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ObjectivePatients with alcohol-associated hepatitis (AH) have a high mortality. Alcohol exacerbates liver damage by inducing gut dysbiosis, bacterial translocation and inflammation, which is characterised by increased numbers of circulating and hepatic neutrophils.DesignIn this study, we performed tandem mass tag (TMT) proteomics to analyse proteins in the faeces of controls (n=19), patients with alcohol-use disorder (AUD; n=20) and AH (n=80) from a multicentre cohort (InTeam). To identify protein groups that are disproportionately represented, we conducted over-representation analysis using Reactome pathway analysis and Gene Ontology to determine the proteins with the most significant impact. A faecal biomarker and its prognostic effect were validated by ELISA in faecal samples from patients with AH (n=70), who were recruited in a second and independent multicentre cohort (AlcHepNet).ResultFaecal proteomic profiles were overall significantly different between controls, patients with AUD and AH (principal component analysis p=0.001, dissimilarity index calculated by the method of Bray-Curtis). Proteins that showed notable differences across all three groups and displayed a progressive increase in accordance with the severity of alcohol-associated liver disease were predominantly those located in neutrophil granules. Over-representation and Reactome analyses confirmed that differentially regulated proteins are part of granules in neutrophils and the neutrophil degranulation pathway. Myeloperoxidase (MPO), the marker protein of neutrophil granules, correlates with disease severity and predicts 60-day mortality. Using an independent validation cohort, we confirmed that faecal MPO levels can predict short-term survival at 60 days.ConclusionsWe found an increased abundance of faecal proteins linked to neutrophil degranulation in patients with AH, which is predictive of short-term survival and could serve as a prognostic non-invasive marker.

Drive systems are an important part of general mechanical engineering, automotive engineering, and various other fields, with shaft–hub connections being an important part of such systems. Decisive aspects in the development of such systems today are, for example, high transmittable forces and torques, low masses, and the cheapest possible production of components. A possibly threefold increase in the force and torque transmission capacity can be achieved by using press–fit connections with an elastic–plastic design as opposed to regular elastically designed alternatives. An elastic–plastic design of the press–fit connection is achieved by using a large interference. A large transition geometry on the shaft (which replaces the conventional chamfer) is required to join such an interference. The material and space requirements have a negative impact on lightweight applications and limited building spaces. Therefore, the objective of the research presented in this paper is to design and analyze a detachable joining device that substitutes this geometry. A simulation study was conducted to determine the geometry of the joining device that improves the stress state and consequently the force and torque transmission capacity of the connection. Moreover, the influence of manufacturing tolerances of the joining device and the shaft, corresponding risks, and measures to mitigate them are analyzed using finite element analysis. The results show that large transition radii, enabled by using a joining device, lead to a homogenous distribution of plastic strain and pressure in the press–fit connection, even for large interferences ξ and soft hub materials like wrought aluminum alloys. The influence of manufacturing tolerances on the stress state was quantified, leading to design guidelines that minimize the risk of, e.g., the front face collision of a shaft and hub, while maximizing the power transmission of the connection. The results show the capability of a detachable joining device to enable elastic–plastic press–fit connections and the corresponding threefold increase in the force and torque transmission capacity in lightweight applications, resulting from the substitution of the installation space consuming and mass increasing the transition geometry of the shaft.

Objective: p63 is a transcription factor involved in multiple biological functions. In the liver, the TAp63 isoform induces lipid accumulation in hepatocytes. However, the role of liver TAp63 in the progression of metabolic dysfunction-associated steatohepatitis (MASH) with fibrosis is unknown. Methods: We evaluated the hepatic p63 levels in different mouse models of steatohepatitis with fibrosis induced by diet. Next, we used virogenetic approaches to manipulate the expression of TAp63 in adult mice under diet-induced steatohepatitis with fibrosis and characterized the disease condition. Finally, we performed proteomics analysis in mice with overexpression and knockdown of hepatic TAp63. Results: Levels of TAp63, but not of ΔN isoform, are increased in the liver of mice with diet-induced steatohepatitis with fibrosis. Both preventive and interventional strategies for the knockdown of hepatic TAp63 significantly ameliorated diet-induced steatohepatitis with fibrosis in mice fed a methionine- and choline-deficient diet (MCDD) and choline deficient and high fat diet (CDHFD). The overexpression of hepatic TAp63 in mice aggravated the liver condition in mice fed a CDHFD. Proteomic analysis in the liver of these mice revealed alteration in multiple proteins and pathways, such as oxidative phosphorylation, antioxidant activity, peroxisome function and LDL clearance. Conclusions: These results indicate that liver TAp63 plays a critical role in the progression of diet-induced steatohepatitis with fibrosis, and its inhibition ameliorates the disease.

