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During the COVID-19 pandemic, many survey programs switched to self-administered modes of data collection, often offering respondents both web-based and paper-based questionnaires. However, there is little guidance as to when to offer which mode, especially when the aim is to recruit participants for a panel survey. This study examines the effectiveness of different mode-sequence designs by analyzing an experiment implemented in the recruitment wave of the German panel study “Family Research and Demographic Analysis.” We randomly assigned 108,256 individuals aged 18–49 years to one of three mode-sequence-design conditions: concurrent, web-first including a paper-based questionnaire with the second reminder (web-first-2), and web-first including a paper-based questionnaire with the third reminder (web-first-3). A fourth, simulated group did not receive a paper-based questionnaire (web-only). We analyzed how different mode-sequence designs affected outcome rates, sample composition, response distributions, data quality, share of paper-based questionnaires, postage costs, number of postal mailings in the recruitment wave, and participation in the first regular wave. Our results show no differences in response distributions and small differences in sample composition across the four mode-sequence designs. As the web-first-2 and simulated web-only designs yielded comparatively good response and recruitment rates at reasonable costs, we recommend their use when surveying adults between 18 and 49 years old.

Due to their high availability and low cost level, passive protection measures are a key factor for reducing the vulnerability of persons within and close to assets against potentially impacting mortar, rocket and artillery threats. Particularly, mortar shelling has even most recently been reported. At risk are permanent and nonpermanent assets of civil, (non)governmental or peacekeeping organizations with corresponding effects, e.g., on civil society, civil services or successful nation building, respectively. Of interest are the identification of vulnerable areas and the assessment of the effectiveness of protective structures while taking also other counter measures into account. To this end, a seven-step quantitative risk and resilience analysis and management methodology is described and applied. It consists of the analysis of scenarios, frequencies, hazards, damage effects and risks and yields individual and collective risks for multi-threat scenarios. Local individual or collective risks can be minimized below criteria, thus reducing vulnerability and increasing resilience in an efficient way, e.g., by using geometrical changes, by structural roof, wall and window retrofits, by mitigating barriers and/or organizational measures. The approach is demonstrated along with three detailed example cases.

Die Behandlung der therapierefraktären atopischen Dermatitis stellt Dermatologen vor große Herausforderungen. Wenn topische Steroidtherapien, UVB Schmalband (UVB-NB) und Immunsuppressiva ausgeschöpft sind, steht nun mit Dupilumab, einem monoklonalen Antikörper gegen Interleukin 4 und Interleukin 23 (IL4/IL13) ein neuer Therapieansatz zur Verfügung. Nach initialer Berechnung von EASI (Eczema Area and Severity Index) und Pruritis NRS (Numeric Rating Scale) werden zunächst als Startdosis 2 × 300 mg s.c. verabreicht, danach 300 mg s.c. in 2‑wöchigem Abstand. In den folgenden vier Fallstudien soll über erste Erfolge im klinischen Alltag berichtet werden.

Followed by the 9/11 attacks in 2001 and the subsequent events, terrorism and other asymmetrical threat situations became increasingly important for security-related efforts of most western societies. In a similar period, the development of data gathering and analysis techniques especially using the methods of machine learning has made rapid progress. Aiming to utilize this development, this paper employs artificial neural networks for long-term time series prediction of terrorist event data. A major focus of the paper lies on the specific use of convolutional neural networks (CNNs) for this task, as well as the comparison to the performance of classical methods for (long-term) time series prediction. As the databases like Global Terrorism Database and Fraunhofer’s terrorist event database are not extensive enough to train a deep learning method, a simple toy model for the generation of time series data from one or more terrorist groups with defined properties is established. Metrics for comparison of the different approaches are collected and discussed, and a customized sliding-window metric is introduced. The study shows the principle applicability of CNNs for this task and offers constraints as well as possible extensions for future studies. Based on these results, continuation and further extension of data collection efforts and ML optimization techniques are encouraged.

