There is a lack of systematic research exploring cross-species variation in liver lobular geometry and zonation patterns of critical drug-metabolizing enzymes, a knowledge gap essential for translational studies. This study investigated the critical interplay between lobular geometry and key cytochrome P450 (CYP) zonation in four species: mouse, rat, pig, and human. We developed an automated pipeline based on whole slide images (WSI) of hematoxylin-eosin-stained liver sections and immunohistochemistry. This pipeline allows accurate quantification of both lobular geometry and zonation patterns of essential CYP proteins. Our analysis of CYP zonal expression shows that all CYP enzymes (besides CYP2D6 with panlobular expression) were observed in the pericentral region in all species, but with distinct differences. Comparison of normalized gradient intensity shows a high similarity between mice and humans, followed by rats. Specifically, CYP1A2 was expressed throughout the pericentral region in mice and humans, whereas it was restricted to a narrow pericentral rim in rats and showed a panlobular pattern in pigs. Similarly, CYP3A4 is present in the pericentral region, but its extent varies considerably in rats and appears panlobular in pigs. CYP2D6 zonal expression consistently shows a panlobular pattern in all species, although the intensity varies. CYP2E1 zonal expression covered the entire pericentral region with extension into the midzone in all four species, suggesting its potential for further cross-species analysis. Analysis of lobular geometry revealed an increase in lobular size with increasing species size, whereas lobular compactness was similar. Based on our results, zonated CYP expression in mice is most similar to humans. Therefore, mice appear to be the most appropriate species for drug metabolism studies unless larger species are required for other purposes, e.g., surgical reasons. CYP selection should be based on species, with CYP2E1 and CYP2D6 being the most preferable to compare four species. CYP1A2 could be considered as an additional CYP for rodent versus human comparisons, and CYP3A4 for mouse/human comparisons. In conclusion, our image analysis pipeline together with suggestions for species and CYP selection can serve to improve future cross-species and translational drug metabolism studies.
View lessThe objective of this observational study was to evaluate the efficacy of a neck-mounted automated activity monitor (AAM) at detecting early postpartum resumed ovarian cyclicity. A total of 192 lactating cows (primiparous = 73 and multiparous = 119) were enrolled in this study. Cows were continuously monitored by a neck-mounted AAM early postpartum (7 to 30 d in milk; DIM). Calving was classified as assisted (forced extraction of a calf) or unassisted (normal calving). Retained fetal membrane, metritis, hyperketonemia, clinical mastitis, and milk production were recorded. Cows were classified as healthy (i.e., no disease events) or sick (i.e., any disease event). Estrus events were alerted by the AAM using a proprietary algorithm set by the AAM company. Blood samples, from the coccygeal vein, were collected at 15, 18, 21, 24, 28, and 30 DIM for progesterone (P4) analysis. Resumption of cyclicity was considered when P4 concentration was ≥1 ng/mL on any collection day. Cows were considered anovular when P4 concentration was <1 ng/mL on all collection days. Cows were classified as true positive: P4 ≥ 1 ng/mL and at least one estrus alert; false positive: P4 < 1 ng/mL and at least one estrus alert; true negative: P4 < 1 ng/mL and no estrus alerts; and false negative: P4 ≥ 1 ng/mL and no estrus alerts. Statistical analyses were performed by frequency distribution and mixed effects logistic regression procedures on SAS (SAS Institute Inc.). The specificity, sensitivity, accuracy, and positive predictive value of the sensor to detect cows that had resumed cyclicity were 84.0%, 34.1%, 52.1%, and 79.2%, respectively. Out of the 192 cows, 35.9% (69/192) were anovulatory and 37.5% (72/192) had no estrus events between 7 to 30 DIM. Healthy cows were more likely to resume cyclicity in early lactation compared with cows that were sick (78.3 ± 1.9 vs. 32.8 ± 3.1%, respectively) independent of parity. In conclusion, the sensor had a high specificity for detecting anovular cows, but it had lower sensitivity, and thus was not effective at detecting cyclic cows, perhaps due to silent ovulation early postpartum.
