradigm in the NICE classification, addressing the prevalent data scarcity issues faced in medical machine learning.
Background
The impact of sex hormones on right and left auricular contractile apparatus function is largely unknown. We evaluated the impact of sex hormones on left and right heart contractility at the level of myocardial filaments harvested from left and right auricles during elective coronary artery bypass surgery.
Methods
150 patients (132 male; 18 female) were enrolled. Preoperative testosterone and estradiol levels were measured with Immunoassay. Calcium induced force measurements were performed with left- and right auricular myofilaments in a skinned fiber model. Correlation analysis was used for comparison of force values and levels of sex hormones and their ratio.
Results
Low testosterone was associated with higher top force values in right-sided myofilaments but not in left-sided myofilaments for both sexes (p = 0.000 in males, p = 0.001 in females). Low estradiol levels were associated with higher top force values in right-sided myofilaments (p 0.000) in females and only borderline significantly associated with higher top force values in males (p 0.056). In females, low estradiol levels correlated with higher top force values in left sided myofilaments (p 0.000). In males, higher Estradiol/Testosterone ratio (E/T ratio) was only associated with higher top force values from right auricular myofilaments (p 0.04) In contrast, in females higher E/T ratio was associated with lower right auricular myofilament top force values (p 0.03) and higher top force values in left-sided myofilaments (p 0.000).
Conclusions
This study shows that patients’ comorbidities influence left and right sided contractility and may blur results concerning influence of sex hormones if not eliminated. A sex hormone dependent influence is obvious with different effects on the left and right ventricle. The E/T ratio and its impact on myofilament top force showed divergent results between genders, and may partially explain gender differences in patients with cardiovascular disease.
Background
Left atrial appendage (LAA) is the origin of most heart thrombi which can lead to stroke or other cerebrovascular event in patients with non-valvular atrial fibrillation (AF). This study aimed to prove safety and low complication rate of surgical LAA amputation using cut and sew technique with control of its effectiveness.
Methods
303 patients who have undergone selective LAA amputation were enrolled in the study in a period from 10/17 to 08/20. The LAA amputation was performed concomitant to routine cardiac surgery on cardiopulmonary bypass with cardiac arrest with or without previous history of AF. The operative and clinical data were evaluated. Extent of LAA amputation was examined intraoperatively by transoesophageal echocardiography (TEE). Six months in follow up, the patients were controlled regarding clinical status and episodes of strokes.
Results
Average age of study population was 69.9 ± 19.2 and 81.9% of patients were male. In only three patients was residual stump after LAA amputation larger than 1 cm with average stump size 0.28 ± 0.34 cm. 3 patients (1%) developed postoperative bleeding. Postoperatively 77 (25.4%) patients developed postoperative AF (POAF), of which 29 (9.6%) still had AF at discharge. On 6 months follow up only 5 patients had NYHA class III and 1 NYHA class IV. Seven patients reported with leg oedema and no patient experienced any cerebrovascular event in early postoperative follow up.
Conclusion
LAA amputation can be performed safely and completely leaving minimal to no LAA residual stump.
Background
Data on the routine use of video-assisted laryngoscopy in peri-operative intubations are rather inconsistent and ambiguous, in part due to small populations and non-uniform outcome measures in past trials. Failed or prolonged intubation procedures are a reason for relevant morbidity and mortality. This study aims to determine whether video-assisted laryngoscopy (with both Macintosh-shaped and hyperangulated blades) is at least equal to the standard method of direct laryngoscopy with respect to the first-pass success rate. Furthermore, validated tools from the field of human factors will be applied to examine within-team communication and task load during this critical medical procedure.
Methods
In this randomized, controlled, three-armed parallel group design, multi-centre trial, a total of more than 2500 adult patients scheduled for perioperative endotracheal intubation will be randomized. In equally large arms, video-assisted laryngoscopy with a Macintosh-shaped or a hyperangulated blade will be compared to the standard of care (direct laryngoscopy with Macintosh blade). In a pre-defined hierarchical analysis, we will test the primary outcome for non-inferiority first. If this goal should be met, the design and projected statistical power also allow for subsequent testing for superiority of one of the interventions.
Various secondary outcomes will account for patient safety considerations as well as human factors interactions within the provider team and will allow for further exploratory data analysis and hypothesis generation.
Discussion
This randomized controlled trial will provide a solid base of data in a field where reliable evidence is of major clinical importance. With thousands of endotracheal intubations performed every day in operating rooms around the world, every bit of performance improvement translates into increased patient safety and comfort and may eventually prevent significant burden of disease. Therefore, we feel confident that a large trial has the potential to considerably benefit patients and anaesthetists alike.
Trial registration
ClincalTrials.gov NCT05228288.
Protocol version
1.1, November 15, 2021.
Background
Perioperative bridging of oral anticoagulation increases the risk of bleeding complications after elective general and visceral surgery. The aim of this study was to explore, whether an individual risk-adjusted bridging regimen can reduce bleeding events, while still protecting against thromboembolic events.
Methods
We performed a quality improvement study comparing bridging parameters and postoperative outcomes before (period 1) and after implementation (period 2) of a new risk-adjusted bridging regimen. The primary endpoint of the study was overall incidence of postoperative bleeding complications during 30 days postoperatively. Secondary endpoints were major postoperative bleeding, minor bleeding, thromboembolic events, postoperative red blood cell transfusion, perioperative length-of-stay (LOS) and in-hospital mortality.
Results
A total of 263 patients during period 1 and 271 patients during period 2 were compared. The included elective operations covered the entire field of general and visceral surgery. The overall incidence of bleeding complications declined from 22.1% during period 1 to 10.3% in period 2 (p < 0.001). This reduction affected both major as well as minor bleeding events (8.4% vs. 4.1%; p = 0.039; 13.7% vs. 6.3%; p = 0.004). The incidence of thromboembolic events remained low (0.8% vs. 1.1%). No changes in mortality or length-of-stay were observed.
Conclusion
It is important to balance the individual thromboembolic and bleeding risks in perioperative bridging management. The risk adjusted bridging regimen reduces bleeding events in general and visceral surgery while the risk of thromboembolism remains comparably low.
The narrow escape theory (NET) predicts the escape time distribution of Brownian particles confined to a domain with reflecting borders except for one small window. Applications include molecular activation events in cell biology and biophysics. Specifically, the mean first passage time τ can be analytically calculated from the size of the domain, the escape window, and the diffusion coefficient of the particles. In this study, we systematically tested the NET in a disc by variation of the escape opening. Our model system consisted of micro-patterned lipid bilayers. For the measurement of τ, we imaged diffusing fluorescently-labeled lipids using single-molecule fluorescence microscopy. We overcame the lifetime limitation of fluorescent probes by re-scaling the measured time with the fraction of escaped particles. Experiments were complemented by matching stochastic numerical simulations. To conclude, we confirmed the NET prediction in vitro and in silico for the disc geometry in the limit of small escape openings, and we provide a straightforward solution to determine τ from incomplete experimental traces.