Cell–cell adhesion is at the center of structure and dynamics of epithelial tissue. E-cadherin–catenin complexes mediate Ca2+-dependent trans-homodimerization and constitute the kernel of adherens junctions. Beyond the basic function of cell–cell adhesion, recent progress sheds light the dynamics and interwind interactions of individual E-cadherin–catenin complex with E-cadherin superclusters, contractile actomyosin and mechanics of the cortex and adhesion. The nanoscale architecture of E-cadherin complexes together with cis-interactions and interactions with cortical actomyosin adjust to junctional tension and mechano-transduction by reinforcement or weakening of specific features of the interactions. Although post-translational modifications such as phosphorylation and glycosylation have been implicated, their role for specific aspects of in E-cadherin function has remained unclear. Here, we provide an overview of the E-cadherin complex in epithelial cell and tissue morphogenesis focusing on nanoscale architectures by super-resolution approaches and post-translational modifications from recent, in particular in vivo, studies. Furthermore, we review the computational modelling in E-cadherin complexes and highlight how computational modelling has contributed to a deeper understanding of the E-cadherin complexes.

Remission of type 2 diabetes can occur as a result of weight loss and is characterised by liver fat and pancreas fat reduction and recovered insulin secretion. In this analysis, we aimed to investigate the mechanisms of weight loss- induced remission in people with prediabetes.

AbstractDifferent disciplines have studied the content of online user comments in various contexts, using manual qualitative/quantitative or (semi-)automated approaches. The broad spectrum and disciplinary divides make it difficult to grasp an overview of those aspects which have already been examined, e.g. to identify findings related to one’s own research, recommendable methodological approaches, and under-researched topics. We introduce a systematic literature review concerning content analyses of user comments in a journalistic context. Our review covers 192 papers identified through a systematic search focussing on communication studies and computer science. We find that research predominantly concentrates on the comment sections of Anglo-American newspaper brands and on aspects like hate speech, general incivility, or users’ opinions on specific issues, while disregarding media from other parts of the world, comments in social media, propaganda, and constructive comments. From our results we derive a research agenda that addresses research gaps and also highlights potentials for automating analyses as well as for cooperation across disciplines.

Fat accumulation outside subcutaneous adipose tissue often has unfavourable effects on systemic metabolism. In addition to non-alcoholic fatty liver disease, which has received considerable attention, pancreatic fat has become an important area of research throughout the past 10 years. While a number of diagnostic approaches are available to quantify pancreatic fat, multi-echo Dixon MRI is currently the most developed method. Initial studies have shown associations between pancreatic fat and the metabolic syndrome, impaired glucose metabolism and type 2 diabetes mellitus. Pancreatic fat is linked to reduced insulin secretion, at least under specific circumstances such as prediabetes, low BMI and increased genetic risk of type 2 diabetes mellitus. This Review summarizes the possible causes and metabolic consequences of pancreatic fat accumulation. In addition, potential therapeutic approaches for addressing pancreatic fat accumulation are discussed.

Three concepts for a 3000 t/a continuous autohydrolysis plant aiming at a full fractionation of agricultural residues (wheat straw as model substrate) into streams rich in xylose, glucose, and lignin, respectively, are developed. For this purpose, two kinetic models based on batch liquid-hot water experiments (30 mL, 170–230 °C, 10–60 min) were investigated. The solid hemicellulose conversion was described with a first-order rate model. The concentration and conversion profile investigation of the solid and liquid phases using the severity factor resulted in a linear equation describing the hemicellulose solubilization: XHC= (0.5839 ∗ log(R0) − 1.7027) ± 0.06. Here, specific process parameter boarders for the maximal hemicellulose concentration and furfural formation at log(R0) = 4.0 considering the liquid phase were identified. These findings were used to propose a multi-step hydrothermal processing approach, with intermediate sugar extraction, tailored to the compositional requirements of the product streams. Seven reactor types were evaluated for its feasibility; in this regard, the screw conveyor reactor (SCR) was evaluated as most promising. For the concepts, the SCR reactors were scaled, based on the generated data. It was found that the process temperature is a major parameter determining the reactor size. It is considered more important than the number of autohydrolysis treatment steps. In brief, the fractionation of agricultural residues using a multi-step continuous plant is evaluated to be very promising for the industrial application, regarding selectivity, handling, investment, and process costs.

