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Abstract Nuclear pore complexes (NPCs) have increasingly recognized interactions with the genome, as exemplified in yeast, where they bind transcribed or damaged chromatin. By combining genome-wide approaches with live imaging of model loci, we uncover a correlation between NPC association and the accumulation of R-loops, which are genotoxic structures formed through hybridization of nascent RNAs with their DNA templates. Manipulating hybrid formation demonstrates that R-loop accumulation per se, rather than transcription or R-loop-dependent damages, is the primary trigger for relocation to NPCs. Mechanistically, R-loop-dependent repositioning involves their recognition by the ssDNA-binding protein RPA, and SUMO-dependent interactions with NPC-associated factors. Preventing R-loop-dependent relocation leads to lethality in hybrid-accumulating conditions, while NPC tethering of a model hybrid-prone locus attenuates R-loop-dependent genetic instability. Remarkably, this relocation pathway involves molecular factors similar to those required for the association of stalled replication forks with NPCs, supporting the existence of convergent mechanisms for sensing transcriptional and genotoxic stresses.

Abstract In this paper, we address the problem of optimal measurement budget allocation to estimate the state of a linear discrete-time dynamical system over a finite horizon. More precisely, our aim is to select the measurement times in order to minimize the variance of the estimation error over a finite horizon. In addition, we investigate the closely related problem of finding a trade-off between number of measurements and signal to noise ratio.First, the optimal measurement budget allocation problem is reduced to a deterministic combinatorial program. Then, we propose a genetic algorithm implementing a count preserving crossover to solve it. On the theoretical side, we provide a one-dimensional analysis that indicates that the benefit of using irregular measurements grows when the system is unstable or when the process noise becomes important. Then, using the duality between estimation and control, we show that the problem of selecting optimal control times for a linear quadratic regulator can be reduced to our initial problem.Finally, numerical implementations demonstrate that using measurement times optimized by our genetic algorithm gives better estimate than regularly spaced measurements. Our method is applied to a discrete version of a continuous-time system and the impact of the discretization time step is studied. It reveals good convergence properties, showing that our method is well suited to both continuous-time and discrete-time setups.

Zika virus (ZIKV) is an emerging arbovirus with recent global expansion. Historically, ZIKV infections with Asian lineages have been associated with mild disease such as rash and fever. However, recent Asian sub-lineages have caused outbreaks in the South Pacific and Latin America with increased prevalence of neurological disorders in infants and adults. Asian sub-lineage differences may partially explain the range of disease severity observed. However, the effect of Asian sub-lineage differences on pathogenesis remains poorly characterized. Current study conducts a head-to-head comparison of three Asian sub-lineages that are representative of the circulating ancestral mild Asian strain (ZIKV-SG), the 2007 epidemic French Polynesian strain (ZIKV-FP), and the 2013 epidemic Brazil strain (ZIKV-Brazil) in adult Cynomolgus macaques. Animals infected intervenously or subcutaneously with either of the three clinical isolates showed sub-lineage-specific differences in viral pathogenesis, early innate immune responses and systemic inflammation. Despite the lack of neurological symptoms in infected animals, the epidemiologically neurotropic ZIKV sub-lineages (ZIKV-Brazil and/or ZIKV-FP) were associated with more sustained viral replication, higher systemic inflammation (i.e. higher levels of TNFα, MCP-1, IL15 and G-CSF) and greater percentage of CD14+ monocytes and dendritic cells in blood. Multidimensional analysis showed clustering of ZIKV-SG away from ZIKV-Brazil and ZIKV-FP, further confirming sub-lineage differences in the measured parameters. These findings highlight greater systemic inflammation and monocyte recruitment as possible risk factors of adult ZIKV disease observed during the 2007 FP and 2013 Brazil epidemics. Future studies should explore the use of anti-inflammatory therapeutics as early treatment to prevent ZIKV-associated disease in adults.

