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- D-1221-2009 (1)
In spinal muscular atrophy (SMA), mutations in or loss of the Survival Motor Neuron 1 (SMN1) gene reduce full-length SMN protein levels, which leads to the degeneration of a percentage of motor neurons. In mouse models of SMA, the development and maintenance of spinal motor neurons and the neuromuscular junction (NMJ) function are altered. Since nifedipine is known to be neuroprotective and increases neurotransmission in nerve terminals, we investigated its effects on cultured spinal cord motor neurons and motor nerve terminals of control and SMA mice. We found that application of nifedipine increased the frequency of spontaneous Ca\(^{2+}\) transients, growth cone size, cluster-like formations of Cav2.2 channels, and it normalized axon extension in SMA neurons in culture. At the NMJ, nifedipine significantly increased evoked and spontaneous release at low-frequency stimulation in both genotypes. High-strength stimulation revealed that nifedipine increased the size of the readily releasable pool (RRP) of vesicles in control but not SMA mice. These findings provide experimental evidence about the ability of nifedipine to prevent the appearance of developmental defects in SMA embryonic motor neurons in culture and reveal to which extent nifedipine could still increase neurotransmission at the NMJ in SMA mice under different functional demands.
By virtue of mitochondrial control of energy production, reactive oxygen species (ROS) generation, and maintenance of Ca\(^{2+}\) homeostasis, mitochondria play an essential role in modulating T cell function. The mitochondrial Ca\(^{2+}\) uniporter (MCU) is the pore-forming unit in the main protein complex mediating mitochondrial Ca\(^{2+}\) uptake. Recently, MCU has been shown to modulate Ca\(^{2+}\) signals at subcellular organellar interfaces, thus fine-tuning NFAT translocation and T cell activation. The mechanisms underlying this modulation and whether MCU has additional T cell subpopulation-specific effects remain elusive. However, mice with germline or tissue-specific ablation of Mcu did not show impaired T cell responses in vitro or in vivo, indicating that ‘chronic’ loss of MCU can be functionally compensated in lymphocytes. The current work aimed to specifically investigate whether and how MCU influences the suppressive potential of regulatory CD4 T cells (Treg). We show that, in contrast to genetic ablation, acute siRNA-mediated downregulation of Mcu in murine Tregs results in a significant reduction both in mitochondrial Ca\(^{2+}\) uptake and in the suppressive capacity of Tregs, while the ratios of Treg subpopulations and the expression of hallmark transcription factors were not affected. These findings suggest that permanent genetic inactivation of MCU may result in compensatory adaptive mechanisms, masking the effects on the suppressive capacity of Tregs.
Preterm infants are susceptible to infection and their defense against pathogens relies largely on innate immunity. The role of the complement system for the immunological vulnerability of preterm infants is less understood. Anaphylatoxin C5a and its receptors C5aR1 and -2 are known to be involved in sepsis pathogenesis, with C5aR1 mainly exerting pro-inflammatory effects. Our explorative study aimed to determine age-dependent changes in the expression of C5aR1 and C5aR2 in neonatal immune cell subsets. Via flow cytometry, we analyzed the expression pattern of C5a receptors on immune cells isolated from peripheral blood of preterm infants (n = 32) compared to those of their mothers (n = 25). Term infants and healthy adults served as controls. Preterm infants had a higher intracellular expression of C5aR1 on neutrophils than control individuals. We also found a higher expression of C5aR1 on NK cells, particularly on the cytotoxic CD56\(^{dim}\) subset and the CD56\(^-\) subset. Immune phenotyping of other leukocyte subpopulations revealed no gestational-age-related differences for the expression of and C5aR2. Elevated expression of C5aR1 on neutrophils and NK cells in preterm infants may contribute to the phenomenon of “immunoparalysis” caused by complement activation or to sustained hyper-inflammatory states. Further functional analyses are needed to elucidate the underlying mechanisms.