Abstract Background Clostridium sticklandii belongs to a cluster of non-pathogenic proteolytic clostridia which utilize amino acids as carbon and energy sources. Isolated by T.C. Stadtman in 1954, it has been generally regarded as a "gold mine" for novel biochemical reactions and is used as a model organism for studying metabolic aspects such as the Stickland reaction, coenzyme-B12- and selenium-dependent reactions of amino acids. With the goal of revisiting its carbon, nitrogen, and energy metabolism, and comparing studies with other clostridia, its genome has been sequenced and analyzed. Results C. sticklandii is one of the best biochemically studied proteolytic clostridial species. Useful additional information has been obtained from the sequencing and annotation of its genome, which is presented in this paper. Besides, experimental procedures reveal that C. sticklandii degrades amino acids in a preferential and sequential way. The organism prefers threonine, arginine, serine, cysteine, proline, and glycine, whereas glutamate, aspartate and alanine are excreted. Energy conservation is primarily obtained by substrate-level phosphorylation in fermentative pathways. The reactions catalyzed by different ferredoxin oxidoreductases and the exergonic NADH-dependent reduction of crotonyl-CoA point to a possible chemiosmotic energy conservation via the Rnf complex. C. sticklandii possesses both the F-type and V-type ATPases. The discovery of an as yet unrecognized selenoprotein in the D-proline reductase operon suggests a more detailed mechanism for NADH-dependent D-proline reduction. A rather unusual metabolic feature is the presence of genes for all the enzymes involved in two different CO2-fixation pathways: C. sticklandii harbours both the glycine synthase/glycine reductase and the Wood-Ljungdahl pathways. This unusual pathway combination has retrospectively been observed in only four other sequenced microorganisms. Conclusions Analysis of the C. sticklandii genome and additional experimental procedures have improved our understanding of anaerobic amino acid degradation. Several specific metabolic features have been detected, some of which are very unusual for anaerobic fermenting bacteria. Comparative genomics has provided the opportunity to study the lifestyle of pathogenic and non-pathogenic clostridial species as well as to elucidate the difference in metabolic features between clostridia and other anaerobes.

BackgroundDespite the putatively targetable genomic landscape of high-grade gliomas, the long-term survival benefit of genomically-tailored targeted therapies remains discouraging.MethodsUsing glioblastoma (GBM) as a representative example of high-grade gliomas, we evaluated the clonal architecture and distribution of hotspot mutations in 388 GBMs from the Cancer Genome Atlas (TCGA). Mutations were matched with 54 targeted therapies, followed by a comprehensive evaluation of drug biochemical properties in reference to the drug’s clinical efficacy in high-grade gliomas. We then assessed clinical outcomes of a cohort of patients with high-grade gliomas with targetable mutations reviewed at the Johns Hopkins Molecular Tumor Board (JH MTB; n = 50).ResultsAmong 1,156 sequence alterations evaluated, 28.6% represented hotspots. While the frequency of hotspot mutations in GBM was comparable to cancer types with actionable hotspot alterations, GBMs harbored a higher fraction of subclonal mutations that affected hotspots (7.0%), compared to breast cancer (4.9%), lung cancer (4.4%), and melanoma (1.4%). In investigating the biochemical features of targeted therapies paired with recurring alterations, we identified a trend toward higher lipid solubility and lower IC50 in GBM cell lines among drugs with clinical efficacy. The drugs’ half-life, molecular weight, surface area and binding to efflux transporters were not associated with clinical efficacy. Among the JH MTB cohort of patients with IDH1 wild-type high-grade gliomas who received targeted therapies, trametinib monotherapy or in combination with dabrafenib conferred radiographic partial response in 75% of patients harboring BRAF or NF1 actionable mutations. Cabozantinib conferred radiographic partial response in two patients harboring a MET and a PDGFRA/KDR amplification. Patients with IDH1 wild-type gliomas that harbored actionable alterations who received genotype-matched targeted therapy had longer progression-free (PFS) and overall survival (OS; 7.37 and 14.72 respectively) than patients whose actionable alterations were not targeted (2.83 and 4.2 months respectively).ConclusionWhile multiple host, tumor and drug-related features may limit the delivery and efficacy of targeted therapies for patients with high-grade gliomas, genotype-matched targeted therapies confer favorable clinical outcomes. Further studies are needed to generate more data on the impact of biochemical features of targeted therapies on their clinical efficacy for high-grade gliomas.