Chikungunya is a mosquito-borne disease that causes periodic but explosive epidemics of acute disease throughout the tropical world. Vaccine development against chikungunya virus (CHIKV) has been hampered by an inability to conduct efficacy trials due to the unpredictability of CHIKV outbreaks. Therefore, immune correlates are being explored to gain inference into vaccine-induced protection. This study is an in-depth serological characterization of Fab- and Fc-mediated antibody responses in selected phase II clinical trial participants following immunization with the recombinant measles-vectored CHIKV vaccine, MV-CHIK. Antibody comparisons were conducted between participants who received prime and those who received prime-boost vaccine regimens. MV-CHIK vaccination elicited potent Fab-mediated antibody responses (such as CHIKV-specific IgG, neutralization, and avidity), including dominant IgG3 responses, which translated into strong antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis. At 1 month, prime-boost immunization led to significantly greater responses in every measured Fab and Fc antibody parameter. Interestingly, prime-boost-elicited antibodies decreased rapidly over time, until at 6 months both vaccine regimens displayed similar antibody profiles. Nonetheless, antibody avidity and antibody-dependent cellular phagocytosis remained significantly greater following boost immunization. Our observations suggest that a prime-boost administration of MV-CHIK will be more appropriate for CHIKV-endemic regions, while a prime-only regimen may be sufficient for travel purposes or outbreak situations.

Understanding the local burden and epidemiology of infectious diseases is crucial to guide public health policy and prioritize interventions. Typically, infectious disease surveillance relies on capturing clinical cases within a healthcare system, classifying cases by etiology and enumerating cases over a period of time. Disease burden is often then extrapolated to the general population. Serology (i.e., examining serum for the presence of pathogen-specific antibodies) has long been used to inform about individuals past exposure and immunity to specific pathogens. However, it has been underutilized as a tool to evaluate the infectious disease burden landscape at the population level and guide public health decisions. In this review, we outline how serology provides a powerful tool to complement case-based surveillance for determining disease burden and epidemiology of infectious diseases, highlighting its benefits and limitations. We describe the current serology-based technologies and illustrate their use with examples from both the pre- and post- COVID-19-pandemic context. In particular, we review the challenges to and opportunities in implementing serological surveillance in low- and middle-income countries (LMICs), which bear the brunt of the global infectious disease burden. Finally, we discuss the relevance of serology data for public health decision-making and describe scenarios in which this data could be used, either independently or in conjunction with case-based surveillance. We conclude that public health systems would greatly benefit from the inclusion of serology to supplement and strengthen existing case-based infectious disease surveillance strategies.

A comprehensive longitudinal understanding of the changing epidemiology of the agents causing bacteraemia and their AMR profiles in key locations is crucial for assessing the progression and magnitude of the global AMR crisis. We performed a retrospective analysis of routine microbiological data from April 1992 to December 2014, studying the time trends of non-Salmonella associated bacteraemia at a single Kathmandu healthcare facility. The distribution of aetiological agents, their antimicrobial susceptibility profiles, and the hospital ward of isolation were assessed. Two hundred twenty-four thousand seven hundred forty-one blood cultures were performed over the study period, of which, 30,353 (13.5%) exhibited growth for non-contaminant bacteria. We observed a significant increasing trend in the proportion of MDR non-Salmonella Enterobacteriaceae (p < 0.001), other Gram-negative organisms (p = 0.006), and Gram-positive organisms (p = 0.006) over time. Additionally, there was an annual increasing trend in the proportion of MDR organisms in bacteria-positive blood cultures originating from patients attending the emergency ward (p = 0.006) and the outpatient department (p = 0.006). This unique dataset demonstrates that community acquired non-Salmonella bacteraemia has become an increasingly important cause of hospital admission in Kathmandu. An increasing burden of bacteraemia associated with MDR organisms in the community underscores the need for preventing the circulation of MDR bacteria within the local population.