In a recent study, we showed in an in vitro murine cerebellar microvascular endothelial cell (cerebEND) model as well as in vivo in rats that Tumor-Treating Fields (TTFields) reversibly open the blood–brain barrier (BBB). This process is facilitated by delocalizing tight junction proteins such as claudin-5 from the membrane to the cytoplasm. In investigating the possibility that the same effects could be observed in human-derived cells, a 3D co-culture model of the BBB was established consisting of primary microvascular brain endothelial cells (HBMVEC) and immortalized pericytes, both of human origin. The TTFields at a frequency of 100 kHz administered for 72 h increased the permeability of our human-derived BBB model. The integrity of the BBB had already recovered 48 h post-TTFields, which is earlier than that observed in cerebEND. The data presented herein validate the previously observed effects of TTFields in murine models. Moreover, due to the fact that human cell-based in vitro models more closely resemble patient-derived entities, our findings are highly relevant for pre-clinical studies.
No abstract available.
Alveolar (AE) and cystic (CE) echinococcosis are two parasitic diseases caused by the tapeworms Echinococcus multilocularis and E. granulosus sensu lato (s. l.), respectively. Currently, AE and CE are mainly diagnosed by means of imaging techniques, serology, and clinical and epidemiological data. However, no viability markers that indicate parasite state during infection are available. Extracellular small RNAs (sRNAs) are short non-coding RNAs that can be secreted by cells through association with extracellular vesicles, proteins, or lipoproteins. Circulating sRNAs can show altered expression in pathological states; hence, they are intensively studied as biomarkers for several diseases. Here, we profiled the sRNA transcriptomes of AE and CE patients to identify novel biomarkers to aid in medical decisions when current diagnostic procedures are inconclusive. For this, endogenous and parasitic sRNAs were analyzed by sRNA sequencing in serum from disease negative, positive, and treated patients and patients harboring a non-parasitic lesion. Consequently, 20 differentially expressed sRNAs associated with AE, CE, and/or non-parasitic lesion were identified. Our results represent an in-depth characterization of the effect E. multilocularis and E. granulosus s. l. exert on the extracellular sRNA landscape in human infections and provide a set of novel candidate biomarkers for both AE and CE detection.
Grading, immunohistochemistry and c-kit mutation status are criteria for assessing the prognosis and therapeutic options of canine cutaneous mast cell tumours (MCTs). As a subset, canine digital MCTs have rarely been explored in this context. Therefore, in this retrospective study, 68 paraffin-embedded canine digital MCTs were analysed, and histological grading was assessed according to Patnaik and Kiupel. The immunohistochemical markers KIT and Ki67 were used, as well as polymerase chain reaction (PCR) for mutational screening in c-kit exons 8, 9, 11 and 14. Patnaik grading resulted in 22.1% grade I, 67.6% grade II and 10.3% grade III tumours. Some 86.8% of the digital MCTs were Kiupel low-grade. Aberrant KIT staining patterns II and III were found in 58.8%, and a count of more than 23 Ki67-positive cells in 52.3% of the cases. Both parameters were significantly associated with an internal tandem duplication (ITD) in c-kit exon 11 (12.7%). French Bulldogs, which tend to form well-differentiated cutaneous MCTs, had a higher proportion of digital high-grade MCTs and ITD in c-kit exon 11 compared with mongrels. Due to its retrospective nature, this study did not allow for an analysis of survival data. Nevertheless, it may contribute to the targeted characterisation of digital MCTs.
