Search

•Biotransformation of acetic acid from cheese whey permeate using Acetobacters.•Acetic acid yield prediction through artificial neural network (ANN).•ANNs capture non-linear relationship between governing parameters and yield.•Average R2> 0.99 and RMSE ≃ 0.03 signifies high ANN model accuracy.

The Discrete element method (DEM) is a robust numerical tool for simulating crack propagation and wear in granular materials. However, the computational cost associated with DEM hinders its applicability to large domains. To address this limitation, we employ DEM to model regions experiencing crack propagation and wear, and utilize the finite element method (FEM) to model regions experiencing small deformation, thus reducing the computational burden. The two domains are linked using a FEM–DEM coupling, which considers an overlapping region where the deformation of the two domains is reconciled. We employ a “strong coupling” formulation, in which each DEM particle in the overlapping region is constrained to an equivalent position obtained by nodal interpolation in the finite element. While the coupling method has been proved capable of handling propagation of small-amplitude waves between domains, we examine in this paper its accuracy to efficiently model for material failure events. We investigate two cases of material failure in the DEM region: the first one involves mode I crack propagation, and the second one focuses on rough surfaces’ shearing leading to debris creation. For each, we consider several DEM domain sizes, representing different distances between the coupling region and the DEM undergoing inelasticity and fracture. The accuracy of the coupling approach is evaluated by comparing it with a pure DEM simulation, and the results demonstrate its effectiveness in accurately capturing the behavior of the pure DEM, regardless of the placement of the coupling region.

ABSTRACTIn 2008, the Council for Social Work Education re-envisioned its accreditation framework. The primary intent was to advance more equitable social work educational environments, which required highlighting curriculum content, and the culture of human interchange. Still, little has been provided regarding their intersectional effects on classroom culture, or students’ educational experiences. To respond to this gap, this study explores the realities of 17 African-American male social work students attending predominantly White collegiate institutions. Interpretive phenomenological analysis, social dominance theory, and Foucauldian power were used to explore and contextualize participants’ experiences. Major findings highlight the nuanced ways gender and race intersect with power, curriculum, and pedagogical practices to protect and promote historically normative structures of racial dominance within social work education.

ABSTRACT:Objective:Isocitrate dehydrogenase (IDH) mutation status is a key diagnostic and prognostic feature of gliomas. It is thought to occur early in glioma tumorigenesis and remain stable over time. However, there are reports documenting a loss of IDH mutation status in a subset of patients with glioma recurrence. Here, we identified patients with a documented loss of IDH mutation status longitudinally and performed multi-platform analysis in order to determine if IDH mutations are stable throughout glioma evolution.Methods:We retrospectively identified patients from our institution from 2009 to 2018 with immunohistochemistry (IHC)-recorded IDH mutation status changes longitudinally. Archived formalin-fixed paraffin-embedded and frozen tissue samples from these patients were collected from our institution’s tumour bank. Samples were analysed using methylation profiling, copy number variation, Sanger sequencing, droplet digital PCR (ddPCR) and IHC.Results:We reviewed 1491 archived glioma samples including 78 patients with multiple IDH mutant tumour samples collected longitudinally. In all instances of documented loss of IDH mutation status, multi-platform profiling identified a mixture of low tumour cell content and non-neoplastic tissue including perilesional, reactive or inflammatory cells.Conclusions:All patients with a documented loss of IDH mutation status longitudinally were resolved through multi-platform analysis. These findings support the hypothesis that IDH mutations occur early in gliomagenesis and in the absence of copy number changes at the IDH loci and are stable throughout tumour treatment and evolution. Our study highlights the importance of accurate surgical sampling and the role of DNA methylome profiling in diagnostically uncertain cases for integrated pathological and molecular diagnosis.