Die Bedeutung des Lernens in und von Organisationen verdeutlicht sich in der hohen Anzahl wissenschaftlicher Publikationen und ist ebenso in den Bemühungen von Organisationen, organisationales Lernen in den Fokus zu nehmen, erkennbar. Organisationales Lernen soll dazu beitragen, sich nachhaltig verbessern zu können, agiler und resilienter zu werden. Das Literatur-Review zielt darauf ab, die Bedeutung des Lernens im Zeitraum 2016–2021 mithilfe der Datenbanken ScienceDirect, Sage Journals und Wiley von einer individuellen bis hin zu einer organisationalen Ebene zu untersuchen und hier insbesondere Faktoren zu identifizieren, die das Zusammenspiel der drei Akteursebenen (Individuum, Gruppe, Organisation) beeinflussen und damit organisationales Lernen bedingen. Das Literatur-Review zeigt auf, dass Lernen in Organisationen zum einen auf dem Zusammenspiel der genannten Ebenen gedacht werden muss und zum anderen sowohl individuelle, gruppenbasierte als auch organisationale Faktoren einen Einfluss auf das Lernen haben. Die Ergebnisse lassen insbesondere den Schluss zu, dass die Interaktion in der Organisation und dabei der Wissensaustausch bzw. das Teilen von Wissen zu den relevanten Einflussfaktoren organisationalen Lernens gehören.

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Hospital stays are often associated with medication changes, which may lead to drug-related problems (DRPs). Medication reconciliation and medication reviews are strategies to detect and resolve DRPs.

The signal transducer and activator of transcription 3 (STAT3) signalling pathway is activated through phosphorylation by Janus kinases in response to a diverse set of immunogenic and non-immunogenic triggers. Several distinct lines of evidence propose an intricate involvement of STAT3 in neural function relevant to behaviour in health and disease. However, in part due to the pleiotropic effects resulting from its DNA binding activity and the consequent regulation of expression of a variety of genes with context-dependent cellular consequences, the precise nature of STAT3 involvement in the neural mechanisms underlying psychopathology remains incompletely understood. Here, we focused on the midbrain serotonergic system, a central hub for the regulation of emotions, to examine the relevance of STAT3 signalling for emotional behaviour in mice by selectively knocking down raphe STAT3 expression using germline genetic (STAT3 KO) and viral-mediated approaches. Mice lacking serotonergic STAT3 presented with reduced negative behavioural reactivity and a blunted response to the sensitising effects of amphetamine, alongside alterations in midbrain neuronal firing activity of serotonergic neurons and transcriptional control of gene networks relevant for neuropsychiatric disorders. Viral knockdown of dorsal raphe (DR) STAT3 phenocopied the behavioural alterations of STAT3 KO mice, excluding a developmentally determined effect and suggesting that disruption of STAT3 signalling in the DR of adult mice is sufficient for the manifestation of behavioural traits relevant to psychopathology. Collectively, these results suggest DR STAT3 as a molecular gate for the control of behavioural reactivity, constituting a mechanistic link between the upstream activators of STAT3, serotonergic neurotransmission and psychopathology.

Während interreligiöse Dialoge durch ikonische architektonische Projekte eine größere öffentliche Sichtbarkeit und mediale Aufmerksamkeit erlangt haben, ist deren breitere gesellschaftliche Wahrnehmung und Wirkung weitestgehend unerforscht. Der Beitrag untersucht gruppenspezifische Wahrnehmungen interreligiöser Beziehungen und Positionierungen zu interreligiösen Dialogen. Im Zentrum der Analyse stehen dabei die Debatten zum Berliner House of One, einem derzeit im Bau befindlichen multireligiösen Gebäude. Unter Rückgriff auf soziologische Konzeptualisierungen zum Verhältnis von Religion, Macht und Stadtraum untersucht der Beitrag, welche unterschiedlichen sozialen Positionen religiöser Akteur*innen (Protestant*innen, Alevit*innen und Muslim*innen) in den kulturellen Hierarchien urbaner Räume sich in solchen Wahrnehmungen dokumentieren. Wir argumentieren, dass die in diskursiven Aushandlungsprozessen zu interreligiösen Dialogen vorgenommenen Positionierungen solche kulturellen Hierarchien auf besondere Weise hervortreten lassen und damit auch auf blinde Flecken des Dialog-Paradigmas aufmerksam machen. Der Beitrag basiert auf Gruppendiskussionen und Einzelinterviews.

Little is known about the effectiveness and drug survival associated with apremilast under real-world conditions.