Improved wall temperature prediction for the LUMEN rocket combustion chamber with neural networks
(2023)
Accurate calculations of the heat transfer and the resulting maximum wall temperature are essential for the optimal design of reliable and efficient regenerative cooling systems. However, predicting the heat transfer of supercritical methane flowing in cooling channels of a regeneratively cooled rocket combustor presents a significant challenge. High-fidelity CFD calculations provide sufficient accuracy but are computationally too expensive to be used within elaborate design optimization routines. In a previous work it has been shown that a surrogate model based on neural networks is able to predict the maximum wall temperature along straight cooling channels with convincing precision when trained with data from CFD simulations for simple cooling channel segments. In this paper, the methodology is extended to cooling channels with curvature. The predictions of the extended model are tested against CFD simulations with different boundary conditions for the representative LUMEN combustor contour with varying geometries and heat flux densities. The high accuracy of the extended model’s predictions, suggests that it will be a valuable tool for designing and analyzing regenerative cooling systems with greater efficiency and effectiveness.
Increased intestinal permeability and inflammation, both fueled by dysbiosis, appear to contribute to rheumatoid arthritis (RA) pathogenesis. This single-center pilot study aimed to investigate zonulin, a marker of intestinal permeability, and calprotectin, a marker of intestinal inflammation, measured in serum and fecal samples of RA patients using commercially available kits. We also analyzed plasma lipopolysaccharide (LPS) levels, a marker of intestinal permeability and inflammation. Furthermore, univariate, and multivariate regression analyses were carried out to determine whether or not there were associations of zonulin and calprotectin with LPS, BMI, gender, age, RA-specific parameters, fiber intake, and short-chain fatty acids in the gut. Serum zonulin levels were more likely to be abnormal with a longer disease duration and fecal zonulin levels were inversely associated with age. A strong association between fecal and serum calprotectin and between fecal calprotectin and LPS were found in males, but not in females, independent of other biomarkers, suggesting that fecal calprotectin may be a more specific biomarker than serum calprotectin is of intestinal inflammation in RA. Since this was a proof-of-principle study without a healthy control group, further research is needed to validate fecal and serum zonulin as valid biomarkers of RA in comparison with other promising biomarkers.
Background: The COVID-19 pandemic has led to a flood of — often contradictory — evidence. HCWs had to develop strategies to locate information that supported their work. We investigated the information-seeking of different HCW groups in Germany. Methods: In December 2020, we conducted online surveys on COVID-19 information sources, strategies, assigned trustworthiness, and barriers — and in February 2021, on COVID-19 vaccination information sources. Results were analyzed descriptively; group comparisons were performed using χ\(^2\)-tests. Results: For general COVID-19-related medical information (413 participants), non-physicians most often selected official websites (57%), TV (57%), and e-mail/newsletters (46%) as preferred information sources — physicians chose official websites (63%), e-mail/newsletters (56%), and professional journals (55%). Non-physician HCWs used Facebook/YouTube more frequently. The main barriers were insufficient time and access issues. Non-physicians chose abstracts (66%), videos (45%), and webinars (40%) as preferred information strategy; physicians: overviews with algorithms (66%), abstracts (62%), webinars (48%). Information seeking on COVID-19 vaccination (2700 participants) was quite similar, however, with newspapers being more often used by non-physicians (63%) vs. physician HCWs (70%). Conclusion: Non-physician HCWs more often consulted public information sources. Employers/institutions should ensure the supply of professional, targeted COVID-19 information for different HCW groups.
PRO-Simat is a simulation tool for analysing protein interaction networks, their dynamic change and pathway engineering. It provides GO enrichment, KEGG pathway analyses, and network visualisation from an integrated database of more than 8 million protein-protein interactions across 32 model organisms and the human proteome. We integrated dynamical network simulation using the Jimena framework, which quickly and efficiently simulates Boolean genetic regulatory networks. It enables simulation outputs with in-depth analysis of the type, strength, duration and pathway of the protein interactions on the website. Furthermore, the user can efficiently edit and analyse the effect of network modifications and engineering experiments. In case studies, applications of PRO-Simat are demonstrated: (i) understanding mutually exclusive differentiation pathways in Bacillus subtilis, (ii) making Vaccinia virus oncolytic by switching on its viral replication mainly in cancer cells and triggering cancer cell apoptosis and (iii) optogenetic control of nucleotide processing protein networks to operate DNA storage. Multilevel communication between components is critical for efficient network switching, as demonstrated by a general census on prokaryotic and eukaryotic networks and comparing design with synthetic networks using PRO-Simat. The tool is available at https://prosimat.heinzelab.de/ as a web-based query server.
