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Quasi-homoepitaxy of hexagonal boron nitride on its own interfacial insertion monolayer
We present an approach to improve the quality of hexagonal boron nitride (hBN) epilayer with a quasi-homoepitaxy mode through the utilization of a hBN interfacial insertion monolayer by using metal-organic chemical vapor deposition. First-principles calculations demonstrate that the insertion of hBN monolayer can not only eliminate the interaction from hetero-substrate but also enhance the surface migration rate during epitaxy. As a result with epitaxial growth, the reduction of initial nucleation density of hBN domains is observed, and meanwhile, the release of misfit stress and higher crystal quality are obtained. Ultimately, this research provides a quasi-homoepitaxial strategy of hBN on arbitrary hetero-substrate.
Cell enlargement modulated by GATA4 and YAP instructs the senescence-associated secretory phenotype
A biodegradable and restorative peripheral neural interface for the interrogation of neuropathic injuries
SGK1 drives hippocampal demyelination and diabetes-associated cognitive dysfunction in mice
Biochemical analyses of cystatin-C dimers and cathepsin-B reveals a trypsin-driven feedback mechanism in acute pancreatitis
Abstract Acute pancreatitis (AP) is characterised by self-digestion of the pancreas by its own proteases. This pathophysiological initiating event in AP occurs inside pancreatic acinar cells where intrapancreatic trypsinogen becomes prematurely activated by cathepsin B (CTSB), and induces the digestive protease cascade, while cathepsin L (CTSL) degrades trypsin and trypsinogen and therefore prevents the development of AP. These proteases are located in the secretory compartment of acinar cells together with cystatin C (CST3), an endogenous inhibitor of CTSB and CTSL. The results are based on detailed biochemical analysis, site-directed mutagenesis and molecular dynamics simulations in combination with an experimental disease model of AP using CST3 deficient mice. This identifies that CST3 is a critical regulator of CTSB and CTSL activity during AP. CST3 deficient mice show a higher intracellular CTSB activity resulting in elevated trypsinogen activation accompanied by an increased disease severity. This reveals that CST3 can be cleaved by trypsin disabling the inhibition of CTSB, but not of CTSL. Furthermore, dimerised CST3 enhances the CTSB activity by binding to an allosteric pocket specific to the CTSB structure. CST3 shifts from an inhibitor to an activator of CTSB and therefore fuels the intrapancreatic protease cascade during the onset of AP.
Resolving discrepancies between chimeric and multiplicative measures of higher-order epistasis
Abstract Epistasis - the interaction between alleles at different genetic loci - plays a fundamental role in biology. However, several recent approaches quantify epistasis using a chimeric formula that measures deviations from a multiplicative fitness model on an additive scale, thus mixing two scales. Here, we show that for pairwise interactions, the chimeric formula yields a different magnitude but the same sign of epistasis compared to the multiplicative formula that measures both fitness and deviations on a multiplicative scale. However, for higher-order interactions, we show that the chimeric formula can have both different magnitude and sign compared to the multiplicative formula. We resolve these inconsistencies by deriving mathematical relationships between the different epistasis formulae and different parametrizations of the multivariate Bernoulli distribution. We argue that the chimeric formula does not appropriately model interactions between the Bernoulli random variables. In simulations, we show that the chimeric formula is less accurate than the classical multiplicative/additive epistasis formulae and may falsely detect higher-order epistasis. Analyzing multi-gene knockouts in yeast, multi-way drug interactions in E. coli, and deep mutational scanning of several proteins, we find that approximately 10% to 60% of inferred higher-order interactions change sign using the multiplicative/additive formula compared to the chimeric formula.