The treatment landscape in multiple myeloma (MM) is shifting from genotoxic drugs to immunotherapies. Monoclonal antibodies, immunoconjugates, T-cell engaging antibodies and CART cells have been incorporated into routine treatment algorithms, resulting in improved response rates. Nevertheless, patients continue to relapse and the underlying mechanisms of resistance remain poorly understood. While Impaired death receptor signaling has been reported to mediate resistance to CART in acute lymphoblastic leukemia, this mechanism yet remains to be elucidated in context of novel immunotherapies for MM. Here, we describe impaired death receptor signaling as a novel mechanism of resistance to T-cell mediated immunotherapies in MM. This resistance seems exclusive to novel immunotherapies while sensitivity to conventional anti-tumor therapies being preserved in vitro. As a proof of concept, we present a confirmatory clinical case indicating that the FADD/BID axis is required for meaningful responses to novel immunotherapies thus we report impaired death receptor signaling as a novel resistance mechanism to T-cell mediated immunotherapy in MM.
Transmission of Trypanosoma brucei by tsetse flies involves the deposition of the cell cycle-arrested metacyclic life cycle stage into mammalian skin at the site of the fly’s bite. We introduce an advanced human skin equivalent and use tsetse flies to naturally infect the skin with trypanosomes. We detail the chronological order of the parasites’ development in the skin by single-cell RNA sequencing and find a rapid activation of metacyclic trypanosomes and differentiation to proliferative parasites. Here we show that after the establishment of a proliferative population, the parasites enter a reversible quiescent state characterized by slow replication and a strongly reduced metabolism. We term these quiescent trypanosomes skin tissue forms, a parasite population that may play an important role in maintaining the infection over long time periods and in asymptomatic infected individuals.
Angle-resolved photoemission spectroscopy (ARPES) is a method that measures orbital and band structure contrast through the momentum distribution of photoelectrons. Its simplest interpretation is obtained in the plane-wave approximation, according to which photoelectrons propagate freely to the detector. The photoelectron momentum distribution is then essentially given by the Fourier transform of the real-space orbital. While the plane-wave approximation is remarkably successful in describing the momentum distributions of aromatic compounds, it generally fails to capture kinetic-energy-dependent final-state interference and dichroism effects. Focusing our present study on quasi-freestanding monolayer graphene as the archetypical two-dimensional (2D) material, we observe an exemplary E\(_{kin}\)-dependent modulation of, and a redistribution of spectral weight within, its characteristic horseshoe signature around the \(\bar {K}\) and \(\bar {K´}\) points: both effects indeed cannot be rationalized by the plane-wave final state. Our data are, however, in remarkable agreement with ab initio time-dependent density functional simulations of a freestanding graphene layer and can be explained by a simple extension of the plane-wave final state, permitting the two dipole-allowed partial waves emitted from the C 2p\(_z\) orbitals to scatter in the potential of their immediate surroundings. Exploiting the absolute photon flux calibration of the Metrology Light Source, this scattered-wave approximation allows us to extract E\(_{kin}\)-dependent amplitudes and phases of both partial waves directly from photoemission data. The scattered-wave approximation thus represents a powerful yet intuitive refinement of the plane-wave final state in photoemission of 2D materials and beyond.
Astrophysical sources of gravitational waves, such as binary neutron star and black hole mergers or core-collapse supernovae, can drive relativistic outflows, giving rise to non-thermal high-energy emission. High-energy neutrinos are signatures of such outflows. The detection of gravitational waves and high-energy neutrinos from common sources could help establish the connection between the dynamics of the progenitor and the properties of the outflow. We searched for associated emission of gravitational waves and high-energy neutrinos from astrophysical transients with minimal assumptions using data from Advanced LIGO from its first observing run O1, and data from the Antares and IceCube neutrino observatories from the same time period. We focused on candidate events whose astrophysical origins could not be determined from a single messenger. We found no significant coincident candidate, which we used to constrain the rate density of astrophysical sources dependent on their gravitational-wave and neutrino emission processes.
We demonstrate monolithic high contrast gratings (MHCG) based on GaSb/AlAs0.08Sb0.92 epitaxial structures with sub-wavelength gratings enabling high reflection of unpolarized mid-infrared radiation at the wavelength range from 2.5 to 5 µm. We study the reflectivity wavelength dependence of MHCGs with ridge widths ranging from 220 to 984 nm and fixed 2.6 µm grating period and demonstrate that peak reflectivity of above 0.7 can be shifted from 3.0 to 4.3 µm for ridge widths from 220 to 984 nm, respectively. Maximum reflectivity of up to 0.9 at 4 µm can be achieved. The experiments are in good agreement with numerical simulations, confirming high process flexibility in terms of peak reflectivity and wavelength selection. MHCGs have hitherto been regarded as mirrors enabling high reflection of selected light polarization. With this work, we show that thoughtfully designed MHCG yields high reflectivity for both orthogonal polarizations simultaneously. Our experiment demonstrates that MHCGs are promising candidates to replace conventional mirrors like distributed Bragg reflectors to realize resonator based optical and optoelectronic devices such as resonant cavity enhanced light emitting diodes and resonant cavity enhanced photodetectors in the mid-infrared spectral region, for which epitaxial growth of distributed Bragg reflectors is challenging.
We study the influence of nodal structures in two-dimensional quantum mechanical densities on wave packet entanglement. This is motivated by our recent study [Entropy, 25, 970 (2023)], which showed that the mutual information derived from the momentum-space probability density of a coupled two-particle system exhibits an unusual time dependence, which is not encountered if the position-space density is employed in the calculation. In studying a model density, here, we identify cases where the mutual information increases with the number of nodes in the wave function and approaches a finite value, whereas in this limit, the linear correlation vanishes. The results of the analytical model are then applied to interpret the correlation measures for coupled electron-nuclear dynamics, which are treated by numerically solving the time-dependent Schrödinger equation.
In DNA-encoded library synthesis, amine-substituted building blocks are prevalent. We explored isocyanide multicomponent reactions to diversify DNA-tagged amines and reported the Ugi-azide reaction with high yields and a good substrate scope. In addition, the Ugi-aza-Wittig reaction and the Ugi-4-center-3-component reaction, which used bifunctional carboxylic acids to provide lactams, were explored. Five-, six-, and seven-membered lactams were synthesized from solid support-coupled DNA-tagged amines and bifunctional building blocks, providing access to structurally diverse scaffolds.
The binding of drugs to plasma proteins is an important process in the human body and has a significant influence on pharmacokinetic parameter. Human serum albumin (HSA) has the most important function as a transporter protein. The binding of ketamine to HSA has already been described in literature, but only of the racemate. The enantiomerically pure S-ketamine is used as injection solution for induction of anesthesia and has been approved by the Food and Drug Administration for the therapy of severe depression as a nasal spray in 2019. The question arises if there is enantioselective binding to HSA. Hence, the aim of this study was to investigate whether there is enantioselective binding of S-and R-ketamine to HSA or not. Ultrafiltration (UF) followed by chiral capillary electrophoretic analysis was used to determine the extent of protein binding. Bound fraction to HSA was 71.2 % and 64.9 % for enantiomerically pure R- and S-ketamine, respectively, and 66.5 % for the racemate. Detailed binding properties were studied by Saturation Transfer Difference (STD)-, waterLOGSY- and Carr-Purcell-Meiboom-Gill (CPMG)-NMR spectroscopy. With all three methods, the aromatic ring and the N-methyl group could be identified as the structural moieties most strongly involved in binding of ketamine to HSA. pK\(_{aff}\) values determined using UF and NMR indicate that ketamine is a weak affinity ligand to HSA and no significant differences in binding behavior were found between the individual enantiomers and the racemate.