Background:The Association of British Neurologists (ABN) 2015 guidelines suggested classifying multiple sclerosis therapies according to their average relapse reduction. We sought to classify newer therapies (cladribine, ocrelizumab, ofatumumab, ozanimod) based on these guidelines. Materials & methods:Therapies were classified by using direct comparative trial results as per ABN guidelines and generating classification probabilities for each therapy based on comparisons versus placebo in a network meta-analysis for annualized relapse rate. Results:For both approaches, cladribine and ofatumumab were classified as high efficacy. Ocrelizumab and ozanimod (1.0 mg) were classified as moderate or high efficacy depending on the approach used. Conclusion:Cladribine and ofatumumab have an efficacy comparable with therapies classified in the ABN guidelines as high efficacy.

The state of intermediate hyperglycemia is indicative of elevated risk of developing type 2 diabetes1. However, the current definition of prediabetes neither reflects subphenotypes of pathophysiology of type 2 diabetes nor is predictive of future metabolic trajectories. We used partitioning on variables derived from oral glucose tolerance tests, MRI-measured body fat distribution, liver fat content and genetic risk in a cohort of extensively phenotyped individuals who are at increased risk for type 2 diabetes2,3to identify six distinct clusters of subphenotypes. Three of the identified subphenotypes have increased glycemia (clusters 3, 5 and 6), but only individuals in clusters 5 and 3 have imminent diabetes risks. By contrast, those in cluster 6 have moderate risk of type 2 diabetes, but an increased risk of kidney disease and all-cause mortality. Findings were replicated in an independent cohort using simple anthropomorphic and glycemic constructs4. This proof-of-concept study demonstrates that pathophysiological heterogeneity exists before diagnosis of type 2 diabetes and highlights a group of individuals who have an increased risk of complications without rapid progression to overt type 2 diabetes.

Rising extremes and varieties of threats towards socio technical systems ask for improved overall risk control and resilience enhancement. Most current classical approaches focus on the assessment of single or multiple threat events countering system objectives. However, more recent approaches ask for the identification, determination and use of time-dependent system performance functions and their assessment in case of disruptions. Thus, the paper discusses advanced risk and resilience analysis approaches for explosions, terroristic events in urban spaces, cascading effects in coupled supply grids, scoring of critical infrastructures, and tabular resilience analysis and management. Summarising respectively the main processes, methods for steps and results, it argues how time-dependent system performance function resilience approaches allow a more direct quantification of overall risk control objectives, since it assesses main system service functions before, during and post disruptions. The approaches are well suited for communication with the public, management and dashboard mobile visualisation.

Community resilience against major disasters is a multidisciplinary research field that garners an ever-increasing interest worldwide. This paper provides summaries of the discussions held on the subject matter and the research outcomes presented during the Second Resilience Workshop in Nanjing and Shanghai. It, thus, offers a community view of present work and future research directions identified by the workshop participants who hail from Asia - including China, Japan and Korea; Europe and the Americas.

Aim:To compare the efficacy of ofatumumab to other disease-modifying therapies (DMTs) for relapsing multiple sclerosis (RMS). Materials & methods:A network meta-analysis was conducted to determine the relative effect of ofatumumab on annualized relapse rate and confirmed disability progression at 3 months and 6 months. Results:For each outcome, ofatumumab was as effective as other highly efficacious monoclonal antibody DMTs (i.e., alemtuzumab, natalizumab and ocrelizumab). Conclusion:Ofatumumab offers beneficial outcomes for RMS by reducing relapse and disability progression risk.