Understanding the interplay between bright and dark exciton states is crucial for deciphering the luminescence properties of low-dimensional materials. The origin of the outstanding brightness of lead halide perovskites remains elusive. Here, we analyze temperature-dependent time-resolved photoluminescence to investigate the population mixing between bright and dark exciton sublevels in individual CsPbBr3nanocrystals in the intermediate confinement regime. We extract bright and dark exciton decay rates and show quantitatively that the decay dynamics can only be reproduced with second-order phonon transitions. Furthermore, we find that any exciton sublevel ordering is compatible with the most likely population transfer mechanism. The remarkable brightness of lead halide perovskite nanocrystals rather stems from a reduced asymmetry between bright-to-dark and dark-to-bright conversion originating from the peculiar second-order phonon-assisted transitions that freeze bright–dark conversion at low temperatures together with the very fast radiative recombination and favorable degeneracy of the bright exciton state.

ABSTRACTIntroductionMolecular Glue Degraders (MGDs) is aconcept that refers to a class of compounds that facilitate the interactionbetween two proteins or molecules within a cell. These compounds act as bridgethat enhances specific Protein-Protein Interactions (PPIs). Over the pastdecade, this technology has gained attention as a potential strategy to targetproteins that were traditionally considered undruggable using small molecules.AreasCoveredThis review presents the concept of cellular homeostasis and the balancebetween protein synthesis and protein degradation. The concept of proteindegradation is concerned with molecular glues, which form part of the broaderfield of Targeted Protein Degradation (TPD). Next, pharmacochemical strategiesfor the rational design of MGDs are detailed and illustrated by examples ofLigand-Based (LBDD), Structure-Based (SBDD) and Fragment-Based Drug Design(FBDD).Expert opinionExpanding the scope of what can beeffectively targeted in the development of treatments for diseases that areincurable or resistant to conventional therapies offers new therapeutic options.The treatment of microbial infections and neurodegenerative diseases is a majorsocietal challenge, and the discovery of MGDs appears to be a promising avenue.Combining different approaches to discover and exploit a variety of innovativetherapeutic agents will create opportunities to treat diseases that are stillincurable.

The present study explores the relationship between bullying victimization and suicidal thoughts among African American adolescents in urban neighborhoods. The study, which was guided by the general strain theory, proposed and tested potential pathways that link bullying victimization with suicidal thoughts through the mediators including emotional distress, low future orientation, hopelessness, and drug use. The study sample included 414 African American adolescents who were between ages 12 and 22 years and residing in low-income Chicago's South Side neighborhoods. Descriptive statistics, bivariate correlation, and path analyses were conducted. Bullying victimization was not significantly related to suicidal thoughts, although it was positively associated with emotional distress and drug use. The association between low future orientation and hopelessness was bidirectional. The study findings have implications for practice, which is important as resources to assist adolescents who are affected by violence tend to be limited.

Brain metastases (BMs) are the most common and among the deadliest brain tumors. Currently, there are no reliable predictors of BM development from primary cancer, which limits early intervention. Lung adenocarcinoma (LUAD) is the most common BM source and here we obtained 402 tumor and plasma samples from a large cohort of patients with LUAD with or without BM (n= 346). LUAD DNA methylation signatures were evaluated to build and validate an accurate model predicting BM development from LUAD, which was integrated with clinical factors to provide comprehensive patient-specific BM risk probabilities in a nomogram. Additionally, immune and cell interaction gene sets were differentially methylated at promoters in BM versus paired primary LUAD and had aligning dysregulation in the proteome. Immune cells were differentially abundant in BM versus LUAD. Finally, liquid biomarkers identified from methylated cell-free DNA sequenced in plasma were used to generate and validate accurate classifiers for early BM detection. Overall, LUAD methylomes can be leveraged to predict and noninvasively identify BM, moving toward improved patient outcomes with personalized treatment.

In this paper, we present a grouping maintenance approach that allows efficiently considering economic dependence between components and also the impact of dynamic context such as changes in the degradation process, limited number of maintenance teams, occurrence of maintenance opportunities, etc. A real industrial case study is used to investigate the applicability and the robustness of the dynamic grouping maintenance approach in the maintenance optimization framework.

