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Sonstige beteiligte Institutionen
- IZKF Nachwuchsgruppe Geweberegeneration für muskuloskelettale Erkrankungen (5)
- Bernhard-Heine-Centrum für Bewegungsforschung (4)
- Zentraleinheit Klinische Massenspektrometrie (3)
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- Arizona State University, Tempe, Arizona, USA (1)
Cellular growth is a fundamental process of life and must be precisely controlled in multicellular organisms. Growth is crucially controlled by the number of functional ribosomes available in cells. The production of new ribosomes depends critically on the activity of RNA polymerase (RNAP) II in addition to the activity of RNAP I and III, which produce ribosomal RNAs. Indeed, the expression of both, ribosomal proteins and proteins required for ribosome assembly (ribosomal biogenesis factors), is considered rate-limiting for ribosome synthesis. Here, we used genetic screening to identify novel transcriptional regulators of cell growth genes by fusing promoters from a ribosomal protein gene (Rpl18) and from a ribosomal biogenesis factor (Fbl) with fluorescent protein genes (RFP, GFP) as reporters. Subsequently, both reporters were stably integrated into immortalized mouse fibroblasts, which were then transduced with a genome-wide sgRNA-CRISPR knockout library. Subsequently, cells with altered reporter activity were isolated by FACS and the causative sgRNAs were identified. Interestingly, we identified two novel regulators of growth genes. Firstly, the exon junction complex protein RBM8A controls transcript levels of the intronless reporters used here. By acute depletion of RBM8A protein using the auxin degron system combined with the genome-wide analysis of nascent transcription, we showed that RBM8A is an important global regulator of ribosomal protein transcripts. Secondly, we unexpectedly observed that the glycolytic enzyme aldolase A (ALDOA) regulates the expression of ribosomal biogenesis factors. Consistent with published observations that a fraction of this protein is located in the nucleus, this may be a mechanism linking transcription of growth genes to metabolic processes and possibly to metabolite availability.
Purpose of Review
We review therapeutic approaches aimed at restoring function of the failing heart by targeting mitochondrial reactive oxygen species (ROS), ion handling, and substrate utilization for adenosine triphosphate (ATP) production.
Recent Findings
Mitochondria-targeted therapies have been tested in animal models of and humans with heart failure (HF). Cardiac benefits of sodium/glucose cotransporter 2 inhibitors might be partly explained by their effects on ion handling and metabolism of cardiac myocytes.
Summary
The large energy requirements of the heart are met by oxidative phosphorylation in mitochondria, which is tightly regulated by the turnover of ATP that fuels cardiac contraction and relaxation. In heart failure (HF), this mechano-energetic coupling is disrupted, leading to bioenergetic mismatch and production of ROS that drive the progression of cardiac dysfunction. Furthermore, HF is accompanied by changes in substrate uptake and oxidation that are considered detrimental for mitochondrial oxidative metabolism and negatively affect cardiac efficiency. Mitochondria lie at the crossroads of metabolic and energetic dysfunction in HF and represent ideal therapeutic targets.
Lower limb bone geometry in adult individuals with X-linked hypophosphatemia: an observational study
(2022)
Summary
We assessed lower-limb geometry in adults with X-linked hypophosphatemia (XLH) and controls. We found large differences in multiple measures including femoral and tibial torsion, bowing and cross-sectional area and acetabular version and coverage which may contribute to clinical problems such as osteoarthritis, fractures and altered gait common in XLH.
Purpose
Individuals with X-linked hypophosphatemia (XLH) are at risk of lower-limb deformities and early onset of osteoarthritis. These two factors may be linked, as altered biomechanics is a risk factor for osteoarthritis. This exploratory evaluation aims at providing clues and concepts for this association to facilitate future larger-scale and longitudinal studies on that aspect.
Methods
For this observational study, 13 patients with XLH, aged 18–65 years (6 female), were compared with sex-, age- and weight-matched healthy individuals at a single German research centre. Femoral and hip joint geometry, including femoral and tibial torsion and femoral and tibial shaft bowing, bone cross-sectional area (CSA) and acetabular version and coverage were measured from magnetic resonance imaging (MRI) scans.
Results
Total femoral torsion was 29° lower in individuals with XLH than in controls (p < 0.001), mainly resulting from lower intertrochanteric torsion (ITT) (p < 0.001). Femoral lateral and frontal bowing, tibial frontal bowing, mechanical axis, femoral mechanical–anatomical angle, acetabular version and acetabular coverage were all greater and tibial torsion lower in individuals with XLH as compared to controls (all p < 0.05). Greater femoral total and marrow cavity CSA, greater tibial marrow cavity CSA and lower cortical CSA were observed in XLH (all p < 0.05).
Discussion
We observed large differences in clinically relevant measures of tibia and particularly femur bone geometry in individuals with XLH compared to controls. These differences may plausibly contribute to clinical manifestations of XLH such as early-onset osteoarthritis, pseudofractures and altered gait and therefore should be considered when planning corrective surgeries.
Dilated cardiomyopathy (DCM) is a common cause of heart failure (HF) and is of familial origin in 20–40% of cases. Genetic testing by next-generation sequencing (NGS) has yielded a definite diagnosis in many cases; however, some remain elusive. In this study, we used a combination of NGS, human-induced pluripotent-stem-cell-derived cardiomyocytes (iPSC-CMs) and nanopore long-read sequencing to identify the causal variant in a multi-generational pedigree of DCM. A four-generation family with familial DCM was investigated. Next-generation sequencing (NGS) was performed on 22 family members. Skin biopsies from two affected family members were used to generate iPSCs, which were then differentiated into iPSC-CMs. Short-read RNA sequencing was used for the evaluation of the target gene expression, and long-read RNA nanopore sequencing was used to evaluate the relevance of the splice variants. The pedigree suggested a highly penetrant, autosomal dominant mode of inheritance. The phenotype of the family was suggestive of laminopathy, but previous genetic testing using both Sanger and panel sequencing only yielded conflicting evidence for LMNA p.R644C (rs142000963), which was not fully segregated. By re-sequencing four additional affected family members, further non-coding LMNA variants could be detected: rs149339264, rs199686967, rs201379016, and rs794728589. To explore the roles of these variants, iPSC-CMs were generated. RNA sequencing showed the LMNA expression levels to be significantly lower in the iPSC-CMs of the LMNA variant carriers. We demonstrated a dysregulated sarcomeric structure and altered calcium homeostasis in the iPSC-CMs of the LMNA variant carriers. Using targeted nanopore long-read sequencing, we revealed the biological significance of the variant c.356+1G>A, which generates a novel 5′ splice site in exon 1 of the cardiac isomer of LMNA, causing a nonsense mRNA product with almost complete RNA decay and haploinsufficiency. Using novel molecular analysis and nanopore technology, we demonstrated the pathogenesis of the rs794728589 (c.356+1G>A) splice variant in LMNA. This study highlights the importance of precise diagnostics in the clinical management and workup of cardiomyopathies.
RNA-cleaving deoxyribozymes have found broad application as useful tools for RNA biochemistry. However, tedious in vitro selection procedures combined with laborious characterization of individual candidate catalysts hinder the discovery of novel catalytic motifs. Here, we present a new high-throughput sequencing method, DZ-seq, which directly measures activity and localizes cleavage sites of thousands of deoxyribozymes. DZ-seq exploits A-tailing followed by reverse transcription with an oligo-dT primer to capture the cleavage status and sequences of both deoxyribozyme and RNA substrate. We validated DZ-seq by conventional analytical methods and demonstrated its utility by discovery of novel deoxyribozymes that allow for cleaving challenging RNA targets or the analysis of RNA modification states.
Bone marrow lesions (BML) represent areas of deteriorated bone structure and metabolism characterized by pronounced water‐equivalent signaling within the trabecular bone on magnetic resonance imaging (MRI). BML are associated with repair mechanisms subsequent to various clinical conditions associated with inflammatory and non‐inflammatory injury to the bone. There is no approved treatment for this condition. Bisphosphonates are known to improve bone stability in osteoporosis and other bone disorders and have been used off‐label to treat BML. A randomized, triple‐blind, placebo‐controlled phase III trial was conducted to assess efficacy and safety of single‐dose zoledronic acid (ZOL) 5 mg iv with vitamin D 1000 IU/d as opposed to placebo with vitamin D 1000 IU/d in 48 patients (randomized 2:1) with BML. Primary efficacy endpoint was reduction of edema volume 6 weeks after treatment as assessed by MRI. After treatment, mean BML volume decreased by 64.53% (±41.92%) in patients receiving zoledronic acid and increased by 14.43% (±150.46%) in the placebo group (p = 0.007). A decrease in BML volume was observed in 76.5% of patients receiving ZOL and in 50% of the patients receiving placebo. Pain level (visual analogue scale [VAS]) and all categories of the pain disability index (PDI) improved with ZOL versus placebo after 6 weeks but reconciled after 6 additional weeks of follow‐up. Six serious adverse events occurred in 5 patients, none of which were classified as related to the study drug. No cases of osteonecrosis or fractures occurred. Therefore, single‐dose zoledronic acid 5 mg iv together with vitamin D may enhance resolution of bone marrow lesions over 6 weeks along with reduction of pain compared with vitamin D supplementation only.
Increasing antibacterial drug resistance threatens global health, unfortunately, however, efforts to find novel antibacterial agents have been scaled back by the pharmaceutical industry due to concerns about a poor return on investment. Nevertheless, there is an urgent need to find novel antibacterial compounds to combat antibacterial drug resistance. The synthesis of novel drugs from natural sources is mostly cost-intensive due to those drugs’ complicated structures. Therefore, it is necessary to find novel antibacterials by simple synthesis to become more attractive for industrial production. We succeeded in the discovery of four antibacterial compound (sub)classes accessible in a simple one-pot reaction based on fluorinated benzothiophene-indole hybrids. They have been evaluated against various S. aureus and MRSA strains. Structure- and substituent-dependent activities have been found within the (sub)classes and promising lead compounds have been identified. In addition, bacterial pyruvate kinase was found to be the molecular target of the active compounds. In conclusion, simple one-pot synthesis of benzothiophene-indoles represents a promising strategy for the search of novel antimicrobial compounds.
A multitude of human tissues, such as bones, tendons, or muscles, are characterized by a hierarchical and highly ordered structure. In many cases, the loss of these tissues requires reconstruction using biocompatible replacement materials. In the field of bone replacement, the pore structure of the material has a crucial influence. Anisotropic porosity would have the advantage of facilitating the ingrowth of cells and newly formed blood vessels as well as the transport of nutrients.
In this thesis, scaffolds with a highly ordered and anisotropic pore structure were fabricated using unidirectional freezing.
Systematic investigations were carried out on biopolymer solutions (alginate and chitosan) to gain a deeper understanding of the freeze-structuring process. The knowledge gained was then applied to the development of anisotropically structured bone substitute materials. Here, the previously existing material platform for anisotropically structured calcium phosphates was extended to low-temperature phases such as calcium deficient hydroxyapatite (CDHA) or the secondary phosphates monetite and brushite.
After the implantation of a biomaterial, the inevitably triggered initial immune response plays a key role in the success of a graft, with immune cells such as neutrophils or macrophages being of particular importance. In this thesis, the influence of anisotropically structured alpha-TCP and CDHA scaffolds as well as their unstructured references on human monocytes/macrophages was investigated. Macrophages produced extracellular traps (ETs) due to mineral nanoparticles formed by the binding of phosphate and calcium ions to human platelet lysate. In particular, incubation of alpha-TCP samples in lysate containing cell culture medium resulted in pronounced particle formation and enhanced release of ETs.
Active vitamin D (1,25(OH)2D3) is known to exert direct anti-cancer actions on various malignant tissues through binding to the vitamin D receptor (VDR). These effects have been demonstrated in breast, prostate, renal and thyroid cancers, which all have a high propensity to metastasise to bone. In addition, there is evidence that vitamin D catabolism via 24-hydroxylase (CYP24A1) is altered in tumour cells, thus, reducing local active vitamin D levels in cancer cells. The aim of this study was to assess VDR and CYP24A1 expression in various types of bone metastases by using immunohistochemistry. Overall, a high total VDR protein expression was detected in 59% of cases (39/66). There was a non-significant trend of high-grade tumours towards the low nuclear VDR expression (p = 0.07). Notably, patients with further distant metastases had a reduced nuclear VDR expression (p = 0.03). Furthermore, a high CYP24A1 expression was detected in 59% (39/66) of bone metastases. There was a significant positive correlation between nuclear VDR and CYP24A1 expression (p = 0.001). Collectively, the VDR and CYP24A1 were widely expressed in a multitude of bone metastases, pointing to a potential role of vitamin D signalling in cancer progression. This is of high clinical relevance, as vitamin D deficiency is frequent in patients with bone metastases.
A series of monomeric chirally substituted indolenine squaraine monomers were successfully synthesized and utilized for the construction of various oligo- and polymers, in order to study their chiroptical properties in terms of exciton chirality. The quaternary carbon atom at the 3-position of the indolenine subunit, as well as the alkyl side chain attached to the indolenine nitrogen were selected as the most suitable site for chiral functionalization.
For the C(3)-chiral derivatives, two synthetic routes depending on the desired substitution at the stereogenic center were established. The chiral side chains were prepared via Evans asymmetric alkylation where the resulting branching point at the 2 position constituted the chiral center. While the chiral substitution only had minor effects on the linear optical properties and geometric structure of the chromophore, all compounds exhibited a distinct and measurable CD signal that correlated with the distance of the chiral center to the central chromophore.
Polymers bearing chiral side chains exhibited a solvent- and temperature-dependent helix-coil equilibrium, which was influenced by the type of side chain used. CD spectroscopy revealed the helical conformation to possess a preferred twist sense, and temperature-dependent measurements showed the degree of homohelicity to be nearly complete in certain cases. Furthermore, a CPL signal was able to be obtained for the helical conformer of one polymer.
Various (co)oligo- and polymers comprising the C(3)-chiral monomers only displayed a solvent-independent J-type absorption behavior and thus did not form helical conformations in solution. CD spectroscopy revealed a solvent-dependent adoption of quasi-enantiomeric conformers, which was elucidated by quantum chemical TDDFT calculations.
Background
CXCR4-directed positron emission tomography/computed tomography (PET/CT) has been used as a diagnostic tool in patients with solid tumors. We aimed to determine a potential correlation between tumor burden and radiotracer accumulation in normal organs.
Methods
Ninety patients with histologically proven solid cancers underwent CXCR4-targeted [\(^{68}\)Ga]Ga-PentixaFor PET/CT. Volumes of interest (VOIs) were placed in normal organs (heart, liver, spleen, bone marrow, and kidneys) and tumor lesions. Mean standardized uptake values (SUV\(_{mean}\)) for normal organs were determined. For CXCR4-positive tumor burden, maximum SUV (SUV\(_{max}\)), tumor volume (TV), and fractional tumor activity (FTA, defined as SUV\(_{mean}\) x TV), were calculated. We used a Spearman's rank correlation coefficient (ρ) to derive correlative indices between normal organ uptake and tumor burden.
Results
Median SUV\(_{mean}\) in unaffected organs was 5.2 for the spleen (range, 2.44 – 10.55), 3.27 for the kidneys (range, 1.52 – 17.4), followed by bone marrow (1.76, range, 0.84 – 3.98), heart (1.66, range, 0.88 – 2.89), and liver (1.28, range, 0.73 – 2.45). No significant correlation between SUV\(_{max}\) in tumor lesions (ρ ≤ 0.189, P ≥ 0.07), TV (ρ ≥ -0.204, P ≥ 0.06) or FTA (ρ ≥ -0.142, P ≥ 0.18) with the investigated organs was found.
Conclusions
In patients with solid tumors imaged with [\(^{68}\)Ga]Ga-PentixaFor PET/CT, no relevant tumor sink effect was noted. This observation may be of relevance for therapies with radioactive and non-radioactive CXCR4-directed drugs, as with increasing tumor burden, the dose to normal organs may remain unchanged.
The strict restrictions introduced by the COVID-19 lockdowns, which started from March 2020, changed people’s daily lives and habits on many different levels. In this work, we investigate the impact of the lockdown on the communication behavior in the mobile instant messaging application WhatsApp. Our evaluations are based on a large dataset of 2577 private chat histories with 25,378,093 messages from 51,973 users. The analysis of the one-to-one and group conversations confirms that the lockdown severely altered the communication in WhatsApp chats compared to pre-pandemic time ranges. In particular, we observe short-term effects, which caused an increased message frequency in the first lockdown months and a shifted communication activity during the day in March and April 2020. Moreover, we also see long-term effects of the ongoing pandemic situation until February 2021, which indicate a change of communication behavior towards more regular messaging, as well as a persisting change in activity during the day. The results of our work show that even anonymized chat histories can tell us a lot about people’s behavior and especially behavioral changes during the COVID-19 pandemic and thus are of great relevance for behavioral researchers. Furthermore, looking at the pandemic from an Internet provider perspective, these insights can be used during the next pandemic, or if the current COVID-19 situation worsens, to adapt communication networks to the changed usage behavior early on and thus avoid network congestion.
In the field of biofabrication, biopolymer-based hydrogels are often used as bulk materials with defined structures or as bioinks. Despite their excellent biocompatibility, biopolymers need chemical modification to fulfill mechanical stability.
In this thesis, the primary alcohol of hyaluronic acid was oxidized using TEMPO/TCC oxidation to generate aldehyde groups without ring-opening mechanism of glycol cleavage using sodium periodate. For crosslinking reaction of the aldehyde groups, adipic acid dihydrazide was used as bivalent crosslinker for Schiff Base chemistry. This hydrogel system with fast and reversible crosslinking mechanism was used successfully as bulk hydrogel for chondrogenic differentiation with human mesenchymal stem cells (hMSC).