DNA alkyltransferase and alkyltransferase-like family proteins are responsible for the repair of highly mutagenic and cytotoxic O\(^6\)-alkylguanine and O\(^4\)-alkylthymine bases in DNA. Their mechanism involves binding to the damaged DNA and flipping the base out of the DNA helix into the active site pocket in the protein. Alkyltransferases then directly and irreversibly transfer the alkyl group from the base to the active site cysteine residue. In contrast, alkyltransferase-like proteins recruit nucleotide excision repair components for O\(^6\)-alkylguanine elimination. One or more of these proteins are found in all kingdoms of life, and where this has been determined, their overall DNA repair mechanism is strictly conserved between organisms. Nevertheless, between species, subtle as well as more extensive differences that affect target lesion preferences and/or introduce additional protein functions have evolved. Examining these differences and their functional consequences is intricately entwined with understanding the details of their DNA repair mechanism(s) and their biological roles. In this review, we will present and discuss various aspects of the current status of knowledge on this intriguing protein family.
Highlights
• Synthesis of a new tracer molecule.
• Robust and easy screening method for a broad range of compound activities.
• FP assay validation considering limited use of starting material, DMSO tolerance, variation in incubation time and temperature.
• Possibility of extension to HTP assay.
Abstract
The macrophage infectivity potentiator (Mip) protein belongs to the immunophilin superfamily. This class of enzymes catalyzes the interconversion between the cis and trans configuration of proline-containing peptide bonds. Mip has been shown to be important for the virulence of a wide range of pathogenic microorganisms, including the Gram-negative bacterium Burkholderia pseudomallei. Small molecules derived from the natural product rapamycin, lacking its immunosuppression-inducing moiety, inhibit Mip's peptidyl-prolyl cis-trans isomerase (PPIase) activity and lead to a reduction in pathogen load in vitro. Here, a fluorescence polarization assay (FPA) to enable the screening and effective development of BpMip inhibitors was established. A fluorescent probe was prepared, derived from previous pipecolic scaffold Mip inhibitors labeled with fluorescein. This probe showed moderate affinity for BpMip and enabled a highly robust FPA suitable for screening large compound libraries with medium- to high-throughput (Z factor ∼ 0.89) to identify potent new inhibitors. The FPA results are consistent with data from the protease-coupled PPIase assay. Analysis of the temperature dependence of the probe's binding highlighted that BpMip's ligand binding is driven by enthalpic rather than entropic effects. This has considerable consequences for the use of low-temperature kinetic assays.
Anxious depression represents a subtype of major depressive disorder and is associated with increased suicidality, severity, chronicity and lower treatment response. Only a few studies have investigated the differences between anxious depressed (aMDD) and non-anxious depressed (naMDD) patients regarding treatment dosage, serum-concentration and drug-specific treatment response. In our naturalistic and prospective study, we investigated whether the effectiveness of therapy including antidepressants (SSRI, SNRI, NaSSA, tricyclics and combinations) in aMDD patients differs significantly from that in naMDD patients. In a sample of 346 patients, we calculated the anxiety somatization factor (ASF) and defined treatment response as a reduction (≥50%) in the Hamilton Depression Rating Scale (HDRS)-21 score after 7 weeks of pharmacological treatment. We did not observe an association between therapy response and the baseline ASF-scores, or differences in therapy outcomes between aMDD and naMDD patients. However, non-responders had higher ASF-scores, and at week 7 aMDD patients displayed a worse therapy outcome than naMDD patients. In subgroup analyses for different antidepressant drugs, venlafaxine-treated aMDD patients showed a significantly worse outcome at week 7. Future prospective, randomized-controlled studies should address the question of a worse therapy outcome in aMDD patients for different psychopharmaceuticals individually.
Dimethyl fumarate attenuates lymphocyte infiltration and reduces infarct size in experimental stroke
(2023)
Ischemic stroke is associated with exacerbated tissue damage caused by the activation of immune cells and the initiation of other inflammatory processes. Dimethyl fumarate (DMF) is known to modulate the immune response, activate antioxidative pathways, and improve the blood–brain barrier (BBB) after stroke. However, the specific impact of DMF on immune cells after cerebral ischemia remains unclear. In our study, male mice underwent transient middle cerebral artery occlusion (tMCAO) for 30 min and received oral DMF (15 mg/kg) or a vehicle immediately after tMCAO, followed by twice-daily administrations for 7 days. Infarct volume was assessed on T2-weighted magnetic resonance images on days 1 and 7 after tMCAO. Brain-infiltrating immune cells (lymphocytes, monocytes) and microglia were quantified using fluorescence-activated cell sorting. DMF treatment significantly reduced infarct volumes and brain edema. On day 1 after tMCAO, DMF-treated mice showed reduced lymphocyte infiltration compared to controls, which was not observed on day 7. Monocyte and microglial cell counts did not differ between groups on either day. In the acute phase of stroke, DMF administration attenuated lymphocyte infiltration, probably due to its stabilizing effect on the BBB. This highlights the potential of DMF as a therapeutic candidate for mitigating immune cell-driven damage in stroke.
RBM20 mutations account for 3 % of genetic cardiomypathies and manifest with high penetrance and arrhythmogenic effects. Numerous mutations in the conserved RS domain have been described as causing dilated cardiomyopathy (DCM), whereas a particular mutation (p.R634L) drives development of a different cardiac phenotype: left-ventricular non-compaction cardiomyopathy. We generated a mutation-induced pluripotent stem cell (iPSC) line in which the RBM20-LVNC mutation p.R634L was introduced into a DCM patient line with rescued RBM20-p.R634W mutation. These DCM-634L-iPSC can be differentiated into functional cardiomyocytes to test whether this RBM20 mutation induces development of the LVNC phenotype within the genetic context of a DCM patient.
During the COVID-19 pandemic, social distancing restricted psycho-oncological care. Therefore, this secondary analysis examines the changes in anxiety, fear of progression, fatigue, and depression in cancer patients after a video-based eHealth intervention. We used a prospective observational design with 155 cancer patients with mixed tumor entities. Data were assessed before and after the intervention and at a three-month follow-up using self-reported questionnaires (GAD-7, FOP-Q-SF, PHQ-8, and EORTC QLQ-FA12). The eight videos included psychoeducation, Acceptance and Commitment Therapy elements, and yoga and qigong exercises. The results showed that three months after finishing the video-based intervention, participants showed significantly reduced fear of progression (d = −0.23), depression (d = −0.27), and fatigue (d = −0.24) compared to the baseline. However, there was no change in anxiety (d = −0.09). Findings indicated marginal improvements in mental distress when using video-based intervention for cancer patients for up to three months, but long-term effectiveness must be confirmed using a controlled design.