Making judgments of learning (JOLs) after studying can directly improve learning. This JOL reactivity has been shown for simple materials but has scarcely been investigated with educationally relevant materials such as expository texts. The few existing studies have not yet reported any consistent gains in text comprehension due to providing JOLs. In the present study, we hypothesized that increasing the chances of covert retrieval attempts when making JOLs after each of five to-be-studied text passages would produce comprehension benefits at 1 week compared to restudy. In a between-subjects design, we manipulated both whether participants (N = 210) were instructed to covertly retrieve the texts, and whether they made delayed target-absent JOLs. The results indicated that delayed, target-absent JOLs did not improve text comprehension after 1 week, regardless of whether prior instructions to engage in covert retrieval were provided. Based on the two-stage model of JOLs, we reasoned that participants’ retrieval attempts during metacomprehension judgments were either insufficient (i.e., due to a quick familiarity assessment) or were ineffective (e.g., due to low retrieval success).
Purpose
To compare the performance of the dominant and nondominant hand during fundamental arthroscopic simulator training.
Methods
Surgical trainees who participated in a 2-day simulator training course between 2021 and 2023 were classified, according to their arthroscopic experience in beginners and competents. Only right-handed individuals with complete data sets were included in the study. Ambidexterity was trained using a box trainer (Fundamentals of Arthroscopic Surgery Training, Virtamed AG, Schlieren, Switzerland).Two tasks, periscoping for learning camera guidance and triangulation for additional instrument handling, were performed 4 times with the camera in the dominant hand and then in the nondominant hand. For each task, exercise time, camera path length, and instrument path length were recorded and analyzed.
Results
Out of 94 participants 74 right-handed individuals (22 females, 52 males) were classified to novices (n = 43, less than 10 independently performed arthroscopies) and competents (n = 31, more than 10 independently performed arthroscopies). Competents performed significantly better than novices. No significant difference was found after changing the guiding hand for the camera from the dominant to the nondominant hand regarding the camera path length and the instrument path length. Notably, tasks were performed even faster when using the camera in the nondominant hand.
Conclusions
Our data demonstrate that the learned manual skills during basic arthroscopic training are quickly transferred to the contralateral side. In consequence, additional fundamental skills training for camera guidance and instrument handling of the nondominant hand are not necessary.
Clinical Relevance
For skillful arthroscopy, camera guidance and instrument handing must be equally mastered with both hands. It is important to understand how hand dominance may affect learning during arthroscopic simulator training.
Present surgical situations require a bone adhesive which has not yet been developed for use in clinical applications. Recently, phosphoserine modified cements (PMC) based on mixtures of o-phosphoserine (OPLS) and calcium phosphates, such as tetracalcium phosphate (TTCP) or α-tricalcium phosphate (α-TCP) as well as chelate setting magnesium phosphate cements have gained increasing popularity for their use as mineral bone adhesives. Here, we investigated new mineral-organic bone cements based on phosphoserine and magnesium phosphates or oxides, which possess excellent adhesive properties. These were analyzed by X-ray diffraction, Fourier infrared spectroscopy and electron microscopy and subjected to mechanical tests to determine the bond strength to bone after ageing at physiological conditions. The novel biomineral adhesives demonstrate excellent bond strength to bone with approximately 6.6–7.3 MPa under shear load. The adhesives are also promising due to their cohesive failure pattern and ductile character. In this context, the new adhesive cements are superior to currently prevailing bone adhesives. Future efforts on bone adhesives made from phosphoserine and Mg2+ appear to be very worthwhile.