Reconfigurable Manufacturing Systems (RMSs) have been proposed to bolster resilience and to efficiently address rapid changes in customer needs. However, notable obstacles to their adoption still persist, such as insufficient integration into operations and inadequate incorporation of distributed control. In this paper, we present a 2-pillar conceptual architecture for enabling the operational integration of RMSs through interoperable Digital Twins (DTs) and propose avenues to enhance their capabilities with distributed and global intelligence technologies. To this end, utilizing DTs based on industrial standards promotes modularity and integrability. Moreover, it enables leveraging decision support methods and tools that may consider economic, energy and environmental aspects at different production levels (from machine level to the whole production system), thus offering a comprehensive framework to enhance adaptability, resilience, and sustainability in RMS.

In the modern industrial landscape, reconfigurable manufacturing systems (RMS) have emerged as a crucial element due to their rapid responsiveness and cost effectiveness to market fluctuations. This importance is demonstrated in the current industrial environment and shows significant potential in the coming era of manufacturing. Maintenance plays an important role in modern industry paradigms to ensure systems are reliable and operate efficiently. However, the integration of maintenance scheduling processes in RMS has not been significantly explored, opening new research directions. This literature review addresses this gap by systematically examining the existing works into two databases of peer-reviewed literature: Scopus and Web of Science. The purpose of this review is to provide a comprehensive understanding of the current state of the art of maintenance methods in RMS, highlighting the need for further investigation. The selected articles were analyzed and synthesized to provide insights into different maintenance strategies related to RMS under two criteria: Maintenance modeling, maintenance policy and optimization. This study also highlights the need to develop enhanced maintenance policies and methods specifically designed for RMS and describes the research challenges and opportunities that lie ahead. In doing so, it seeks to advance future research efforts and serve as a valuable resource for both researchers and practitioners in the field, paving the way for innovation and advances in RMS maintenance.

In the Industry 4.0 environment, the maintenance of industrial assets is of increasing importance, and, in this domain, the recently emerged technology of Cognitive Digital Twin (CDT) is particularly suitable for the satisfaction of today’s manufacturers’ needs for flexibility, dynamism, broad vision of the systems, and responsiveness to stimuli. Although this technology shows considerable potential in supporting the execution of maintenance applications with minimum human intervention, in most cases the to-date technological level is not capable of achieving full automation, making the human role still fundamental in relation to the existing Digital Twin (DT) technologies. In this context, this paper proposes the development of an ontology-based DT aiming at supporting the maintenance fault diagnosis decision-making process in manufacturing systems through the synergistic exploitation of the maintenance ontology KARMA supported by algorithms and database technologies integrated with human knowledge. The solution is meant to enable the cognitive capabilities leading toward the CDT concept. The ontology-based Digital Twin has been applied and assessed in the reality-like facility TELMA, at the Research Center for Automatic Control (CRAN) in Nancy, through the implementation of a fault scenario.

AbstractA limited number of findings from empirical studies show that biracial adolescents are at a heightened risk of peer victimization. Black/White biracial adolescents are frequent targets of peer victimization due to racism and systematic oppression that are inherent in U.S. schools. Similar to adolescents of other racial and ethnic groups, biracial adolescents who are victimized by their peers are likely to exhibit psychosocial and behavioral issues. However, little is known about protective factors that might buffer the link between peer victimization and adverse outcomes of these youth. The study examines whether perceived ease of talking with parents and siblings moderates the association between peer victimization and psychosocial problems among Black/White biracial early adolescents. Data were derived from the Health Behavior in School-Aged Children (HBSC) study. Participants were 158 early adolescents, ages 10–14, who self-reported as both Black and White. Adolescents who perceived their fathers as easy to talk to were less likely to bully others or carry a weapon when victimized by their peers. Adolescents who perceived their mothers to be easy to talk to were less likely to carry a weapon. There were also lower rates of psychosomatic symptoms for youth who reported perceived ease talking with siblings.Impact StatementThe current study is one of the few empirical studies that examined the association between peer victimization and adverse psychosocial wellbeing as well as protective factors that buffer this association among a sample of Black/White biracial adolescents. Findings from this study contribute to a growing demand for additional research on biracial adolescents and their peer victimization experiences, which provides concrete insights for possible interventions. In this perspective, the study findings can also bring relevance to the development and implementation of antibullying programs that are culturally appropriate for biracial adolescents.