Salmonella serovars Typhi (S. Typhi) and Paratyphi A (S. Paratyphi A), the causative agents of enteric fever, have been routinely isolated organisms from the blood of febrile patients in the Kathmandu Valley since the early 1990s. Susceptibility against commonly used antimicrobials for treating enteric fever has gradually changed throughout South Asia since this time, posing serious treatment challenges. Here, we aimed to longitudinally describe trends in the isolation of Salmonella enterica and assess changes in their antimicrobial susceptibility in Kathmandu over a 23-year period.We conducted a retrospective analysis of standardised microbiological data from April 1992 to December 2014 at a single healthcare facility in Kathmandu, examining time trends of Salmonella-associated bacteraemia and the corresponding antimicrobial susceptibility profiles of the isolated organisms.Over 23 years there were 30,353 positive blood cultures. Salmonella enterica accounted for 65.4% (19,857/30,353) of all the bacteria positive blood cultures. S. Typhi and S. Paratyphi A were the dominant serovars, constituting 68.5% (13,592/19,857) and 30.5% (6,057/19,857) of all isolated Salmonellae. We observed (i) a peak in the number of Salmonella-positive cultures in 2002, a year of heavy rainfall and flooding in the Kathmandu Valley, followed by a decline toward pre-flood baseline by 2014, (ii) an increase in the proportion of S. Paratyphi in all Salmonella-positive cultures between 1992 and 2014, (iii) a decrease in the prevalence of MDR for both S. Typhi and S. Paratyphi, and (iv) a recent increase in fluoroquinolone non-susceptibility in both S. Typhi and S. Paratyphi isolates.Our work describes significant changes in the epidemiology of Salmonella enterica in the Kathmandu Valley during the last quarter of a century. We highlight the need to examine current treatment protocols for enteric fever and suggest a change from fluoroquinolone monotherapy to combination therapies of macrolides or cephalosporins along with older first-line antimicrobials that have regained their efficacy.

BACKGROUND:Dengue is a mosquito-borne virus that causes extensive morbidity and economic loss in many tropical and subtropical regions of the world. Often present in cities, dengue virus is rapidly spreading due to urbanization, climate change and increased human movements. Dengue cases are often heterogeneously distributed throughout cities, suggesting that small-scale determinants influence dengue urban transmission. A better understanding of these determinants is crucial to efficiently target prevention measures such as vector control and education. The aim of this study was to determine which socioeconomic and environmental determinants were associated with dengue incidence in an urban setting in the Pacific. METHODOLOGY:An ecological study was performed using data summarized by neighborhood (i.e. the neighborhood is the unit of analysis) from two dengue epidemics (2008-2009 and 2012-2013) in the city of Nouméa, the capital of New Caledonia. Spatial patterns and hotspots of dengue transmission were assessed using global and local Moran's I statistics. Multivariable negative binomial regression models were used to investigate the association between dengue incidence and various socioeconomic and environmental factors throughout the city. PRINCIPAL FINDINGS:The 2008-2009 epidemic was spatially structured, with clusters of high and low incidence neighborhoods. In 2012-2013, dengue incidence rates were more homogeneous throughout the city. In all models tested, higher dengue incidence rates were consistently associated with lower socioeconomic status (higher unemployment, lower revenue or higher percentage of population born in the Pacific, which are interrelated). A higher percentage of apartments was associated with lower dengue incidence rates during both epidemics in all models but one. A link between vegetation coverage and dengue incidence rates was also detected, but the link varied depending on the model used. CONCLUSIONS:This study demonstrates a robust spatial association between dengue incidence rates and socioeconomic status across the different neighborhoods of the city of Nouméa. Our findings provide useful information to guide policy and help target dengue prevention efforts where they are needed most.

Automata, Logic and Semantics

The development of a compelling murine model of dengue virus (DENV) infection has been challenging, because dengue virus clinical isolates do not readily replicate or cause pathology in immunocompetent mice. However, research using immunocompromised mice and/or mouse-adapted viruses allows to investigate questions that may be impossible to address in human studies. In this review, we discuss the potential strengths and limitations of existing mouse models of dengue disease. Human studies are descriptive by nature; moreover, the strain, time, and sequence of infection are often unknown. In contrast, in mice, the conditions of infection are well defined and a large number of experimental parameters can be varied at will. Therefore, mouse models offer an opportunity to experimentally test hypotheses that are based on epidemiological observations. In particular, gain-of-function or loss-of-function models can be established to assess how different components of the immune system (either alone or in combination) contribute to protection or pathogenesis during secondary infections or after vaccination. In addition, mouse models have been used for pre-clinical testing of antiviral drug or for vaccine development studies. Conclusions based on mouse experiments must be extrapolated to DENV infection in humans with caution due to the inherent limitations of animal models. However, research in mouse models is a useful complement to in vitro and epidemiological data, and may delineate new areas that deserve attention during future human studies.