During the COVID-19 pandemic, the novel coronavirus had an impact not only on public health but also on the mental health of the population. Public sentiment on mental health and depression is often captured only in small, survey-based studies, while work based on Twitter data often only looks at the period during the pandemic and does not make comparisons with the pre-pandemic situation. We collected tweets that included the hashtags #MentalHealth and #Depression from before and during the pandemic (8.5 months each). We used LDA (Latent Dirichlet Allocation) for topic modeling and LIWC, VADER, and NRC for sentiment analysis. We used three machine-learning classifiers to seek evidence regarding an automatically detectable change in tweets before vs. during the pandemic: (1) based on TF-IDF values, (2) based on the values from the sentiment libraries, (3) based on tweet content (deep-learning BERT classifier). Topic modeling revealed that Twitter users who explicitly used the hashtags #Depression and especially #MentalHealth did so to raise awareness. We observed an overall positive sentiment, and in tough times such as during the COVID-19 pandemic, tweets with #MentalHealth were often associated with gratitude. Among the three classification approaches, the BERT classifier showed the best performance, with an accuracy of 81% for #MentalHealth and 79% for #Depression. Although the data may have come from users familiar with mental health, these findings can help gauge public sentiment on the topic. The combination of (1) sentiment analysis, (2) topic modeling, and (3) tweet classification with machine learning proved useful in gaining comprehensive insight into public sentiment and could be applied to other data sources and topics.
The cystine/glutamate antiporter xCT is an important source of cysteine for cancer cells. Once taken up, cystine is reduced to cysteine and serves as a building block for the synthesis of glutathione, which efficiently protects cells from oxidative damage and prevents ferroptosis. As melanomas are particularly exposed to several sources of oxidative stress, we investigated the biological role of cysteine and glutathione supply by xCT in melanoma. xCT activity was abolished by genetic depletion in the Tyr::CreER; Braf\(^{CA}\); Pten\(^{lox/+}\) melanoma model and by acute cystine withdrawal in melanoma cell lines. Both interventions profoundly impacted melanoma glutathione levels, but they were surprisingly well tolerated by murine melanomas in vivo and by most human melanoma cell lines in vitro. RNA sequencing of human melanoma cells revealed a strong adaptive upregulation of NRF2 and ATF4 pathways, which orchestrated the compensatory upregulation of genes involved in antioxidant defence and de novo cysteine biosynthesis. In addition, the joint activation of ATF4 and NRF2 triggered a phenotypic switch characterized by a reduction of differentiation genes and induction of pro-invasive features, which was also observed after erastin treatment or the inhibition of glutathione synthesis. NRF2 alone was capable of inducing the phenotypic switch in a transient manner. Together, our data show that cystine or glutathione levels regulate the phenotypic plasticity of melanoma cells by elevating ATF4 and NRF2.
Salivary gland tumors (SGTs) are a relevant, highly diverse subgroup of head and neck tumors whose entity determination can be difficult. Confocal Raman imaging in combination with multivariate data analysis may possibly support their correct classification. For the analysis of the translational potential of Raman imaging in SGT determination, a multi-stage evaluation process is necessary. By measuring a sample set of Warthin tumor, pleomorphic adenoma and non-tumor salivary gland tissue, Raman data were obtained and a thorough Raman band analysis was performed. This evaluation revealed highly overlapping Raman patterns with only minor spectral differences. Consequently, a principal component analysis (PCA) was calculated and further combined with a discriminant analysis (DA) to enable the best possible distinction. The PCA-DA model was characterized by accuracy, sensitivity, selectivity and precision values above 90% and validated by predicting model-unknown Raman spectra, of which 93% were classified correctly. Thus, we state our PCA-DA to be suitable for parotid tumor and non-salivary salivary gland tissue discrimination and prediction. For evaluation of the translational potential, further validation steps are necessary.
Highlights
• The integrated stress response leads to a general ATF4-dependent activation of NRF2
• ATF4 causes a CHAC1-dependent GSH depletion, resulting in NRF2 stabilization
• An elevation of NRF2 transcript levels fosters this effect
• NRF2 supports the ISR/ATF4 pathway by improving cystine and antioxidant supply
Summary
The redox regulator NRF2 becomes activated upon oxidative and electrophilic stress and orchestrates a response program associated with redox regulation, metabolism, tumor therapy resistance, and immune suppression. Here, we describe an unrecognized link between the integrated stress response (ISR) and NRF2 mediated by the ISR effector ATF4. The ISR is commonly activated after starvation or ER stress and plays a central role in tissue homeostasis and cancer plasticity. ATF4 increases NRF2 transcription and induces the glutathione-degrading enzyme CHAC1, which we now show to be critically important for maintaining NRF2 activation. In-depth analyses reveal that NRF2 supports ATF4-induced cells by increasing cystine uptake via the glutamate-cystine antiporter xCT. In addition, NRF2 upregulates genes mediating thioredoxin usage and regeneration, thus balancing the glutathione decrease. In conclusion, we demonstrate that the NRF2 response serves as second layer of the ISR, an observation highly relevant for the understanding of cellular resilience in health and disease.
This retrospective study aims to provide an intra-individual comparison of aortic CT angiographies (CTAs) using first-generation photon-counting-detector CT (PCD-CT) and third-generation energy-integrating-detector CT (EID-CT). High-pitch CTAs were performed with both scanners and equal contrast-agent protocols. EID-CT employed automatic tube voltage selection (90/100 kVp) with reference tube current of 434/350 mAs, whereas multi-energy PCD-CT scans were generated with fixed tube voltage (120 kVp), image quality level of 64, and reconstructed as 55 keV monoenergetic images. For image quality assessment, contrast-to-noise ratios (CNRs) were calculated, and subjective evaluation (overall quality, luminal contrast, vessel sharpness, blooming, and beam hardening) was performed independently by three radiologists. Fifty-seven patients (12 women, 45 men) were included with a median interval between examinations of 12.7 months (interquartile range 11.1 months). Using manufacturer-recommended scan protocols resulted in a substantially lower radiation dose in PCD-CT (size-specific dose estimate: 4.88 ± 0.48 versus 6.28 ± 0.50 mGy, p < 0.001), while CNR was approximately 50% higher (41.11 ± 8.68 versus 27.05 ± 6.73, p < 0.001). Overall image quality and luminal contrast were deemed superior in PCD-CT (p < 0.001). Notably, EID-CT allowed for comparable vessel sharpness (p = 0.439) and less pronounced blooming and beam hardening (p < 0.001). Inter-rater agreement was good to excellent (0.58–0.87). Concluding, aortic PCD-CTAs facilitate increased image quality with significantly lower radiation dose compared to EID-CTAs
The pathophysiology of tremor in Parkinson’s disease (PD) is evolving towards a complex alteration to monoaminergic innervation, and increasing evidence suggests a key role of the locus coeruleus noradrenergic system (LC-NA). However, the difficulties in imaging LC-NA in patients challenge its direct investigation. To this end, we studied the development of tremor in a reserpinized rat model of PD, with or without a selective lesioning of LC-NA innervation with the neurotoxin DSP-4. Eight male rats (Sprague Dawley) received DSP-4 (50 mg/kg) two weeks prior to reserpine injection (10 mg/kg) (DR-group), while seven male animals received only reserpine treatment (R-group). Tremor, rigidity, hypokinesia, postural flexion and postural immobility were scored before and after 20, 40, 60, 80, 120 and 180 min of reserpine injection. Tremor was assessed visually and with accelerometers. The injection of DSP-4 induced a severe reduction in LC-NA terminal axons (DR-group: 0.024 ± 0.01 vs. R-group: 0.27 ± 0.04 axons/um\(^2\), p < 0.001) and was associated with significantly less tremor, as compared to the R-group (peak tremor score, DR-group: 0.5 ± 0.8 vs. R-group: 1.6 ± 0.5; p < 0.01). Kinematic measurement confirmed the clinical data (tremor consistency (% of tremor during 180 s recording), DR-group: 37.9 ± 35.8 vs. R-group: 69.3 ± 29.6; p < 0.05). Akinetic–rigid symptoms did not differ between the DR- and R-groups. Our results provide preliminary causal evidence for a critical role of LC-NA innervation in the development of PD tremor and foster the development of targeted therapies for PD patients.