A sarcophagus found in Tarquinia at the end of the 19th century discloses an original iconography featuring infernal scenes with banqueters, Turms, Vanth, and winged snakes. One interpretation proposed in the 1990s was that this monument bears witness to esoteric doctrines of Greek origin in Etruria, in particular Orphism and Pythagoreanism. However, this proposal is not satisfactory and needs to be reconsidered. It seems more likely that this sarcophagus refers to the world of perfumes and, potentially, to the well-known anecdote of the flying snakes guarding the frankincense trees. This new interpretation sheds further light on the role of scents in Etruria, particularly in the world of the dead.

Strong electric field annihilation by particle–antiparticle pair creation, also known as the Schwinger effect, is a non-perturbative prediction of quantum electrodynamics. Its experimental demonstration remains elusive, as threshold electric fields are extremely strong and beyond current reach. Here, we propose a mesoscopic variant of the Schwinger effect in graphene, which hosts Dirac fermions with an approximate electron–hole symmetry. Using transport measurements, we report on universal one-dimensional Schwinger conductance at the pinchoff of ballistic graphene transistors. Strong pinchoff electric fields are concentrated within approximately 1 μm of the transistor’s drain and induce Schwinger electron–hole pair creation at saturation. This effect precedes a collective instability towards an ohmic Zener regime, which is rejected at twice the pinchoff voltage in long devices. These observations advance our understanding of current saturation limits in ballistic graphene and provide a direction for further quantum electrodynamic experiments in the laboratory.

Nosema ceranaeinfects midgut epithelial cells of the Apisspecies and has jumped from its original host A. ceranato A. melliferaworldwide, raising questions about the response of the new host. We compared the responses of these two species to N. ceranaeisolates from A. cerana, A. melliferafrom Thailand and A. melliferafrom France. Proteomics and transcriptomics results were combined to better understand the impact on the immunity of the two species. This is the first combination of omics analyses to evaluate the impact of N. ceranaespores from different origins and provides new insights into the differential immune responses in honeybees inoculated with N. ceranaefrom original A. cerana. No difference in the antimicrobial peptides (AMPs) was observed in A. mellifera, whereas these peptides were altered in A. ceranacompared to controls. Inoculation of A. melliferaor A. ceranawith N. ceranaeupregulated AMP genes and cellular-mediated immune genes but did not significantly alter apoptosis-related gene expression. A. ceranashowed a stronger immune response than A. melliferaafter inoculation with different N. ceranaeisolates. N. ceranaefrom A. ceranahad a strong negative impact on the health of A. melliferaand A. ceranacompared to other Nosemaisolates.

Le corticosurrénalome (CCS) est un cancer souvent diagnostiqué tardivement avec des métastases chez 35 % des patients et qui touche principalement les femmes. Les approches thérapeutiques actuelles ont peu d’impact sur la survie globale qui reste inférieure à 15 mois. Afin d’identifier de nouveaux leviers thérapeutiques, nous avons développé un modèle de souris déficient pour Znrf3(Znrf3 KO), l’altération la plus fréquemment retrouvée chez les patients. L’inactivation de Znrf3 conduit, comme chez les patients, à un développement tumoral sexuellement dimorphique : les femelles développent une hyperplasie conduisant progressivement à la formation de carcinomes métastatiques, tandis que les mâles présentent une régression de cette hyperplasie via le recrutement de macrophages tumoricides. Nos résultats montrent que le traitement à la testostérone des femelles Znrf3 KO inhibe la progression tumorale et la dissémination métastatique, en permettant le recrutement de ces macrophages [1]. La testostérone présentant des effets secondaires potentiellement incompatibles avec son utilisation en clinique, notre objectif est d’identifier son mode d’action antitumoral. Nos résultats préliminaires montrent que le traitement de souris Znrf3 KO femelles par la testostérone inhibe l’expression de l’oncogène MYC, conduisant à un blocage du cycle, une accumulation de cassures ADN, et un déclenchement de sénescence et d’apoptose, associées au recrutement de macrophages tumoricides. Ces résultats suggèrent que des traitements ciblant la réparation de l’ADN et l’induction de la sénescence et/ou de l’apoptose pourraient remplacer efficacement la testostérone dans le contexte du CCS.