View less(1) Background: This retrospective study evaluated perioperative and intensive care unit (ICU) variables to predict colonic ischemia (CI) after infrarenal ruptured abdominal aortic aneurysm (RAAA) surgery. (2) Materials and Methods: We retrospectively analyzed the data of the patients treated for infrarenal RAAA from January 2011 to December 2020 in our hospital. (3) Results: A total of 135 (82% male) patients were admitted to ICU after treatment of infrarenal RAAA. The median age of all patients was 75 years (IQR 68–81 years). Of those, 24 (18%) patients developed CI, including 22 (92%) cases within the first three postoperative days. CI was found more often after open repair compared to endovascular treatment (22% vs. 5%, p = 0.021). Laboratory findings in the first seven PODs revealed statistically significant differences between CI and non-CI patients for serum lactate, minimum pH, serum bicarbonate, and platelet count. Norepinephrine (NE) was used in 92 (68%) patients during ICU stay. The highest daily dose of norepinephrine was administered to CI patients at POD1. Multivariable analysis revealed that NE > 64 µg/kg (RD 0.40, 95% CI: 0.25–0.55, p < 0.001), operating time ≥ 200 min (RD 0.18, 95% CI: 0.05–0.31, p = 0.042), and pH < 7.3 (RD 0.21, 95% CI: 0.07–0.35, p = 0.019), significantly predicted the development of CI. A total of 23 (17%) patients died during the hospital stay, including 8 (33%) patients from the CI group and 15 (7%) from the non-CI group (p = 0.032). (4) Conclusions: CI after RAAA is a sever complication occurring most frequently within the first 3 postoperative days. Our study identified many surrogate markers associated with colonic ischemia after aortic RAAA, including norepinephrine dose > 64 µg/kg, operating time ≥ 200 min, and PH < 7.3. Future studies are needed to support these results.
View lessBackground: The objective of this study was to assess the performance of the first publicly available automated 3D segmentation for spontaneous intracerebral hemorrhage (ICH) based on a 3D neural network before and after retraining. Methods: We performed an independent validation of this model using a multicenter retrospective cohort. Performance metrics were evaluated using the dice score (DSC), sensitivity, and positive predictive values (PPV). We retrained the original model (OM) and assessed the performance via an external validation design. A multivariate linear regression model was used to identify independent variables associated with the model's performance. Agreements in volumetric measurements and segmentation were evaluated using Pearson's correlation coefficients (r) and intraclass correlation coefficients (ICC), respectively. With 1040 patients, the OM had a median DSC, sensitivity, and PPV of 0.84, 0.79, and 0.93, compared to thoseo f 0.83, 0.80, and 0.91 in the retrained model (RM). However, the median DSC for infratentorial ICH was relatively low and improved significantly after retraining, at p < 0.001. ICH volume and location were significantly associated with the DSC, at p < 0.05. The agreement between volumetric measurements (r > 0.90, p > 0.05) and segmentations (ICC & GE; 0.9, p < 0.001) was excellent. Conclusion: The model demonstrated good generalization in an external validation cohort. Location-specific variances improved significantly after retraining. External validation and retraining are important steps to consider before applying deep learning models in new clinical settings.