Verlustbehaftete Kapazitäten sind für kommerzielle Kapazitätssensoren, die nur einen Kapazitätswert ausgeben, problematisch: der parasitäre ohmsche Widerstand parallel zur Kapazität verfälscht das Messergebnis. Bei Messungen an Flüssigkeiten im Rahmen der elektrischen Kapazitätstomographie (ECT) kann der Einfluss gravierend werden. Mit erhöhtem Messaufwand könnte man die ECT zur elektrischen Impedanztomographie (EIT) erweitern und damit sowohl die Kapazität als auch den Widerstand der verlustbehafteten Kapazität messen. Als aufwandsarme Alternative stellen wir hier einen modellbasierten De-Embedding-Ansatz vor. Er ertüchtigt kommerzielle Kapazitätssensoren, die die Kapazität über die Messung einer Entladezeitkonstante bestimmen, auch mit stärker verlustbehafteten Kapazitäten zurechtzukommen. Der Ansatz beruht auf dem Ersatzschaltbild der realen Messsituation, dessen zugehörige Differentialgleichung im Zeitbereich gelöst wird. Durch Variation der gesuchten Kapazität und des gesuchten Widerstands wird die vom Sensor ermittelte Zeitkonstante über die Anzahl der nacheinander durchgeführten Lade-/Entladevorgänge (Perioden) ermittelt. Das Verfahren wird an einem diskreten Aufbau aus konzentrierten Elementen und an einer typischen ECT-Messsituation getestet. Die ermittelten Zeitkonstanten bei einer realen ECT-Messsituation mit Leitungswasser als zu vermessendem Medium zeigen einen Unterschied zum diskreten Aufbau mit den konzentrierten Elementen.

A wealth of specialized neuroendocrine command systems intercalated within the hypothalamus control the most fundamental physiological needs in vertebrates1,2. Nevertheless, we lack a developmental blueprint that integrates the molecular determinants of neuronal and glial diversity along temporal and spatial scales of hypothalamus development3. Here we combine single-cell RNA sequencing of 51,199 mouse cells of ectodermal origin, gene regulatory network (GRN) screens in conjunction with genome-wide association study-based disease phenotyping, and genetic lineage reconstruction to show that nine glial and thirty-three neuronal subtypes are generated by mid-gestation under the control of distinct GRNs. Combinatorial molecular codes that arise from neurotransmitters, neuropeptides and transcription factors are minimally required to decode the taxonomical hierarchy of hypothalamic neurons. The differentiation of γ-aminobutyric acid (GABA) and dopamine neurons, but not glutamate neurons, relies on quasi-stable intermediate states, with a pool of GABA progenitors giving rise to dopamine cells4. We found an unexpected abundance of chemotropic proliferation and guidance cues that are commonly implicated in dorsal (cortical) patterning5in the hypothalamus. In particular, loss of SLIT–ROBO signalling impaired both the production and positioning of periventricular dopamine neurons. Overall, we identify molecular principles that shape the developmental architecture of the hypothalamus and show how neuronal heterogeneity is transformed into a multimodal neural unit to provide virtually infinite adaptive potential throughout life.

Insulin acts on the CNS to modulate behaviour and systemic metabolism. Disturbances in brain insulin action represent a possible link between metabolic and cognitive health. Current findings from human research suggest that boosting central insulin action in the brain modulates peripheral metabolism, enhancing whole-body insulin sensitivity and suppressing endogenous glucose production. Moreover, central insulin action curbs food intake by reducing the salience of highly palatable food cues and increasing cognitive control. Animal models show that the mesocorticolimbic circuitry is finely tuned in response to insulin, driven mainly by the dopamine system. These mechanisms are impaired in people with obesity, which might increase their risk of developing type 2 diabetes and associated diseases. Overall, current findings highlight the role of insulin action in the brain and its consequences on peripheral metabolism and cognition. Hence, improving central insulin action could represent a therapeutic option for people at an increased risk of developing metabolic and cognitive diseases.

Nephropathic cystinosis is a rare autosomal recessive lysosomal storage disorder, which causes loss of renal proximal tubular function and progressive loss of glomerular function, finally leading to end stage renal failure at school age. In the course of the disease most patients will need kidney transplantation if treatment has not been started before clinical manifestation. With an effective treatment available, a newborn screening assay is highly demanded. Since newborns with cystinosis usually do not show symptoms within the first months of life and no biochemical markers are easily detectable, a DNA-based method seems to be an obvious tool for early diagnosis. Screening was performed using high-throughput nucleic acid extraction followed by 384-well qPCR and melting analysis for the three most frequent variants (57 kb deletion NC_000017.11:g.3600934_3658165del (GRCh38); c.18_21del GACT; c.926dupG) responsible for the defective lysosomal membrane protein cystinosin (CTNS). To increase sensitivity, all heterozygous samples identified in qPCR assay were verified and screened for additional variants by applying next generation sequencing. From January 2018 to July 2019 nearly 292,000 newborns were successfully screened. We identified two newborns with a homozygous 57 kb deletion and a second one with heterozygous 57 kb deletion and a G>C substitution at position c.-512 on the second allele. Cystinosis is an example for diseases caused by a limited number of high prevalence and a high number of low prevalence variants. We have shown that qPCR combined with NGS can be used as a high throughput, cost effective tool in newborn screening for such diseases.