p21Cip1(p21) is a universal cyclin-dependent kinase (CDK) inhibitor that halts cell proliferation and tumor growth by multiple mechanisms. The expression of p21 is often downregulated in cancer cells as a result of the loss of function of transcriptional activators, such as p53, or the increased degradation rate of the protein. To identify small molecules that block the ubiquitin-mediated degradation of p21 as a future avenue for cancer drug discovery, we have screened a compound library using a cell-based reporter assay of p21 degradation. This led to the identification of a benzodiazepine series of molecules that induce the accumulation of p21 in cells. Using a chemical proteomic strategy, we identified the ubiquitin-conjugating enzyme UBCH10 as a cellular target of this benzodiazepine series. We show that an optimized benzodiazepine analogue inhibits UBCH10 ubiquitin-conjugating activity and substrate proteolysis by the anaphase-promoting complex.

Designing diagnostic assays to genotype rapidly mutating viruses remains a challenge despite the overall improvements in nucleic acid detection technologies. RT-PCR and next-generation sequencing are unsuitable for genotyping during outbreaks or in point-of-care detection due to their infrastructure requirements and longer turnaround times. We developed a quantum dot barcode multiplexing system to genotype mutated viruses. We designed multiple quantum dot barcodes to target conserved, wildtype, and mutated regions of SARS-CoV-2. We calculated ratios of the signal output from different barcodes that enabled SARS-CoV-2 detection and identified SARS-CoV-2 variant strains from a sample. We detected different sequence types, including conserved genes, nucleotide deletions, and single nucleotide substitutions. Our system detected SARS-CoV-2 patient specimens with 98% sensitivity and 94% specificity across 91 patient samples. Further, we leveraged our barcoding and ratio system to track the emergence of the N501Y SARS-CoV-2 mutation from December 2020 to May 2021 and demonstrated that the more transmissible N501Y mutation started to dominate infections by April 2021. Our barcoding and signal ratio approach can genotype viruses and track the emergence of viral mutations in a single diagnostic test. This technology can be extended to tracking other viruses. Combined with smartphone detection technologies, this assay can be adapted for point-of-care tracking of viral mutations in real time.

Late‐life aging is often associated with appetite reduction and weight loss. Physical activity (PA) may prevent these processes, but the molecular mechanisms involved remain elusive. The present study investigated the putative mediating aspect of growth differentiation factor 15 (GDF‐15), a stress signalling protein involved in aging, exercise and appetite control, on the association between PA and late‐life‐associated weight loss. One thousand eighty‐three healthy adults (63.8% women) aged 70 years and over who participated in the Multidomain Alzheimer Preventive Trial were included. Bodyweight (kg) and PA levels (square root of metabolic equivalent of task‐min/week) were assessed repeatedly from baseline to the 3‐year visit, whereas plasma GDF‐15 (pg/mL) was measured at the 1‐year visit. Multiple linear regressions were performed to test the association between first‐year mean PA level, 1‐year visit GDF‐15 concentration and subsequent bodyweight changes. Mediation analyses were used to investigate whether GDF‐15 mediated the association between first‐year mean PA levels and consecutive bodyweight changes. Multiple regression analyses demonstrated that higher first‐year mean PA levels significantly predicted lower GDF‐15 and bodyweight at 1 year (B = −2.22; SE = 0.79; P= 0.005). In addition, higher 1‐year visit GDF‐15 levels were associated with faster subsequent bodyweight loss (Time × GDF‐15 interaction B = −0.0004; SE = 0.0001; P= 0.003). Mediation analyses confirmed that GDF‐15 mediated the association between first‐year mean PA levels and subsequent bodyweight changes (mediated effect ab = 0.0018; bootstrap SE = 0.001; P< 0.05) and revealed that mean PA had no direct effect on subsequent bodyweight changes (c′ = 0.006; SE = 0.008; P> 0.05). This study suggests that GDF‐15 may be one of the molecules mediating the link between PA and late‐life weight loss, but mechanistic studies are necessary to further support the present findings.