Gelatin was modified with pentenoic acid for crosslinking reaction via light controllable thiol-ene reaction, using thiolated 4-arm sPEG as multivalent crosslinker. Due to preservation of the thermo responsive property of gelatin by avoiding chain degradation during modification reaction, this gelatin-based hydrogel system was successfully processed via 3D printing with low polymer concentration. Good cell viability was achieved using hMSC in various concentrations after 3D bioprinting and chondrogenic differentiation showed promising results.
Chemical synapses are a physically and functionally varied type of cell-cell contact specialized in conducting communication between neurons. They are the smallest "computational" unit of the brain and are often classified as electrical and chemical, and they can be distinguished based on their transmission mechanism. These categories could be further broken into many kinds, each having a specific structure-function repertoire that is hypothesized to provide neural networks with distinct computational capabilities. Heterogeneity refers to the variety of structures and functions present in a particular category of synapses. Contributing factors for this heterogeneity may be the synaptic vesicles, the active zone (AZ), the synaptic cleft, the postsynaptic density, and the glial processes associated with the synaptic contacts. Each of these five structural modules has its own set of functions, and their combination determines the spectrum of functional heterogeneity at mammalian excitatory synapses. This work focused on the changes in AZ protein expression after chemical induction of plasticity with forskolin in synaptic contacts of the hippocampal mossy fibers. With the nanoscopic resolution provided by dSTORM, along with the multicolor SIM imaging capabilities, changes in expression of key presynaptic AZ components were analyzed. Using SIM imaging along with a standardized stimulation protocol in acute brain slices from male 16-week old Thy1-mEGFP (Lsi1) mice, the changes of the key AZ proteins Bassoon, Munc 13-1 and Tomosyn were investigated 30 min after stimulation with forskolin (50 μM for 30 min). Forskolin induced changes in these proteins largely in small synaptic contacts whereas no clear changes were detected in large mossy fiber boutons. However, due to the high variability it cannot be ruled out that forskolin may differentially modify AZ protein composition depending on experimental circumstances such as age and gender of mice or the time point and duration of forskolin stimulation. The dSTORM data demonstrated feasibility to perform single molecule 3D imaging of hippocampal presynaptic AZs and allowed quantitative mapping of molecular changes in AZ proteins after induction of plasticity. The findings suggest high heterogeneity in mossy fiber synaptic contacts that may have an impact on the function of neural networks. These imaging approaches may now be used to identify potential differences in functional molecular rearrangements of synaptic proteins in healthy and diseased brain (e.g. after induction of traumatic brain injury).
Manipulation under anesthesia (MUA) for stiffness within 6 to 12 weeks after mechanically aligned total knee arthroplasty (TKA) generally yields better outcome scores than an MUA performed later. However, the timing of MUA after unrestricted, caliper-verified, kinematically aligned (KA) TKA remains uncertain. A retrospective review identified 82 of 3558 (2.3%) KA TKA patients treated with an MUA between 2010 and 2017. Thirty patients treated with an MUA within 3 months of the TKA (i.e., early) and 24 in the late group (i.e., >3 months) returned a questionnaire after a mean of 6 years and 5 years, respectively. Mean outcome scores for the early vs. late group were 78 vs. 62 for the Forgotten Joint Score (FJS) (p = 0.023) and 42 vs. 39 for the Oxford Knee Score (OKS) (p = 0.037). Subjectively, the early vs. late group responses indicated that 83% vs. 67% walked without a limp, 73% vs. 54% had normal extension, and 43% vs. 25% had normal flexion. An MUA within 3 months after unrestricted KA TKA provided excellent FJS and OKS at final follow-up relative to a late MUA. A late MUA performed after 3 months is worth consideration because of the good FJS and OKS scores, albeit with a risk of a persistent limp and limitation in knee extension and flexion.
Diabetes mellitus is a common disease affecting more than 537 million adults worldwide. The microvascular complications that occur during the course of the disease are widespread and affect a variety of organ systems in the body. Diabetic retinopathy is one of the most common long-term complications, which include, amongst others, endothelial dysfunction, and thus, alterations in the blood-retinal barrier (BRB). This particularly restrictive physiological barrier is important for maintaining the neuroretina as a privileged site in the body by controlling the inflow and outflow of fluid, nutrients, metabolic end products, ions, and proteins. In addition, people with diabetic retinopathy (DR) have been shown to be at increased risk for systemic vascular complications, including subclinical and clinical stroke, coronary heart disease, heart failure, and nephropathy. DR is, therefore, considered an independent predictor of heart failure. In the present review, the effects of diabetes on the retina, heart, and kidneys are described. In addition, a putative common microRNA signature in diabetic retinopathy, nephropathy, and heart failure is discussed, which may be used in the future as a biomarker to better monitor disease progression. Finally, the use of miRNA, targeted neurotrophin delivery, and nanoparticles as novel therapeutic strategies is highlighted.
Tumor necrosis factor (TNF) receptor associated factor-2 (TRAF2) has been originally identified as a protein interacting with TNF receptor 2 (TNFR2) but also binds to several other receptors of the TNF receptor superfamily (TNFRSF). TRAF2, often in concert with other members of the TRAF protein family, is involved in the activation of the classical NFκB pathway and the stimulation of various mitogen-activated protein (MAP) kinase cascades by TNFRSF receptors (TNFRs), but is also required to inhibit the alternative NFκB pathway. TRAF2 has also been implicated in endoplasmic reticulum (ER) stress signaling, the regulation of autophagy, and the control of cell death programs. TRAF2 fulfills its functions by acting as a scaffold, bringing together the E3 ligase cellular inhibitor of apoptosis-1 (cIAP1) and cIAP2 with their substrates and various regulatory proteins, e.g., deubiquitinases. Furthermore, TRAF2 can act as an E3 ligase by help of its N-terminal really interesting new gene (RING) domain. The finding that TRAF2 (but also several other members of the TRAF family) interacts with the latent membrane protein 1 (LMP1) oncogene of the Epstein–Barr virus (EBV) indicated early on that TRAF2 could play a role in the oncogenesis of B-cell malignancies and EBV-associated non-keratinizing nasopharyngeal carcinoma (NPC). TRAF2 can also act as an oncogene in solid tumors, e.g., in colon cancer by promoting Wnt/β-catenin signaling. Moreover, tumor cell-expressed TRAF2 has been identified as a major factor-limiting cancer cell killing by cytotoxic T-cells after immune checkpoint blockade. However, TRAF2 can also be context-dependent as a tumor suppressor, presumably by virtue of its inhibitory effect on the alternative NFκB pathway. For example, inactivating mutations of TRAF2 have been associated with tumor development, e.g., in multiple myeloma and mantle cell lymphoma. In this review, we summarize the various TRAF2-related signaling pathways and their relevance for the oncogenic and tumor suppressive activities of TRAF2. Particularly, we discuss currently emerging concepts to target TRAF2 for therapeutic purposes.
(1) Background: Data on coronavirus 2 infection during pregnancy vary. We aimed to describe maternal characteristics and clinical presentation of SARS-CoV-2 positive women requiring intensive care treatment for COVID-19 during pregnancy and postpartum period based on data of a comprehensive German surveillance system in obstetric patients. (2) Methods: Data from COVID-19 Related Obstetric and Neonatal Outcome Study (CRONOS), a prospective multicenter registry for SARS-CoV-2 positive pregnant women, was analyzed with respect to ICU treatment. All women requiring intensive care treatment for COVID-19 were included and compared regarding maternal characteristics, course of disease, as well as maternal and neonatal outcomes. (3) Results: Of 2650 cases in CRONOS, 101 women (4%) had a documented ICU stay. Median maternal age was 33 (IQR, 30–36) years. COVID-19 was diagnosed at a median gestational age of 33 (IQR, 28–35) weeks. As the most invasive form of COVID-19 treatment interventions, patients received either continuous monitoring of vital signs without further treatment requirement (n = 6), insufflation of oxygen (n = 30), non-invasive ventilation (n = 22), invasive ventilation (n = 28), or escalation to extracorporeal membrane oxygenation (n = 15). No significant clinical differences were identified between patients receiving different forms of ventilatory support for COVID-19. Prevalence of preterm delivery was significantly higher in women receiving invasive respiratory treatments. Four women died of COVID-19 and six fetuses were stillborn. (4) Conclusions: Our cohort shows that progression of COVID-19 is rare in pregnant and postpartum women treated in the ICU. Preterm birth rate is high and COVID-19 requiring respiratory support increases the risk of poor maternal and neonatal outcome.
Background
Anthocyanin-containing plant extracts and carotenoids, such as astaxanthin, have been well-known for their antiviral and anti-inflammatory activity, respectively. We hypothesised that a mixture of Ribes nigrum L. (Grossulariaceae) (common name black currant (BC)) and Vaccinium myrtillus L. (Ericaceae) (common name bilberry (BL)) extracts (BC/BL) with standardised anthocyanin content as well as single plant extracts interfered with the replication of Measles virus and Herpesviruses in vitro.
Methods
We treated cell cultures with BC/BL or defined single plant extracts, purified anthocyanins and astaxanthin in different concentrations and subsequently infected the cultures with the Measles virus (wild-type or vaccine strain Edmonston), Herpesvirus 1 or 8, or murine Cytomegalovirus. Then, we analysed the number of infected cells and viral infectivity and compared the data to non-treated controls.
Results
The BC/BL extract inhibited wild-type Measles virus replication, syncytia formation and cell-to-cell spread. This suppression was dependent on the wild-type virus-receptor-interaction since the Measles vaccine strain was unaffected by BC/BL treatment. Furthermore, the evidence was provided that the delphinidin-3-rutinoside chloride, a component of BC/BL, and purified astaxanthin, were effective anti-Measles virus compounds. Human Herpesvirus 1 and murine Cytomegalovirus replication was inhibited by BC/BL, single bilberry or black currant extracts, and the BC/BL component delphinidin-3-glucoside chloride. Additionally, we observed that BC/BL seemed to act synergistically with aciclovir. Moreover, BC/BL, the single bilberry and black currant extracts, and the BC/BL components delphinidin-3-glucoside chloride, cyanidin-3-glucoside, delphinidin-3-rutinoside chloride, and petunidin-3-galactoside inhibited human Herpesvirus 8 replication.
Conclusions
Our data indicate that Measles viruses and Herpesviruses are differentially susceptible to a specific BC/BL mixture, single plant extracts, purified anthocyanins and astaxanthin. These compounds might be used in the prevention of viral diseases and in addition to direct-acting antivirals, such as aciclovir.
For the treatment of large bone defects, the commonly used technique of autologous bone grafting presents several drawbacks and limitations. With the discovery of the bone-inducing capabilities of bone morphogenetic protein 2 (BMP2), several delivery techniques were developed and translated to clinical applications. Implantation of scaffolds containing adsorbed BMP2 showed promising results. However, off-label use of this protein-scaffold combination caused severe complications due to an uncontrolled release of the growth factor, which has to be applied in supraphysiological doses in order to induce bone formation. Here, we propose an alternative strategy that focuses on the covalent immobilization of an engineered BMP2 variant to biocompatible scaffolds. The new BMP2 variant harbors an artificial amino acid with a specific functional group, allowing a site-directed covalent scaffold functionalization. The introduced artificial amino acid does not alter BMP2′s bioactivity in vitro. When applied in vivo, the covalently coupled BMP2 variant induces the formation of bone tissue characterized by a structurally different morphology compared to that induced by the same scaffold containing ab-/adsorbed wild-type BMP2. Our results clearly show that this innovative technique comprises translational potential for the development of novel osteoinductive materials, improving safety for patients and reducing costs.
The propounded thesis investigated fear learning including fear conditioning, its generalization as well as its extinction in 133 healthy children and adolescents aged 8 to 17 years. The main goal was to analyze these processes also in the course of childhood and adolescence due to far less research in this age span compared to adults. Of note, childhood is the typical period for the onset of anxiety disorders. To achieve this, an aversive discriminative fear conditioning, generalization and extinction paradigm, which based on the “screaming lady paradigm” from Lau et al. (2008) and was adapted by Schiele & Reinhard et al. (2016), was applied. All probands traversed the pre-acquisition (4 x CS-, 4 x CS+, no US), the acquisition (12 x CS-, 12 x CS+, reinforcement rate: 83%), the generalization (12 x CS-, 12 x GS4, 12 x GS3, 12 x GS2, 12 x GS1, 12 x CS+, reinforcement rate: 50%) and the extinction (18 x CS-, 18 x CS+, no US). The generalization stimuli, i.e. GS1-GS4, were built out of CS- and CS+ in different mixtures on a percentage basis in steps of 20% from CS- to CS+. Pictures of faces of two actresses with a neutral expression were used for the discriminative conditioning, whereby the CS+ was paired with a 95-dB loud female scream at the same time together with a fearful facial expression (US). CS- and GS1-GS4 were never followed by the US. Subjective ratings (arousal, valence and US expectancy) were collected and further the psychophysiological measure of the skin conductance response (SCR). The hypotheses were 1) that underage probands show a negative correlation between age and overgeneralization and 2) that anxiety is positively correlated with overgeneralization in the same sample. ANOVAs with repeated measures were conducted for all four dependent variables with phase (pre-acquisition phase, 1. + 2. acquisition phase, 1. + 2. generalization phase, 1. - 3. extinction phase) and stimulus type
(CS-, CS+, GS1-GS4) as within-subject factors. For the analyses of the modulatory effects of age and anxiety in additional separate ANCOVAs were conducted including a) age, b) the STAIC score for trait anxiety and c) the CASI score for anxiety sensitivity as covariates. Sex was always included as covariate of no interest. On the one hand, findings indicated that the general extent of the reactions (arousal, valence and US expectancy ratings and the SCR) decreased with growing age, i.e. the older the probands the lower their reactions towards the stimuli regardless of the type of dependent variable. On the other hand, ratings of US expectancy, i.e. the likelihood that a stimulus is followed by a US (here: female scream coupled with a fearful facial expression), showed better discrimination skills the older the probands were, resulting in a smaller overgeneralization within older probands. It must be emphasized very clearly that no causality can be derived. Thus, it was only an association revealed between
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age and generalization of conditioned fear, which is negative. Furthermore, no obvious impact of trait anxiety could be detected on the different processes of fear learning. Especially, no overgeneralization was expressed by the probands linked to higher trait anxiety. In contrast to trait anxiety, for anxiety sensitivity there was an association between its extent and the level of fear reactions. This could be described best with a kind of parallel shifts: the higher the anxiety sensitivity, the stronger the fear reactions. Likewise, for anxiety sensitivity no overgeneralization due to a stronger extent of anxiety sensitivity could be observed.
Longitudinal follow-up examinations and, furthermore, neurobiological investigations are needed for replication purposes and purposes of gaining more supporting or opposing insights, but also for the profound exploration of the impact of hormonal changes during puberty and of the maturation processes of different brain structures. Finally, the question whether enhanced generalization of conditioned fear facilitates the development of anxiety disorders or vice versa remains unsolved yet.
The objective of this thesis was the synthesis and characterisation of two linear multifunctional PEG-alternatives for bioconjugation and hydrogel formation: i) Hydrophilic acrylate based copolymers containing peptide binding units and ii) hydrophilic polyether based copolymers containing different functional groups for a physical crosslinking.
In section 3.1 the successful synthesis of water soluble and linear acrylate based polymers containing oligo(ethylene glycol) methyl ether acrylate with either linear thioester functional 2-hydroxyethyl acrylate, thiolactone acrylamide, or vinyl azlactone via the living radical polymerisation technique Reversible Addition Fragmentation Chain Transfer (RAFT) and via free-radical polymerisation is described. The obtained polymers were characterized via GPC, 1H NMR, IR and RAMAN spectroscopy.
The RAFT end group was found to be difficult to remove from these short polymer chains and accordingly underwent the undesired side reaction aminolysis with the peptide during the conjugation studies. Besides that, polymers without RAFT end groups did not show any binding of the peptide at the thioester groups, which can be improved in future by using higher reactant concentrations and higher amount of binding units at the polymer. Polymers containing the highly reactive azlactone group showed a peptide binding of 19 %, but unfortunately this function also underwent spontaneous hydrolysis before the peptide could even be bound. In all cases, oligo(ethylene glycol) methyl ether acrylate was used with a relatively high molecular weight (Mn = 480 Da) was used, which eventually was efficiently shielding the introduced binding units from the added peptide. In future, a shorter monomer with Mn = 300 Da or less or hydrophilic N,N’-dialkyl acrylamide based polymers with less steric hindrance could be used to improve this bioconjugation system. Additionally, the amount of monomers containing peptide binding units in the polymer can be increased and have an additional spacer to achieve higher loading efficiency.
The water soluble, linear and short polyether based polymers, so called polyglycidols, were successfully synthesized and modified as described in section 3.2. The obtained polymers were characterized using GPC, 1H NMR, 31P{1H} NMR, IR, and RAMAN spectroscopy. The allyl groups which were present up to 20 % were used for radical induced thiol-ene chemistry for the introduction of functional groups intended for the formation of the physically crosslinking hydrogels. For the positively charged polymers, first a chloride group had to be introduced for the subsequent nucleophilic substitution with the imidazolium compound. There, degrees of modifications were found in the range 40-97 % due to the repulsion forces of the charges, decreased concentration of active chloride groups, and limiting solution concentrations of the polymer for this reaction. For the negatively charged polymers, first a protected phosphonamide moiety was introduced with a deprotection step afterwards showing 100 % conversion for all reactions. Preliminary hydrogel tests did not show a formation of a three-dimensional network of the polymer chains which was attributed to the short backbone length of the used polymers, but the gained knowledge about the synthetic routes for the modification of the polymer was successfully transferred to longer linear polyglycidols. The same applies to the introduction of electron rich and electron poor compounds showing π-π stacking interactions by UV-vis spectroscopy.