(1) Background: C-X-C Motif Chemokine Receptor 4 (CXCR4) and Fibroblast Activation Protein Alpha (FAP) are promising theranostic targets. However, it is unclear whether CXCR4 and FAP positivity mark distinct microenvironments, especially in solid tumors. (2) Methods: Using Random Forest (RF) analysis, we searched for entity-independent mRNA and microRNA signatures related to CXCR4 and FAP overexpression in our pan-cancer cohort from The Cancer Genome Atlas (TCGA) database — representing n = 9242 specimens from 29 tumor entities. CXCR4- and FAP-positive samples were assessed via StringDB cluster analysis, EnrichR, Metascape, and Gene Set Enrichment Analysis (GSEA). Findings were validated via correlation analyses in n = 1541 tumor samples. TIMER2.0 analyzed the association of CXCR4 / FAP expression and infiltration levels of immune-related cells. (3) Results: We identified entity-independent CXCR4 and FAP gene signatures representative for the majority of solid cancers. While CXCR4 positivity marked an immune-related microenvironment, FAP overexpression highlighted an angiogenesis-associated niche. TIMER2.0 analysis confirmed characteristic infiltration levels of CD8+ cells for CXCR4-positive tumors and endothelial cells for FAP-positive tumors. (4) Conclusions: CXCR4- and FAP-directed PET imaging could provide a non-invasive decision aid for entity-agnostic treatment of microenvironment in solid malignancies. Moreover, this machine learning workflow can easily be transferred towards other theranostic targets.
The metastatic suppressor BRMS1 interacts with critical steps of the metastatic cascade in many cancer entities. As gliomas rarely metastasize, BRMS1 has mainly been neglected in glioma research. However, its interaction partners, such as NFκB, VEGF, or MMPs, are old acquaintances in neurooncology. The steps regulated by BRMS1, such as invasion, migration, and apoptosis, are commonly dysregulated in gliomas. Therefore, BRMS1 shows potential as a regulator of glioma behavior. By bioinformatic analysis, in addition to our cohort of 118 specimens, we determined BRMS1 mRNA and protein expression as well as its correlation with the clinical course in astrocytomas IDH mutant, CNS WHO grade 2/3, and glioblastoma IDH wild-type, CNS WHO grade 4. Interestingly, we found BRMS1 protein expression to be significantly decreased in the aforementioned gliomas, while BRMS1 mRNA appeared to be overexpressed throughout. This dysregulation was independent of patients’ characteristics or survival. The protein and mRNA expression differences cannot be finally explained at this stage. However, they suggest a post-transcriptional dysregulation that has been previously described in other cancer entities. Our analyses present the first data on BRMS1 expression in gliomas that can provide a starting point for further investigations.
In recent years, various forms of caloric restriction (CR) and amino acid or protein restriction (AAR or PR) have shown not only success in preventing age-associated diseases, such as type II diabetes and cardiovascular diseases, but also potential for cancer therapy. These strategies not only reprogram metabolism to low-energy metabolism (LEM), which is disadvantageous for neoplastic cells, but also significantly inhibit proliferation. Head and neck squamous cell carcinoma (HNSCC) is one of the most common tumour types, with over 600,000 new cases diagnosed annually worldwide. With a 5-year survival rate of approximately 55%, the poor prognosis has not improved despite extensive research and new adjuvant therapies. Therefore, for the first time, we analysed the potential of methionine restriction (MetR) in selected HNSCC cell lines. We investigated the influence of MetR on cell proliferation and vitality, the compensation for MetR by homocysteine, the gene regulation of different amino acid transporters, and the influence of cisplatin on cell proliferation in different HNSCC cell lines.