View lessThe arachidonic acid lipoxygenase 15B (ALOX15B) orthologs of men and mice form different reaction products when arachidonic acid is used as the substrate. Tyr603Asp+His604Val double mutation in mouse arachidonic acid lipoxygenase 15b humanized the product pattern and an inverse mutagenesis strategy murinized the specificity of the human enzyme. As the mechanistic basis for these functional differences, an inverse substrate binding at the active site of the enzymes has been suggested, but experimental proof for this hypothesis is still pending. Here we expressed wildtype mouse and human arachidonic acid lipoxygenase 15B orthologs as well as their humanized and murinized double mutants as recombinant proteins and analyzed the product patterns of these enzymes with different polyenoic fatty acids. In addition, in silico substrate docking studies and molecular dynamics simulation were performed to explore the mechanistic basis for the distinct reaction specificities of the different enzyme variants. Wildtype human arachidonic acid lipoxygenase 15B converted arachidonic acid and eicosapentaenoic acid to their 15-hydroperoxy derivatives but the Asp602Tyr+Val603His exchange murinized the product pattern. The inverse mutagenesis strategy in mouse arachidonic acid lipoxygenase 15b (Tyr603Asp+His604Val exchange) humanized the product pattern with these substrates, but the situation was different with docosahexaenoic acid. Here, Tyr603Asp+His604Val substitution in mouse arachidonic acid lipoxygenase 15b also humanized the specificity but the inverse mutagenesis (Asp602Tyr+Val603His) did not murinize the human enzyme. With linoleic acid Tyr603Asp+His604Val substitution in mouse arachidonic acid lipoxygenase 15b humanized the product pattern but the inverse mutagenesis in human arachidonic acid lipoxygenase 15B induced racemic product formation. Amino acid exchanges at critical positions of human and mouse arachidonic acid lipoxygenase 15B orthologs humanized/murinized the product pattern with C20 fatty acids, but this was not the case with fatty acid substrates of different chain lengths. Asp602Tyr+Val603His exchange murinized the product pattern of human arachidonic acid lipoxygenase 15B with arachidonic acid, eicosapentaenoic acid, and docosahexaenoic acid. An inverse mutagenesis strategy on mouse arachidonic acid lipoxygenase 15b (Tyr603Asp+His604Val exchange) did humanize the reaction products with arachidonic acid and eicosapentaenoic acid, but not with docosahexaenoic acid.
View lessObjectives and Background: Gestational diabetes (GDM) is a common pregnancy complication defined as a glucose intolerance diagnosis during pregnancy. GDM is strongly associated with adverse fetal and maternal outcomes. In Germany, to screen and diagnose GDM we use a 1 h 50 g oGCT (oral glucose challenge test) followed by a 2 h 75 g oGTT if the first was pathological. This analysis examines the correlation of 75 g oGTT glucose levels and fetomaternal outcome. Methods: Data from 1664 patients from a gestational diabetes consultation clinic at the Charité University Hospital in Berlin, Germany, were analyzed retrospectively from 2015 to 2022. The 75 g oGTT blood glucose levels were categorized into isolated fasting hyperglycemia (GDM-IFH), isolated post-load hyperglycemia (GDM-IPH) and combined hyperglycemia (GDM-CH), using the levels of the fasting, 1 h and 2 h values, after glucose application. These subtypes were compared based on their baseline characteristics as well as fetal and maternal outcome. Results: GDM-IFH and GDM-CH women displayed higher pre-conceptional BMI and required insulin therapy more frequently (p < 0.001). The GDM-IFH group was at higher risk of having a primary cesarean section (p = 0.047), while GDM-IPH women were significantly more likely to have an emergent cesarean section (p = 0.013). The offspring of GDM-IFH and GDM-CH women were born with a significantly higher mean birthweight (p < 0.001) and birth weight percentiles (p < 0.001) and were at increased risk of being large for gestational age (LGA) (p = 0.004). Women from the GDM-IPH group delivered significantly more neonates who were small for gestational age (p = 0.027) or with low fetal weight <30th percentile (p = 0.003). Conclusion: This analysis shows a strong association between the glucose response pattern in the 75 g oGTT and adverse perinatal fetomaternal outcome. The differences among the subgroups, specifically concerning insulin therapy, mode of delivery and fetal growth, suggest an individualized approach to prenatal care after a GDM diagnosis.
View lessDieses Workbook unterstützt bei und leitet durch einen Reflexionsprozess über die eigene Hochschullehre mit textgenerativer KI als Reflexionspartner. Das Workbook enthält Anregungen, Hinweise und Mega-Prompts für die Anwendung.
Background: Sex-related discrepancies in the prognosis of oral cancer patients have not been clarified. This study aimed to assess survival outcomes and potential prognostic factors in female and male patients with oral cancer.
