Discovery of YAP1/TAZ pathway inhibitors through phenotypic screening with potent anti-tumor activity via blockade of Rho-GTPase signaling.

This study describes the identification and target deconvolution of small molecule inhibitors of oncogenic Yes-associated protein (YAP1)/TAZ activity with potent anti-tumor activity in vivo. A high-throughput screen (HTS) of 3.8 million compounds was conducted using a cellular YAP1/TAZ reporter assay. Target deconvolution studies identified the geranylgeranyltransferase-I (GGTase-I) complex as the direct target of YAP1/TAZ pathway inhibitors. The small molecule inhibitors block the activation of Rho-GTPases, leading to subsequent inactivation of YAP1/TAZ and inhibition of cancer cell proliferation in vitro. Multi-parameter optimization resulted in BAY-593, an in vivo probe with favorable PK properties, which demonstrated anti-tumor activity and blockade of YAP1/TAZ signaling in vivo.

Physical activity interventions in workplace health promotion: objectives, related outcomes, and consideration of the setting-a scoping review of reviews.

Background: The workplace is a recognized setting for promoting health among adults, and physical activity (PA) interventions are an integral part of workplace health promotion (WHP). Objectives: The present review of reviews aims to provide an overview of the main objectives and related outcomes addressed in WHP-related PA interventions, as well as the setting-specific aspects considered in the research field. Methods: A scoping review of reviews was conducted. Reviews were included if they were peer-reviewed, written in English, and focused on PA interventions conducted in the context of WHP. A literature search was conducted in PubMed, SPORTDiscus, and Web of Science. Reviews were included if they had been published after the year 2000. Information on the following dimensions was extracted: author, region, number of primary studies included, target group(s), PA interventions included, main objective(s), related outcomes, and setting-specific aspects. Results: A total of 17 reviews were included. Six reviews aimed at solely identifying the effectiveness of promoting daily PA and reducing sedentary behavior. Eleven reviews showed a combined approach considering physical activity behavior and/or health and job-related outcomes. Outcomes in the primary studies were heterogeneous. None of the reviews had an explicit definition of WHP and setting-specific information was very general and sparse. The reported setting-specific information was referred to the general importance of the workplace setting, the specific importance as an access route to target groups, and implementation aspects. Regarding the additional characteristics of the reviews, the selection of primary studies was restricted to a specific region in 2 of the 17 reviews in advance. Three reviews restricted the target group (sedentary workers, women, desk-based workers), while eleven reviews included working adults in general and, three reviews gave no information about the target group. Eleven intervention approaches of the reviews were behaviorally oriented, two focused solely on environmental interventions, and four reviews can be attributed to a combined approach considering behavioral and environmental interventions. Conclusion: For sustainable future developments, the present results indicate a strong need for conceptual consolidation of WHP in the research field of PA interventions. Therefore, both WHP and health-related PA interventions need to take a comprehensive approach comprising behavioral and environmental interventions.

How to contour the different heart subregions for future deep-learning modeling of the heart: A practical pictorial proposal for radiation oncologists.

There are currently no accurate rules for manually delineating the subregions of the heart (cavities, vessels, aortic/mitral valves, Planning organ at Risk Volumes for coronary arteries) with the perspective of deep-learning based modeling. Our objective was to present a practical pictorial view for radiation oncologists, based on the RTOG atlas and anatomical complementary considerations for the cases where the RTOG guidelines are missing.

Pressure-Induced Dislocations and Their Influence on Ionic Transport in Li+-Conducting Argyrodites.

The influence of the microstructure on the ionic conductivity and cell performance is a topic of broad scientific interest in solid-state batteries. The current understanding is that interfacial decomposition reactions during cycling induce local strain at the interfaces between solid electrolytes and the anode/cathode, as well as within the electrode composites. Characterizing the effects of internal strain on ion transport is particularly important, given the significant local chemomechanical effects caused by volumetric changes of the active materials during cycling. Here, we show the effects of internal strain on the bulk ionic transport of the argyrodite Li6PS5Br. Internal strain is reproducibly induced by applying pressures with values up to 10 GPa. An internal permanent strain is observed in the material, indicating long-range strain fields typical for dislocations. With increasing dislocation densities, an increase in the lithium ionic conductivity can be observed that extends into improved ionic transport in solid-state battery electrode composites. This work shows the potential of strain engineering as an additional approach for tuning ion conductors without changing the composition of the material itself.