Finally, long linear polyglycidyl ethers were synthesised successfully up to molecular weights of Mn ~ 30 kDa in section 3.3, which was also proven by GPC, 1H NMR, IR and RAMAN spectroscopy. This applies to the homopolymerisation of ethoxyethyl glycidyl ether, allyl glycidyl ether and their copolymerisation with an amount of the allyl compound ~ 10 %. Attempts for higher molecular weights up to 100 kDa showed an uncontrolled polymerisation behaviour and eventually can be improved in future by choosing a lower initiation temperature. Also, the allyl side groups were modified via radical induced thiol-ene chemistry to obtain positively charged functionalities via imidazolium moieties (85 %) and negatively charged functionalities via phosphonamide moieties (100 %) with quantitative degree of modifications. Hydrogel tests have still shown a remaining solution by using long linear polyglycidols carrying negative charges with long/short linear polyglycidols carrying positive charges. The addition of calcium chloride led to a precipitate of the polymer instead of a three-dimensional network formation representing a too high concentration of ions and therefore shielding water molecules with prevention from dissolving the polymer. These systems can be improved by tuning the polymers structure like longer polymer chains, longer spacer between polymer backbone and charge, and higher amount of functional groups.
The objective of the thesis was partly reached containing detailed investigated synthetic routes for the design and characterisation of functional polymers which could be used in future with improvements for bioconjugation and hydrogel formation tests.
Inland surface water is often the most accessible freshwater source. As opposed to groundwater, surface water is replenished in a comparatively quick cycle, which makes this vital resource — if not overexploited — sustainable. From a global perspective, freshwater is plentiful. Still, depending on the region, surface water availability is severely limited. Additionally, climate change and human interventions act as large-scale drivers and cause dramatic changes in established surface water dynamics. Actions have to be taken to secure sustainable water availability and usage. This requires informed decision making based on reliable environmental data. Monitoring inland surface water dynamics is therefore more important than ever. Remote sensing is able to delineate surface water in a number of ways by using optical as well as active and passive microwave sensors. In this review, we look at the proceedings within this discipline by reviewing 233 scientific works. We provide an extensive overview of used sensors, the spatial and temporal resolution of studies, their thematic foci, and their spatial distribution. We observe that a wide array of available sensors and datasets, along with increasing computing capacities, have shaped the field over the last years. Multiple global analysis-ready products are available for investigating surface water area dynamics, but so far none offer high spatial and temporal resolution.
In recent years, it has become increasingly apparent that bone marrow (BM) failures and myeloid malignancy predisposition syndromes are characterized by a wide phenotypic spectrum and that these diseases must be considered in the differential diagnosis of children and adults with unexplained hematopoiesis defects. Clinically, hypocellular BM failure still represents a challenge in pathobiology-guided treatment. There are three fundamental topics that emerged from our review of the existing data. An exogenous stressor, an immune defect, and a constitutional genetic defect fuel a vicious cycle of hematopoietic stem cells, immune niches, and stroma compartments. A wide phenotypic spectrum exists for inherited and acquired BM failures and predispositions to myeloid malignancies. In order to effectively manage patients, it is crucial to establish the right diagnosis. New theragnostic windows can be revealed by exploring BM failure pathomechanisms.
Growing evidence points to multiple myeloma (MM) and its stromal microenvironment using several mechanisms to subvert effective immune and anti-tumor responses. Recent advances have uncovered the tumor-stromal cell influence in regulating the immune-microenvironment and have envisioned targeting these suppressive pathways to improve therapeutic outcomes. Nevertheless, some subgroups of patients include those with particularly unfavorable prognoses. Biological stratification can be used to categorize patient-, disease- or therapy-related factors, or alternatively, these biological determinants can be included in a dynamic model that customizes a given treatment to a specific patient. Genetic heterogeneity and current knowledge enforce a systematic and comprehensive bench-to-bedside approach. Given the increasing role of cancer stem cells (CSCs) in better characterizing the pathogenesis of solid and hematological malignancies, disease relapse, and drug resistance, identifying and describing CSCs is of paramount importance in the management of MM. Even though the function of CSCs is well-known in other cancer types, their role in MM remains elusive. With this review, we aim to provide an update on MM homing and resilience in the bone marrow micro milieu. These data are particularly interesting for clinicians facing unmet medical needs while designing novel treatment approaches for MM.
Angiogenesis in metastatic castration-resistant prostate cancer (mCRPC) has been extensively investigated as a promising druggable biological process. Nonetheless, targeting angiogenesis has failed to impact overall survival (OS) in patients with mCRPC despite promising preclinical and early clinical data. This discrepancy prompted a literature review highlighting the tumor heterogeneity and biological context of Prostate Cancer (PCa). Narrowing the gap between the bench and bedside appears critical for developing novel therapeutic strategies. Searching clinicaltrials.gov for studies examining angiogenesis inhibition in patients with PCa resulted in n=20 trials with specific angiogenesis inhibitors currently recruiting (as of September 2021). Moreover, several other compounds with known anti-angiogenic properties – such as Metformin or Curcumin – are currently investigated. In general, angiogenesis-targeting strategies in PCa include biomarker-guided treatment stratification – as well as combinatorial approaches. Beyond established angiogenesis inhibitors, PCa therapies aiming at PSMA (Prostate Specific Membrane Antigen) hold the promise to have a substantial anti-angiogenic effect – due to PSMA´s abundant expression in tumor vasculature.
It’s time to go …
(2022)
Risk prediction in patients with heart failure (HF) is essential to improve the tailoring of preventive, diagnostic, and therapeutic strategies for the individual patient, and effectively use health care resources. Risk scores derived from controlled clinical studies can be used to calculate the risk of mortality and HF hospitalizations. However, these scores are poorly implemented into routine care, predominantly because their calculation requires considerable efforts in practice and necessary data often are not available in an interoperable format. In this work, we demonstrate the feasibility of a multi-site solution to derive and calculate two exemplary HF scores from clinical routine data (MAGGIC score with six continuous and eight categorical variables; Barcelona Bio-HF score with five continuous and six categorical variables). Within HiGHmed, a German Medical Informatics Initiative consortium, we implemented an interoperable solution, collecting a harmonized HF-phenotypic core data set (CDS) within the openEHR framework. Our approach minimizes the need for manual data entry by automatically retrieving data from primary systems. We show, across five participating medical centers, that the implemented structures to execute dedicated data queries, followed by harmonized data processing and score calculation, work well in practice. In summary, we demonstrated the feasibility of clinical routine data usage across multiple partner sites to compute HF risk scores. This solution can be extended to a large spectrum of applications in clinical care.
Chemical warfare or terrorism attacks with organophosphates may place intoxicated subjects under immediate life-threatening and psychologically demanding conditions. Antidotes, such as the oxime HI-6, which must be formulated as a powder for reconstitution reflecting the molecule’s light sensitivity and instability in aqueous solutions, dramatically improve recovery—but only if used soon after exposure. Muscle tremors, anxiety, and loss of consciousness after exposure jeopardize proper administration, translating into demanding specifications for the dissolution of HI-6. Reflecting the patients’ catastrophic situation and anticipated desire to react immediately to chemical weapon exposure, the dissolution should be completed within ten seconds. We are developing multi-dose and single-dose autoinjectors to reliably meet these dissolution requirements. The temporal and spatial course of dissolution within the various autoinjector designs was profiled colorimetrically. Based on these colorimetric insights with model dyes, we developed experimental setups integrating online conductometry to push experiments toward the relevant molecule, HI-6. The resulting blueprints for autoinjector designs integrated small-scale rotor systems, boosting dissolution across a wide range of viscosities, and meeting the required dissolution specifications driven by the use of these drug products in extreme situations.
Husserl’s taxonomy of action
(2022)
In the present article I discuss, in confrontation with the most recent studies on Husserl’s phenomenology of acting and willing, the taxonomy of action that is collected in the volume ‘Wille und Handlung’ of the Husserliana edition Studien zur Struktur des Bewussteins. In so doing, I first present Husserl’s universal characterization of action (Handlung) as a volitional process (willentlicher Vorgang). Then, after clarifying what it means for a process to have a character of volitionality (Willentlichkeit), I illustrate the various types of actions, which Husserl distinguishes as ‘straightforward’ (schlicht) or ‘deciding’ (entscheidend), ‘primary’ (primär) or ‘secondary’ (sekundär), ‘inner’ (innere) or ‘outer’ (äußere), ‘immediate’ (unmittelbar) or mediate (mittelbar), ‘simple’ (einfach) or ‘compound’ (zusammengesetzt). Finally, I consider Husserl’s discussion of the direction and foundation of action.
Charge transfer in ternary solar cells employing two fullerene derivatives: where do electrons go?
(2022)
Earlier reports demonstrated that ternary organic solar cells (OSC) made of donor polymers (D) blended with different mixtures of fullerene acceptors (A : A) performed very similarly. This finding is surprising, as the corresponding fullerene LUMO levels are slightly different, which might result in decisive differences in the charge transfer step. We investigate ternary OSC (D : A : A) made of the donor polymer P3HT with stoichiometric mixtures of different fullerene derivatives, PC\(_{60}\)BM : PC\(_{70}\)BM and PC\(_{70}\)BM : IC\(_{60}\)BA, respectively. Using quantitative electron paramagnetic resonance (EPR) we can distinguish between positive and negative polarons, localized on the specific molecules. We found that after the initial charge transfer step, the electrons are re-distributed over two nearby acceptors in agreement with their stoichiometry and their relative LUMO energy difference. Remarkably, the measured ΔLUMO differences in fullerene mixtures are reduced by an order of magnitude compared to that of the pristine materials, i. e., below 1 meV for PC\(_{60}\)BM : PC\(_{70}\)BM and (20±5) meV for PC\(_{70}\)BM : IC\(_{60}\)BA. Furthermore, we found that this reduced ΔLUMO explains the shift in open circuit voltage for D : A : A organic solar cells. We attribute these findings to hybridization, leading to an effective fullerene LUMO. Consequently, multi-acceptor blends are indeed a viable option for photodetectors and solar cells, as they combine the best electron acceptor and light absorbing properties.
The A\(_{2A}\) adenosine receptor (A\(_{2A}\)AR) is one of the four subtypes activated by nucleoside adenosine, and the molecules able to selectively counteract its action are attractive tools for neurodegenerative disorders. In order to find novel A\(_{2A}\)AR ligands, two series of compounds based on purine and triazolotriazine scaffolds were synthesized and tested at ARs. Compound 13 was also tested in an in vitro model of neuroinflammation. Some compounds were found to possess high affinity for A\(_{2A}\)AR, and it was observed that compound 13 exerted anti-inflammatory properties in microglial cells. Molecular modeling studies results were in good agreement with the binding affinity data and underlined that triazolotriazine and purine scaffolds are interchangeable only when 5- and 2-positions of the triazolotriazine moiety (corresponding to the purine 2- and 8-positions) are substituted.
Fabry disease (FD) is a rare life-threatening disorder caused by deficiency of the alpha-galactosidase A (GLA) enzyme with a characteristic pain phenotype. Impaired GLA production or function leads to the accumulation of the cell membrane compound globotriaosylceramide (Gb3) in the neurons of the dorsal root ganglia (DRG) of FD patients. Applying immunohistochemistry (IHC) and quantitative real-time polymerase chain reaction (qRT PCR) analysis on DRG tissue of the GLA knockout (KO) mouse model of FD, we address the question of how Gb3 accumulation may contribute to FD pain and focus on the immune system and pain-associated ion channel gene expression. We show a higher Gb3 load in the DRG of young (<6 months) (p < 0.01) and old (≥12 months) (p < 0.001) GLA KO mice compared to old wildtype (WT) littermates, and an overall suppressed immune response in the DRG of old GLA KO mice, represented by a reduced number of CD206\(^+\) macrophages (p < 0.01) and lower gene expression levels of the inflammation-associated targets interleukin(IL)1b (p < 0.05), IL10 (p < 0.001), glial fibrillary acidic protein (GFAP) (p < 0.05), and leucine rich alpha-2-glycoprotein 1 (LRG1) (p < 0.01) in the DRG of old GLA KO mice compared to old WT. Dysregulation of immune-related genes may be linked to lower gene expression levels of the pain-associated ion channels calcium-activated potassium channel 3.1 (KCa3.1) and transient receptor potential ankyrin 1 channel (TRPA1). Ion channel expression might further be disturbed by impaired sphingolipid recruitment mediated via the lipid raft marker flotillin-1 (FLOT1). This impairment is represented by an increased number of FLOT1\(^+\) DRG neurons with a membranous expression pattern in old GLA KO mice compared to young GLA KO, young WT, and old WT mice (p < 0.001 each). Further, we provide evidence for aberrant behavior of GLA KO mice, which might be linked to dysregulated ion channel gene expression levels and disturbed FLOT1 distribution patterns. Behavioral testing revealed mechanical hypersensitivity in young (p < 0.01) and old (p < 0.001) GLA KO mice compared to WT, heat hypersensitivity in young GLA KO mice (p < 0.001) compared to WT, age-dependent heat hyposensitivity in old GLA KO mice (p < 0.001) compared to young GLA KO mice, and cold hyposensitivity in young (p < 0.001) and old (p < 0.001) GLA KO mice compared to WT, which well reflects the clinical phenotype observed in FD patients.
Environmental gradients generate and maintain biodiversity on Earth. Mountain slopes are among the most pronounced terrestrial environmental gradients, and the elevational structure of species and their interactions can provide unique insight into the processes that govern community assembly and function in mountain ecosystems. We recorded bumble bee–flower interactions over 3 years along a 1400‐m elevational gradient in the German Alps. Using nonlinear modeling techniques, we analyzed elevational patterns at the levels of abundance, species richness, species β‐diversity, and interaction β‐diversity. Though floral richness exhibited a midelevation peak, bumble bee richness increased with elevation before leveling off at the highest sites, demonstrating the exceptional adaptation of these bees to cold temperatures and short growing seasons. In terms of abundance, though, bumble bees exhibited divergent species‐level responses to elevation, with a clear separation between species preferring low versus high elevations. Overall interaction β‐diversity was mainly caused by strong turnover in the floral community, which exhibited a well‐defined threshold of β‐diversity rate at the tree line ecotone. Interaction β‐diversity increased sharply at the upper extreme of the elevation gradient (1800–2000 m), an interval over which we also saw steep decline in floral richness and abundance. Turnover of bumble bees along the elevation gradient was modest, with the highest rate of β‐diversity occurring over the interval from low‐ to mid‐elevation sites. The contrast between the relative robustness bumble bee communities and sensitivity of plant communities to the elevational gradient in our study suggests that the strongest effects of climate change on mountain bumble bees may be indirect effects mediated by the responses of their floral hosts, though bumble bee species that specialize in high‐elevation habitats may also experience significant direct effects of warming.
Patterns of resource use by animals can clarify how ecological communities have assembled in the past, how they currently function and how they are likely to respond to future perturbations. Bumble bees (Hymentoptera: Bombus spp.) and their floral hosts provide a diverse yet tractable system in which to explore resource selection in the context of plant–pollinator networks. Under conditions of resource limitation, the ability of bumble bees species to coexist should depend on dietary niche overlap. In this study, we report patterns and dynamics of floral morphotype preferences in a mountain bumble bee community based on ~13 000 observations of bumble bee floral visits recorded along a 1400 m elevation gradient. We found that bumble bees are highly selective generalists, rarely visiting floral morphotypes at the rates predicted by their relative abundances. Preferences also differed markedly across bumble bee species, and these differences were well-explained by variation in bumble bee tongue length, generating patterns of preference similarity that should be expected to predict competition under conditions of resource limitation. Within species, though, morphotype preferences varied by elevation and season, possibly representing adaptive flexibility in response to the high elevational and seasonal turnover of mountain floral communities. Patterns of resource partitioning among bumble bee communities may determine which species can coexist under the altered distributions of bumble bees and their floral hosts caused by climate and land use change.
Agrochemicals like systemic active ingredients (AI) need to penetrate the outermost barrier of the plant, known as the plant cuticle, to reach its right target site. Therefore, adjuvants are added to provide precise and efficient biodelivery by i.a. modifying the cuticular barrier and increasing the AI diffusion. This modification process is depicted as plasticization of the cuticular wax which mainly consists of very long-chain aliphatic (VLCA) and cyclic compounds. Plasticization of cuticular waxes is pictured as an increase of amorphous domains and/or a decrease of crystalline fractions, but comprehensive, experimental proof is lacking to date. Hence, the objective of this thesis was to i) elucidate the permeation barrier of the plant cuticle to AIs in terms of the different wax fractions and ii) holistically investigate the modification of this barrier using selected oil and surface active adjuvants, an aliphatic leaf wax and an artificial model wax. Therefore, the oil adjuvant methyl oleate (MeO) and other oil derivatives like methyl linolenate (MeLin), methyl stearate (MeSt) and oleic acid (OA) were selected. Three monodisperse, non-ionic alcohol ethoxylates with increasing ethylene oxide monomer (EO) number (C10E2, C10E5, C10E8) were chosen as representatives of the group of surface active agents (surfactants). Both adjuvant classes are commonly used as formulation aids for agrochemicals which are known for its penetration enhancing effect. The aliphatic leaf wax of Schefflera elegantissima was selected, as well as a model wax comprising the four most abundant cuticular wax compounds of this species. Permeation, transpiration and penetration studies were conducted using enzymatically isolated cuticles of Prunus laurocerasus and Garcinia xanthochymus.