Methods: A retrospective search of the TriNetX network (TriNetX, Cambridge, Massachusetts, USA) was conducted to identify patients diagnosed with oral cancer (International Classification of Diseases (ICD)-10 codes C02–C06), within the past 20 years from the access date April 21, 2023. Patients were categorized according to sex (female vs. male). Following matching for age and risk factors such as nicotine dependence and alcohol abuse, Kaplan-Meier analysis was performed and risk, odds, and hazard ratios were calculated. Outcome variables were five-year disease-free survival (DFS) and overall survival (OS). Additionally, the female and male patient cohort were compared with regard to the novel diagnosis of depression (depressive episode, major depressive disorder, dysthymic disorder) after the tumor diagnosis.
Results: A total of 77,348 patients were assessed. After propensity score matching, 26,578 male and 26,578 female patients were included in each group (mean age 63 years). DFS (71.92% in females vs. 68.29% in males; hazard ratio (HR) 0.870; p < 0.001) and OS (77.08% in females vs. 71.74% in males; HR 0.793; p < 0.001) were significantly higher in the female cohort. However, in patients diagnosed with depression after the initial cancer diagnosis (N = 4,824), survival was worse in female patients compared to male patients (82.48% in females vs. 86.10% in males; HR 1.341; p < 0.001).
Conclusion: This retrospective case-control study showed that females with oral cancer had a better DFS and OS than males. However, survival in females with a newly diagnosed depression after the oral cancer diagnosis was worse compared to those of male oral cancer patients. Depression may be a relevant prognostic factor that contributes to sex disparities in oral cancer patients.
View lessBackground: Mycosis fungoides (MF) is an indolent T-cell lymphoma that mainly affects the skin and presents with itch in more than half of the patients. Recently, the expression of Mas-related G protein-coupled receptor X2 (MRGPRX2), a receptor of mast cell (MC) responsible for the IgE-independent non-histaminergic itch, has been shown in lesional skin of patients with pruritic skin diseases, including chronic urticaria, prurigo, and mastocytosis. As of yet, limited knowledge exists regarding the MRGPRX2 expression in the skin of patients with MF.
Objectives: To investigate the number of MRGPRX2-expressing (MRGPRX2+) cells in the skin of patients with MF and its correlation with clinical and laboratory characteristics of the disease.
Methods: MRGPRX2 was analyzed in lesional and non-lesional skin of MF patients and healthy skin tissues by immunohistochemistry. Co-localization of MRGPRX2 with the MC marker tryptase was assessed by immunofluorescence. Public single-cell RNAseq data was reanalyzed to identify the MRGPRX2 expression on the distinct cell types.
Results: In lesional skin of MF patients, MRGPRX2+ cell number was higher than in non-lesional skin and healthy control skin (mean:15.12 vs. 6.84 vs. 5.51 cells/mm2, p=0.04), and correlated with MC numbers (r=0.73, p=0.02). MC was the primary cell type expressing MRGPRX2 in MF patients. The ratio of MRGPRX2+ MCs to MRGPRX2+ cells in lesional and non-lesional skin correlated with the severity of disease (r=0.71, p=0.02 and r=0.67, p=0.03, respectively).
Conclusions: Our findings point to the role of MRGPRX2 and MC in the pathogenesis of MF that should be investigated in further studies.
View lessIntroduction: While numerous studies have identified an increase in symptoms of depression as well as anxiety and distress due to the COVID-19 pandemic, relatively few studies have investigated the new-onset of psychiatric diseases during the pandemic.
Methods: This study focuses on the number of psychiatric new-onset diagnoses in a psychiatric emergency department (pED) in Berlin, Germany during the second wave of the pandemic (i.e. from 09/15/2020 to 03/01/2021 = COVID-19-period) compared to pre-pandemic times (09/15/2019 to 03/01/2020 = control period). We focused on diagnostic subgroups and performed logistic regression analysis to investigate potential risk groups based on covariables such as age, gender, homelessness, attending in police custody and familial relationship.