Alpine bumble bees are the most important pollinators in temperate mountain ecosystems. Although they are used to encounter small-scale successions of very different climates in the mountains, many species respond sensitively to climatic changes, reflected in spatial range shifts and declining populations worldwide. Cuticular hydrocarbons (CHCs) mediate climate adaptation in some insects. However, whether they predict the elevational niche of bumble bees or their responses to climatic changes remains poorly understood. Here, we used three different approaches to study the role of bumble bees’ CHCs in the context of climate adaptation: using a 1,300 m elevational gradient, we first investigated whether the overall composition of CHCs, and two potentially climate-associated chemical traits (proportion of saturated components, mean chain length) on the cuticle of six bumble bee species were linked to the species’ elevational niches. We then analyzed intraspecific variation in CHCs of Bombus pascuorum along the elevational gradient and tested whether these traits respond to temperature. Finally, we used a field translocation experiment to test whether CHCs of Bombus lucorum workers change, when translocated from the foothill of a cool and wet mountain region to (a) higher elevations, and (b) a warm and dry region. Overall, the six species showed distinctive, species-specific CHC profiles. We found inter- and intraspecific variation in the composition of CHCs and in chemical traits along the elevational gradient, but no link to the elevational distribution of species and individuals. According to our expectations, bumble bees translocated to a warm and dry region tended to express longer CHC chains than bumble bees translocated to cool and wet foothills, which could reflect an acclimatization to regional climate. However, chain lengths did not further decrease systematically along the elevational gradient, suggesting that other factors than temperature also shape chain lengths in CHC profiles. We conclude that in alpine bumble bees, CHC profiles and traits respond at best secondarily to the climate conditions tested in this study. While the functional role of species-specific CHC profiles in bumble bees remains elusive, limited plasticity in this trait could restrict species’ ability to adapt to climatic changes.
Introduction: Grasslands cover one third of the agricultural area in Germany and are mainly used for fodder production. However, grasslands fulfill many other ecosystem functions, like carbon storage, water filtration and the provision of habitats. In Germany, grasslands are mown and/or grazed multiple times during the year. The type and timing of management activities and the use intensity vary strongly, however co-determine grassland functions. Large-scale spatial information on grassland activities and use intensity in Germany is limited and not openly provided. In addition, the cause for patterns of varying mowing intensity are usually not known on a spatial scale as data on the incentives of farmers behind grassland management decisions is not available.
Methods: We applied an algorithm based on a thresholding approach utilizing Sentinel-2 time series to detect grassland mowing events to investigate mowing dynamics in Germany in 2018–2021. The detected mowing events were validated with an independent dataset based on the examination of public webcam images. We analyzed spatial and temporal patterns of the mowing dynamics and relationships to climatic, topographic, soil or socio-political conditions.
Results: We found that most intensively used grasslands can be found in southern/south-eastern Germany, followed by areas in northern Germany. This pattern stays the same among the investigated years, but we found variations on smaller scales. The mowing event detection shows higher accuracies in 2019 and 2020 (F1 = 0.64 and 0.63) compared to 2018 and 2021 (F1 = 0.52 and 0.50). We found a significant but weak (R2 of 0–0.13) relationship for a spatial correlation of mowing frequency and climate as well as topographic variables for the grassland areas in Germany. Further results indicate a clear value range of topographic and climatic conditions, characteristic for intensive grassland use. Extensive grassland use takes place everywhere in Germany and on the entire spectrum of topographic and climatic conditions in Germany. Natura 2000 grasslands are used less intensive but this pattern is not consistent among all sites.
Discussion: Our findings on mowing dynamics and relationships to abiotic and socio-political conditions in Germany reveal important aspects of grassland management, including incentives of farmers.
Xiphophorus fish exhibit a clear phenotypic polymorphism in puberty onset and reproductive strategies of males. In X. nigrensis and X. multilineatus, puberty onset is genetically determined and linked to a melanocortin 4 receptor (Mc4r) polymorphism of wild-type and mutant alleles on the sex chromosomes. We hypothesized that Mc4r mutant alleles act on wild-type alleles by a dominant negative effect through receptor dimerization, leading to differential intracellular signaling and effector gene activation. Depending on signaling strength, the onset of puberty either occurs early or is delayed. Here, we show by Förster Resonance Energy Transfer (FRET) that wild-type Xiphophorus Mc4r monomers can form homodimers, but also heterodimers with mutant receptors resulting in compromised signaling which explains the reduced Mc4r signaling in large males. Thus, hetero- vs. homo- dimerization seems to be the key molecular mechanism for the polymorphism in puberty onset and body size in male fish.
Background
Adrenal incidentalomas with cortisol autonomy are associated with increased cardiovascular morbidity and mortality. Specific data on the clinical and biochemical course of affected patients are lacking.
Methods
Retrospective study from a tertiary referral centre in Germany. After exclusion of overt hormone excess, malignancy and glucocorticoid medication, patients with adrenal incidentalomas were stratified according to serum cortisol after 1 mg dexamethasone: autonomous cortisol secretion (ACS), >5.0; possible ACS (PACS), 1.9-5.0; non-functioning adenomas (NFA), ≤1.8 µg/dl.