Discovery of IRAK4 Inhibitors BAY1834845 (Zabedosertib) and BAY1830839.

Interleukin-1 receptor-associated kinase 4 (IRAK4) plays a critical role in innate inflammatory processes. Here, we describe the discovery of two clinical candidate IRAK4 inhibitors, BAY1834845 (zabedosertib) and BAY1830839, starting from a high-throughput screening hit derived from Bayer's compound library. By exploiting binding site features distinct to IRAK4 using an in-house docking model, liabilities of the original hit could surprisingly be overcome to confer both candidates with a unique combination of good potency and selectivity. Favorable DMPK profiles and activity in animal inflammation models led to the selection of these two compounds for clinical development in patients.

Confinement-enhanced Li+ ion dynamics in an ionic liquid-based electrolyte in porous material.

While Ionic Liquids (IL) are promising liquid electrolyte components for Li-ion batteries due to their high electrochemical stability and low volatility and flammability, unfavorable Lithium-anion clusters lead to poor Li+ transport properties such as low transference numbers. A confinement of ILs in nanoporous materials could overcome these problems, based on altered structural and dynamic properties of the confined ILs. We investigate the coordination and the Li+ dynamics in an IL/Li-salt mixture of 1-butyl-1-methylpyrrolidinium bis(trifluormethyl-sulfonyl)imide (Pyr14TFSA) and LiTFSA and reveal in how far the confinement has positive or negative effects on ion clustering in the electrolyte. To this end, the electrolyte is confined in mesoporous silica SBA-15 (pore diameter 8 nm or 4 nm) or the metal-organic framework (MOF) ZIF-8 (pore diameter 1.16 nm). Raman spectra elucidate the Li-anion coordination and the interaction of the ions with the walls. Temperature-dependent 7Li spin relaxation rates, analyzed within the model of Bloembergen, Purcell and Pound (BPP), allow statements on the local Li+ environment, the local Li+ dynamics and its activation. In the SBA-15 materials the Li+ coordination is unchanged with persisting Li-TFSA clusters. Furthermore, the local dynamics of Li+ is reduced upon confinement, as expected due to geometrical restrictions. At the same time, however, both structural and dynamic parameters do not show a pronounced dependence on the pore size. Surprisingly, upon confinement in ZIF-8 Li+ displays faster local dynamics and a more asymmetric environment in comparison to the bulk electrolyte. The enhanced dynamics is accompanied by a reduced coordination to TFSA-, suggesting the breakup of Li-TFSA clusters. Differences between the porous materials are attributed to the nature of the wall surface, as Raman spectra suggest that in SBA-15 the TFSA- ion is preferentially interacting with the pore walls, whereas in ZIF-8 the Pyr14+ ion is immobilized by the pore walls. These results demonstrate a strong influence of internal interfaces on IL structure and dynamics and bear potential for further tailoring ion dynamics.

Chylomicrons Regulate Lacteal Permeability and Intestinal Lipid Absorption.

BACKGROUND: Lymphatic vessels are responsible for tissue drainage, and their malfunction is associated with chronic diseases. Lymph uptake occurs via specialized open cell-cell junctions between capillary lymphatic endothelial cells (LECs), whereas closed junctions in collecting LECs prevent lymph leakage. LEC junctions are known to dynamically remodel in development and disease, but how lymphatic permeability is regulated remains poorly understood. METHODS: We used various genetically engineered mouse models in combination with cellular, biochemical, and molecular biology approaches to elucidate the signaling pathways regulating junction morphology and function in lymphatic capillaries. RESULTS: By studying the permeability of intestinal lacteal capillaries to lipoprotein particles known as chylomicrons, we show that ROCK (Rho-associated kinase)-dependent cytoskeletal contractility is a fundamental mechanism of LEC permeability regulation. We show that chylomicron-derived lipids trigger neonatal lacteal junction opening via ROCK-dependent contraction of junction-anchored stress fibers. LEC-specific ROCK deletion abolished junction opening and plasma lipid uptake. Chylomicrons additionally inhibited VEGF (vascular endothelial growth factor)-A signaling. We show that VEGF-A antagonizes LEC junction opening via VEGFR (VEGF receptor) 2 and VEGFR3-dependent PI3K (phosphatidylinositol 3-kinase)/AKT (protein kinase B) activation of the small GTPase RAC1 (Rac family small GTPase 1), thereby restricting RhoA (Ras homolog family member A)/ROCK-mediated cytoskeleton contraction. CONCLUSIONS: Our results reveal that antagonistic inputs into ROCK-dependent cytoskeleton contractions regulate the interconversion of lymphatic junctions in the intestine and in other tissues, providing a tunable mechanism to control the lymphatic barrier.