Cuticular permeability to the three organic solutes theobromine, caffeine and azoxystrobin differing in lipophilicity was measured using a steady-state two-chamber system separated by the isolated leaf cuticles of the evergreen species P. laurocerasus and G. xanthochymus. Treating the isolated cuticles with methanol selectively removed the cyclic fraction, and membrane permeability to the organic compounds was not altered. In contrast, fully dewaxing the membranes using chloroform resulted in a statistically significant increase in permeance for all compounds and species, except caffeine with cuticles of G. xanthochymus due to a matrix-specific influence on the semi-hydrophilic compound. Crystalline regions may reduce the accessibility to the lipophilic pathway across the waxes and also block hydrophilic domains in the cuticle.
Knowing that the aliphatic wax fraction builds the cuticular diffusion barrier, the influence of the adjuvants on the phase behaviour of an aliphatic cuticular wax as well as the influence on the cuticular penetration of AIs were investigated. Differential scanning calorimetry (DSC) and Fourier-transform infrared spectroscopy (FTIR) were selected to investigate the phase behaviour and thus possible plasticization of pure Schefflera elegantissima leaf wax, its artificial model wax comprising the four most abundant compounds (n-nonacosane, n-hentriacontane, 1-triacontanol and 1-dotriacontanol) and wax adjuvant mixtures. DSC thermograms showed a shift of the melting ranges to lower temperatures and decreased absolute values of the total enthalpy of transition (EOT) for all adjuvant leaf wax blends at 50 % (w/w) adjuvant proportion. The highest decrease was found for C10E2 followed by MeO > OA and C10E8 > MeLin > MeSt. The aliphatic crystallinity determined by FTIR yielded declined values for the leaf and the artificial wax with 50 % MeO. All other adjuvant leaf wax blends did not show a significant decrease of crystallinity. As it is assumed that the cuticular wax is formed by crystalline domains which consist of aliphatic hydrocarbon chains and an amorphous fraction comprising aliphatic chain ends and functional groups, the plasticizers are depicted as wax disruptors influencing amorphization and/or crystallization. The adjuvants can increase crystalline domains using the aliphatic tail whereas their more hydrophilic head is embedded in the amorphous wax fraction. DSC and FTIR showed similar trends using the leaf wax and the model wax in combination with the adjuvants.
In general, cuticular transpiration increased after adding the pure adjuvants to the surface of isolated cuticles or leaf envelopes. As waxes build the cuticular permeation barrier not only to AIs but also to water, the adjuvant wax interaction might affect the cuticular barrier properties leading to increased transpiration. Direct evidence for increased AI penetration with the adjuvants was given using isolated cuticles of P. laurocerasus in combination with the non-steady-state setup simulation of foliar penetration (SOFP) and caffeine at relative humidity levels (RH) of 30, 50 and 80 %. The increase in caffeine penetration was much more pronounced using C10E5 and C10E8 than MeO but always independent of RH. Only C10E2 exhibited an increased penetration enhancing effect positively related to RH. The role of the molecular structure of adjuvants in terms of humectant and plasticizer properties are discussed.
Hence, the current work shows for the first time that the cuticular permeation barrier is associated with the VLCAs rather than the cyclic fraction and that adjuvants structurally influence this barrier resulting in penetration enhancing effects. Additionally, this work demonstrates that an artificial model wax is feasible to mimic the wax adjuvant interaction in conformity with a leaf wax, making it feasible for in-vitro experiments on a larger scale (e.g. screenings). This provides valuable knowledge about the cuticular barrier modification to enhance AI penetration which is a crucial factor concerning the optimization of AI formulations in agrochemistry.
Latency is an inherent problem of computing systems. Each computation takes time until the result is available. Virtual reality systems use elaborated computer resources to create virtual experiences. The latency of those systems is often ignored or assumed as small enough to provide a good experience.
This cumulative thesis is comprised of published peer reviewed research papers exploring the behaviour and effects of latency. Contrary to the common description of time invariant latency, latency is shown to fluctuate. Few other researchers have looked into this time variant behaviour. This thesis explores time variant latency with a focus on randomly occurring latency spikes. Latency spikes are observed both for small algorithms and as end to end latency in complete virtual reality systems. Most latency measurements gather close to the mean latency with potentially multiple smaller clusters of larger latency values and rare extreme outliers. The latency behaviour differs for different implementations of an algorithm. Operating system schedulers and programming language environments such as garbage collectors contribute to the overall latency behaviour. The thesis demonstrates these influences on the example of different implementations of message passing.
The plethora of latency sources result in an unpredictable latency behaviour. Measuring and reporting it in scientific experiments is important. This thesis describes established approaches to measuring latency and proposes an enhanced setup to gather detailed information. The thesis proposes to dissect the measured data with a stacked z-outlier-test to separate the clusters of latency measurements for better reporting.
Latency in virtual reality applications can degrade the experience in multiple ways. The thesis focuses on cybersickness as a major detrimental effect. An approach to simulate time variant latency is proposed to make latency available as an independent variable in experiments to understand latency's effects. An experiment with modified latency shows that latency spikes can contribute to cybersickness. A review of related research shows that different time invariant latency behaviour also contributes to cybersickness.
When interacting with sophisticated digital technologies, people often fall back on the same interaction scripts they apply to the communication with other humans—especially if the technology in question provides strong anthropomorphic cues (e.g., a human-like embodiment). Accordingly, research indicates that observers tend to interpret the body language of social robots in the same way as they would with another human being. Backed by initial evidence, we assumed that a humanoid robot will be considered as more dominant and competent, but also as more eerie and threatening once it strikes a so-called power pose. Moreover, we pursued the research question whether these effects might be accentuated by the robot’s body size. To this end, the current study presented 204 participants with pictures of the robot NAO in different poses (expansive vs. constrictive), while also manipulating its height (child-sized vs. adult-sized). Our results show that NAO’s posture indeed exerted strong effects on perceptions of dominance and competence. Conversely, participants’ threat and eeriness ratings remained statistically independent of the robot’s depicted body language. Further, we found that the machine’s size did not affect any of the measured interpersonal perceptions in a notable way. The study findings are discussed considering limitations and future research directions.
Purpose: To treat patients with tricompartimental knee osteoarthritis (OA), a customized cruciate-retaining total knee arthroplasty (CCR-TKA) system can be used, including both individualized instrumentation and implants. The objective of this monocentric cohort study was to analyze patient-reported and functional outcomes in a series of patients implanted with the second generation of this customized implant. Methods: At our arthroplasty center, we prospectively recruited a cohort of patients with tricompartmental gonarthrosis to be treated with total knee replacement (TKA) using a customized cruciate-retaining (CCR) implant design. Inclusion criteria for patients comprised the presence of intact posterior cruciate and collateral ligaments and a knee deformity that was restricted to <15° varus, valgus, or flexion contracture. Patients were assessed for their range of motion (ROM), Knee Society Score (KSS), Western Ontario and McMaster University osteoarthritis index (WOMAC), and short form (SF)-12 physical and mental scores, preoperatively, at 3 and 6 months, as well as at 1, 2, 3, and 5 years of follow-up (FU) postoperatively. Results: The average age of the patient population was 64 years (range: 40–81), the average BMI was 31 (range: 23–42), and in total, 28 female and 45 male patients were included. Implant survivorship was 97.5% (one septic loosening) at an average follow-up of 2.5 years. The KSS knee and function scores improved significantly (p < 0.001) from, respectively, 41 and 53 at the pre-operative visit, to 92 and 86, respectively, at the 5-year post-operative time point. The SF-12 Physical and Mental scores significantly (p < 0.001) improved from the pre-operative values of 28 and 50, to 50 and 53 at the 5-year FU, respectively. Patients experienced significant improvements in their overall knee range of motion, from 106° at the preoperative visit to 122°, on average, 5 years postoperatively. The total WOMAC score significantly (p < 0.001) improved from 49.1 preoperatively to 11.4 postoperatively at 5-year FU. Conclusions: Although there was no comparison to other implants within this study, patients reported high overall satisfaction and improvement in functional outcomes within the first year from surgery, which continued over the following years. These mid-term results are excellent compared with those reported in the current literature. Comparative long-term studies with this device are needed. Level of evidence 3b (individual case–control study).
Virtual environments (VEs) can evoke and support emotions, as experienced when playing emotionally arousing games. We theoretically approach the design of fear and joy evoking VEs based on a literature review of empirical studies on virtual and real environments as well as video games’ reviews and content analyses. We define the design space and identify central design elements that evoke specific positive and negative emotions. Based on that, we derive and present guidelines for emotion-inducing VE design with respect to design themes, colors and textures, and lighting configurations. To validate our guidelines in two user studies, we 1) expose participants to 360° videos of VEs designed following the individual guidelines and 2) immerse them in a neutral, positive and negative emotion-inducing VEs combining all respective guidelines in Virtual Reality. The results support our theoretically derived guidelines by revealing significant differences in terms of fear and joy induction.
Purpose
Patients suffering from aggressive systemic peripheral lymphoma with primary central nervous system involvement (PCL) are a rare and sparsely investigated population. Recommended treatment regimens include a combination of intrathecal and systemic chemotherapy as well as whole brain radiotherapy while offering relatively poor survival.
Methods
We conducted a single-center retrospective study that analyzed safety and outcome of 4 + 4 cycles Rituximab (R)-CHOP and R-high-dose Methotrexate (HD-MTX) for newly diagnosed, transplant-eligible patients ("Ping-Pong"), followed by Cytarabine (AraC)/Thiotepa (TT), BCNU/TT, and autologous hematologic stem cell transplantation (aHSCT). We retrospectively analyzed a set of 16 patients with high-intermediate or high-risk IPI status.
Results
Overall response rate to Ping-Pong was 100% measured by CT/MRI, including 93.75% complete remissions after BCNU/TT followed by PBSCT. One patient failed to qualify for high-dose chemotherapy due to progression when receiving Cytarabine/TT. All patients experienced grade III adverse events, 3 of them a grade IV adverse event. Estimated progression-free survival is 93.75% after a 4.8-year follow-up currently.
Conclusion
Our study suggests high effectivity of R-CHOP with mid-cycle MTX with aHSCT consolidation towards acceptable OS results in this challenging patient population.
There has been a steady increase (annual percentage growth rate of 19.2%, average of 18.3 citations per document) in capsule endoscopy (CE) publications from a global, interdisciplinary research community on a growing range of CE applications over the last 20+ years. We here present the status of CE as a field of research, tracing its evolution over time and providing insight into its potential for diagnostics, prevention and treatment of gastrointestinal (GI) tract diseases. To portray the development of the CE research landscape in the 2000–2021 time span, we analyzed 5764 scientific publications. Analyses were performed using the R language and environment for statistical computing and graphics and VOSviewer, a software developed for scientific literature analysis by scientometricians. The aim of this paper is to provide a wide comprehensive analysis of the trends in CE publications. We thus performed subgroup analysis on the selected papers, including indications, annual percentage growth rate, average citations per document, most publications from research areas/interdisciplinary field of the articles, geography, collaboration networks through institutions, specific clinical keywords and device type. The firm increase in CE publications over the last two decades highlights the overall strength of the technology in GI applications. Furthermore, the introduction to the field of artificial intelligence (AI) tools has been promoting a range of technological advances that keep on affecting the diagnostic potential of CE.
There is a lack of standardized treatment recommendations for orofacial granulomatosis, a chronic inflammatory condition aetiologically related to Crohn disease. To assess clinical baseline parameters and treatment strategies, we retrospectively analysed 61 consecutive cases from our institutional database. Disease-related functional/psychological impairment and long-term outcomes were descriptively evaluated using a standardized self-reporting questionnaire. The median age of patients was 45 (7–77) years. Oral steroids were given in 41.0% of cases, but only produced short-term disease control, while response to steroid-sparing agents was inconsistent. Only a minority of patients reported relevant disease-related functional impairment in eating (21.7%) or speaking (4.3%), but the majority perceived psychological distress due to the cosmetic aspects of the disease (69.6%), comments from others (65.2%) and/or general anxiety/insecurity (73.9%). Regardless of the initial treatment, long-term outcomes after 71 months (range 7–304 months) were beneficial, with most patients being in complete remission (52.2%) or reporting only mild residual swelling (43.5%).
Background
Correct recognition of risk factors enables individualized management and treatment of venom allergic patients.
Methods
Systematic research and review of current literature regarding the risk of (1) severe sting-induced anaphylaxis, (2) anaphylactic adverse event during venom immunotherapy (VIT), and (3) treatment failure.
Results and discussion
(1) Mastocytosis is the most important risk factor for severe sting-induced anaphylaxis. Hereditary α‑tryptasemia was recently identified as a genetic predictor of severe reactions. Older age is clearly associated with an increased risk; the respective impact of defined cardiovascular comorbidities has yet to be determined. Recent data do not support an aggravation of venom-induced anaphylaxis by intake of β‑blockers or angiotensin-converting enzyme (ACE) inhibitors. A higher risk in men can be attributed to more intensive exposure to stinging insects. (2) Anaphylactic side effects of VIT are most common during the buildup phase, particularly in the course of (ultra-)rush protocols involving a high number of injections and high cumulative daily doses. They are significantly more frequent during honeybee compared to Vespula VIT. Data supporting a negative effect of mastocytosis on the tolerability of VIT are scarce. Older age and cardiovascular medication are not associated with a higher incidence of VIT-induced anaphylaxis. (3) Relapsing anaphylactic reactions to both field and challenge stings are significantly more common during and after honeybee compared to Vespula VIT. Reports of severe field-sting reactions in mastocytosis patients suggest an increased risk of treatment failure which may be overcome by higher maintenance doses and longer duration of VIT.
To counteract insect decline, it is essential to understand the underlying causes, especially for key pollinators such as nocturnal moths whose ability to orientate can easily be influenced by ambient light conditions. These comprise natural light sources as well as artificial light, but their specific relevance for moth orientation is still unknown. We investigated the influence of moonlight on the reproductive behavior of privet hawkmoths (Sphinx ligustri) at a relatively dark site where the Milky Way was visible while the horizon was illuminated by distant light sources and skyglow. We show that male moths use the moon for orientation and reach females significantly faster with increasing moon elevation. Furthermore, the choice of flight direction depended on the cardinal position of the moon but not on the illumination of the horizon caused by artificial light, indicating that the moon plays a key role in the orientation of male moths.
Background: Muscle injuries are common in humans and are often associated with irrecoverable damage and disability. Upon muscle injury, TNF-α signaling pathways modulate the healing process and are predominantly associated with tissue degradation. In this study we assumed that TNF-α inhibition could reduce the TNF-α-associated tissue degradation after muscle injury. Materials and methods: Therefore, the left soleus muscle of 42 male Wistar rats was injured using a standardized open muscle injury model. All rats were treated immediately after injury either with infliximab (single i.p. injection; 10 mg/kg b.w.) or saline solution i.p. Final measurements were conducted at day one, four, and 14 post injury. The muscle force, the muscle cell proliferation, the muscle cell coverage as well as the myofiber diameter served as read out parameters of our experiment. Results: Systemic application of infliximab could significantly reduce the TNF-α levels in the injured muscle at day four upon trauma compared to saline treated animals. The ratio of muscle weight to body weight was increased and the twitch muscle force showed a significant rise 14 days after trauma and TNF-α inhibition. Quantification of myofiber diameter in the penumbra zone showed a significant difference between both groups at day one and four after injury, indicated by muscle hypertrophy in the infliximab group. Planimetric analysis of the injured muscle at day 14 revealed increased muscle tissue fraction in the infliximab group compared to the control animals. Muscle cell proliferation did not differ between both groups. Conclusions: These data provide evidence that the TNF-α blockade positively regulates the restauration of skeletal muscles upon injury.
Purpose
The goal of our study was to conduct an online survey that highlights patterns of practice during total hip arthroplasty (THA).
Methods
The survey was conducted in June and August 2020. Three hundred thirteen members of the German Society for Endoprosthesis participated in the survey.
Results
The anterolateral approach is by far the most popular approach used for primary total hip arthroplasty, followed by the anterior approach during minimally invasive (55% for the anterolateral and 29% for the anterior) and regular surgery (52% for the anterolateral and 20% for the anterior). Two-thirds of the orthopaedic surgeons do not use drainages during THA. Moreover, 80% of the survey participants routinely apply tranexamic acid during surgery. Surgeons who perform minimally invasive surgery for THA use more frequently fast-track-concepts for post-operative rehabilitation. According to the interviewees, the application of fast-track-concepts leads to reduced periods of hospital stay after THA.
Conclusion
Our data demonstrate that patterns of practice during THA in Germany are in line with the evidence provided by current literature. This study can be seen as a stimulus to conduct similar surveys in other countries in order to promote minimally invasive surgery for THA.
Reconstruction of the donor site after radial forearm flap harvesting is a common procedure in maxillofacial plastic surgery. It is normally carried out with split-thickness or full-thickness free skin grafts. Unfortunately, free skin graft transplantation faces wound healing impairments such as necrosis, (partial) graft loss, or tendon exposure. Several studies have investigated methods to reduce these impairments and demonstrated improvements if the wound bed is optimised, for example, through negative-pressure wound therapy or vacuum-assisted closure. However, these methods are device-dependent, expansive, and time-consuming. Therefore, the application of platelet-rich fibrin (PRF) to the wound bed could be a simple, cost-effective, and device-independent method to optimise wound-bed conditions instead. In this study, PRF membranes were applied between the wound bed and skin graft. Results of this study indicate improvements in the PRF versus non-PRF group (93.44% versus 86.96% graft survival, p = 0.0292). PRF applied to the wound bed increases graft survival and reduces impairments. A possible explanation for this is the release of growth factors, which stimulate angiogenesis and fibroblast migration. Furthermore, the solid PRF membranes act as a mechanical barrier (“lubrication” layer) to protect the skin graft from tendon motion. The results of this study support the application of PRF in donor-site reconstruction with free skin grafts.