Results: Overall, there was a 59.7% increase in new-onset psychiatric diagnoses during the COVID-19-period. Increases in the following diagnoses were observed: new-onset of substance-related and addictive disorders (+192.5%), depressive disorders (+115.8%), schizophrenia spectrum and psychotic disorders (+113.3%) and anxiety disorders (+63.6%). These diagnostic subgroups, together with attending in police custody, were found to predict pED presentations with new-onset during the COVID-19-period. Interestingly, in the group of new-onset psychiatric diseases in the COVID-19-period, higher amounts of job loss and living alone as well as a relative decrease in familial relationships were observed.
Discussion: COVID-19 infections and post-COVID-19 syndrome are unlikely to have played a substantial role in the increase of new-onset diseases in this study. Conclusion: Our findings underline the role of indirect factors in new-onset of psychiatric diseases during the pandemic and should be a caveat for future pandemic control policies.
View lessAim: Healthcare professionals are at increased risk of burnout, primarily due to workplace-related stressors. The COVID-19 pandemic has further increased this risk. Different interventions exist with varying degrees of effectiveness; little is reported on the content and implementation of such programs. This review fills this gap, with attention to recent programs using digital components.
Methods: PubMed, Embase, PsycInfo, and Google Scholar were searched between January 24th and 28th, 2022, limited to the last 5 years (≥2017). Articles were included if they (1) focused on stress reduction or burnout prevention for nurses and medical doctors within workplace health promotion for nurses or medical doctors, (2) included a digital program component, (3) were conducted in high-income country contexts, and (4) were clinical studies published in English or German. Data was extracted using a priori designed spreadsheets. A group of at least 2 authors at each stage carried out the screening, selection, and data extraction.
Results: The search strategy identified 153 articles, all except 7 were excluded. Two studies were conducted in the USA, two in Spain, one in the Netherlands, Poland, and Korea each. Four studies used a randomized study design, all but one had a control group. A wide range of outcome measures was used. The types of interventions included an adapted mindfulness-based stress reduction program combined with aspects of behavioral therapies, cognitive behavioral therapy, or acceptance and commitment therapy. The digital components used were apps (4 studies), a digital platform, blended learning, and a web-based intervention (1 study each). Six studies focused on individual interventions, one included organizational interventions.
Conclusion: Despite an acute burnout crisis in the healthcare sector, only seven recent interventions were found that integrated digital components. Several problems emerged during the implementation of the interventions that made it clear that organizational support is urgently needed for successful implementation. Although interventions for stress reduction and burnout prevention should combine individual and organizational measures to be as successful as possible, this was only partially the case in one of the intervention programs. The results of this scoping review can be used to further develop or optimize stress and burnout prevention programs.
View lessIntroduction: In recent decades, various new psychotherapy approaches have been developed in an effort to overcome issues of non-response, referred to as “third-wave psychotherapies.” How third-wave therapies perform in comparison to each other, to classical CBT, or other common comparators in the treatment of depression has not yet been systematically assessed.
Methods: We firstly determined the scope of the term “third-wave” by conducting a systematic search. The identified approaches were then used as search terms for the systematic review and network meta-analysis (NMA). We searched MEDLINE, CENTRAL, PsychINFO and Web of Science from inception until 31 July 2022. We assessed randomized controlled trials comparing third-wave psychotherapies to each other, CBT, treatment as usual (TAU), medication management, active control conditions, or waitlist (WL) in adult populations with depressive disorders. The treatments included were acceptance and commitment therapy, behavioral activation, cognitive behavioral analysis system of psychotherapy, dialectical behavioral therapy, mindfulness-based cognitive therapy, meta-cognitive therapy, positive psychotherapy and schema therapy. The primary outcome was depression severity (efficacy) at study endpoint, and the secondary outcome was all-cause discontinuation (acceptability). This review was registered in PROSPERO, identifier CRD42020147535.