Previous work has shown that floor slabs make up most of the material mass of building structures and are typically made of reinforced concrete. Considering the associated resource consumption and greenhouse gas emissions, new approaches are needed in order to reduce the built environment’s impact on the ongoing climate crisis. Various studies have demonstrated that adaptive building structures offer a potential solution for reducing material resource consumption and associated emissions. Adaptive structures have the ability to improve load-bearing performance by specifically reacting to external loads. This work applies the concept of adaptive structures to reinforced concrete slabs through the integration of fluidic actuators into the cross-section. The optimal integration of actuators in reinforced concrete slabs is a challenging interdisciplinary design problem that involves many parameters. In this work, actuation influence matrices are extended to slabs and used as an analysis and evaluation tool for deriving actuation concepts for adaptive slabs with integrated fluidic actuators. To define requirements for the actuator concept, a new procedure for the selection of actuation modes, actuator placement and the computation of actuation forces is developed. This method can also be employed to compute the required number of active elements for a given load case. The new method is highlighted in a case study of a 2 m × 2 m floor.

A high proportion of the CO2 emissions worldwide are caused by the construction sector or are associated with buildings. Every part of the industry needs to reduce its share of emissions, so the building sector must also do its part. One possible solution for achieving this reduction in the field of load-bearing structures is the use of adaptive structures. This research focuses on adaptive slab structures, which require specific actuators to be integrated into the system. Conventional actuators are not suitable due to the prevailing requirements, namely installation space and performance. For this investigation, the actuator is divided into different functional components. A rough description of the requirements for one component, namely the energy converter, is given. Different concepts are developed, tested, and compared with numerical results. Due to the requirements, the concepts are limited to hydraulics. The authors then present a comparison of different simulation strategies for the energy converter. Overall, this paper provides a new contribution to the design of energy converter concepts for integrated hydraulic actuators in slabs, along with experimental verification of the working principle of the energy converters to meet the requirements. A simplified numerical model is proposed to estimate the behavior of the energy converter during the early design phase.

Today, there are a number of analytical and numerical calculation methods for the elastic-plastic design of press-fit connections. However, these are largely constrained by their restriction to elastic-ideal-plastic material behavior. In addition, recommendations for limiting the plasticized hub cross section that have been provided to date do not exploit the full potential of the materials, with the result that opportunities for lightweight design and improved transmission capacity have remained unused so far. Yet, no experimental validations exist to this end, which is why the existing design method could not be validated until today. In addition, there is still a lack of research on how to evaluate the potential for increasing the force and torque transmission under consideration of the strain hardening of the material during plastic deformation. The lack of knowledge today prevents a targeted design and thereby the industrial application of this type of connection; the transmission capacity and lightweight design potentials have thus remained unused until now (Kröger and Binz, 2020). This article presents the actual design and joining limits of hubs made of EN AW-5083 (AlMg4,5Mn), which were determined as part of an Industrial Collective Research (IGF) project. This allows the hub materials to be better utilized, which leads to a reduction in mass and/or an increase in the force and torque transmission. In addition, the experimental validation of the numerical investigations helps to establish the design method in industrial practice.