UBE2N protein belongs to the UE2s family and plays a crucial role in DNA repair, making it an exciting target for the development of innovative anticancer therapies. With the aim of discovering UBE2N inhibitors (UBE2Ni), this perspective seeks to review and provide elements to guide the design of new compounds. We propose a chemoinformatic structural analysis of the protein and its areas of interaction with its different partners. While covalent UBE2Ni are the most advanced molecules in their development, noncovalent inhibitors offer significant advantages that could overcome the limitations of covalent ones, particularly in terms of selectivity. Lastly, to obtain a drug candidate, early assessment of the druggability of compounds is essential in a hit to lead process. For existing UBE2Ni, a critical challenge lies in their pharmacokinetic properties and will obviously have to be considered as early as possible to hope for an application in human therapy.

Background: During aging, the human methylome undergoes both differential and variable shifts, accompanied by increased entropy. The distinction between variably methylated positions (VMPs) and differentially methylated positions (DMPs), their contribution to epigenetic age, and the role of cell type heterogeneity remain unclear. Results: We conduct a comprehensive analysis of > 32,000 human blood methylomes from 56 datasets (age range = 6–101 years). We find a significant proportion of the blood methylome that is differentially methylated with age (48% DMPs; FDR &lt; 0.005) and variably methylated with age (37% VMPs; FDR &lt; 0.005), with considerable overlap between the two groups (59% of DMPs are VMPs). Bivalent and Polycomb regions become increasingly methylated and divergent between individuals, while quiescent regions lose methylation more uniformly. Both chronological and biological clocks, but not pace-of-aging clocks, show a strong enrichment for CpGs undergoing both mean and variance changes during aging. The accumulation of DMPs shifting towards a methylation fraction of 50% drives the increase in entropy, smoothening the epigenetic landscape. However, approximately a quarter of DMPs exhibit anti-entropic effects, opposing this direction of change. While changes in cell type composition minimally affect DMPs, VMPs and entropy measurements are moderately sensitive to such alterations. Conclusion: This study represents the largest investigation to date of genome-wide DNA methylation changes and aging in a single tissue, providing valuable insights into primary molecular changes relevant to chronological and biological aging.

Hydrogels were prepared at high solid contents (70–100 g/L) with cellulose nanocrystals (CNC) and very short xyloglucans (XGs). At 70 g/L, CNCs form cholesteric liquid crystals regularly spaced by a distance of 30 nm. This structure was preserved after adsorption of XG with a molar mass (Mw) of 20,000 g/mol (XG20) but was lost at 40,000 g/mol (XG40). Rheological measurements discriminated domains where an increasing Mwfrom XG20 to XG40 gave rise to drastic changes in storage moduli (on 3 orders of magnitude). At 40,000 g/mol, transient systems were obtained and a re-entrant glass–gel–glass transition was observed with increasing XG concentrations. This was interpreted in terms of the length and stiffness of the chain in relation to the inter-CNC distance. Liquid-to-glass-to-gel transitions were attributed to an XG adsorption type according to train or trail conformations or interconnected structures. Such tunable properties may further have implications on the in vivo role of XG during cell wall extension.

Factory of the Future and Industry 4.0 bring new challenges for manufacturing systems. At the same time, new maintenance strategies have become a major pillar to keep manufacturing systems performances and competitiveness. Such strategies allow to anticipate failure thanks to prognostics process. As such, promising prognostics approaches use data-driven machine learning techniques, however the recorded data set for learning is often “small” as failure occurrences are rare. Therefore, this study investigates data augmentation methods for improving prognostics by adding new samples generated from existing ones. This paper use a public prognostics data set to assess the performances of data transformation methods based on transformation hyper-parameters optimization using cross-validation.