With 2.5 billion people at risk, dengue is a major emerging disease threat and an escalating public health problem worldwide. Dengue virus causes disease ranging from a self-limiting febrile illness (dengue fever) to the potentially fatal dengue hemorrhagic fever/dengue shock syndrome. Severe dengue disease is associated with sub-protective levels of antibody, which exacerbate disease upon re-infection. A dengue vaccine should generate protective immunity without increasing severity of disease. To date, the determinants of vaccine-mediated protection against dengue remain unclear, and additional correlates of protection are urgently needed. Here, mice were immunized with viral replicon particles expressing the dengue envelope protein ectodomain to assess the relative contribution of humoral versus cellular immunity to protection. Vaccination with viral replicon particles provided robust protection against dengue challenge. Vaccine-induced humoral responses had the potential to either protect from or exacerbate dengue disease upon challenge, whereas cellular immune responses were beneficial. This study explores the immunological basis of protection induced by a dengue vaccine and suggests that a safe and efficient vaccine against dengue should trigger both arms of the immune system.

Abstract The Arctic Ocean is undergoing a major transition as a result of global warming, with uncertain consequences for its ecosystems. Our study introduces an integrated analytical approach using co-occurrence networks, convergent cross-mapping, and energy landscape analysis. Applied to four years of amplicon data from Fram Strait, located at the boundary between Arctic and Atlantic waters, our method identifies keystone species in seasonal microbial communities, elucidates causal interactions, and predicts stable configurations across changing environments. We find strong evidence for a “winter reset”, implying that organisms representing the spring bloom are largely determined by prevailing environmental conditions during winter. In addition, our analysis suggests that winter communities may adapt more readily to expected Atlantification than summer communities. These results highlight the utility of innovative time-series analyses in disentangling ecosystem dynamics. This approach provides critical insights into Arctic ecological interactions, dynamics, and resilience and aids in understanding ecosystem responses to environmental change.

Objectives: Our goal was to conduct a hemodynamic analysis of a novel animal model of Fontan physiology. Poor late-term outcomes in Fontan patients are believed to arise from Fontan-induced hemodynamics, but the mechanisms remain poorly understood. Recent advances in surgical experimentation have resulted in the development of a chronic sheep model of Fontan physiology; however, detailed analysis of this model is lacking. Methods: We created a single-stage Fontan model in juvenile sheep with normal biventricular circulation. The superior vena cava was anastomosed to the main pulmonary artery, and the inferior vena cava was connected to the main pulmonary artery using an expanded polytetrafluoroethylene conduit. Longitudinal hemodynamics, including catheterization and magnetic resonance imaging were evaluated. Results: Four out of 12 animals survived, with the longest surviving animal living 3 years after single-stage Fontan. We showed a significant era effect regarding survival (1 out of 8 and subsequently 3 out of 4 animals surviving beyond 2 months) attributed in large part to the procedural learning curve. Key characteristics of Fontan hemodynamics, namely systemic venous hypertension and low normal cardiac output, were observed. However, recapitulation of passive human Fontan hemodynamics is affected by volume loading of the right ventricle given an anatomic difference in sheep azygous venous anatomy draining to the coronary sinus. Conclusions: A significant learning curve exists to ensure long-term survival and future surgical modifications, including banding of the main pulmonary artery and ligation of the azygous to coronary sinus connection are promising strategies to improve the fidelity of model hemodynamics.

Abstract Crossover interference is a phenomenon that affects the number and positioning of crossovers in meiosis and thus affects genetic diversity and chromosome segregation. Yet, the underlying mechanism is not fully understood, partly because quantification is difficult. To overcome this challenge, we introduce the interference length L int that quantifies changes in crossover patterning due to interference. We show that it faithfully captures known aspects of crossover interference and provides superior statistical power over previous measures such as the interference distance and the gamma shape parameter. We apply our analysis to empirical data and unveil a similar behavior of L int across species, which hints at a common mechanism. A recently proposed coarsening model generally captures these aspects, providing a unified view of crossover interference. Consequently, L int facilitates model refinements and general comparisons between alternative models of crossover interference.