Results
A total of 260 patients were enrolled (147 women (56.5%), median follow-up 8.8 (2.0-20.8) years). At initial diagnosis, median age was 59.5 (20-82) years, and median tumour size was 27 (10-116) mm. Bilateral tumours were more prevalent in ACS (30.0%) and PACS (21.9%) than in NFA (8.1%). Over time, 40/124 (32.3%) patients had a shift of their hormonal secretion pattern (NFA to PACS/ACS, n=15/53; PACS to ACS, n=6/47; ACS to PACS, n=11/24; PACS to NFA, n=8/47). However, none of the patients developed overt Cushing’s syndrome. Sixty-one patients underwent adrenalectomy (NFA, 17.9%; PACS, 24.0%; ACS, 39.0%). When non-operated patients with NFA were compared to PACS and ACS at last follow-up, arterial hypertension (65.3% vs. 81.9% and 92.0%; p<0.05), diabetes (23.8% vs. 35.6% and 40.0%; p<0.01), and thromboembolic events (PACS: HR 3.43, 95%-CI 0.89-13.29; ACS: HR 5.96, 95%-CI 1.33-26.63; p<0.05) were significantly less frequent, along with a trend towards a higher rate of cardiovascular events in case of cortisol autonomy (PACS: HR 2.23, 95%-CI 0.94-5.32; ACS: HR 2.60, 95%-CI 0.87-7.79; p=0.1). Twenty-five (12.6%) of the non-operated patients died, with higher overall mortality in PACS (HR 2.6, 95%-CI 1.0-4.7; p=0.083) and ACS (HR 4.7, 95%-CI 1.6-13.3; p<0.005) compared to NFA. In operated patients, prevalence of arterial hypertension decreased significantly (77.0% at diagnosis to 61.7% at last follow-up; p<0.05). The prevalence of cardiovascular events and mortality did not differ significantly between operated and non-operated patients, whereas thromboembolic events were significantly less frequent in the surgical treatment group.
Conclusion
Our study confirms relevant cardiovascular morbidity in patients with adrenal incidentalomas (especially those with cortisol autonomy). These patients should therefore be monitored carefully, including adequate treatment of typical cardiovascular risk factors. Adrenalectomy was associated with a significantly decreased prevalence of hypertension. However, more than 30% of patients required reclassification according to repeated dexamethasone suppression tests. Thus, cortisol autonomy should ideally be confirmed before making any relevant treatment decision (e.g. adrenalectomy).
The transition to school is a key juncture in an individual’s educational trajectory, with far-reaching effects on the development of children and their families. Successful transitions require flexibility in the design of the transition process, addressing the needs of the persons involved in an adaptive manner. Adaptivity is also considered crucial for the success of inclusive transitions. However, a systematic breakdown of the aspects that characterize the concept of adaptivity in the context of inclusive school entry is not available at this point. This article therefore provides a conceptualization of adaptivity in the inclusive transition to school as well as a review of the current literature focusing this topic. The goal is to develop a model that structures the various aspects of adaptivity at school entry and offers an overview of the way these aspects are important to design the transition successfully according to current findings of empirical research. Building on a concept of transitions informed by ecological systems theory, we are guided by the assumption that adaptivity at transition to school may occur in three forms: as a feature of the persons involved in the transition; as a feature of the processes that moderate the course of the transition; and as a feature of the structures that frame the transition. Based on this distinction, we develop a model that presents adaptivity in the inclusive transition to school.
Providing adaptive, independence-preserving and theory-guided support to students in dealing with real-world problems in mathematics lessons is a major challenge for teachers in their professional practice. This paper examines this challenge in the context of simulations and mathematical modelling with digital tools: in addition to mathematical difficulties when autonomously working out individual solutions, students may also experience challenges when using digital tools. These challenges need to be closely examined and diagnosed, and might – if necessary – have to be overcome by intervention in such a way that the students can subsequently continue working independently. Thus, if a difficulty arises in the working process, two knowledge dimensions are necessary in order to provide adapted support to students. For teaching simulations and mathematical modelling with digital tools, more specifically, these knowledge dimensions are: pedagogical content knowledge about simulation and modelling processes supported by digital tools (this includes knowledge about phases and difficulties in the working process) and pedagogical content knowledge about interventions during the mentioned processes (focussing on characteristics of suitable interventions as well as their implementation and effects on the students’ working process). The two knowledge dimensions represent cognitive dispositions as the basis for the conceptualisation and operationalisation of a so-called adaptive intervention competence for teaching simulations and mathematical modelling with digital tools. In our article, we present a domain-specific process model and distinguish different types of teacher interventions. Then we describe the design and content of a university course at two German universities aiming to promote this domain-specific professional adaptive intervention competence, among others. In a study using a quasi-experimental pre-post design (N = 146), we confirm that the structure of cognitive dispositions of adaptive intervention competence for teaching simulations and mathematical modelling with digital tools can be described empirically by a two-dimensional model. In addition, the effectiveness of the course is examined and confirmed quantitatively. Finally, the results are discussed, especially against the background of the sample and the research design, and conclusions are derived for possibilities of promoting professional adaptive intervention competence in university courses.
Following the implementation of 2018’s laws on the rights of persons with disabilities (PWDs) in Egypt, students with disabilities (SWDs) have both legal and moral rights to meaningful learning opportunities and inclusive education. Despite that, SWDs still have very limited education resources which limit their career aspirations and quality of life. In this respect, education whether as part of formal education or lifelong learning is central to the museum’s mission. Museums, as part of non-formal education, are being acknowledged for their educative powers and investments in the development of quality formal, non-formal, and informal learning experiences. Further, phrases such as “inclusivity,” “accessibility,” and “diversity” were notably included in the newly approved museum definition by ICOM (2022) emphasizing museums’ obligations to embrace societal issues and shape a cultural attitude concerning disability rights, diversity, and equality together with overcoming exclusionary educational practices. The study seeks to investigate the existing resources and inclusive practices in Egyptian museums to achieve non-formal education for SWDs. Qualitative research approaches have been employed to answer a specific question: How can Egyptian museums work within their governing systems to support the learning of SWDs beyond their formal education system? The study aims to assess the potential of Egyptian museums in facilitating learning for SWDs. Further, it examines the capability of Egyptian museums in contributing to informal and non-formal learning for SWDs and striving for inclusive education inspired by the social model of disability that fosters inclusive educational programs and adopts a human rights-based approach. The results revealed that Egyptian museums contributed to the learning of SWDs, yet small-scale programs and individual efforts, but they are already engaged in active inclusive practices that address the learning of SWDs. The study suggests that they need to be acknowledged and supported by the government as state instruments and direct actors in advancing inclusive education and implementing appropriate pedagogies in favor of SWDs.
Ultra-high field cardiac MRI in large animals and humans for translational cardiovascular research
(2023)
A key step in translational cardiovascular research is the use of large animal models to better understand normal and abnormal physiology, to test drugs or interventions, or to perform studies which would be considered unethical in human subjects. Ultrahigh field magnetic resonance imaging (UHF-MRI) at 7 T field strength is becoming increasingly available for imaging of the heart and, when compared to clinically established field strengths, promises better image quality and image information content, more precise functional analysis, potentially new image contrasts, and as all in-vivo imaging techniques, a reduction of the number of animals per study because of the possibility to scan every animal repeatedly. We present here a solution to the dual use problem of whole-body UHF-MRI systems, which are typically installed in clinical environments, to both UHF-MRI in large animals and humans. Moreover, we provide evidence that in such a research infrastructure UHF-MRI, and ideally combined with a standard small-bore UHF-MRI system, can contribute to a variety of spatial scales in translational cardiovascular research: from cardiac organoids, Zebra fish and rodent hearts to large animal models such as pigs and humans. We present pilot data from serial CINE, late gadolinium enhancement, and susceptibility weighted UHF-MRI in a myocardial infarction model over eight weeks. In 14 pigs which were delivered from a breeding facility in a national SARS-CoV-2 hotspot, we found no infection in the incoming pigs. Human scanning using CINE and phase contrast flow measurements provided good image quality of the left and right ventricle. Agreement of functional analysis between CINE and phase contrast MRI was excellent. MRI in arrested hearts or excised vascular tissue for MRI-based histologic imaging, structural imaging of myofiber and vascular smooth muscle cell architecture using high-resolution diffusion tensor imaging, and UHF-MRI for monitoring free radicals as a surrogate for MRI of reactive oxygen species in studies of oxidative stress are demonstrated. We conclude that UHF-MRI has the potential to become an important precision imaging modality in translational cardiovascular research.