Bone concentration of ampicillin/sulbactam: a pilot study in patients with osteonecrosis of the jaw
(2022)
Osteonecrosis of the jaw (ONJ) occurs typically after irradiation of the head and neck area or after the intake of antiresorptive agents. Both interventions can lead to compromised bone perfusion and can ultimately result in infection and necrosis. Treatment usually consists of surgical necrosectomy and prolonged antibiotic therapy, usually through beta-lactams such as ampicillin/sulbactam. The poor blood supply in particular raises the question as to whether this form of antibiosis can achieve sufficient concentrations in the bone. Therefore, we investigated the antibiotic concentration in plasma and bone samples in a prospective study. Bone samples were collected from the necrosis core and in the vital surrounding bone. The measured concentrations in plasma for ampicillin and sulbactam were 126.3 ± 77.6 and 60.2 ± 35.0 µg/mL, respectively. In vital bone and necrotic bone samples, the ampicillin/sulbactam concentrations were 6.3 ± 7.8/1.8 ± 2.0 µg/g and 4.9 ± 7.0/1.7 ± 1.7 µg/g, respectively. These concentrations are substantially lower than described in the literature. However, the concentration seems sufficient to kill most bacteria, such as Streptococci and Staphylococci, which are mostly present in the biofilm of ONJ. We, therefore, conclude that intravenous administration of ampicillin/sulbactam remains a valuable treatment in the therapy of ONJ. Nevertheless, increasing resistance of Escherichia coli towards beta-lactam antibiotics have been reported and should be considered.
Objectives
Mechanisms of wound healing are often impaired in patients with osteonecrosis of the jaw (ONJ). According to the guidelines for the treatment of this disease, early surgical intervention is indicated. However, surgery often faces complications such as wound healing disorders. The application of platelet-rich fibrin (PRF) after necrosectomy between bone and mucosa may constitute a promising approach to improve surgical results. An aspect that was not investigated until now is that PRF acts as a “bio-carrier” for antibiotics previously applied intravenously.
Materials and methods
We investigated the antimicrobial properties of PRF in 24 patients presenting ONJ undergoing systemic antibiosis with ampicillin/sulbactam. We measured the concentration of ampicillin/sulbactam in plasma and PRF and performed agar diffusion tests. Ampicillin/sulbactam was applied intravenously to the patient 10 minutes for blood sampling for PRF. No further incorporation of patients’ blood or PRF product with antibiotic drugs was obtained. Four healthy patients served as controls.
Results
Our results revealed that PRF is highly enriched with ampicillin/sulbactam that is released to the environment. The antibiotic concentration in PRF was comparable to the plasma concentration of ampicillin/sulbactam. The inhibition zone (IZ) of PRF was comparable to the standard ampicillin/sulbactam discs used in sensitivity testing.
Conclusions
The results of our study demonstrated that PRF is a reliable bio-carrier for systemic applied antibiotics and exhibits a large antimicrobial effect.
Clinical relevance
We describe a clinically useful feature of PRF as a bio-carrier for antibiotics. Especially when applied to poorly perfused tissues and bone such as in ONJ, the local release of antibiotics can reduce wound healing disorders like infections.
Background
Joint aspiration with analysis of synovial fluid white blood cell count (WBC) and microbiological culture is a widely established aspect in the diagnosis of shoulder joint infections (SJI). In case of a two stage revision for SJI, joint aspiration before re−/implantation of a total shoulder arthroplasty (TSA) was used to rule out persistent infection for years but its value is under debate. Shoulder specific data on all aspects is rare. The current study aims to answer the following research questions: Does joint aspiration have an insufficient predictive value in the diagnosis of SJI in (1) initial workup and (2) before definite arthroplasty with polymethylmethacrylate (PMMA)-Spacer in place?
Methods
This retrospective evaluation investigates 35 patients that were treated for SJI with a two staged implantation of a TSA after debridement and implantation of an PMMA-Spacer. Joint aspirations were performed preoperatively (PA) and before re−/implantation of the prosthesis while spacer was in place (interstage aspiration, IA). Samples were taken for microbiological culture and analysis of WBC. Sensitivity and specificity were calculated with reference to intraoperative microbiological samples. Receiver Operating Characteristic (ROC), Area-Under-Curve analysis (AUC) and calculation of the Youden index were performed to find optimum cut-off for WBC.
Results
The sensitivity of microbiological cultures from PA was 58.3% and the specificity was 88.9%. The mean WBC was 27,800 leucocytes/mm3 (range 400-96,300). The maximum Youden index (0.857) was a cut-off of 2600 leucocytes/mm3 with a sensitivity of 85.7% and a specificity of 100.0%. The sensitivity and specificity of IA were 0.0% and 88.5%, respectively.
Conclusions
Preoperative aspiration is likely to miss Cutibacteria spp. and CoNS and cannot rule out infection for sure. However, we recommend it for its advantages of targeted antibiotic therapy in case of germ identification. Empiric antibiotic therapy should cover Cutibacteria and CoNS even if aspiration showed negative microbiological cultures. In contrast, the diagnostic value of interstage aspiration does not qualify for its routine use.
The phenomenon of individual variability in susceptibility/resilience to stress and depression, in which the hippocampus plays a pivotal role, is attracting increasing attention. We investigated the potential role of hippocampal cyclooxygenase-2 (COX-2), which regulates plasticity, neuroimmune function, and stress responses that are all linked to this risk dichotomy. We used a four-week-long chronic mild stress (CMS) paradigm, in which mice could be stratified according to their susceptibility/resilience to anhedonia, a key feature of depression, to investigate hippocampal expression of COX-2, a marker of microglial activation Iba-1, and the proliferation marker Ki67. Rat exposure, social defeat, restraints, and tail suspension were used as stressors. We compared the effects of treatment with either the selective COX-2 inhibitor celecoxib (30 mg/kg/day) or citalopram (15 mg/kg/day). For the celecoxib and vehicle-treated mice, the Porsolt test was used. Anhedonic (susceptible) but not non-anhedonic (resilient) animals exhibited elevated COX-2 mRNA levels, increased numbers of COX-2 and Iba-1-positive cells in the dentate gyrus and the CA1 area, and decreased numbers of Ki67-positive cells in the subgranular zone of the hippocampus. Drug treatment decreased the percentage of anhedonic mice, normalized swimming activity, reduced behavioral despair, and improved conditioned fear memory. Hippocampal over-expression of COX-2 is associated with susceptibility to stress-induced anhedonia, and its pharmacological inhibition with celecoxib has antidepressant effects that are similar in size to those of citalopram.
Background
Influenza virus infections in immunologically naïve children (primary infection) may be more severe than in children with re-infections who are already immunologically primed. We compared frequency and severity of influenza virus primary and re-infections in pre-school children requiring outpatient treatment.
Methods
Influenza-unvaccinated children 1–5 years of age presenting at pediatric practices with febrile acute respiratory infection < 48 h after symptom onset were enrolled in a prospective, cross-sectional, multicenter surveillance study (2013–2015). Influenza types/subtypes were PCR-confirmed from oropharyngeal swabs. Influenza type/subtype-specific IgG antibodies serving as surrogate markers for immunological priming were determined using ELISA/hemagglutination inhibition assays. The acute influenza disease was defined as primary infection/re-infection by the absence/presence of influenza type-specific immunoglobulin G (IgG) and, in a second approach, by the absence/presence of subtype-specific IgG. Socio-demographic and clinical data were also recorded.
Results
Of 217 influenza infections, 178 were due to influenza A (87 [49%] primary infections, 91 [51%] re-infections) and 39 were due to influenza B (38 [97%] primary infections, one [3%] re-infection). Children with “influenza A primary infections” showed fever with respiratory symptoms for a shorter period than children with “influenza A re-infections” (median 3 vs. 4 days; age-adjusted p = 0.03); other disease characteristics were similar. If primary infections and re-infections were defined based on influenza A subtypes, 122 (87%) primary infections (78 “A(H3N2) primary infections”, 44 “A(H1N1)pdm09 primary infections”) and 18 (13%) re-infections could be classified (14 “A(H3N2) re-infections” and 4 “A(H1N1)pdm09 re-infections”). Per subtype, primary infections and re-infections were of similar disease severity. Children with re-infections defined on the subtype level usually had non-protective IgG titers against the subtype of their acute infection (16 of 18; 89%). Some patients infected by one of the influenza A subtypes showed protective IgG titers (≥ 1:40) against the other influenza A subtype (32/140; 23%).
Conclusions
Pre-school children with acute influenza A primary infections and re-infections presented with similar frequency in pediatric practices. Contrary to expectation, severity of acute “influenza A primary infections” and “influenza A re-infections” were similar. Most “influenza A re-infections” defined on the type level turned out to be primary infections when defined based on the subtype. On the subtype level, re-infections were rare and of similar disease severity as primary infections of the same subtype. Subtype level re-infections were usually associated with low IgG levels for the specific subtype of the acute infection, suggesting only short-time humoral immunity induced by previous infection by this subtype. Overall, the results indicated recurring influenza virus infections in this age group and no or only limited heterosubtypic antibody-mediated cross-protection.
Diagnosis and therapy of Mycobacterium marinum: a single-center 21-year retrospective analysis
(2022)
Background and Objectives
In Europe, infections with Mycobacterium (M.) marinum are rare. We conducted a retrospective single-center study to assess the clinical spectrum of M. marinum infection and its diagnosis, treatment and outcome under real-world conditions.
Patients and Methods
Eighteen patients presenting with M. marinum infections between 1998 and 2018 were identified in the data warehouse of the University Hospital Würzburg and considered for detailed analysis.
Results
Twelve patients reported aquatic exposure. In 16/18 cases the upper extremities were affected. No invasive infections were detected. Mean time to diagnosis was 15 weeks. Histology revealed granulomatous inflammation in 14 patients while mycobacterial cultures were positive for M. marinum in 16 cases. Most patients received antibiotic monotherapy (14/18) while combination therapy was administered in four cases. Treatment (with a median duration of 10 weeks) was successful in 13 patients. Five patients were lost to follow-up.
Conclusions
Our retrospective analysis of M. marinum infections at a German tertiary referral center revealed a considerable diagnostic delay and the relevance of microbiological culture, PCR and histology for diagnosis. Monotherapy with clarithromycin (rather than doxycycline) appeared as a reasonable treatment option while immunosuppressed or -compromised patients and those with extended disease received combination therapy.
Quantum point contacts (QPCs) are one-dimensional constrictions in an otherwise extended two-dimensional electron or hole system. Since their first realization in GaAs based two-dimensional electron gases, QPCs have become basic building blocks of mesoscopic physics and are used in manifold experimental contexts. A so far unrealized goal however is the implementation of QPCs in the new material class of two-dimensional topological insulators, which host the emergence of the so-called quantum spin Hall (QSH) effect. The latter is characterized by the formation of conducting one-dimensional spin-polarized states at the device edges, while the bulk is insulating. Consequently, an implemented QPC technology can be utilized to bring the QSH edge channels in close spatial proximity, thus for example enabling the study of interaction effects between the edge states. The thesis at hand describes the technological realization as well as the subsequent experimental characterization and analysis of QPCs in a QSH system for the first time.
After an introduction is given in Chapter 1, the subsequent Chapter 2 starts with discussing the peculiar band structure of HgTe. The emergence of the QSH phase for HgTe quantum wells with an inverted band structure is explained. For the band inversion to occur, the quantum wells have to exhibit a well thickness d_QW above a critical value (d_QW > d_c = 6.3 nm). Subsequently, the concept of QPCs is explicated and the corresponding transport behaviour is analytically described. Following the discussion of relevant constraints when realizing a QPC technology in a QSH system, a newly developed lithography process utilizing a multi-step wet etching technique for fabricating QPC devices based on HgTe quantum wells is presented. Transport measurements of exemplary devices show the expected conductance quantization in steps of ΔG ≈ 2e^2/h within the conduction band for a topological as well as for a trivial (d_QW < d_c) QPC. For the topological case, the residual conductance within the bulk band gap saturates at G_QSH ≈ 2e^2/h due to presence of the QSH state, while it drops to G ≈ 0 for the trivial device. Moreover, bias voltage dependent measurements of the differential conductance of an inverted sample provide explicit proof of the unperturbed coexistence of topological and trivial transport modes.
In a next step, Chapter 3 describes the emergence of a QSH interferometer state in narrow QPC devices with a quantum well thickness of d_QW = 7 nm. Presented band structure calculations reveal that the spatial extension of the QSH edge states depends on the position of the Fermi energy within the bulk band gap. As a consequence, reservoir electrons with randomized spin couple to both edge channels with the same probability under certain conditions, thus causing the formation of a QSH ring. A straightforward model capturing and specifying the occurrence of such a QSH interferometer is provided as well as substantiated by two experimental plausibility checks. After relevant quantum phases are theoretically introduced, the discussion of the obtained data reveals the accumulation of an Aharonov-Bohm phase, of a dynamical Aharonov-Casher phase as well as of a spin-orbit Berry phase of π in appropriate QPC devices. These results are consistent with analytic model considerations.
The last part of this thesis, Chapter 4, covers the observation of an unexpected conductance pattern for QPC samples fabricated from quantum wells with d_QW = 10.5 nm. In these devices, an anomalous plateau at G ≈ e^2/h = 0.5 x G_QSH emerges in addition to the QSH phase entailed residual conductance of G_QSH ≈ 2e^2/h. This so-called 0.5 anomaly occurs only for a specific interval of QPC width values, while it starts to get lost for too large sample widths. Furthermore, presented temperature and bias voltage dependent measurements insinuate that the emergence of the 0.5 anomaly is related to a gapped topological state. Additional characterization of this peculiar transport regime is provided by the realization of a novel device concept, which integrates a QPC within a standard Hall bar geometry. The results of the experimental analysis of such a sample link the occurrence of the 0.5 anomaly to a backscattered QSH channel. Thus, following a single particle perspective argumentation, it is reasoned that only one edge channel is transmitted in the context of the 0.5 anomaly. Two theoretic models possibly explaining the emergence of the 0.5 anomaly -- based on electron-electron interactions -- are discussed.
To conclude, the implementation of a working QPC technology in a QSH system represents a paramount development in the context of researching two-dimensional topological insulators and enables a multitude of future experiments. QPC devices realized in a QSH system are for example envisaged to allow for the detection of Majorana fermions and parafermions. Furthermore, the reported formation of a QSH interferometer state in appropriate QPC devices is of high interest. The observed dynamical Aharonov-Casher phase in the QSH regime enables a controllable modulation of the topological conductance, thus providing the conceptual basis for a topological transistor. Moreover, due to the resilience of geometric phases against dephasing, the presence of a spin-orbit Berry phase of π represents a promising perspective with regard to possible quantum computation concepts. Besides that, the transmission of only one QSH edge channel due to the emergence of the 0.5 anomaly is equivalent to 100 % spin polarization, which is an essential ingredient for realizing spintronic applications. Hence, the thesis at hand covers the experimental detection of three effects of fundamental importance in the context of developing new generations of logic devices -- based on QPCs fabricated from topological HgTe quantum wells.
Objective
At high altitude (HA), acute mountain sickness (AMS) is accompanied by neurologic and upper gastrointestinal symptoms (UGS). The primary aim of this study was to test the hypothesis that delayed gastric emptying (GE), assessed by \(^{13}\)C-octanoate breath testing (OBT), causes UGS in AMS. The secondary aim was to assess post-gastric mechanisms of OBT, which could confound results under these conditions, by determination of intermediary metabolites, gastrointestinal peptides, and basal metabolic rate.
Methods
A prospective trial was performed in 25 healthy participants (15 male) at 4559 m (HA) and at 490 m (Zurich). GE was assessed by OBT (428 kcal solid meal) and UGS by visual analogue scales (VAS). Blood sampling of metabolites (glucose, free fatty acids (FFA), triglycerides (TG), beta-hydroxyl butyrate (BHB), L-lactate) and gastrointestinal peptides (insulin, amylin, PYY, etc.) was performed as well as blood gas analysis and spirometry. Statistical analysis: variance analyses, bivariate correlation, and multilinear regression analysis.
Results
After 24 h under hypoxic conditions at HA, participants developed AMS (p < 0.001). \(^{13}\)CO\(_{2}\) exhalation kinetics increased (p < 0.05) resulting in reduced estimates of gastric half-emptying times (p < 0.01). However, median resting respiratory quotients and plasma profiles of TG indicated that augmented beta-oxidation was the main predictor of accelerated \(^{13}\)CO\(_{2}\)-generation under these conditions.
Conclusion
Quantification of \(^{13}\)C-octanoate oxidation by a breath test is sensitive to variation in metabolic (liver) function under hypoxic conditions. \(^{13}\)C-breath testing using short-chain fatty acids is not reliable for measurement of gastric function at HA and should be considered critically in other severe hypoxic conditions, like sepsis or chronic lung disease.