IMPORTANCE: Blood sample–based biomarkers that are associated with clinically meaningful outcomes for patients with multiple sclerosis (MS) have not been developed. OBJECTIVE: To evaluate the potential of serum neurofilament light chain (sNFL) measurements as a biomarker of disease activity and progression in a longitudinal MS data set. DESIGN, SETTING, AND PARTICIPANTS: Single-center, ongoing, prospective observational cohort study of 607 patients with MS from the longitudinal EPIC (Expression, Proteomics, Imaging, Clinical) study at the University of California, San Francisco from July 1, 2004, through August 31, 2017. Clinical evaluations and sample collection were performed annually for 5 years, then at different time points for up to 12 years, with a median follow-up duration of 10 (interquartile range, 7-11) years. Serum NFL levels were measured using a sensitive single molecule array platform and compared with clinical and magnetic resonance imaging variables with the use of univariable and multivariable analyses. MAIN OUTCOMES AND MEASURES: The main outcomes were disability progression defined as clinically significant worsening on the Expanded Disability Status Scale (EDSS) score and brain fraction atrophy. RESULTS: Mean (SD) age of the 607 study participants at study entry was 42.5 (9.8) years; 423 (69.7%) were women; and all participants were of non-Hispanic European descent. Of 3911 samples sequentially collected, 3904 passed quality control for quantification of sNFL. Baseline sNFL levels showed significant associations with EDSS score (β, 1.080; 95% CI, 1.047-1.114; P < .001), MS subtype (β, 1.478; 95% CI, 1.279-1.707; P < .001), and treatment status (β, 1.120; 95% CI, 1.007-1.245; P = .04). A significant interaction between EDSS worsening and change in levels of sNFL over time was found (β, 1.015; 95% CI, 1.007-1.023; P < .001). Baseline sNFL levels alone were associated with approximately 11.6% of the variance in brain fraction atrophy at year 10. In a multivariable analysis that considered sex, age, and disease duration, baseline sNFL levels were associated with 18.0% of the variance in brain fraction atrophy at year 10. After 5 years’ follow-up, active treatment was associated with lower levels of sNFL, with high-potency treatments associated with the greater decreases in sNFL levels compared with platform therapies (high-potency vs untreated: β, 0.946; 95% CI, 0.915-0.976; P < .001; high-potency vs platform: β, 0.972; 95% CI, 0.948-0.998; P = .04). CONCLUSIONS AND RELEVANCE: This study found that statistically significant associations of sNFL with relevant clinical and neuroimaging outcomes in MS were confirmed and extended, supporting the potential of sNFL as an objective surrogate of ongoing MS disease activity. In this data set of patients with MS who received early treatment, the prognostic power of sNFL for relapse activity and long-term disability progression was limited. Further prospective studies are necessary to assess the assay’s utility for decision-making in individual patients.

This paper investigates the use of common thermal storage systems for demand side management in off-grid situations for nearly zero energy buildings. Typical parameters and characteristics were analyzed to develop mathematical models for freezers, water heaters and space heating/cooling. The models used in this work are based on simplified equations derived from differential equations. Simplified models of a battery storage and a PV-system have been added. Models for the thermal storages, PV-system and battery storage were merged to one system model. All models and simulations were designed and conducted with Matlab. Various pre-defined price based set point calculation algorithms were modified to work with the off-grid system based on the system’s voltage and available PV-power. Voltage and battery’s state of charge based algorithms are developed in this work. In a system with a freezer, water heater and space heating/cooling that is powered by a PV-system only, a possible battery storage capacity reduction of up to 50% with PV-power based and up to 36% with SOC based algorithms compared to the same system with fixed set point thermostatic control could be achieved. Additionally, the capacity could even be reduced by up to 18% by solely reacting to voltage drops.

Cluster analyses have proposed different diabetes phenotypes using age, BMI, glycaemia, homoeostasis model estimates, and islet autoantibodies. We tested whether comprehensive phenotyping validates and further characterises these clusters at diagnosis and whether relevant diabetes-related complications differ among these clusters, during 5-years of follow-up.