The access to pertinent data from the implementation of new Industry 4.0 technologies has challenged and ameliorated many areas of the industry. In that way, industrial maintenance area has seen some of its deployment strategies greatly improved by data-driven deployment approaches. It is truer for predictive maintenance strategy. Indeed, for example, data-based prognostics allows calculating a RUL closer to the real degradation of the system to be maintained. However, not all the predictive maintenance processes are well addressed by the scientific community. More precisely, those related to drift detection and drift diagnosis of heterogeneous production processes are few investigated. To face this issue, the scope of this paper is to propose a methodology based on Artificial Intelligence techniques to support the development of these two processes. Then, the methodology is validated on two heterogeneous production processes of a French SEW-USOCOME factory supplying electrical motors.

As esports grow, public authorities have many concerns about the potential negative health effects of this “sedentary” practice. This work proposes a systematic review on the links between esports and physical activity (PA). The research questions guiding this review are as follows: (1) What is the PA level of esports players? (2) Do data exist regarding the influence of participation in esports on players’ PA? (3) Based on these findings, what future research questions should be asked and what studies should be conducted? Eighteen studies met the inclusion criteria. The analysis revealed that esports players appeared to be active, exceeding World Health Organization recommendations, in 13 studies and inactive or low-active in four studies. The different populations of players do not appear to have the same degree of PA. High-level, professional, and/or supervised players appear to be more physically active. However, some data are inconsistent, and our review highlights several biases and methodological limitations. Additionally, while we have found no studies providing data on the influence of esports on PA, five studies highlight several factors that could push players to engage in PA. Finally, further research is needed using objective measurement tools and characterizing and accurately distinguishing between players’ levels of expertise and the type of game played. The nature and modalities of the PA also need to be clarified. We encourage supplementing these quantitative data with qualitative data obtained through interviews to provide a description and understanding of the influence of esports on PA engagement, re-engagement, retention, and withdrawal.

Oral NEPA is the fixed‐combination antiemetic comprising netupitant (neurokinin‐1 receptor antagonist [NK1RA]) and palonosetron (5‐hydroxytryptamine‐3 receptor antagonist [5‐HT3RA]). Intravenous (IV) NEPA, containing fosnetupitant, a water‐soluble N‐phosphoryloxymethyl prodrug of netupitant, has been developed. Fosnetupitant does not require excipients or solubility enhancers often used to increase IV NK1RA water solubility, preventing the occurrence of hypersensitivity and infusion‐site reactions associated with these products. In this phase 1 study, subjects received a 30‐minute placebo or fosnetupitant (17.6–353 mg) infusion and an oral NEPA or placebo capsule, with 2‐sequence crossover treatment for fosnetupitant 118‐ to 353‐mg dose cohorts. IV fosnetupitant safety and pharmacokinetics were evaluated, and its equivalence to an oral netupitant 300‐mg dose was defined. Overall, 158 healthy volunteers were enrolled. All adverse events (AEs) were mild or moderate in intensity. Doppler‐identified infusion‐site asymptomatic thrombosis occurred in 5.4% (fosnetupitant) and 1.2% (oral NEPA) of subjects. The frequency or number of treatment‐related AEs did not increase with ascending fosnetupitant doses. The most common treatment‐related AEs were headache (fosnetupitant, 8.1%; oral NEPA, 12.7%) and constipation (fosnetupitant, 1.4%; oral NEPA, 7.5%). A fosnetupitant 235‐mg dose was equivalent, in terms of netupitant exposure, to 300‐mg oral netupitant. The safety profile of a single fosnetupitant 235‐mg infusion was similar to that of single‐dose oral NEPA.