Over the past years, scholars have explored eudaimonic video game experiences—profound entertainment responses that include meaningfulness, reflection, and others. In a comparatively short time, a plethora of explanations for the formation of such eudaimonic gaming experiences has been developed across multiple disciplines, making it difficult to keep track of the state of theory development. Hence, we present a theoretical overview of these explanations. We first provide a working definition of eudaimonic gaming experiences (i.e., experiences that reflect human virtues and encourage players to develop their potential as human beings fully) and outline four layers of video games—agency, narrative, sociality, and aesthetics—that form the basis for theorizing. Subsequently, we provide an overview of the theoretical approaches, categorizing them based on which of the four game layers their explanation mainly rests upon. Finally, we suggest the contingency of the different theoretical approaches for explaining eudaimonic experiences by describing how their usefulness varies as a function of interactivity. As different types of games offer players various levels of interactivity, our overview suggests which theories and which game layers should be considered when examining eudaimonic experiences for specific game types.
Fungal infections are a major global health burden where Candida albicans is among the most common fungal pathogen in humans and is a common cause of invasive candidiasis. Fungal phenotypes, such as those related to morphology, proliferation and virulence are mainly driven by gene expression, which is primarily regulated by kinase signaling cascades. Serine-arginine (SR) protein kinases are highly conserved among eukaryotes and are involved in major transcriptional processes in human and S. cerevisiae. Candida albicans harbors two SR protein kinases, while Sky2 is important for metabolic adaptation, Sky1 has similar functions as in S. cerevisiae. To investigate the role of these SR kinases for the regulation of transcriptional responses in C. albicans, we performed RNA sequencing of sky1Δ and sky2Δ and integrated a comprehensive phosphoproteome dataset of these mutants. Using a Systems Biology approach, we study transcriptional regulation in the context of kinase signaling networks. Transcriptomic enrichment analysis indicates that pathways involved in the regulation of gene expression are downregulated and mitochondrial processes are upregulated in sky1Δ. In sky2Δ, primarily metabolic processes are affected, especially for arginine, and we observed that arginine-induced hyphae formation is impaired in sky2Δ. In addition, our analysis identifies several transcription factors as potential drivers of the transcriptional response. Among these, a core set is shared between both kinase knockouts, but it appears to regulate different subsets of target genes. To elucidate these diverse regulatory patterns, we created network modules by integrating the data of site-specific protein phosphorylation and gene expression with kinase-substrate predictions and protein-protein interactions. These integrated signaling modules reveal shared parts but also highlight specific patterns characteristic for each kinase. Interestingly, the modules contain many proteins involved in fungal morphogenesis and stress response. Accordingly, experimental phenotyping shows a higher resistance to Hygromycin B for sky1Δ. Thus, our study demonstrates that a combination of computational approaches with integration of experimental data can offer a new systems biological perspective on the complex network of signaling and transcription. With that, the investigation of the interface between signaling and transcriptional regulation in C. albicans provides a deeper insight into how cellular mechanisms can shape the phenotype.
The signals that coordinate and control movement in vertebrates are transmitted from motoneurons (MNs) to their target muscle cells at neuromuscular junctions (NMJs). Human NMJs display unique structural and physiological features, which make them vulnerable to pathological processes. NMJs are an early target in the pathology of motoneuron diseases (MND). Synaptic dysfunction and synapse elimination precede MN loss suggesting that the NMJ is the starting point of the pathophysiological cascade leading to MN death. Therefore, the study of human MNs in health and disease requires cell culture systems that enable the connection to their target muscle cells for NMJ formation. Here, we present a human neuromuscular co-culture system consisting of induced pluripotent stem cell (iPSC)-derived MNs and 3D skeletal muscle tissue derived from myoblasts. We used self-microfabricated silicone dishes combined with Velcro hooks to support the formation of 3D muscle tissue in a defined extracellular matrix, which enhances NMJ function and maturity. Using a combination of immunohistochemistry, calcium imaging, and pharmacological stimulations, we characterized and confirmed the function of the 3D muscle tissue and the 3D neuromuscular co-cultures. Finally, we applied this system as an in vitro model to study the pathophysiology of Amyotrophic Lateral Sclerosis (ALS) and found a decrease in neuromuscular coupling and muscle contraction in co-cultures with MNs harboring ALS-linked SOD1 mutation. In summary, the human 3D neuromuscular cell culture system presented here recapitulates aspects of human physiology in a controlled in vitro setting and is suitable for modeling of MND.
Diagnosing any of the more than 30 types of T-cell lymphomas is considered a challenging task for many pathologists and currently requires morphological expertise as well as the integration of clinical data, immunophenotype, flow cytometry and clonality analyses. Even considering all available information, some margin of doubt might remain using the current diagnostic procedures. In recent times, the genetic landscape of most T-cell lymphomas has been elucidated, showing a number of diagnostically relevant mutations. In addition, recent data indicate that some of these genetic alterations might bear prognostic and predictive value. Extensive genetic analyses, such as whole exome or large panel sequencing are still expensive and time consuming, therefore limiting their application in routine diagnostic. We therefore devoted our effort to develop a lean approach for genetic analysis of T-cell lymphomas, focusing on maximum efficiency rather than exhaustively covering all possible targets. Here we report the results generated with our small amplicon-based panel that could be used routinely on paraffin-embedded and even decalcified samples, on a single sample basis in parallel with other NGS-panels used in our routine diagnostic lab, in a relatively short time and with limited costs. We tested 128 available samples from two German reference centers as part of our routine work up (among which 116 T-cell lymphomas), which is the largest routine diagnostic series reported to date. Our results showed that this assay had a very high rate of technical success (97%) and could detect mutations in the majority (79%) of tested T-cell lymphoma samples.