Vaping Behavior in Young Adults During the COVID-19 Pandemic.

BACKGROUND: Electronic nicotine delivery systems (ENDS) continue to be popular among young adults. These devices are often advertised as a healthy alternative to quitting tobacco cigarettes. However, young adults represent a population who view it as a novel behavior that provides a sense of popularity, social acceptance, and desired physiologic properties. The objective of this study was to examine characteristics of vaping behavior among college students and explore possible associations between groups of vaping behavior (stopped, initiated, increased, decreased, stayed the same). METHODS: In a multi-center cross-sectional study, 656 students from University of Tampa in the United States and University of Applied Sciences in Germany (IST) were recruited to answer a 31-item online questionnaire. A chi-square test was used to evaluate associations between the groups. RESULTS: Prevalence rates indicated approximately 31% of all students were currently using ENDS. Even though more negative than positive experiences with ENDS were reported, most students stated their vaping increased during COVID-19 lockdowns. Addiction and stress relief emerged to be predictors (P < .001) of an increase in vaping, whereas social motives were not statistically significant. Living situation (P = .63) and depression (P = .10) were not significantly associated with vaping behavior. CONCLUSIONS: ENDS products continue to yield very high levels of nicotine creating addiction in young adults. Addiction counseling and evidenced-based practices should be employed at every level (individual, community, and school). Additionally, mental health counseling for students in pandemic and high-stress environments may help to combat stress in a more proactive manner than self-medicating.

Investigating the Li+ substructure and ionic transport in Li10GeP2-xSbxS12 (0 ≤ x ≤ 0.25).

Understanding the correlation between ionic motion and crystal structure is crucial for improving solid electrolyte conductivities. Several substitution series in the Li10GeP2S12 structure have shown a favorable impact on the ionic conductivity, e.g. the replacement of P(+V) by Sb(+V) in Li10GeP2S12. However, here the interplay between the structure and ionic motion remains elusive. X-Ray diffraction, high-resolution neutron diffraction, Raman spectroscopy and potentionstatic impedance spectroscopy are employed to explore the impact of Sb(+V) on the Li10GeP2S12 structure. The introduction of antimony elongates the unit cell in the c-direction and increases the M(1)/P(1) and Li(2) polyhedral volume. Over the solid solution range, the Li+ distribution remains similar, an inductive effect seems to be absent and the ionic conductivity is comparable for all compositions. The effect of introducing Sb(+V) in Li10GeP2S12 cannot be corroborated.

African swine fever virus - variants on the rise.

African swine fever virus (ASFV), a large and complex DNA-virus circulating between soft ticks and indigenous suids in sub-Saharan Africa, has made its way into swine populations from Europe to Asia. This virus, causing a severe haemorrhagic disease (African swine fever) with very high lethality rates in wild boar and domestic pigs, has demonstrated a remarkably high genetic stability for over 10 years. Consequently, analyses into virus evolution and molecular epidemiology often struggled to provide the genetic basis to trace outbreaks while few resources have been dedicated to genomic surveillance on whole-genome level. During its recent incursion into Germany in 2020, ASFV has unexpectedly diverged into five clearly distinguishable linages with at least ten different variants characterized by high-impact mutations never identified before. Noticeably, all new variants share a frameshift mutation in the 3' end of the DNA polymerase PolX gene O174L, suggesting a causative role as possible mutator gene. Although epidemiological modelling supported the influence of increased mutation rates, it remains unknown how fast virus evolution might progress under these circumstances. Moreover, a tailored Sanger sequencing approach allowed us, for the first time, to trace variants with genomic epidemiology to regional clusters. In conclusion, our findings suggest that this new factor has the potential to dramatically influence the course of the ASFV pandemic with unknown outcome. Therefore, our work highlights the importance of genomic surveillance of ASFV on whole-genome level, the need for high-quality sequences and calls for a closer monitoring of future phenotypic changes of ASFV.