Author Correction: Hallmarks of a genomically distinct subclass of head and neck cancer
Effectiveness of strain and dopants on breaking the activity-stability trade-off of RuO2 acidic oxygen evolution electrocatalysts
A roadmap to precision medicine through post-genomic electronic medical records
Author Correction: Acute particulate matter exposure diminishes executive cognitive functioning after four hours regardless of inhalation pathway
Impact of household size and co-resident multimorbidity on unplanned hospitalisation and transition to care home
Abstract The ability to manage ill health and care needs might be affected by who a person lives with. This study examined how the risk of unplanned hospitalisation and transition to living in a care home varied according to household size and co-resident multimorbidity. Here we show results from a cohort study using Welsh nationwide linked healthcare and census data, that employed multilevel multistate models to account for the competing risk of death and clustering within households. The highest rates of unplanned hospitalisation and care home transition were in those living alone. Event rates were lower in all shared households and lowest when co-residents did not have multimorbidity. These differences were more substantial for care home transition. Therefore, living alone or with co-residents with multimorbidity poses additional risk for unplanned hospitalisation and care home transition beyond an individual’s sociodemographic and health characteristics. Understanding the mechanisms behind these associations is necessary to inform targeted intervention strategies.
CHAMP1 complex directs heterochromatin assembly and promotes homology-directed DNA repair
BMP signaling promotes zebrafish heart regeneration via alleviation of replication stress
Abstract In contrast to mammals, adult zebrafish achieve complete heart regeneration via proliferation of cardiomyocytes. Surprisingly, we found that regenerating cardiomyocytes experience DNA replication stress, which represents one reason for declining tissue regeneration during aging in mammals. Pharmacological inhibition of ATM and ATR kinases revealed that DNA damage response signaling is essential for zebrafish heart regeneration. Manipulation of Bone Morphogenetic Protein (BMP)-Smad signaling using transgenics and mutants showed that BMP signaling alleviates cardiomyocyte replication stress. BMP signaling also rescues neonatal mouse cardiomyocytes, human fibroblasts and human hematopoietic stem and progenitor cells (HSPCs) from replication stress. DNA fiber spreading assays indicate that BMP signaling facilitates re-start of replication forks after replication stress-induced stalling. Our results identify the ability to overcome replication stress as key factor for the elevated zebrafish heart regeneration capacity and reveal a conserved role for BMP signaling in promotion of stress-free DNA replication.
Determining human resource management key indicators and their impact on organizational performance using deep reinforcement learning
Effectiveness of a hepatitis E vaccine against medically-attended symptomatic infection in HBsAg-positive adults from a test-negative design study
Impact of Covid-19 pandemic on trajectories of patients with severe alcohol use disorder treated with disulfiram
Abstract The manifestations and progression of alcohol use disorder (AUD) are influenced by a number of contextual factors, with the current coronavirus pandemic being a significant example. This pandemic has profoundly impacted nearly all aspects of human life and has, therefore, strongly influenced patients suffering from AUD. In some cases, the pandemic has led to a reduction in severity, while in others, it has had the opposite effect. In our own work we have been investigating the negative impact of the pandemic on 45 patients with AUD who were undergoing outpatient treatment, including supervised use of disulfiram (Antabuse), in a close-knit program. A linear trend analysis demonstrated significant alterations in the retention rate over a 3-year period, encompassing the pre-pandemic, pandemic, and post-pandemic periods. During the pandemic the number of treatment cancellations virtually increased. Following the pandemic, a tendency towards the normalization of patient numbers was observed. Our data indicate a high level of vulnerability among patients with severe AUD and highlight a need for the development of alternative, possibly telemedical, treatment methods.
Time-resolved X-ray solution scattering unveils the events leading to hemoglobin heme capture by staphylococcal IsdB
STK11 genetic alterations in metastatic EGFR mutant lung cancer
Autonomous platform for solution processing of electronic polymers
Abstract The manipulation of electronic polymers’ solid-state properties through processing is crucial in electronics and energy research. Yet, efficiently processing electronic polymer solutions into thin films with specific properties remains a formidable challenge. We introduce Polybot, an artificial intelligence (AI) driven automated material laboratory designed to autonomously explore processing pathways for achieving high-conductivity, low-defect electronic polymers films. Leveraging importance-guided Bayesian optimization, Polybot efficiently navigates a complex 7-dimensional processing space. In particular, the automated workflow and algorithms effectively explore the search space, mitigate biases, employ statistical methods to ensure data repeatability, and concurrently optimize multiple objectives with precision. The experimental campaign yields scale-up fabrication recipes, producing transparent conductive thin films with averaged conductivity exceeding 4500 S/cm. Feature importance analysis and morphological characterizations reveal key design factors. This work signifies a significant step towards transforming the manufacturing of electronic polymers, highlighting the potential of AI-driven automation in material science.