Results: Of 7,971 search results, 55 trials were included in our NMA (5,827 patients). None of the third-wave therapies were more efficacious than CBT but most were superior to TAU [standardized mean differences (SMD) ranging between 0.42 (95% CI −0.37; 1.19) and 1.25 (0.48; 2.04)]. Meta-cognitive therapy (MCT) was more efficacious than three other third-wave therapy approaches. None of the third-wave treatments were more acceptable than WL or CBT. Twenty-seven percent of the trials were rated as low risk of bias. Confidence in the evidence was largely low according to GRADE. Inconsistency emerged for a small number of comparisons.
Interpretations: Third-wave therapies are largely efficacious and acceptable alternatives to CBT when compared to TAU, with few differences between them. The evidence so far does not point toward superiority or inferiority over CBT. Patient-level research may offer possibilities for tailoring individual psychotherapies to the needs of individual patients and future trials should make this data available. The evidence base needs to be broadened by sufficiently powered trials.
View lessBackground: The supplementary motor area (SMA) is important for motor and language function. Damage to the SMA may harm these functions, yet tools for a preoperative assessment of the area are still sparse.
Objective: The aim of this study was to validate a mapping protocol using repetitive navigated transcranial magnetic stimulation (rnTMS) and extend this protocol for both hemispheres and lower extremities.
Methods: To this purpose, the SMA of both hemispheres were mapped based on a finger tapping task for 30 healthy subjects (35.97 ± 15.11, range 21–67 years; 14 females) using rnTMS at 20 Hz (120% resting motor threshold (RMT)) while controlling for primary motor cortex activation. Points with induced errors were marked on the corresponding MRI. Next, on the identified SMA hotspot a bimanual finger tapping task and the Nine-Hole Peg Test (NHPT) were performed. Further, the lower extremity was mapped at 20 Hz (140%RMT) using a toe tapping task.
Results: Mean finger tapping scores decreased significantly during stimulation (25.70taps) compared to baseline (30.48; p < 0.01). Bimanual finger tapping led to a significant increase in taps during stimulation (28.43taps) compared to unimanual tapping (p < 0.01). Compared to baseline, completion time for the NHPT increased significantly during stimulation (baseline: 13.6 s, stimulation: 16.4 s; p < 0.01). No differences between hemispheres were observed.
Conclusion: The current study validated and extended a rnTMS based protocol for the mapping of the SMA regarding motor function of upper and lower extremity. This protocol could be beneficial to better understand functional SMA organisation and improve preoperative planning in patients with SMA lesions.
View lessBackground: For therapy planning in cancer patients multidisciplinary team meetings (MDM) are mandatory. Due to the high number of cases being discussed and significant workload of clinicians, Clinical Decision Support System (CDSS) may improve the clinical workflow.
Methods: This review and meta-analysis aims to provide an overview of the systems utilized and evaluate the correlation between a CDSS and MDM.
Results: A total of 31 studies were identified for final analysis. Analysis of different cancers shows a concordance rate (CR) of 72.7% for stage I-II and 73.4% for III-IV. For breast carcinoma, CR for stage I-II was 72.8% and for III-IV 84.1%, P≤ 0.00001. CR for colorectal carcinoma is 63% for stage I-II and 67% for III-IV, for gastric carcinoma 55% and 45%, and for lung carcinoma 85% and 83% respectively, all P>0.05. Analysis of SCLC and NSCLC yields a CR of 94,3% and 82,7%, P=0.004 and for adenocarcinoma and squamous cell carcinoma in lung cancer a CR of 90% and 86%, P=0.02.
Conclusion: CDSS has already been implemented in clinical practice, and while the findings suggest that its use is feasible for some cancers, further research is needed to fully evaluate its effectiveness.