Our starting point is the Jacobsthal function \(j(m)\), defined for each positive integer \(m\) as the smallest number such that every \(j(m)\) consecutive integers contain at least one integer relatively prime to \(m\). It has turned out that improving on upper bounds for \(j(m)\) would also lead to advances in understanding the distribution of prime numbers among arithmetic progressions. If \(P_r\) denotes the product of the first \(r\) prime numbers, then a conjecture of Montgomery states that \(j(P_r)\) can be bounded from above by \(r (\log r)^2\) up to some constant factor. However, the until now very promising sieve methods seem to have reached a limit here, and the main goal of this work is to develop other combinatorial methods in hope of coming a bit closer to prove the conjecture of Montgomery. Alongside, we solve a problem of Recamán about the maximum possible length among arithmetic progressions in the least (positive) reduced residue system modulo \(m\). Lastly, we turn towards three additive representation functions as introduced by Erdős, Sárközy and Sós who studied their surprising different monotonicity behavior. By an alternative approach, we answer a question of Sárközy and demostrate that another conjecture does not hold.
Background
Remote monitoring of patients with New York Heart Association (NYHA) functional class III heart failure (HF) using daily transmission of pulmonary artery (PA) pressure values has shown a reduction in HF-related hospitalizations and improved quality of life in patients.
Objectives
PASSPORT-HF is a prospective, randomized, open, multicenter trial evaluating the effects of a hemodynamic-guided, HF nurse-led care approach using the CardioMEMS™ HF-System on clinical end points.
Methods and results
The PASSPORT-HF trial has been commissioned by the German Federal Joint Committee (G-BA) to ascertain the efficacy of PA pressure-guided remote care in the German health-care system. PASSPORT-HF includes adult HF patients in NYHA functional class III, who experienced an HF-related hospitalization within the last 12 months. Patients with reduced ejection fraction must be on stable guideline-directed pharmacotherapy. Patients will be randomized centrally 1:1 to implantation of a CardioMEMS™ sensor or control. All patients will receive post-discharge support facilitated by trained HF nurses providing structured telephone-based care. The trial will enroll 554 patients at about 50 study sites. The primary end point is a composite of the number of unplanned HF-related rehospitalizations or all-cause death after 12 months of follow-up, and all events will be adjudicated centrally. Secondary end points include device/system-related complications, components of the primary end point, days alive and out of hospital, disease-specific and generic health-related quality of life including their sub-scales, and laboratory parameters of organ damage and disease progression.
Conclusions
PASSPORT-HF will define the efficacy of implementing hemodynamic monitoring as a novel disease management tool in routine outpatient care.
Trial registration
ClinicalTrials.gov; NCT04398654, 13-MAY-2020.
Effective lifting of the topological protection of quantum spin Hall edge states by edge coupling
(2022)
The scientific interest in two-dimensional topological insulators (2D TIs) is currently shifting from a more fundamental perspective to the exploration and design of novel functionalities. Key concepts for the use of 2D TIs in spintronics are based on the topological protection and spin-momentum locking of their helical edge states. In this study we present experimental evidence that topological protection can be (partially) lifted by pairwise coupling of 2D TI edges in close proximity. Using direct wave function mapping via scanning tunneling microscopy/spectroscopy (STM/STS) we compare isolated and coupled topological edges in the 2D TI bismuthene. The latter situation is realized by natural lattice line defects and reveals distinct quasi-particle interference (QPI) patterns, identified as electronic Fabry-Pérot resonator modes. In contrast, free edges show no sign of any single-particle backscattering. These results pave the way for novel device concepts based on active control of topological protection through inter-edge hybridization for, e.g., electronic Fabry-Pérot interferometry.
In this contribution, we illustrate uranium complexes bearing a pendant borate (i.e. 1 and 2) or a pendant borane (i.e. 3 and 4) moiety via reaction of the highly strained uranacycle I with various 3‐coordinate boranes. Complexes 3 and 4 represent the first examples of uranium complexes with a pendant borane Lewis acid. Moreover, complex 3 was capable of activation of CO, delivering a new CO activation mode, and an abnormal CO 1,2‐insertion pathway into a U−N bond. The importance of the pendant borane moiety was confirmed by the controlled experiments.
The blood-brain barrier (BBB) is a highly specialized structure that separates the brain from the blood and allows the exchange of molecules between these two compartments through selective channels. The breakdown of the BBB is implicated in the development of severe neurological diseases, especially stroke and traumatic brain injury. Oxygen-glucose deprivation is used to mimic stroke and traumatic brain injury in vitro. Pathways that trigger BBB dysfunction include an imbalance of oxidative stress, excitotoxicity, iron metabolism, cytokine release, cell injury, and cell death. MicroRNAs are small non-coding RNA molecules that regulate gene expression and are emerging as biomarkers for the diagnosis of central nervous system (CNS) injuries. In this review, the regulatory role of potential microRNA biomarkers and related therapeutic targets on the BBB is discussed. A thorough understanding of the potential role of various cellular and linker proteins, among others, in the BBB will open further therapeutic options for the treatment of neurological diseases.
Activating Organic Phosphorescence via Heavy Metal–π Interaction Induced Intersystem Crossing
(2022)
Heavy‐atom‐containing clusters, nanocrystals, and other semiconductors can sensitize the triplet states of their surface‐bonded chromophores, but the energy loss, such as nonradiative deactivation, often prevents the synergistic light emission in their solid‐state coassemblies. Cocrystallization allows new combinations of molecules with complementary properties for achieving functionalities not available in single components. Here, the cocrystal formation that employs platinum(II) acetylacetonate (Pt(acac)\(_{2}\)) as a triplet sensitizer and electron‐deficient 1,4,5,8‐naphthalene diimides (NDIs) as organic phosphors is reported. The hybrid cocrystals exhibit room‐temperature phosphorescence confined in the low‐lying, long‐lived triplet state of NDIs with photoluminescence (PL) quantum yield (Φ\(_{PL}\)) exceeding 25% and a phosphorescence lifetime (τ\(_{Ph}\)) of 156 µs. This remarkable PL property benefits from the noncovalent electronic and spin–orbital coupling between the constituents.
Background: The adequate choice of perioperative antibiotic prophylaxis (PAP) could influence the risk of surgical site infections (SSIs) in general surgery. A new local PAP guideline was implemented in May 2017 and set the first-generation cefazolin (CFZ) instead the second-generation cefuroxime (CXM) as the new standard prophylactic antibiotic. The aim of this study was to compare the risk of SSIs after this implementation in intra-abdominal infections (IAIs) without sepsis. Methods: We performed a single center-quality improvement study at a 1500 bed sized university hospital in Germany analyzing patients after emergency surgery during 2016 to 2019 (n = 985), of which patients receiving CXM or CFZ were selected (n = 587). Propensity score matching was performed to ensure a comparable risk of SSIs in both groups. None-inferiority margin for SSIs was defined as 8% vs. 4%. Results: Two matched cohorts with respectively 196 patients were compared. The rate of SSIs was higher in the CFZ group (7.1% vs. 3.6%, p = 0.117) below the non-inferiority margin. The rate of other postoperative infections was significantly higher in the CFZ group (2.0% vs. 8.7%, p = 0.004). No other differences including postoperative morbidity, mortality or length-of-stay were observed. Conclusion: Perioperative antibiotic prophylaxis might be safely maintained by CFZ even in the treatment of intra-abdominal infections.
Bacterial small RNAs (sRNAs) are widespread post-transcriptional regulators that control bacterial stress responses and virulence. Nevertheless, little is known about how they arise and evolve. Homologs can be difficult to identify beyond the strain level using sequence-based approaches, and similar functionalities can arise by convergent evolution. Here, we found that the virulence-associated CJnc190 sRNA of the foodborne pathogen Campylobacter jejuni resembles the RepG sRNA from the gastric pathogen Helicobacter pylori. However, while both sRNAs bind G-rich sites in their target mRNAs using a C/U-rich loop, they largely differ in their biogenesis. RepG is transcribed from a stand-alone gene and does not require processing, whereas CJnc190 is transcribed from two promoters as precursors that are processed by RNase III and also has a cis-encoded antagonist, CJnc180. By comparing CJnc190 homologs in diverse Campylobacter species, we show that RNase III-dependent processing of CJnc190 appears to be a conserved feature even outside of C. jejuni. We also demonstrate the CJnc180 antisense partner is expressed in C. coli, yet here might be derived from the 3’UTR (untranslated region) of an upstream flagella-related gene. Our analysis of G-tract targeting sRNAs in Epsilonproteobacteria demonstrates that similar sRNAs can have markedly different biogenesis pathways.
The interaction between brain serotonin (5-HT) deficiency and environmental adversity may predispose females to excessive aggression. Specifically, complete inactivation of the gene encoding tryptophan hydroxylase-2 (Tph2) results in the absence of neuronal 5-HT synthesis and excessive aggressiveness in both male and female null mutant (Tph2\(^{−/−}\)) mice. In heterozygous male mice (Tph2\(^{+/−}\)), there is a moderate reduction in brain 5-HT levels, and when they are exposed to stress, they exhibit increased aggression. Here, we exposed female Tph2\(^{+/−}\) mice to a five-day rat predation stress paradigm and assessed their emotionality and social interaction/aggression-like behaviors. Tph2\(^{+/−}\) females exhibited excessive aggression and increased dominant behavior. Stressed mutants displayed altered gene expression of the 5-HT receptors Htr1a and Htr2a, glycogen synthase kinase-3 β (GSK-3β), and c-fos as well as myelination-related transcripts in the prefrontal cortex: myelin basic protein (Mbp), proteolipid protein 1 (Plp1), myelin-associated glycoprotein (Mag), and myelin oligodendrocyte glycoprotein (Mog). The expression of the plasticity markers synaptophysin (Syp) and cAMP response element binding protein (Creb), but not AMPA receptor subunit A2 (GluA2), were affected by genotype. Moreover, in a separate experiment, naïve female Tph2\(^{+/−}\) mice showed signs of enhanced stress resilience in the modified swim test with repeated swimming sessions. Taken together, the combination of a moderate reduction in brain 5-HT with environmental challenges results in behavioral changes in female mice that resemble the aggression-related behavior and resilience seen in stressed male mutants; additionally, the combination is comparable to the phenotype of null mutants lacking neuronal 5-HT. Changes in myelination-associated processes are suspected to underpin the molecular mechanisms leading to aggressive behavior.
FGF/FGFR signaling regulates embryogenesis, angiogenesis, tissue homeostasis and wound repair by modulating proliferation, differentiation, survival, migration and metabolism of target cells. Understandably, compelling evidence for deregulated FGF signaling in the development and progression of different types of tumors continue to emerge and FGFR inhibitors arise as potential targeted therapeutic agents, particularly in tumors harboring aberrant FGFR signaling. There is first evidence of a dual role of the FGF/FGFR system in both organogenesis and tumorigenesis, of which this review aims to provide an overview. FGF-1 and FGF-2 are expressed in the adrenal cortex and are the most powerful mitogens for adrenocortical cells. Physiologically, they are involved in development and maintenance of the adrenal gland and bind to a family of four tyrosine kinase receptors, among which FGFR1 and FGFR4 are the most strongly expressed in the adrenal cortex. The repeatedly proven overexpression of these two FGFRs also in adrenocortical cancer is thus likely a sign of their participation in proliferation and vascularization, though the exact downstream mechanisms are not yet elucidated. Thus, FGFRs potentially offer novel therapeutic targets also for adrenocortical carcinoma, a type of cancer resistant to conventional antimitotic agents.
Purpose
Dose-escalated external beam radiation therapy (EBRT) and EBRT + high-dose-rate brachytherapy (HDR-BT) boost are guideline-recommended treatment options for localized prostate cancer. The purpose of this study was to compare long-term outcome and toxicity of dose-escalated EBRT versus EBRT + HDR-BT boost.
Methods
From 2002 to 2019, 744 consecutive patients received either EBRT or EBRT + HDR-BT boost, of whom 516 patients were propensity score matched. Median follow-up was 95.3 months. Cone beam CT image-guided EBRT consisted of 33 fractions of intensity-modulated radiation therapy with simultaneous integrated boost up to 76.23 Gy (D\(_{Mean}\)). Combined treatment was delivered as 46 Gy (D\(_{Mean}\)) EBRT, followed by two fractions HDR-BT boost with 9 Gy (D\(_{90\%}\)). Propensity score matching was applied before analysis of the primary endpoint, estimated 10-year biochemical relapse-free survival (bRFS), and the secondary endpoints metastasis-free survival (MFS) and overall survival (OS). Prognostic parameters were analyzed by Cox proportional hazard modelling. Genitourinary (GU)/gastrointestinal (GI) toxicity evaluation used the Common Toxicity Criteria for Adverse Events (v5.0).
Results
The estimated 10-year bRFS was 82.0% vs. 76.4% (p = 0.075) for EBRT alone versus combined treatment, respectively. The estimated 10-year MFS was 82.9% vs. 87.0% (p = 0.195) and the 10-year OS was 65.7% vs. 68.9% (p = 0.303), respectively. Cumulative 5‑year late GU ≥ grade 2 toxicities were seen in 23.6% vs. 19.2% (p = 0.086) and 5‑year late GI ≥ grade 2 toxicities in 11.1% vs. 5.0% of the patients (p = 0.002); cumulative 5‑year late grade 3 GU toxicity occurred in 4.2% vs. 3.6% (p = 0.401) and GI toxicity in 1.0% vs. 0.3% (p = 0.249), respectively.
Conclusion
Both treatment groups showed excellent long-term outcomes with low rates of severe toxicity.
Simple Summary
Prostate cancer often relapses after initial radical prostatectomy, and salvage radiotherapy offers a second chance of cure for relapsed patients. Modern imaging techniques, especially prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT), enable radiation oncologists to target radiotherapy at the involved sites of disease. In a group of patients, PSMA PET/CT imaging can detect a macroscopic local recurrence with or without locoregional lymph node metastasis. In these cases, an escalation of the radiotherapy dose is often considered for controlling the visible tumor mass. As the evidence for dose-escalated salvage radiotherapy for macroscopic recurrent prostate cancer after PSMA PET/CT imaging is still limited, we address this topic in the current analysis. We found that the outcome of patients with dose-escalated salvage radiotherapy for macroscopic prostate cancer recurrence is encouragingly favorable, while the toxicity is very limited.
Abstract
Background: The purpose of this study was to access the oncological outcome of prostate-specific membrane antigen positron emission tomography (PSMA PET/CT)-guided salvage radiotherapy (SRT) for localized macroscopic prostate cancer recurrence. Methods: Between February 2010 and June 2021, 367 patients received SRT after radical prostatectomy. Out of the 367 screened patients, 111 patients were staged by PSMA PET/CT before SRT. A total of 59 out of these 111 (53.2%) patients were treated for PSMA PET-positive macroscopic prostatic fossa recurrence. Dose-escalated SRT was applied with a simultaneous integrated boost at a median prescribed dose of 69.3 Gy (IQR 69.3–72.6 Gy). The oncological outcome was investigated using Kaplan-Meier and Cox regression analyses. The genitourinary (GU)/gastrointestinal (GI) toxicity evaluation utilized Common Toxicity Criteria for Adverse Events (version 5.0). Results: The median follow-up was 38.2 months. The three-year biochemical progression-free survival rate was 89.1% (95% CI: 81.1–97.8%) and the three-year metastasis-free survival rate reached 96.2% (95% CI: 91.2–100.0%). The cumulative three-year late grade 3 GU toxicity rate was 3.4%. No late grade 3 GI toxicity occurred. Conclusions: Dose-escalated PSMA PET/CT-guided salvage radiotherapy for macroscopic prostatic fossa recurrence resulted in favorable survival and toxicity rates.
Simple Summary
Patients, who suffer from oligorecurrent prostate cancer with limited nodal involvement, may be offered positron emission tomography (PET)-directed salvage nodal radiotherapy to delay disease progression. This current analysis aimed to access salvage radiotherapy for nodal oligorecurrent prostate cancer with simultaneous integrated boost to PET-involved lymph nodes as metastasis-directed therapy. A long-term oncological outcome was favorable after salvage nodal radiotherapy and severe toxicity rates were low. Androgen deprivation therapy plays a major role in recurrent prostate cancer management and demonstrates a positive influence on the rate of biochemical progression in patients receiving salvage nodal radiotherapy. The present long-term analysis may help clinicians identify patients who would benefit from salvage nodal radiotherapy and androgen deprivation therapy, as a multimodal treatment strategy for oligorecurrent prostate cancer.
Abstract
Background: The study aimed to access the long-term outcome of salvage nodal radiotherapy (SNRT) in oligorecurrent prostate cancer. Methods: A total of 95 consecutive patients received SNRT for pelvic and/or extrapelvic nodal recurrence after prostate-specific membrane antigen (PSMA) or choline PET from 2010 to 2021. SNRT was applied as external beam radiotherapy with simultaneous integrated boost up to a median total dose of 62.9 Gy (EQD2\(_{1.5Gy}\)) to the recurrent lymph node metastases. The outcome was analyzed by cumulative incidence functions with death as the competing risk. Fine–Gray regression analyses were performed to estimate the relative hazards of the outcome parameters. Genitourinary (GU)/gastrointestinal (GI) toxicity evaluation utilized Common Toxicity Criteria for Adverse Events (v5.0). The results are as follows: the median follow-up was 47.1 months. The five-year biochemical progression rate (95% CI) was 50.1% (35.7–62.9%). Concomitant androgen deprivation therapy (ADT) was adminstered in 60.0% of the patients. The five-year biochemical progression rate was 75.0% (42.0–90.9%) without ADT versus 35.3% (19.6–51.4%) with ADT (p = 0.003). The cumulative five-year late grade 3 GU toxicity rate was 2.1%. No late grade 3 GI toxicity occured. Conclusions: Metastasis-directed therapy through SNRT for PET-staged oligorecurrent prostate cancer demonstrated a favorable long-term oncologic outcome. Omittance of ADT led to an increased biochemical progression.