While glioblastoma (GBM) is still challenging to treat, novel immunotherapeutic approaches have shown promising effects in preclinical settings. However, their clinical breakthrough is hampered by complex interactions of GBM with the tumor microenvironment (TME). Here, we present an analysis of TME composition in a patient-derived organoid model (PDO) as well as in organotypic slice cultures (OSC). To obtain a more realistic model for immunotherapeutic testing, we introduce an enhanced PDO model. We manufactured PDOs and OSCs from fresh tissue of GBM patients and analyzed the TME. Enhanced PDOs (ePDOs) were obtained via co-culture with PBMCs (peripheral blood mononuclear cells) and compared to normal PDOs (nPDOs) and PT (primary tissue). At first, we showed that TME was not sustained in PDOs after a short time of culture. In contrast, TME was largely maintained in OSCs. Unfortunately, OSCs can only be cultured for up to 9 days. Thus, we enhanced the TME in PDOs by co-culturing PDOs and PBMCs from healthy donors. These cellular TME patterns could be preserved until day 21. The ePDO approach could mirror the interaction of GBM, TME and immunotherapeutic agents and may consequently represent a realistic model for individual immunotherapeutic drug testing in the future.
Objectives: Positron emission tomography (PET) is currently considered the non-invasive reference standard for lymph node (N-)staging in lung cancer. However, not all patients can undergo this diagnostic procedure due to high costs, limited availability, and additional radiation exposure. The purpose of this study was to predict the PET result from traditional contrast-enhanced computed tomography (CT) and to test different feature extraction strategies. Methods: In this study, 100 lung cancer patients underwent a contrast-enhanced \(^{18}\)F-fluorodeoxyglucose (FDG) PET/CT scan between August 2012 and December 2019. We trained machine learning models to predict FDG uptake in the subsequent PET scan. Model inputs were composed of (i) traditional “hand-crafted” radiomics features from the segmented lymph nodes, (ii) deep features derived from a pretrained EfficientNet-CNN, and (iii) a hybrid approach combining (i) and (ii). Results: In total, 2734 lymph nodes [555 (20.3%) PET-positive] from 100 patients [49% female; mean age 65, SD: 14] with lung cancer (60% adenocarcinoma, 21% plate epithelial carcinoma, 8% small-cell lung cancer) were included in this study. The area under the receiver operating characteristic curve (AUC) ranged from 0.79 to 0.87, and the scaled Brier score (SBS) ranged from 16 to 36%. The random forest model (iii) yielded the best results [AUC 0.871 (0.865–0.878), SBS 35.8 (34.2–37.2)] and had significantly higher model performance than both approaches alone (AUC: p < 0.001, z = 8.8 and z = 22.4; SBS: p < 0.001, z = 11.4 and z = 26.6, against (i) and (ii), respectively). Conclusion: Both traditional radiomics features and transfer-learning deep radiomics features provide relevant and complementary information for non-invasive N-staging in lung cancer.
The aim of this research was to characterize cognitive abilities in patients with Glut1-Deficiency syndrome (Glut1DS) following ketogenic diet therapy (KDT). Methods: The cognitive profiles of eight children were assessed using the Wechsler Intelligence Scale (WISC-IV). The effect of ketogenic diet therapy (KDT) on individual subareas of intelligence was analyzed considering the potential influence of speech motor impairments. Results: Patients with Glut1DS showed a wide range of cognitive performance levels. Some participants showed statistically and clinically significant discrepancies between individual subdomains of intelligence. Both variables, KDT initiation as well as duration, had a positive effect on the overall IQ score. Significant correlations were partially found between the time of KDT initiation and the level of IQ scores, depending on the presence of expressive language test demands of the respective subtests of the WISC-IV. Accordingly, the participants benefited les in the linguistic cognitive domain. The discrepancies in cognitive performance profiles of patients with Glut1DS can be attributed to the possibility of a negative distortion of the results due to the influence of speech motor impairments. Conclusions: The individual access skills of test persons should be more strongly considered in test procedures for the assessment of intelligence to reduce the negative influence of motor deficits on test performance. Specific characterization and systematization of the speech disorder are indispensable for determining the severity of speech motor impairment in Glut1DS. Therefore, a stronger focus on dysarthria during diagnosis and therapy is necessary.