Spreading the disease: Protest in times of pandemics.

This study analyzes the impact of large anti-lockdown protests on the spread of SARS-CoV-2 in Germany. Since protesters at such large gatherings are very mobile and largely neglect SARS-CoV-2 containment strategies, they may contribute to the regional transmission of the coronavirus. Employing novel data on bus connections of travel companies specialized in driving protesters to these gatherings, and exploiting the timing of two large-scale demonstrations in November 2020, we estimate the causal impact of these protests on the spread of SARS-CoV-2 using an event study framework. Our findings imply sizable increases in infection rates in protesters' origin regions after these demonstrations. A month after the protests, treated areas face a relative increase in infection rates up to 35% compared to non-treated areas. Our results shed light on public health consequences of behavior that ignores potential externalities for the society during a pandemic.

Identification of a neural development gene expression signature in colon cancer stem cells reveals a role for EGR2 in tumorigenesis.

Recent evidence demonstrates that colon cancer stem cells (CSCs) can generate neurons that synapse with tumor innervating fibers required for tumorigenesis and disease progression. Greater understanding of the mechanisms that regulate CSC driven tumor neurogenesis may therefore lead to more effective treatments. RNA-sequencing analyses of ALDHPositive CSCs from colon cancer patient-derived organoids (PDOs) and xenografts (PDXs) showed CSCs to be enriched for neural development genes. Functional analyses of genes differentially expressed in CSCs from PDO and PDX models demonstrated the neural crest stem cell (NCSC) regulator EGR2 to be required for tumor growth and to control expression of homebox superfamily embryonic master transcriptional regulator HOX genes and the neural stem cell and master cell fate regulator SOX2. These data support CSCs as the source of tumor neurogenesis and suggest that targeting EGR2 may provide a therapeutic differentiation strategy to eliminate CSCs and block nervous system driven disease progression.

Generalized synthesis of NaCrO2 particles for high-rate sodium ion batteries prepared by microfluidic synthesis in segmented flow.

NaCrO2 particles for high-rate sodium ion batteries were prepared on a multigram scale in segmented flow from chromium nitrate and sodium nitrate using a segregated flow water-in-oil emulsion drying process. Microfluidic processing is an environmentally friendly and rapid synthetic method, which can produce large-scale industrial implementation for the production of materials with superior properties. The reaction time for NaCrO2 particles was reduced by almost one order of magnitude compared to a normal flask synthesis and by several orders of magntitude compared to a conventional solid-state reaction. In addition, it allows for an easy upscaling and was generalized for the synthesis of other layered oxides NaMO2 (M = Cr, Fe, Co, Al). The automated water-in-oil emulsion approach circumvents the diffusion limits of solid-state reactions by allowing a rapid intermixing of the components at a molecular level in submicrometer-sized micelles. A combination of Raman and nuclear magnetic resonance spectroscopy (1H, 23Na), thermal analysis, X-ray diffraction and high resolution transmission electron microscopy provided insight into the formation mechanism of NaCrO2 particles. The new synthesis method allows cathode materials of different types to be produced in a large scale, constant quality and in short reaction times in an automated manner.

The Role of Self-Efficacy, Work-Related Autonomy and Work-Family Conflict on Employee's Stress Level during Home-Based Remote Work in Germany.

Home-based remote work becomes increasingly popular. The facets of remote work, especially working from home, are multifaceted and can become stressors that affect a person's health. At the same time, self-efficacy is an important personal resource to deal with health-related stressors. The objective of this study is therefore to explore the relationship between self-efficacy (SE), work-related stress (WRS), health outcomes (health and anxiety), contributing factors (autonomy and experience) and work-family conflict (WFC) in a remote work setting. Using a PLS-model (partial least square) with a sample of n = 5163 responses, we found that SE significantly reduces WRS (ß = −0.164; p < 0.001). Moreover, WFC increases WRS and anxiety, while SE reduces WFC and mediates health outcomes (anxiety: ß = −0.065; p < 0.001; health: ß = −0.048; p < 0.001). At the same time, autonomy (ß = 0.260; p < 0.001) and experience (ß = 0.215; p < 0.001) increase SE. Our results have high practical implications for employers and employees, underlining the importance of self-efficacy as a personal resource to buffer WRS and WFC while promoting overall health at the same time.