We report diverse C–N cross-coupling reactions of aryl thianthrenium salts that are formed site-selectively by direct C–H functionalization. The scope of N-nucleophiles ranges from primary and secondary alkyl and aryl amines to various N-containing heterocycles, and the overall transformation is applicable to late-stage functionalization of complex, drug-like small molecules.

Here, we report the fragment-based discovery of BI-9321, a potent, selective and cellular active antagonist of the NSD3-PWWP1 domain. The human NSD3 protein is encoded by the WHSC1L1gene located in the 8p11-p12 amplicon, frequently amplified in breast and squamous lung cancer. Recently, it was demonstrated that the PWWP1 domain of NSD3 is required for the viability of acute myeloid leukemia cells. To further elucidate the relevance of NSD3 in cancer biology, we developed a chemical probe, BI-9321, targeting the methyl-lysine binding site of the PWWP1 domain with sub-micromolar in vitro activity and cellular target engagement at 1 µM. As a single agent, BI-9321 downregulates Myc messenger RNA expression and reduces proliferation in MOLM-13 cells. This first-in-class chemical probe BI-9321, together with the negative control BI-9466, will greatly facilitate the elucidation of the underexplored biological function of PWWP domains. A chemical probe BI-9321 for the PWWP1 domain of NSD3 and its inactive analog were identified. BI-9321 binds to the methyl-lysine binding site, reduces the association of NSD3 with chromatin and inhibits proliferation of acute myeloid leukemia cells.

The effect of a lifestyle intervention to reduce liver fat content in nonalcoholic fatty liver disease in humans is influenced by genetics. We hypothesized that the amino acid exchange in human Gly388Arg (mouse homolog: Gly385Arg) in fibroblast growth factor receptor 4 (FGFR4), which regulates bile acid, lipid, and glucose metabolism, could determine hepatic lipid accumulation and insulin sensitivity. Mechanisms of this substitution were studied in mice under normal chow and high-fat diets.

Urban physical security and resilience with respect to accidental and intentional explosive events are an increasing issue regarding civil safety and security of modern societies and their citizens. Examples include industrial on-site explosions, gas explosions or terrorist attacks. In particular, multiple, simultaneous and maliciously time-coordinated events are an increasing event type such as complex attack events consisting of targeted combinations of improvised explosive devices. The paper presents a comprehensive, tailorable and stepwise process. This includes methodologies for scenario, hazard, damage, exposure, event frequency, risk and resilience analysis that have been developed, refined and praxis-tested over decades. The focus is on a summarizing description of the modern best practice approach, the validation efforts undertaken for each step as well as two detailed case studies for exemplary presentation and overall validation. In a comprehensive table, the present approach is compared with other state-of-the-art approaches. The paper shows a refined process how to systematically improve resilience when using the tool, in particular through barriers at explosive sites and at exposed sites of various geometries. Furthermore, along the presentation a set of quality requirements regarding explosive event risk and resilience analyses are provided as collected over the years from the in-field, user group and engineering science perspective as well as a broad outlook on extension options for the future.

The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing worldwide. In some patients with NAFLD, isolated steatosis can progress to advanced stages with non-alcoholic steatohepatitis (NASH) and fibrosis, increasing the risk of cirrhosis and hepatocellular carcinoma. Furthermore, NAFLD is believed to be involved in the pathogenesis of common disorders such as type 2 diabetes and cardiovascular disease. In this Review, we highlight novel concepts related to diagnosis, risk prediction, and treatment of NAFLD. First, because NAFLD is a heterogeneous disease, the advanced stages of which seem to be strongly affected by comorbidities such as insulin resistance and type 2 diabetes, early use of reliable, non-invasive diagnostic tools is needed, particularly in patients with insulin resistance or diabetes, to allow the identification of patients at different disease stages. Second, although the strongest genetic risk alleles for NAFLD (ie, the 148Met allele in PNPLA3and the 167Lys allele in TM6SF2) are associated with increased liver fat content and progression to NASH and cirrhosis, these alleles are also unexpectedly associated with an apparent protection from cardiovascular disease. If consistent across diverse populations, this discordance in NAFLD-related risk prediction between hepatic and extrahepatic disease might need to be accounted for in the management of NAFLD. Third, drug treatments assessed in NAFLD seem to differ with respect to cardiometabolic and antifibrotic efficacy, suggesting the need to better identify and tailor the most appropriate treatment approach, or to use a combination of approaches. These emerging concepts could contribute to the development of a multidisciplinary approach for endocrinologists and hepatologists working together in the management of NAFLD.