Abstract Background Primary Care Physicians have a central role in assisting individuals with dementia and evaluating their preparedness to care these patients is fundamental. Our aim is to evaluate the knowledge and attitudes regarding dementia of the Primary Care Physicians (PCP) in Rio Grande do Sul (RS) state, Southern Brazil. Methods We collected sociodemographic data, volume of patients with dementia treated/referred and perception of difficulties in caring for these patients. A previously validated questionnaire was sent: "Quiz on Knowledge and Attitudes in Dementia". Results From March/2022 to June/2023, 296 PCP responded to the questionnaire. They were mostly women (52.7%, 156), with a median [IQR] age of 35 [29–44] years, mostly were White (82.1%, 243) and had 7 (4–16) years of experience as a physician. Less than half of the physicians performed cognitive screening (43.9%) and Mini Mental State Examination was the most screening (63.5%) test used. The mean percentage of correct answers in the Knowledge Quiz was 46.4%. In the attitude quiz, we identified 3 factors: 1) frankly positive attitudes; 2) perceive primary care as important but have a pessimistic attitude towards them; 3) see primary care as important for patient care. Conclusion Knowledge about dementia is low among PCP in RS; however, most have positive attitudes towards these patients or think primary care is important to these patient's care.

Abstract This review investigates the pervasive issue of dye effluent pollution in African surface waters, focusing on its significant adverse effects on both human health and environmental quality. Drawing from 63 articles published between 2004 and 2022, the review includes studies from Northern, Western, Eastern, Central, and Southern Africa, illustrating the widespread nature of dye contamination across the continent. Five primary sources of dye effluents are identified: textiles, food industries, dye producers, artisan dyes, and tannery-paint industries, all of which contribute substantially to the degradation of water quality. The physicochemical properties of dye effluents show high toxicity levels in surface waters, with significant regional variations. These variations highlight the importance of considering the specific characteristics of dye types and processing chemicals to fully understand the contamination levels. In evaluating treatment methods, the review finds that adsorption, coagulation/flocculation, filtration, and advanced oxidation processes (AOPs) such as photocatalysis, photo-Fenton oxidation, and plasma-chemical treatment are effective in mitigating dye pollution. The application of these methods varies across different African regions, indicating the need for region-specific approaches based on local conditions and available resources. The review also examines the impact of dye effluents on aquatic ecosystems and human health, with risk assessments revealing effects ranging from acute to chronic. This demonstrates the urgent need for targeted interventions to address dye effluent pollution in African surface waters, thereby protecting both environmental and public health. Graphical Abstract

Abstract Background Informal caregivers often experience multiple negative consequences as a result of the informal care they provide. Among other factors, employment status, financial resources, and mental health are related to informal caregiving. This analysis examined the association between informal caregivers’ employment status and their mental health, as well as the moderating effect of net household income on this relationship. Methods The research question was addressed with data from the German Socio-Economic Panel (SOEP) survey, comprising 3,053 informal caregivers (1,007 male; 2,046 female). Data were obtained through self-reports, and mental health was measured with the Summary Scale Mental Score. Stepwise adjusted multiple linear regression models were used to examine the association between employment status and mental health. The moderating effects were tested with interaction terms. All analyses were also stratified for gender. Results Informal caregivers with full-time jobs reported better mental health than unemployed or marginally employed caregivers (β = 0.077, p

Biodiversity data, particularly species occurrence and abundance, are indispensable for testing empirical hypothesis in natural sciences. However, datasets built for research programmes do not often meet FAIR (findable, accessible, interoperable and reusable) principles, which raises questions about data quality, accuracy and availability. The 21st century has markedly been a new era for data science and analytics and every effort to aggregate, standardise, filter and share biodiversity data from multiple sources have become increasingly necessary. In this study, we propose a framework for refining and conforming secondary biodiversity data to FAIR standards to make them available for use such as macroecological modelling and other studies. We relied on a Darwin Core base model to standardise and further facilitate the curation and validation of data related including the occurrence and abundance of multiple taxa of a region that encompasses estuarine ecosystems in an ecotonal area bordering the easternmost Amazonia. We further discuss the significance of feeding standardised public data repositories to advance scientific progress and highlight their role in contributing to the biodiversity management and conservation.