The Irish cattle population structured by enterprise type: overview, trade & trends.

BACKGROUND: The cattle sector is the most important economic production unit of the Irish farming and agri-food sector. Despite its relevance, there has been limited quantitative information about the structure of differing cattle production types and of the connections between them. This paper addresses this gap by providing, for the first time, an overview of the Irish cattle population structured by enterprise type. METHODS & RESULTS: We collected data from the cattle register for the period 2015 to 2019 and assigned registered herds to one of 18 different herd types using a recently published herd type classification approach. This allows, for the first time, to exploring changes in enterprise types and subtypes over time, and describing the movements between these subtypes and from these subtypes to slaughter. CONCLUSIONS: The overview and associated classification presented in this study will form the basis for a number of future comparative studies, including cross-sectoral assessments of profitability, estimation of the extent of animal health losses on Irish cattle farms or structural analysis of Greenhouse Gas (GHG) emissions across production systems.

Model-based extrapolation of ecological systems under future climate scenarios: The example of Ixodes ricinus ticks.

Models can be applied to extrapolate consequences of climate change for complex ecological systems in the future. The acknowledged systems' behaviour at present is projected into the future considering climate projection data. Such an approach can be used to addresses the future activity and density of the castor bean tick Ixodes ricinus, the most widespread tick species in Europe. It is an important vector of pathogens causing Lyme borreliosis and tick-borne encephalitis. The population dynamics depend on several biotic and abiotic factors. Such complexity makes it difficult to predict the future dynamics and density of I. ricinus and associated health risk for humans. The objective of this study is to force ecological models with high-resolution climate projection data to extrapolate I. ricinus tick density and activity patterns into the future. We used climate projection data of temperature, precipitation, and relative humidity for the period 1971-2099 from 15 different climate models. Tick activity was investigated using a climate-driven cohort-based population model. We simulated the seasonal population dynamics using climate data between 1971 and 2099 and observed weather data since 1949 at a specific location in southern Germany. We evaluated derived quantities of local tick ecology, e.g. the maximum questing activity of the nymphal stage. Furthermore, we predicted spatial density changes by extrapolating a German-wide tick density model. We compared the tick density of the reference period (1971-2000) with the counter-factual densities under the near-term scenario (2012-2041), mid-term scenario (2050-2079) and long-term scenario (2070-2099). We found that the nymphal questing peak would shift towards early seasons of the year. Also, we found high spatial heterogeneity across Germany, with predicted hotspots of up to 2,000 nymphs per 100 m2 and coldspots with constant density. As our results suggest extreme changes in tick behaviour and density, we discuss why caution is needed when extrapolating climate data-driven models into the distant future when data on future climate drive the model projection.

Zebrafish mutants in vegfab can affect endothelial cell proliferation without altering ERK phosphorylation and are phenocopied by loss of PI3K signaling.

The formation of appropriately patterned blood vessel networks requires endothelial cell migration and proliferation. Signaling through the Vascular Endothelial Growth Factor A (VEGFA) pathway is instrumental in coordinating these processes. mRNA splicing generates short (diffusible) and long (extracellular matrix bound) Vegfa isoforms. The differences between these isoforms in controlling cellular functions are not understood. In zebrafish, vegfaa generates short and long isoforms, while vegfab only generates long isoforms. We found that mutations in vegfaa had an impact on endothelial cell (EC) migration and proliferation. Surprisingly, mutations in vegfab more strongly affected EC proliferation in distinct blood vessels, such as intersegmental blood vessels in the zebrafish trunk and central arteries in the head. Analysis of downstream signaling pathways revealed no change in MAPK (ERK) activation, while inhibiting PI3 kinase signaling phenocopied vegfab mutant phenotypes in affected blood vessels. Together, these results suggest that extracellular matrix bound Vegfa might act through PI3K signaling to control EC proliferation in a distinct set of blood vessels during angiogenesis.

Workplace health promotion interventions for nurses in Germany: a systematic review based on the RE-AIM framework.