View lessBackground and Aims: Intestinal epithelial cells separate the luminal flora from lamina propria immune cells and regulate innate immune responses in the gut. An imbalance of the mucosal immune response and disrupted intestinal barrier integrity contribute to the evolution of inflammatory bowel diseases. Interleukin (IL)-37 has broad anti- inflammatory activity and is expressed by the human intestinal epithelium. Mice ectopically expressing human IL-37 show reduced epithelial damage and inflammation after DSS-induced colitis. Here, we investigated the impact of IL-37 on the innate immune response and tight junction protein expression of mouse intestinal organoids and the modulation of IL37 expression in human intestinal organoids.
Methods: Murine intestinal organoids were generated from IL-37tg and wildtype mice. Human ileal organoids were generated from healthy young donors.
Results: Expression of transgene IL-37 or recombinant IL-37 protein did not significantly reduce overall proinflammatory cytokine mRNA expression in murine intestinal organoids. However, higher IL37 expression correlated with a reduced proinflammatory cytokine response in murine colonic organoids. IL37 mRNA expression in human ileal organoids was modulated by proinflammatory cytokines showing an increased expression upon TNF-α-stimulation and decreased expression upon IFN-gamma stimulation. Transgene IL-37 expression did not rescue TNF-α-induced changes in morphology as well as ZO-1, occludin, claudin-2, and E-cadherin expression patterns of murine jejunal organoids.
Conclusions: We speculate that the anti-inflammatory activity of IL-37 in the intestine is mainly mediated by lamina propria immune cells protecting intestinal epithelial integrity.
View lessStress drop is an earthquake property indicative for the characteristic relation of slip to fault dimension. It is furthermore affected by fault strength, fault topography, the presence of fluids, rupture size, slip, and velocity. In this article, the stress drop image of an entire subduction zone, namely for the seismically highly active northernmost part of Chile, is combined with mapped b-values and their corresponding magnitude distribution in order to better constrain the conditions under which earthquakes of different provenances may nucleate. The underlying recent earthquake catalog contains over 180,000 events, covering 15 years of seismicity, from which more than 50,000 stress drop estimates were computed. Their spatial average segments the subduction zone into different parts, i.e., average stress drop between seismotectonic areas is different, although this difference is small compared to the natural scatter of stress drop values. By considering stress drop variations, b-value map, magnitude distribution, and thermal models, candidate earthquake nucleation mechanisms are identified which can explain the observed distributions. This is done for two exemplary regions: (1) The plate interface, where principally lower stress drop events are found, while at the same time a high spatial heterogeneity of stress drop values is observed. This indicates relatively smooth or lubricated rupture surfaces, and locally it suggests the existence of alternating regions controlled by strong asperities, weaker material, or creep. (2) The highly active intermediate depth (ID) seismicity region, where the variation of stress drop and b-value point to a gradual change of nucleation mechanism from dehydration embrittlement at the top of the ID cloud, over dehydration driven stress transfer in its central part, to thermal runaway shear mechanisms at its bottom. In both cases, the combination of stress drop and b-value distribution helps to better understand the origin and the differences of the observed seismicity.
View lessProtein-ligand docking is an established tool in drug discovery and development to narrow down potential therapeutics for experimental testing. However, a high-quality protein structure is required and often the protein is treated as fully or partially rigid. Here we develop an AI system that can predict the fully flexible all-atom structure of protein-ligand complexes directly from sequence information. We find that classical docking methods are still superior, but depend upon having crystal structures of the target protein. In addition to predicting flexible all-atom structures, predicted confidence metrics (plDDT) can be used to select accurate predictions as well as to distinguish between strong and weak binders. The advances presented here suggest that the goal of AI-based drug discovery is one step closer, but there is still a way to go to grasp the complexity of protein-ligand interactions fully. Umol is available at: https://github.com/patrickbryant1/Umol.