Ionic liquids-assisted ring opening of three-membered heterocycles with thio- and seleno-silanes
(2022)
Ring opening reactions of strained heterocycles (epoxides, aziridines, thiiranes) by silyl chalcogenides, such as thiosilanes and selenosilanes, can be efficiently performed in a variety of ionic liquids, which can behave as reaction media and in some cases also as catalysts. This protocol enables an alternative access to β-functionalized sulfides and selenides under mild conditions.
(1) Background: Global incidence of type 1 diabetes (T1D) is rising and nearly half occurred in adults. However, it is unclear if certain early-life childhood T1D risk factors were also associated with adult-onset T1D. This study aimed to assess associations between birth order, delivery mode or daycare attendance and type 1 diabetes (T1D) risk in a population-based cohort and whether these were similar for childhood- and adult-onset T1D (cut-off age 15); (2) Methods: Data were obtained from the German National Cohort (NAKO Gesundheitsstudie) baseline assessment. Self-reported diabetes was classified as T1D if: diagnosis age ≤ 40 years and has been receiving insulin treatment since less than one year after diagnosis. Cox regression was applied for T1D risk analysis; (3) Results: Analyses included 101,411 participants (100 childhood- and 271 adult-onset T1D cases). Compared to “only-children”, HRs for second- or later-born individuals were 0.70 (95% CI = 0.50–0.96) and 0.65 (95% CI = 0.45–0.94), respectively, regardless of parental diabetes, migration background, birth year and perinatal factors. In further analyses, higher birth order reduced T1D risk in children and adults born in recent decades. Caesarean section and daycare attendance showed no clear associations with T1D risk; (4) Conclusions: Birth order should be considered in both children and adults’ T1D risk assessment for early detection.
Patients suffering from coronavirus disease-2019 (COVID-19) are susceptible to deadly secondary fungal infections such as COVID-19-associated pulmonary aspergillosis and COVID-19-associated mucormycosis. Despite this clinical observation, direct experimental evidence for severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2)-driven alterations of antifungal immunity is scarce. Using an ex-vivo whole blood stimulation assay, we challenged blood from twelve COVID-19 patients with Aspergillus fumigatus and Rhizopus arrhizus antigens and studied the expression of activation, maturation, and exhaustion markers, as well as cytokine secretion. Compared to healthy controls, T-helper cells from COVID-19 patients displayed increased expression levels of the exhaustion marker PD-1 and weakened A. fumigatus- and R. arrhizus-induced activation. While baseline secretion of proinflammatory cytokines was massively elevated, whole blood from COVID-19 patients elicited diminished release of T-cellular (e.g., IFN-γ, IL-2) and innate immune cell-derived (e.g., CXCL9, CXCL10) cytokines in response to A. fumigatus and R. arrhizus antigens. Additionally, samples from COVID-19 patients showed deficient granulocyte activation by mold antigens and reduced fungal killing capacity of neutrophils. These features of weakened anti-mold immune responses were largely decoupled from COVID-19 severity, the time elapsed since diagnosis of COVID-19, and recent corticosteroid uptake, suggesting that impaired anti-mold defense is a common denominator of the underlying SARS-CoV-2 infection. Taken together, these results expand our understanding of the immune predisposition to post-viral mold infections and could inform future studies of immunotherapeutic strategies to prevent and treat fungal superinfections in COVID-19 patients.
Risperidone is commonly used to treat different psychiatric disorders worldwide. Knowledge on dose–concentration relationships of risperidone treatment in children and adolescents with schizophrenia or other psychotic disorders is, however, scarce and no age-specific therapeutic ranges have been established yet. Multicenter data of a therapeutic drug monitoring service were analyzed to evaluate the relationship between risperidone dose and serum concentration of the active moiety (risperidone (RIS) plus its main metabolite 9-hydroxyrisperidone (9-OH-RIS)) in children and adolescents with psychotic disorders. Patient characteristics, doses, serum concentrations and therapeutic outcomes were assessed by standardized measures. The study also aimed to evaluate whether the therapeutic reference range for adults (20–60 ng/ml) is applicable for minors. In the 64 patients (aged 11–18 years) included, a positive correlation between daily dose and the active moiety (RIS\(_{am}\)) concentration was found (r\(_s\) = 0.49, p = 0.001) with variation in dose explaining 24% (r\(_s\)\(^2\) = 0.240) of the variability in serum concentrations. While the RIS\(_{am}\) concentration showed no difference, RIS as well 9-OH-RIS concentrations and the parent to metabolite ratio varied significantly in patients with co-medication of a CYP2D6 inhibitor. Patients with extrapyramidal symptoms (EPS) had on average higher RIS\(_{am}\) concentrations than patients without (p = 0.05). Considering EPS, the upper threshold of the therapeutic range of RIS\(_{am}\) was determined to be 33 ng/ml. A rough estimation method also indicated a possibly decreased lower limit of the preliminary therapeutic range in minors compared to adults. These preliminary data may contribute to the definition of a therapeutic window in children and adolescents with schizophrenic disorders treated with risperidone. TDM is recommended in this vulnerable population to prevent concentration-related adverse drug reactions.
A series of five new homoleptic, linear nickel d\(^{9}\)‐complexes of the type [Ni\(^{I}\)(NHC)\(_{2}\)]\(^{+}\) is reported. Starting from the literature known Ni(0) complexes [Ni(Mes\(_{2}\)Im)\(_{2}\)] 1, [Ni(Mes\(_{2}\)Im\(^{H2}\))2] 2, [Ni(Dipp\(_{2}\)Im)\(_{2}\)] 3, [Ni(Dipp\(_{2}\)Im\(^{H2}\))\(_{2}\)] 4 and [Ni(cAAC\(^{Me}\))\(_{2}\)] 5 (Mes\(_{2}\)Im=1,3‐bis(2,4,6‐trimethylphenyl)‐imidazolin‐2‐ylidene, Mes\(_{2}\)Im\(^{H2}\)=1,3‐bis(2,4,6‐trimethylphenyl)‐imidazolidin‐2‐ylidene, Dipp\(_{2}\)Im=1,3‐bis(2,6‐diisopropylphenyl)‐imidazolin‐2‐ylidene, Dipp\(_{2}\)Im\(^{H2}\)=1,3‐bis(2,6‐diisopropylphenyl)‐imidazolidin‐2‐ylidene, cAAC\(^{Me}\)=1‐(2,6‐diisopropylphenyl)‐3,3,5,5‐tetramethylpyrrolidin‐2‐yliden), their oxidized Ni(I) analogues [Ni\(^{I}\)(Mes\(_{2}\)Im)\(_{2}\)][BPh\(_{4}\)] 1\(^{+}\), [Ni\(^{I}\)(Mes\(_{2}\)Im\(^{H2}\))\(_{2}\)][BPh\(_{4}\)] 2\(^{+}\), [Ni\(^{I}\)(Dipp\(_{2}\)Im)\(_{2}\)][BPh\(_{4}\)] 3\(^{+}\), [Ni\(^{I}\)(Dipp\(_{2}\)Im\(^{H2}\))\(_{2}\)][BPh\(_{4}\)] 4\(^{+}\) and [Ni\(^{I}\)(cAAC\(^{Me}\))\(_{2}\)][BPh\(_{4}\)] 5\(^{+}\) were synthesized by one‐electron oxidation with ferrocenium tetraphenyl‐borate. The complexes 1\(^{+}\)–5\(^{+}\) were fully characterized including X‐ray structure analysis. The complex cations reveal linear geometries in the solid state and NMR spectra with extremely broad, paramagnetically shifted resonances. DFT calculations predicted an orbitally degenerate ground state leading to large magnetic anisotropy, which was verified by EPR measurements in solution and on solid samples. The magnetic anisotropy of the complexes is highly dependent from the steric protection of the metal atom, which results in a noticeable decrease of the g‐tensor anisotropy for the N‐Mes substituted complexes 1\(^{+}\) and 2\(^{+}\) in solution due to the formation of T‐shaped THF adducts.
Intracranial hemorrhage results in devastating forms of cerebral damage. Frequently, these results also present with cardiac dysfunction ranging from ECG changes to Takotsubo syndrome (TTS). This suggests that intracranial bleeding due to subarachnoid hemorrhage (SAH) disrupts the neuro–cardiac axis leading to neurogenic stress cardiomyopathy (NSC) of different degrees. Following this notion, SAH and secondary TTS could be directly linked, thus contributing to poor outcomes. We set out to test if blood circulation is the driver of the brain–heart axis by investigating serum samples of TTS patients. We present a novel in vitro model combining SAH and secondary TTS to mimic the effects of blood or serum, respectively, on blood–brain barrier (BBB) integrity using in vitro monolayers of an established murine model. We consistently demonstrated decreased monolayer integrity and confirmed reduced Claudin-5 and Occludin levels by RT-qPCR and Western blot and morphological reorganization of actin filaments in endothelial cells. Both tight junction proteins show a time-dependent reduction. Our findings highlight a faster and more prominent disintegration of BBB in the presence of TTS and support the importance of the bloodstream as a causal link between intracerebral bleeding and cardiac dysfunction. This may represent potential targets for future therapeutic inventions in SAH and TTS.
A first assessment of canopy cover loss in Germany's forests after the 2018–2020 drought years
(2022)
Central Europe was hit by several unusually strong periods of drought and heat between 2018 and 2020. These droughts affected forest ecosystems. Cascading effects with bark beetle infestations in spruce stands were fatal to vast forest areas in Germany. We present the first assessment of canopy cover loss in Germany for the period of January 2018–April 2021. Our approach makes use of dense Sentinel-2 and Landsat-8 time-series data. We computed the disturbance index (DI) from the tasseled cap components brightness, greenness, and wetness. Using quantiles, we generated monthly DI composites and calculated anomalies in a reference period (2017). From the resulting map, we calculated the canopy cover loss statistics for administrative entities. Our results show a canopy cover loss of 501,000 ha for Germany, with large regional differences. The losses were largest in central Germany and reached up to two-thirds of coniferous forest loss in some districts. Our map has high spatial (10 m) and temporal (monthly) resolution and can be updated at any time.
Background
Endovascular revascularization has become the first-line treatment of chronic mesenteric ischemia (CMI). The qualitative visual analysis of digital subtraction angiography (DSA) is dependent on observer experience and prone to interpretation errors. We evaluate the feasibility of 2D-Perfusion Angiography (2D-PA) for objective, quantitative treatment response assessment in CMI.
Methods
49 revascularizations in 39 patients with imaging based evidence of mesenteric vascular occlusive disease and clinical signs of CMI were included in this retrospective study. To assess perfusion changes by 2D-PA, DSA-series were post-processed using a dedicated, commercially available software. Regions of interest (ROI) were placed in the pre- and post-stenotic artery segment. In aorto-ostial disease, the inflow ROI was positioned at the mesenteric artery orifice. The ratios outflow to inflow ROI for peak density (PD), time to peak and area-under-the-curve (AUC) were computed and compared pre- and post-interventionally. We graded motion artifacts by means of a four-point scale. Feasibility of 2D-PA and changes of flow parameters were evaluated.
Results
Motion artifacts due to a mobile vessel location beneath the diaphragm or within the mesenteric root, branch vessel superimposition and inadequate contrast enhancement at the inflow ROI during manually conducted DSA-series via selective catheters owing to steep vessel angulation, necessitated exclusion of 26 measurements from quantitative flow evaluation. The feasibility rate was 47%. In 23 technically feasible assessments, PD\(_{outflow}\)/PD\(_{inflow}\) increased by 65% (p < 0.001) and AUC\(_{outflow}\)/AUC\(_{inflow}\) increased by 85% (p < 0.001). The time to peak density values in the outflow ROI accelerated only minimally without reaching statistical significance. Age, BMI, target vessel (celiac trunk, SMA or IMA), stenosis location (ostial or truncal), calcification severity, plaque composition or the presence of a complex stenosis did not reach statistical significance in their distribution among the feasible and non-feasible group (p > 0.05).
Conclusions
Compared to other vascular territories and indications, the feasibility of 2D-PA in mesenteric revascularization for CMI was limited. Unfavorable anatomic conditions contributed to a high rate of inconclusive 2D-PA results.
Characterization and modification of light-sensitive phosphodiesterases from choanoflagellates
(2022)
Enzyme rhodopsins, including cyclase opsins (Cyclops) and rhodopsin phosphodiesterases (RhoPDEs), were recently discovered in fungi, algae and protists. In contrast to the well-developed light-gated guanylyl/adenylyl cyclases as optogenetic tools, ideal light-regulated phosphodiesterases are still in demand. Here, we investigated and engineered the RhoPDEs from Salpingoeca rosetta, Choanoeca flexa and three other protists. All the RhoPDEs (fused with a cytosolic N-terminal YFP tag) can be expressed in Xenopus oocytes, except the AsRhoPDE that lacks the retinal-binding lysine residue in the last (8th) transmembrane helix. An N296K mutation of YFP::AsRhoPDE enabled its expression in oocytes, but this mutant still has no cGMP hydrolysis activity. Among the RhoPDEs tested, SrRhoPDE, CfRhoPDE1, 4 and MrRhoPDE exhibited light-enhanced cGMP hydrolysis activity. Engineering SrRhoPDE, we obtained two single point mutants, L623F and E657Q, in the C-terminal catalytic domain, which showed ~40 times decreased cGMP hydrolysis activity without affecting the light activation ratio. The molecular characterization and modification will aid in developing ideal light-regulated phosphodiesterase tools in the future.
Gifted underachievers perform worse in school than would be expected based on their high intelligence. Possible causes for underachievement are low motivational dispositions (need for cognition) and metacognitive competences. This study tested the interplay of these variables longitudinally with gifted and non-gifted students from Germany (N = 341, 137 females) in Grades 6 (M = 12.02 years at t1) and 8 (M = 14.07 years). Declarative and procedural metacognitive competences were assessed in the domain of reading comprehension. Path analyses showed incremental effects of procedural metacognition over and above intelligence on the development of school achievement in gifted students (β = .139). Moreover, declarative metacognition and need for cognition interactively predicted procedural metacognition (β = .169), which mediated their effect on school achievement.
Tribenzotriquinacene (TBTQ) is a polycyclic aromatic framework with a particularly rigid, C3v symmetrical, bowl-shaped core bearing three mutually fused indane wings. It has been discussed as a defect center for a nanographene by Kuck and colleagues. Therefore, extended TBTQ structures are promising models for saturated defect structures in graphene and graphene like molecules and could be used to investigate the role of defects for the electronic properties of graphene. With this motivation, three different pi-extended TBTQ derivatives have been synthesized in this work. Several different Scholl reaction conditions were tried to obtain fully annulated product of hexaphenyl substituted TBTQ. The desired benzannulated TBTQ derivative could not be obtained due to unfavourable electron density in the respective positions of the molecule and increased reactivity of the bay position of the precursor. As an another method for benzannulation is the on-surface synthesis of graphene flakes and can be carried out using electron beams e.g. in a tunneling microscope (STM). According to our previous research, the parent system TBTQ and centro-methyl TBTQ on silver and gold surfaces showed that the gas phase deposition of these molecules gives rise to the formation of highly ordered two-dimensional assemblies with unique structural features. This shows the feasibility for the formation of defective graphene networks starting from the parent structures. Therefore, the same deposition technique was used to deposit Me-TBTQ(OAc)3Ph6, and investigate the molecular self-assembly properties directly on the surface of Cu (111). In summary, the substrate temperature dependent self-assembly of Me-TBTQ(OAc)3Ph6 molecules on Cu(111), shows the following evolution of orientations. At room temperature, molecules form dimers, which construct a higher-coverage honeycomb lattice. Furthermore, one of the acetyl group located in the bay positions of the TBTQ core is cleaved and the remaining two induce the metal-molecule interaction. It was presumed that by increasing the temperature to 393 K, the remaining acetyl and methyl groups would beeliminated from the molecular structure.In addition, the smaller TBTQ-Ph6 molecules preferably lie flat on Cu(111) crystal and allowing the molecules to settle into a C3-symmetry and form a dense hexagonal structure.
Eukaryotic cells react to various stress conditions with the rapid formation of membrane-less organelles called stress granules (SGs). SGs form by multivalent interactions between RNAs and RNA-binding proteins and are believed to protect stalled translation initiation complexes from stress-induced degradation. SGs contain hundreds of different mRNAs and proteins, and their assembly and disassembly are tightly controlled by post-translational modifications. The ubiquitin system, which mediates the covalent modification of target proteins with the small protein ubiquitin (‘ubiquitylation’), has been implicated in different aspects of SG metabolism, but specific functions in SG turnover have only recently emerged. Here, we summarize the evidence for the presence of ubiquitylated proteins at SGs, review the functions of different components of the ubiquitin system in SG formation and clearance, and discuss the link between perturbed SG clearance and the pathogenesis of neurodegenerative disorders. We conclude that the ubiquitin system plays an important, medically relevant role in SG biology.
Vibrational spectroscopy can detect characteristic biomolecular signatures and thus has the potential to support diagnostics. Fabry disease (FD) is a lipid disorder disease that leads to accumulations of globotriaosylceramide in different organs, including the heart, which is particularly critical for the patient’s prognosis. Effective treatment options are available if initiated at early disease stages, but many patients are late- or under-diagnosed. Since Coherent anti-Stokes Raman (CARS) imaging has a high sensitivity for lipid/protein shifts, we applied CARS as a diagnostic tool to assess cardiac FD manifestation in an FD mouse model. CARS measurements combined with multivariate data analysis, including image preprocessing followed by image clustering and data-driven modeling, allowed for differentiation between FD and control groups. Indeed, CARS identified shifts of lipid/protein content between the two groups in cardiac tissue visually and by subsequent automated bioinformatic discrimination with a mean sensitivity of 90–96%. Of note, this genotype differentiation was successful at a very early time point during disease development when only kidneys are visibly affected by globotriaosylceramide depositions. Altogether, the sensitivity of CARS combined with multivariate analysis allows reliable diagnostic support of early FD organ manifestation and may thus improve diagnosis, prognosis, and possibly therapeutic monitoring of FD.