Over time, the human DNA methylation landscape accrues substantial damage, which has been associated with a broad range of age-related diseases, including cardiovascular disease and cancer. Various age-related DNA methylation changes have been described, including at the level of individual CpGs, such as differential and variable methylation, and at the level of the whole methylome, including entropy and correlation networks. Here, we review these changes in the ageing methylome as well as the statistical tools that can be used to quantify them. We detail the evidence linking DNA methylation to ageing phenotypes and the longevity strategies aimed at altering both DNA methylation patterns and machinery to extend healthspan and lifespan. Lastly, we discuss theories on the mechanistic causes of epigenetic ageing.

Hematopoietic stem cell (HSC) dormancy is understood as supportive of HSC function and its long-term integrity. Although regulation of stress responses incurred as a result of HSC activation is recognized as important in maintaining stem cell function, little is understood of the preventive machinery present in human HSCs that may serve to resist their activation and promote HSC self-renewal. We demonstrate that the transcription factor PLAG1 is essential for long-term HSC function and, when overexpressed, endows a 15.6-fold enhancement in the frequency of functional HSCs in stimulatory conditions. Genome-wide measures of chromatin occupancy and PLAG1-directed gene expression changes combined with functional measures reveal that PLAG1 dampens protein synthesis, restrains cell growth and division, and enhances survival, with the primitive cell advantages it imparts being attenuated by addition of the potent translation activator, c-MYC. We find PLAG1 capitalizes on multiple regulatory factors to ensure protective diminished protein synthesis including 4EBP1 and translation-targeting miR-127 and does so independently of stress response signaling. Overall, our study identifies PLAG1 as an enforcer of human HSC dormancy and self-renewal through its highly context-specific regulation of protein biosynthesis and classifies PLAG1 among a rare set of bona fide regulators of messenger RNA translation in these cells. Our findings showcase the importance of regulated translation control underlying human HSC physiology, its dysregulation under activating demands, and the potential if its targeting for therapeutic benefit.

Retinal pigment epithelium (RPE) tear is a common complication in the context of neovascular age-related macular degeneration treated by intravitreal injections of antivascular endothelial growth factor drugs. There are some reports of such complications after trabeculectomy but none after nonpenetrating deep sclerectomy (NPDS). A 57-year-old man presented to our hospital with uncontrolled advanced glaucoma of his left eye. NPDS with adjunctive use of mitomycin C was performed with no intraoperative complication. On the seventh postoperative day clinical examination and multimodal imaging revealed a macular RPE tear in the operated eye. Subretinal fluid induced by the tear resolved within 2 months with an increase in intraocular pressure. To the best of our knowledge, this article discusses the first reported case of RPE tear occurring just after NPDS.

La sénescence cellulaire et les tumeurs ont une relation paradoxale, la sénescence pouvant être un mécanisme anticancéreux crucial ou un contributeur actif à la tumorigenèse, en fonction du contexte. Dans le cas du corticosurrénalome, un cancer rare et agressif du cortex surrénalien, des analyses multi-omiques des data du TCGA ont révélé que l’expression du régulateur de la sénescence cellulaire CDKN2Aou des gènes reliés à la sénescence cellulaire sont associés avec un mauvais pronostic et une faible survie. Cependant, le rôle de la sénescence comme inducteur de la croissance tumorale et/ou de la progression métastatique est encore inconnu. En utilisant un modèle de souris portant à la fois l’inactivation de Znrf3 et Trp53, les altérations les plus observées chez les patients avec des corticosurrénalomes les plus agressifs, nous avons mis en évidence la présence de cellules sénescentes dans les tumeurs primaires les plus agressives et dans les métastases correspondantes. Des analyses de single-nuclei RNASeq, de transcriptomique spatiale et d’immunohistochimie ont montré que la sénescence touche à la fois les cellules tumorales, les cellules endothéliales et les macrophages comme associés aux tumeurs. Ces derniers expriment fortement des molécules de point de contrôle immunitaire, associées à un environnement immunosuppresseur. Ces résultats suggèrent un rôle des cellules sénescentes pour favoriser la progression métastatique, notamment en inhibant la réponse immunitaire anti-tumorale. Nous évaluons donc actuellement le potentiel thérapeutique de sénolytiques, dans notre modèle murin de corticosurrénalome.