BACKGROUND: The German health care system is faced with a serious shortage of nurses. This is associated, amongst other things, with difficult working conditions and work-related health burdens. Workplace health promotion (WHP) is considered a promising approach to promote the health of nurses. The present review aims to give an overview on existing interventions in different nursing settings (acute care hospitals, long-term care (LTC) facilities and home-based long-term care) in Germany. METHODS: A systematic literature search was conducted in PubMed and PubPsych. Studies were included if published after 2010 and provided data of intervention studies on workplace health promotion among nurses in Germany (RCTs, non-RCTs, non-controlled intervention studies and pilot studies). The setting in which the study was conducted (acute medical care hospital, inpatient LTC facilities, home-based LTC, cross-setting) as well as the health issue assessed (physical health, mental health and/or violence experience) were extracted. The intervention was reported against the background of the quality criteria for prevention measures of the statutory health insurers in Germany. The results of the studies were presented according to the RE-AIM framework. RESULTS: Eleven studies on WHP for nurses were included, whereof seven studies were conducted in acute medical care hospitals and four in LTC facilities. No study reported results on WHP for nurses working in the setting of home-based LTC. Most studies aimed at improving mental health. The intervention contents and forms of implementation were heterogeneous. According to the RE-AIM criteria, the reporting of most studies showed several limitations, especially a lack of reporting on Implementation and Adoption. Most studies showed no statistically significant effect on the respective outcomes (Effectiveness). Four studies reported results on Maintenance indicating a sustained effectiveness. CONCLUSION: Despite the high relevance for health promotion for nurses, our review showed a striking lack of intervention studies in this field. From this we derive a high need of tailored interventions, taking into account the setting-specific development, implementation of WHP interventions for nurses. With regard to the evaluation, the RE-AIM criteria should be taken more into account in order to meet the requirements of evaluating complex interventions and thus contribute to evidence development of WHP in nursing. In terms of content, the topic of violence prevention and dealing with experiences of violence should also be taken into account. Regarding the settings, the working conditions and health burdens in LTC facilities, home-based LTC and acute medical hospitals must be considered. TRIAL REGISTRATION: PROSPERO registration number: CRD42021231891.

Synergistic Effects of Surface Coating and Bulk Doping in Ni-Rich Lithium Nickel Cobalt Manganese Oxide Cathode Materials for High-Energy Lithium-Ion Batteries.

Invited for this month's cover is a combined work of the Helmholtz Institute Münster together with the MEET Battery Research Center and the Universities of Münster and Mainz. The cover shows multiple treatment choices for the modification of cathode active materials for lithium-ion batteries. Similar to a car wash program, the treatment will typically result in an improvement of the status quo. However, the best treatment procedure will only become clear if all modification pathways are explored. The Research Article itself is available at 10.1002/cssc.202102220.

Pneumonia in pediatric critical care medicine and the adherence to guidelines.

BACKGROUND: Different studies in adults reported significant outcome improvement for patients treated with high adherence to guidelines. The present study was initiated to evaluate the impact of adherence to antibiotic prescription guidelines on health outcomes of children on pediatric Intensive Care Unit (PICU) suffering from pneumonia. METHODS: This retrospective cohort study was conducted on a pediatric Intensive Care Unit at Charité Hospital Berlin. All patients with a length of stay (LOS) >24 hours, age <18 years, antimicrobial therapies, and a radiologically confirmed diagnosis of pneumonia according to the "Centers for Disease Control and Prevention" definitions were included during the study period of 2009 and 2010. Adherence to national guidelines was evaluated daily and two groups were defined: Low adherence group (LAG) with a presence of <70% of days with compliant therapy and high adherence group (HAG) with an adherence of ≥70%. RESULTS: High adherence was observed in 65 patients compared with 61 in low-adherence group. Number of patients needing invasive ventilation did not vary between HAG and LAG (N.=37 vs. N.=41; P=0.235). There was a statistically significant shorter duration of ventilation in HAG patients (P=0.031). Time to clinical recovery from pneumonia tended to be shorter in HAG patients (7.5d vs. 10.9d; P=0.07). There was a significant reduction in LOS in HAG patients (9.3d vs. 13.7d; P=0.016). However, mortality appeared comparable between groups. CONCLUSIONS: Similar to previous evidence in adult patients, children with pneumonia seem to benefit from guideline-based antibiotic therapy. Further studies are needed to explore strategies to improve guideline adherence.