Drive systems are an important part of general mechanical engineering, automotive engineering, and various other fields, with shaft–hub connections being an important part of such systems. Decisive aspects in the development of such systems today are, for example, high transmittable forces and torques, low masses, and the cheapest possible production of components. A possibly threefold increase in the force and torque transmission capacity can be achieved by using press–fit connections with an elastic–plastic design as opposed to regular elastically designed alternatives. An elastic–plastic design of the press–fit connection is achieved by using a large interference. A large transition geometry on the shaft (which replaces the conventional chamfer) is required to join such an interference. The material and space requirements have a negative impact on lightweight applications and limited building spaces. Therefore, the objective of the research presented in this paper is to design and analyze a detachable joining device that substitutes this geometry. A simulation study was conducted to determine the geometry of the joining device that improves the stress state and consequently the force and torque transmission capacity of the connection. Moreover, the influence of manufacturing tolerances of the joining device and the shaft, corresponding risks, and measures to mitigate them are analyzed using finite element analysis. The results show that large transition radii, enabled by using a joining device, lead to a homogenous distribution of plastic strain and pressure in the press–fit connection, even for large interferences ξ and soft hub materials like wrought aluminum alloys. The influence of manufacturing tolerances on the stress state was quantified, leading to design guidelines that minimize the risk of, e.g., the front face collision of a shaft and hub, while maximizing the power transmission of the connection. The results show the capability of a detachable joining device to enable elastic–plastic press–fit connections and the corresponding threefold increase in the force and torque transmission capacity in lightweight applications, resulting from the substitution of the installation space consuming and mass increasing the transition geometry of the shaft. [ABSTRACT FROM AUTHOR]

The US Food and Drug Administration (FDA) receives millions of postmarket adverse event reports for drug and therapeutic biologic products every year. One of the most salient issues with these submissions is report duplication, where an adverse event experienced by one patient is reported multiple times to the FDA. Duplication has important negative implications for data analysis. We improved and optimized an existing deduplication algorithm that used both structured and free-text data, developed a web-based application to support data processing, and conducted a 6-month dedicated evaluation to assess the potential operationalization of the deduplication process in the FDA. Comparing algorithm predictions with reviewer determinations of duplicates for twenty-seven files for case series reviews (with a median size of 281 reports), the average pairwise recall and precision were equal to 0.71 (SD ± 0.32) and 0.67 (SD ± 0.34). Overall, reviewers felt confident about the algorithm and expressed their interest in using it. These findings support the operationalization of the deduplication process for case series review as a supplement to human review.

Ukraine is a country that has lacked access to adequately trained mental health professionals. As in other countries the development of the field of Counseling in Ukraine has some parallels to that of the US. One of the most notable parallels is the push for a better and more effective approach to mental health, driven by the impact of war, with WWII being the catalyst for refinement in the US and current war in Ukraine as the drive there. As the American Psychology Association and American Counseling Association have highlighted, the effects of trauma and unresolved problems do not need to last a lifetime. A developing initiative in Ukraine was brought by U.S.-based teams that established a postgraduate Counselor Education Program. Professional American Counselor Educators, trained in the trenches of wars abroad and representing vast ranges of experience, have volunteered their time as visiting faculty and distance supervisors. This study measures the initial progression of treatment symptomology of clients seen by Postgraduate Program in Psychological Counseling and Trauma Therapy trained Counselors. This study utilized an analysis of repeated measures over the first five sessions of counseling with the program-trained Counselor. The following measurement methods were utilized: Outcome Rating Scale (ORS), Impact Event Scale (IES-R), Beck Depression Inventory (BDI II), PTSD Checklist (PCL-5), Symptom Checklist (SCL-9). The resulting data obtained from the clients was compared to the outcomes of treatment with similarly trained therapists in the United States, United Kingdom, Australia and Denmark. Results indicated overall significance as measured on 3 out of 5 instruments (ORS, BDI-II, IES-R). The data from this sample revealed similarities to the outcomes of comparable early treatment research, conducted outside of Ukraine. These results provide a preliminary overview of how effective mental health counselors (educated by the American standards) are in mitigating client mental health symptomology. This study is a logical and necessary step in the continued development of the field of Counseling in Ukraine.

Compared to conventional façades, adaptive façades (AFs) can adjust their properties in response to environmental changes and user requirements. Often performed through the integration of actuators, sensors, and control units, this provides benefits such as reduced energy consumption in buildings but also increases the complexity of the façade design. To efficiently deal with the higher complexity, this article aims to provide suitable decision support for the early design phase, identify suitable design goals, and compare these to previously implemented Afs (make-or-buy decision). There is particular focus on the AF-specific characteristics, as these are new compared to well-known conventional façades. To systematically develop decision support, requirements are identified in expert interviews and the literature, and the current state of the art is evaluated against these. Research gaps found in current methods are addressed in this article, and continuous decision support is developed for the early design phase of an integrated design process. This support includes a checklist with AF-specific characteristics and a digitally implemented database of AFs. Based on the requirements, an evaluation is performed for both methods: this includes the comparison of the results to three ongoing AF projects and the assignment of 40 case studies to the database.