The execution of voluntary movements is primarily governed by the cerebral hemisphere contralateral to the moving limb. Previous research indicates that the ipsilateral motor network, comprising the primary motor cortex (M1), supplementary motor area (SMA), and premotor cortex (PM), plays a crucial role in the planning and execution of limb movements. However, the precise functions of this network and its interplay in different task contexts have yet to be fully understood. Twenty healthy right-handed participants (10 females, mean age 26.1 ± 4.6 years) underwent functional MRI scans while performing biceps brachii representations such as bilateral, unilateral flexion, and bilateral flexion-extension. Ipsilateral motor evoked potentials (iMEPs) were obtained from the identical set of participants in a prior study using transcranial magnetic stimulation (TMS) targeting M1 while employing the same motor tasks. The voxel time series was extracted based on the region of interest (M1, SMA, ventral PM and dorsal PM). Directed functinal connectivity was derived from the extracted time series using time-resolved partial directed coherence. We found increased connectivity from left-PMv to both sides M1, as well as right-PMv to both sides SMA, in unilateral flexion compared to bilateral flexion. Connectivity from left M1 to left-PMv, and left-SMA to right-PMd, also increased in both unilateral flexion and bilateral flexion-extension compared to bilateral flexion. However, connectivity between PMv and right-M1 to left-PMd decreased during bilateral flexion-extension compared to unilateral flexion. Additionally, during bilateral flexion-extension, the connectivity from right-M1 to right-SMA had a negative relationship with the area ratio of iMEP in the dominant side. Our results provide corroborating evidence for prior research suggesting that the ipsilateral motor network is implicated in the voluntary movements and underscores its involvement in cognitive processes such as movement planning and coordination. Moreover, ipsilateral connectivity from M1 to SMA on the dominant side can modulate the degree of ipsilateral M1 activation during bilateral antagonistic contraction.
Introduction: National and international guidelines recommend early integration of evidence-based multimodal interventions and programs, especially with a focus on relaxation techniques and other Mind–Body-based methods to maintain the quality of life of oncology patients, improve treatment tolerability, and promote healthy lifestyle behaviors. Consequently, we aim to understand what drives patients and how they navigate integrative medicine to best advise them. This study aimed to detect possible topics of particular interest to patients and identify the patient groups that could benefit most from further programs. Furthermore, we aimed to investigate if patients are open-minded toward integrative oncology concepts and learn about their motivational level to maintain or change behavior.
Methods: Between August 2019 and October 2020 we surveyed patients undergoing oncological therapy in a university oncological outpatient center using a custom-developed questionnaire based on established Mind–Body Medicine concepts.
Results: We included 294 patients with various cancers. More than half reported problems sleeping through (61%) and 42% felt stressed frequently, invariably rating this as detrimental to their health. Moreover, a slight majority (52%) felt physically limited due to their disease and only 30% performed defined exercise programs. Women were significantly more likely to feel stressed and reported with alarming frequency that they often feel “everything was up to them.” The 40–65-year-olds reported significantly less restful sleep, more stress and were more dissatisfied with their situation. However, this group already used natural remedies most frequently and was most often motivated to use relaxation techniques in the next 6 months. The lower the perceived individual energy level (EL), the less frequently patients did sport, the more frequently they felt their disease impaired their activity, mostly feeling stressed and tense. We also found significant associations between negative emotions/thoughts and the variables “sleep,” “use of relaxation techniques,” “personal stress perception,” and “successful lifestyle modification.”
Conclusion: Mind–Body programs that focus on patient’s individual resources, with tools to explore impairing patterns of self-perception and cognitive biases, can be a valuable resource for oncology patients and should therefore be part of an integrative medical treatment concept.
Introduction: In this study, we investigated the impact of age on mate selection preferences in males and females, and explored how the formation and duration of committed relationships depend on the sex of the person making the selection.
Methods: To this end, we utilized data from the television dating shows The Bachelor and The Bachelorette. In these programs, either a single man (“bachelor”) or a woman (“bachelorette”) has the opportunity to select a potential long-term partner from a pool of candidates. Our analysis encompassed a total of n = 169 seasons from 23 different countries, beginning with the first airing in 2002.
Results: We found that the likelihood of the final couple continuing their relationship beyond the broadcast was higher in The Bachelorette than in The Bachelor, although the duration of these relationships was not significantly influenced by the type of show. On average, women were younger, both when selecting their partner and when being chosen. However, men exhibited a greater preference for larger age differences than women. Furthermore, the age of the chosen male partners significantly increased with the age of the “bachelorettes,” whereas “bachelors” consistently favored women around 25.5 years old, regardless of their own age.
Discussion: We discuss these findings within the context of parental investment theory and sexual strategies theory.
Aim: The climate and ecological crises are considered fundamental threats to human health. Healthcare workers in general and doctors in particular can contribute as change agents in mitigation and adaptation. Planetary health education (PHE) aims to harness this potential. This study explores perspectives among stakeholders involved in PHE at German medical schools on the characteristics of high-quality PHE and compares them to existing PHE frameworks.
Methods: In 2021, we conducted a qualitative interview study with stakeholders from German medical schools involved in PHE. Three different groups were eligible: faculty members, medical students actively involved in PHE, and study deans of medical schools. Recruitment was performed through national PHE networks and snowball sampling. Thematic qualitative text analysis according to Kuckartz was used for the analysis. Results were systematically compared to three existing PHE frameworks.
Results: A total of 20 participants (13 female) from 15 different medical schools were interviewed. Participants covered a wide range of professional backgrounds and experience in PHE education. The analysis revealed ten key themes: (1) Complexity and systems thinking, (2) inter- and transdisciplinarity, (3) ethical dimension, (4) responsibility of health professionals, (5) transformative competencies including practical skills, (6) space for reflection and resilience building, (7) special role of students, (8) need for curricular integration, (9) innovative and proven didactic methods, and (10) education as a driver of innovation. Six of our themes showed substantial overlap with existing PHE frameworks. Two of our themes were only mentioned in one of the frameworks, and two others were not explicitly mentioned. Few important elements of the frameworks did not emerge from our data.
Conclusions: In the light of increased attention regarding the connections of the climate and ecological crises and health, our results can be useful for anyone working toward the integration of planetary health into medical schools' and any health professions' curricula and should be considered when designing and implementing new educational activities.
Background: According to socio-ecological theories, physical activity behaviors are linked to the physical and social neighborhood environment. Reliable and contextually adapted instruments are needed to assess environmental characteristics related to physical activity. This work aims to develop an audit toolbox adapted to the German context, to urban and rural settings, for different population groups, and different types of physical activity; and to evaluate its inter-rater reliability.
Methods: We conducted a systematic literature search to collect existing audit tools and to identify the latest evidence of environmental factors influencing physical activity in general, as well as in German populations. The results guided the construction of a category system for the toolbox. Items were assigned to the categories based on their relevance to physical activity and to the German context as well as their comprehensibility. We piloted the toolbox in different urban and rural areas (100 street segments, 15 parks, and 21 playgrounds) and calculated inter-rater reliability by Cohen's Kappa.
Results: The audit toolbox comprises a basic streetscape audit with seven categories (land use and destinations, traffic safety, pedestrian infrastructure, cycling infrastructure, attractiveness, social environment, and subjective assessment), as well as supplementary tools for children and adolescents, seniors and people with impaired mobility, parks and public open spaces, playgrounds, and rural areas. 76 % of all included items had moderate, substantial, or almost perfect inter-rater reliability (κ > 0.4).
Conclusions: The audit toolbox is an innovative and reliable instrument for the assessment of the physical activity friendliness of urban and rural environments in Germany.