Primary dysregulation of adipose tissue lipolysis caused by genetic variation and independent of insulin resistance could explain unhealthy body fat distribution and its metabolic consequences.

Introduction The volume of prescriptions for proton pump inhibitors (PPIs) remains high, although the literature increasingly points to excessive prescribing in relation to guideline recommendations. No very recent data is available on the specific situation in Germany, particularly on the proportion of PPI consumption from over-the-counter (OTC) sales and self-selection, following PPI down-scheduling. The aim of this study was to determine the actual amount of prescribed and OTC PPIs in Germany.Methods For this retrospective study, several IQVIA databases were used, representing all prescriptions billed to statutory and private health insurers in Germany, as well as OTC sales. Analyses were performed for the period November 2020 to October 2021 or partially November 2018 to October 2021 and were descriptive in nature. Mainly, data were collected from IQVIATM PharmaScope National® as well as IQVIA TM DPM® databases.Results A total of 2.87 billion PPI tablets were shown to have been sold between November 2020 and October 2021, with most drugs prescribed in the largest packages and strengths. In addition, the OTC PPI market increased by an average of 14% per year over a 3-year period.Conclusions The results of this study suggest the substantial size of the PPI market in Germany is based on prescriptions, a consistent increase in OTC PPI purchases and a recent increase in prescriptions.

We develop a convex relaxation for the minimum energy control problem of the well-known unicycle model in the form of a semidefinite program. Through polynomialization techniques, the infinite-dimensional optimal control problem is first reformulated as a non-convex, infinite-dimensional quadratic program which can be viewed as a trajectory generation problem. This problem is then discretized to arrive at a finite-dimensional, albeit, non-convex quadratically constrained quadratic program. By applying the moment relaxation method to this quadratic program, we obtain a hierarchy of semidefinite relaxations. We construct an approximate solution for the infinite-dimensional trajectory generation problem by solving the first- or second-order moment relaxation. A comprehensive simulation study provided in this paper suggests that the second-order moment relaxation is lossless.

Reduced β-cell mass, impaired islet function, and dedifferentiation are considered causal to development of hyperglycemia and type 2 diabetes. In human cohort studies, changes of islet cell-specific expression patterns have been associated with diabetes but not directly with in vivo insulin secretion.

Recently, alterations in maternal lipid metabolism were associated with gestational diabetes mellitus (GDM). However, detailed plasma lipid profiles and their relevance for placental and fetal metabolism are currently not understood.

In this work, we demonstrated that the simple substitution of the 1,2,4-triazole moiety in 5-(4H-1,2,4-triazol-4-yl)isophthalic acid (5-TIA) by the 1H-1,2,3-triazol-5-yl unit enables the preparation of a hydrogelator (click-TIA). In sharp contrast to 5-TIA, its isostere click-TIAundergoes self-assembly in water upon sonication, leading to the formation of stable supramolecular viscoelastic hydrogels with a critical gelation concentration of 6 g/L. Hydrogels made of click-TIAas well as hybrid hydrogels made of the mixture click-TIA+ 5-TIA(molar ratio 1:0.2) were used to compare different properties of the materials (i.e., rheological properties, thermal properties, mechanical stability, morphology). In terms of toxicity, neither click-TIAnor 5-TIAshowed cytotoxic effects on cellular viability of HeLa cells up to 2.3 × 10–3g/L when compared to untreated cells incubated with DMSO. Furthermore, the hydrogels were used for the encapsulation and in vitrocontrolled release of oxytetracycline that followed first-order kinetics. For the hydrogel made of click-TIA, a maximum drug release of ∼60% was reached after ∼8 h within a pH range between 6.5 and 10. However, the release rate was reduced to approximately half of its value at pH values between 1.2 and 5.0, whereas the use of hybrid hydrogels made of click-TIA+ 5-TIAallowed to reduce the original rate at pH ≤ 6.5.