View lessThe initiation of ductile shear zones commonly occurs spatially associated with fluid-rock reactions along brittle precursors. In many cases the relative timing of fracturing, fluid infiltration, reaction, and recrystallisation is unclear, making it difficult to disentangle mechanisms of shear zone initiation from subsequent deformation and recrystallisation. Here we present the study of the transition from a dry plagioclase-diopside-garnet-scapolite host granulite-facies lithology to (1) a low strain amphibolite-facies rock, and (2) a transition from low strain to high strain amphibolite-facies lithologies. Hydration of the granulite-facies precursor at amphibolite-facies conditions produces an assemblage comprised dominantly of plagioclase-amphibole-zoisite-clinozoisite-kyanite-scapolite-quartz. Detailed study of plagioclase chemistry and microstructures across these two transitions using Electron Backscatter Diffraction (EBSD) and Wavelength Dispersive Spectrometry (WDS) allows us to assess the degree of coupling between deformation and fluid-rock reaction across the outcrop. Plagioclase behaves dominantly in a brittle manner at the hydration interface and so the initial weakening of the rock is attributed to grain size reduction caused by fracture damage and fluid infiltration at amphibolite-facies conditions. Extensive fracturing-induced grain size reduction locally increases permeability and allows for continuing plagioclase and secondary mineral growth during shear. Based on plagioclase microstructures, such as, an inherited but dispersed crystallographic preferred orientation (CPO), truncation of chemical zoning, and the dominance of fine (5–150 µm), slightly elongate, polygonal grains we conclude that deformation is dominantly facilitated by dissolution–precipitation creep assisted by grain boundary sliding in the shear zone.
View lessDesigning materials capable of disinfecting water without releasing harmful by-products is an ongoing challenge. Here, we report a novel polycationic sponge material synthesized from chitosan derivatives and cellulose fibers, exhibiting antibacterial properties. The design of such material is based on three key principles. First, the formation of a highly porous structure through cryogelation for an extensive surface area. Second, the incorporation of cationic quaternary ammonium moieties onto chitosan to enhance bacterial adsorption and antibacterial activity. Lastly, the reinforcement of mechanical properties through integration of cellulose fibers. The presented sponge materials exhibit up to a 4-log (99.99%) reduction within 6 h against both gram-positive B. subtilis and gram-negative E. coli. Notably, QCHI90/Cell, with the highest surface charge, exhibits a 2–4.5 log reduction within 1 h of incubation time. The eco-friendly synthesis from water and readily available biomaterials, along with cost-effectiveness and simplicity, underscores its versatility and feasibility of upscaling. Together with its outstanding antibacterial activity, this macroporous biomaterial emerges as a promising candidate for water disinfection applications.
View lessBackground
Significant variations exist in the forms of ZnO, making it impossible to test all forms in in vivo inhalation studies. Hence, grouping and read-across is a common approach under REACH to evaluate the toxicological profile of familiar substances. The objective of this paper is to investigate the potential role of dissolution, size, or coating in grouping ZnO (nano)forms for the purpose of hazard assessment. We performed a 90-day inhalation study (OECD test guideline no. (TG) 413) in rats combined with a reproduction/developmental (neuro)toxicity screening test (TG 421/424/426) with coated and uncoated ZnO nanoforms in comparison with microscale ZnO particles and soluble zinc sulfate. In addition, genotoxicity in the nasal cavity, lungs, liver, and bone marrow was examined via comet assay (TG 489) after 14-day inhalation exposure.
Results
ZnO nanoparticles caused local toxicity in the respiratory tract. Systemic effects that were not related to the local irritation were not observed. There was no indication of impaired fertility, developmental toxicity, or developmental neurotoxicity. No indication for genotoxicity of any of the test substances was observed. Local effects were similar across the different ZnO test substances and were reversible after the end of the exposure.
Conclusion
With exception of local toxicity, this study could not confirm the occasional findings in some of the previous studies regarding the above-mentioned toxicological endpoints. The two representative ZnO nanoforms and the microscale particles showed similar local effects. The ZnO nanoforms most likely exhibit their effects by zinc ions as no particles could be detected after the end of the exposure, and exposure to rapidly soluble zinc sulfate had similar effects. Obviously, material differences between the ZnO particles do not substantially alter their toxicokinetics and toxicodynamics. The grouping of ZnO nanoforms into a set of similar nanoforms is justified by these observations.
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