This study aimed to discover expert opinion on the surgical techniques and materials most likely to achieve maximum postoperative residual hearing preservation in cochlear implant (CI) surgery and to determine how these opinions have changed since 2010. A previously published questionnaire used in a study published in 2010 was adapted and expanded. The questionnaire was distributed to an international group of experienced CI surgeons. Present results were compared, via descriptive statistics, to those from the 2010 survey. Eighteen surgeons completed the questionnaire. Respondents clearly favored the following: round window insertion, slow array insertion, and the peri- and postoperative use of systematic antibiotics. Insertion depth was regarded as important, and electrode arrays less likely to induce trauma were preferred. The usefulness of dedicated soft-surgery training was also recognized. A lack of agreement was found on whether the middle ear cavity should be flushed with a non-aminoglycoside antibiotic solution or whether a sheath or insertion tube should be used to avoid contaminating the array with blood or bone dust. In conclusion, this paper demonstrates how beliefs about CI soft surgery have changed since 2010 and shows areas of current consensus and disagreement.
In the Spessart, a low mountain range in central Germany, a feud during the Middle Ages led to the construction of numerous castles in this region. This study analyzes the mutual influence of (paleo-)relief development and medieval building activity using a geomorphological and geoarchaeological multimethod approach to expand the knowledge of human-environmental interactions during this time. For this purpose, GIS-based terrain analysis and geophysical measurements were conducted and combined with sedimentological information to create 1D-3D models of the subsurface and to assess knowledge of the landscape and relief evolution at various medieval castle and mining sites. The interpretation of all these data led to the answering of numerous site-specific questions on various geomorphological, geoarchaeological, geologic, and archaeological topics that have been explored in this work and have greatly increased our knowledge of each study site. In addition to these key contributions to the archaeological and geomorphological interpretation of individual study sites, a quantification of the anthropogenic influence on the relief development was conducted, a generalized model of the influence was derived, and new methodological and interpretative approaches were developed. Overall, this study links geomorphological/geological and (geo-)archaeological investigations at five medieval sites and delivers important information on human-environmental interactions within the Spessart and beyond.
Within the Spessart low mountain range in central Germany, numerous castle ruins of the 13th century ce exist. Their construction and destruction were often determined by the struggle for political and economic supremacy in the region and for control over the Spessart's natural resources. Wahlmich Castle is located in a relatively uncommon strategic and geomorphological position, characterized by a fairly remote position and atypical rough relief. In order to reconstruct the local relief development and possible human impact, a multi-method approach was applied combining two-dimensional geoelectrical measurements, geomorphological mapping and stratigraphic-sedimentological investigations. This provides new insights into the influence of landscape characteristics on choices of castle locations.
The combined geoelectrical, geomorphological and stratigraphic-sedimentological data show that the rough relief is of natural origin and influenced by regional faulting, which triggered sliding and slumping as well as weathering and dissection of the surface deposits. The rough relief and the lithology permitted intensive land use and building activities. However, the location of the castle offered access to and possibly control over important medieval traffic routes and also represented certain ownership claims in the Aschaff River valley.
The economic situation combined with rivalry between different elites led to the castle being built in a geomorphological challenging and strategically less valuable location. Focusing on castles located in rare and challenging geomorphological positions may therefore lead to a better understanding of castle siting in the future.
Acute ischemic cardiac injury predisposes one to cognitive impairment, dementia, and depression. Pathophysiologically, recent positron emission tomography data suggest astroglial activation after experimental myocardial infarction (MI). We analyzed peripheral surrogate markers of glial (and neuronal) damage serially within 12 months after the first ST-elevation MI (STEMI). Serum levels of glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) were quantified using ultra-sensitive molecular immunoassays. Sufficient biomaterial was available from 45 STEMI patients (aged 28 to 78 years, median 56 years, 11% female). The median (quartiles) of GFAP was 63.8 (47.0, 89.9) pg/mL and of NfL 10.6 (7.2, 14.8) pg/mL at study entry 0–4 days after STEMI. GFAP after STEMI increased in the first 3 months, with a median change of +7.8 (0.4, 19.4) pg/mL (p = 0.007). It remained elevated without further relevant increases after 6 months (+11.7 (0.6, 23.5) pg/mL; p = 0.015), and 12 months (+10.3 (1.5, 22.7) pg/mL; p = 0.010) compared to the baseline. Larger relative infarction size was associated with a higher increase in GFAP (ρ = 0.41; p = 0.009). In contrast, NfL remained unaltered in the course of one year. Our findings support the idea of central nervous system involvement after MI, with GFAP as a potential peripheral biomarker of chronic glial damage as one pathophysiologic pathway.
Background
Chronic heart failure (HF) is known to increase the risk of developing Alzheimer’s dementia significantly. Thus, detecting and preventing mild cognitive impairment, which is common in patients with HF, is of great importance. Serum biomarkers are increasingly used in neurological disorders for diagnostics, monitoring, and prognostication of disease course. It remains unclear if neuronal biomarkers may help detect cognitive impairment in this high-risk population. Also, the influence of chronic HF and concomitant renal dysfunction on these biomarkers is not well understood.
Methods
Within the monocentric Cognition.Matters-HF study, we quantified the serum levels of phosphorylated tau protein 181 (pTau) and neurofilament light chain (NfL) of 146 extensively phenotyped chronic heart failure patients (aged 32 to 85 years; 15.1% women) using ultrasensitive bead-based single-molecule immunoassays. The clinical work-up included advanced cognitive testing and cerebral magnetic resonance imaging (MRI).
Results
Serum concentrations of NfL ranged from 5.4 to 215.0 pg/ml (median 26.4 pg/ml) and of pTau from 0.51 to 9.22 pg/ml (median 1.57 pg/ml). We detected mild cognitive impairment (i.e., T-score < 40 in at least one cognitive domain) in 60% of heart failure patients. pTau (p = 0.014), but not NfL, was elevated in this group. Both NfL (ρ = − 0.21; p = 0.013) and pTau (ρ = − 0.25; p = 0.002) related to the cognitive domain visual/verbal memory, as well as white matter hyperintensity volume and cerebral and hippocampal atrophy. In multivariable analysis, both biomarkers were independently influenced by age (T = 4.6 for pTau; T = 5.9 for NfL) and glomerular filtration rate (T = − 2.4 for pTau; T = − 3.4 for NfL). Markers of chronic heart failure, left atrial volume index (T = 4.6) and NT-proBNP (T = 2.8), were further cardiological determinants of pTau and NfL, respectively. In addition, pTau was also strongly affected by serum creatine kinase levels (T = 6.5) and ferritin (T = − 3.1).
Conclusions
pTau and NfL serum levels are strongly influenced by age-dependent renal and cardiac dysfunction. These findings point towards the need for longitudinal examinations and consideration of frequent comorbidities when using neuronal serum biomarkers.
Aims
Cognitive dysfunction occurs frequently in patients with heart failure (HF), but early detection remains challenging. Serum glial fibrillary acidic protein (GFAP) is an emerging biomarker of cognitive decline in disorders of primary neurodegeneration such as Alzheimer's disease. We evaluated the utility of serum GFAP as a biomarker for cognitive dysfunction and structural brain damage in patients with stable chronic HF.
Methods and results
Using bead-based single molecule immunoassays, we quantified serum levels of GFAP in patients with HF participating in the prospective Cognition.Matters-HF study. Participants were extensively phenotyped, including cognitive testing of five separate domains and magnetic resonance imaging (MRI) of the brain. Univariable and multivariable models, also accounting for multiple testing, were run. One hundred and forty-six chronic HF patients with a mean age of 63.8 ± 10.8 years were included (15.1% women). Serum GFAP levels (median 246 pg/mL, quartiles 165, 384 pg/mL; range 66 to 1512 pg/mL) did not differ between sexes. In the multivariable adjusted model, independent predictors of GFAP levels were age (T = 5.5; P < 0.001), smoking (T = 3.2; P = 0.002), estimated glomerular filtration rate (T = −4.7; P < 0.001), alanine aminotransferase (T = −2.1; P = 0.036), and the left atrial end-systolic volume index (T = 3.4; P = 0.004). NT-proBNP but not serum GFAP explained global cerebral atrophy beyond ageing. However, serum GFAP levels were associated with the cognitive domain visual/verbal memory (T = −3.0; P = 0.003) along with focal hippocampal atrophy (T = 2.3; P = 0.025).
Conclusions
Serum GFAP levels are affected by age, smoking, and surrogates of the severity of HF. The association of GFAP with memory dysfunction suggests that astroglial pathologies, which evade detection by conventional MRI, may contribute to memory loss beyond ageing in patients with chronic HF.
Cellular stress can induce DNA lesions that threaten the stability of genes. The DNA damage response (DDR) recognises and repairs broken DNA to maintain genome stability. Intriguingly, components of nuclear paraspeckles like the non-POU domain containing octamer-binding protein (NONO) participate in the repair of DNA double-strand breaks (DSBs). NONO is a multifunctional RNA-binding protein (RBP) that facilitates the retention and editing of messenger (m)RNA as well as pre-mRNA processing. However, the role of NONO in the DDR is poorly understood. Here, we establish a novel human U2OS cell line that expresses NONO fused to the engineered ascorbate peroxidase 2 (U2OS:NONO-APEX2-HA). We show that NONO-APEX2-HA accumulates in the nucleolus in response to DNA damage. Combining viability assays, subcellular localisation studies, coimmunoprecipitation experiments and in vivo proximity labeling, we demonstrate that NONO-APEX2-HA is a stably expressed fusion protein that mimics endogenous NONO in terms of expression, localisation and bona fide interactors. We propose that in vivo proximity labeling in U2OS:NONO-APEX2-HA cells is capable for the assessment of NONO interactomes by downstream assays. U2OS:NONO-APEX2-HA cells will likely be a valuable resource for the investigation of NONO interactome dynamics in response to DNA damage and other stimuli.
Adult stem cells in aging
(2022)
Protein kinase D2 drives chylomicron-mediate lipid transport in the intestine and promotes obesity
(2022)
Obesity and associated metabolic syndrome are growing concerns in modern society due to the negative consequences for human health and well-being. Cardiovascular diseases and type 2 diabetes are only some of the pathologies associated to overweight. Among the main causes are decreased physical activity and food availability and composition. Diets with high content of fat are energy-dense and their overconsumption leads to an energy imbalance, which ultimately promotes energy storage as fat and obesity. Aberrant activation of signalling cascades and hormonal imbalances are characteristic of this disease and members of the Protein Kinase D (PKD) family have been found to be involved in several mechanisms mediating metabolic homeostasis. Therefore, we aimed to investigate the role of Protein Kinase D2 (PKD2) in the regulation of metabolism. Our investigation initiated with a mice model for global PKD2 inactivation, which allowed us to prove a direct involvement of this kinase in lipids homeostasis and obesity. Inactivation of PKD2 protected the mice from high-fat diet-induced obesity and improved their response to glucose, insulin and lipids. Furthermore, the results indicated that, even though there were no changes in energy intake or expenditure, inactivation of PKD2 limited the absorption of fat from the intestine and promoted energy excretion in feces. These results were verified in a mice model for specific deletion of intestinal PKD2. These mice not only displayed an improved metabolic fitness but also a healthier gut microbiome profile. In addition, we made use of a small-molecule inhibitor of PKD in order to prove that local inhibition of PKD2 in the intestine was sufficient to inhibit lipid absorption. The usage of the inhibitor not only protected the mice from obesity but also was efficient in avoiding additional body-weight gain after obesity was pre-established in mice. Mechanistically, we determined that PKD2 regulates lipids uptake in enterocytes by phosphorylation of Apolipoprotein A4 (APOA4) and regulation of chylomicron-mediated triglyceride absorption. PKD2 deletion or inactivation increased abundance of APOA4 and decreased the size of chylomicrons and therefore lipids absorption from the diet. Moreover, intestinal activation of PKD2 in human obese patients correlated with higher levels of triglycerides in circulation and a detrimental blood profile. In conclusion, we demonstrated that PKD2 is a key regulator of dietary fat absorption in murine and human context, and its inhibition might contribute to the treatment of obesity.
The covalent modification of target proteins with ubiquitin or ubiquitin-like modifiers is initiated by E1 activating enzymes, which typically transfer a single modifier onto cognate conjugating enzymes. UBA6 is an unusual E1 since it activates two highly distinct modifiers, ubiquitin and FAT10. Here, we report crystal structures of UBA6 in complex with either ATP or FAT10. In the UBA6-FAT10 complex, the C-terminal domain of FAT10 binds to where ubiquitin resides in the UBA1-ubiquitin complex, however, a switch element ensures the alternate recruitment of either modifier. Simultaneously, the N-terminal domain of FAT10 interacts with the 3-helix bundle of UBA6. Site-directed mutagenesis identifies residues permitting the selective activation of either ubiquitin or FAT10. These results pave the way for studies investigating the activation of either modifier by UBA6 in physiological and pathophysiological settings.
Heat and excessive solar radiation can produce abiotic stresses during apple maturation, resulting fruit quality. Therefore, the monitoring of temperature on fruit surface (FST) over the growing period can allow to identify thresholds, above of which several physiological disorders such as sunburn may occur in apple.
The current approaches neglect spatial variation of FST and have reduced repeatability, resulting in unreliable predictions. In this study, LiDAR laser scanning and thermal imaging were employed to detect the temperature on fruit surface by means of 3D point cloud. A process for calibrating the two sensors based on an active board target and producing a 3D thermal point cloud was suggested. After calibration, the sensor system was utilised to scan the fruit trees, while temperature values assigned in the corresponding 3D point cloud were based on the extrinsic calibration. Whereas a fruit detection algorithm was performed to segment the FST from each apple.
• The approach allows the calibration of LiDAR laser scanner with thermal camera in order to produce a 3D thermal point cloud.
• The method can be applied in apple trees for segmenting FST in 3D. Whereas the approach can be utilised to predict several physiological disorders including sunburn on fruit surface.
A balanced and moist wound environment and surface increases the effect of various growth factors, cytokines, and chemokines, stimulating cell growth and wound healing. Considering this fact, we tested in vitro and in vivo water evaporation rates from the cellulose dressing epicite\(^{hydro}\) when combined with different secondary dressings as well as the resulting wound healing efficacy in a porcine donor site model. The aim of this study was to evaluate how the different rates of water evaporation affected wound healing efficacy. To this end, epicite\(^{hydro}\) primary dressing, in combination with different secondary dressing materials (cotton gauze, JELONET\(^◊\), AQUACEL\(^®\) Extra\(^™\), and OPSITE\(^◊\) Flexifix), was placed on 3 × 3 cm-sized dermatome wounds with a depth of 1.2 mm on the flanks of domestic pigs. The healing process was analyzed histologically and quantified by morphometry. High water evaporation rates by using the correct secondary dressing, such as cotton gauze, favored a better re-epithelialization in comparison with the low water evaporation resulting from an occlusive secondary dressing, which favored the formation of a new and intact dermal tissue that nearly fully replaced all the dermis that was removed during wounding. This newly available evidence may be of great benefit to clinical wound management.
Background and purpose
Impaired kidney function is associated with an increased risk of vascular events in acute stroke patients, when assessed by single measurements of estimated glomerular filtration rate (eGFR). It is unknown whether repeated measurements provide additional information for risk prediction.
Methods
The MonDAFIS (Systematic Monitoring for Detection of Atrial Fibrillation in Patients with Acute Ischemic Stroke) study randomly assigned 3465 acute ischemic stroke patients to either standard procedures or an additive Holter electrocardiogram. Baseline eGFR (CKD‐EPI formula) were dichotomized into values of < versus ≥60 ml/min/1.73 m\(^{2}\). eGFR dynamics were classified based on two in‐hospital values as “stable normal” (≥60 ml/min/1.73 m\(^{2}\)), “increasing” (by at least 15% from baseline, second value ≥ 60 ml/min/1.73 m\(^{2}\)), “decreasing” (by at least 15% from baseline of ≥60 ml/min/1.73 m\(^{2}\)), and “stable decreased” (<60 ml/min/1.73 m\(^{2}\)). The composite endpoint (stroke, major bleeding, myocardial infarction, all‐cause death) was assessed after 24 months. We estimated hazard ratios in confounder‐adjusted models.
Results
Estimated glomerular filtration rate at baseline was available in 2947 and a second value in 1623 patients. After adjusting for age, stroke severity, cardiovascular risk factors, and randomization, eGFR < 60 ml/min/1.73 m\(^{2}\) at baseline (hazard ratio [HR] = 2.2, 95% confidence interval [CI] = 1.40–3.54) as well as decreasing (HR = 1.79, 95% CI = 1.07–2.99) and stable decreased eGFR (HR = 1.64, 95% CI = 1.20–2.24) were independently associated with the composite endpoint. In addition, eGFR < 60 ml/min/1.732 at baseline (HR = 3.02, 95% CI = 1.51–6.10) and decreasing eGFR were associated with all‐cause death (HR = 3.12, 95% CI = 1.63–5.98).
Conclusions
In addition to patients with low eGFR levels at baseline, also those with decreasing eGFR have increased risk for vascular events and death; hence, repeated estimates of eGFR might add relevant information to risk prediction.