Abstract Background Cardiovascular diseases remain a leading global cause of mortality worldwide especially in older adults. Although it is known that regular exercise reduces cardiovascular diseases incidence, its effects on specific cardiovascular aging parameters considering the influence of sex and different exercise designs are still not fully understood. Therefore, this systematic review and meta-analysis aims to evaluate the effects of different physical exercise protocols on age-related cardiovascular outcomes in older adults. Methods This systematic review and meta-analysis will be reported in agreement with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Articles will be eligible if they are randomized controlled trials with a primary objective of evaluating the chronic effects of exercise interventions on cardiovascular aging parameters. Search strategy will be performed from the inception to September 30th, 2023, in the following electronic databases: MEDLINE (Ovid), SCOPUS (Elsevier), Embase, Sport Discus (EBSCO), Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science Core Collection (Clarivate Analytics). Data will be extracted and managed through Research Electronic Data Capture (REDCap) software. The Tool for the assEssment of Study qualiTy and reporting in EXercise (TESTEX) will be used to assess the methodological quality of included studies. Additionally, the quality of the findings will be evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) profiler. Meta-analysis based on the random-effects model will be performed (if deemed suitable, considering the methodological and clinical heterogeneity of the studies) to estimate the effects of exercise training on cardiovascular aging variables (i.e., cardiac output; arterial stiffness; stroke volume; endothelial function; and carotid intima-media thickness). Heterogeneity will be assessed with the I 2 statistics, while the publication bias will be assessed based on Egger’s test. Discussion To the best of our knowledge, this will be the first systematic review and meta-analysis to investigate the impact of sex and training protocols on the cardiovascular aging parameters. Moreover, the findings of this systematic review and meta-analysis will provide evidence for health professionals in the management of elderly patients in order to optimize the exercise prescription to face the cardiovascular alterations related to the aging process, considering the effects of different protocols according to sex. Systematic review registration PROSPERO CRD42023441015 .

Abstract Long COVID has been linked to a decline in physical activity and functional capacity. However, it remains unclear which physical symptoms are associated with specific aspects of movement behaviors and functional capacity. We aimed to investigate the associations of fatigue, dyspnea, post-exertional malaise, myalgia, and the co-occurrence of symptoms with movement behaviors and functional capacity in individuals with Long COVID. A cross-sectional multicenter study was conducted. Questionnaires were used to assess fatigue, dyspnea, post-exertional malaise, and myalgia. Accelerometry was employed to assess sedentary time, steps per day, light physical activity, and moderate-to-vigorous physical activity. The six-minute walk test, 30-s chair stand test, and timed up and go were used to assess functional capacity. One hundred and two community-dwelling individuals who had been living with Long COVID for 15 ± 10 months participated in the study. Fatigue, post-exertional malaise, and the co-occurrence of physical symptoms showed a negative association with step count, while post-exertional malaise was also negatively associated with moderate-to-vigorous physical activity. Dyspnea showed a negative association with the functional score, including all tests. Our findings suggest that fatigue, post-exertional malaise, and the co-occurrence of physical symptoms are negatively associated with physical activity, while dyspnea is negatively associated with functional capacity in individuals with Long COVID.

Abstract During meiosis, nucleoprotein filaments of the strand exchange proteins RAD51 and DMC1 are crucial for repairing SPO11-generated DNA double-strand breaks (DSBs) by homologous recombination (HR). A balanced activity of positive and negative RAD51/DMC1 regulators ensures proper recombination. Fidgetin-like 1 (FIGNL1) was previously shown to negatively regulate RAD51 in human cells. However, FIGNL1’s role during meiotic recombination in mammals remains unknown. Here, we decipher the meiotic functions of FIGNL1 and FIGNL1 Interacting Regulator of Recombination and Mitosis (FIRRM) using male germline-specific conditional knock-out (cKO) mouse models. Both FIGNL1 and FIRRM are required for completing meiotic prophase in mouse spermatocytes. Despite efficient recruitment of DMC1 on ssDNA at meiotic DSB hotspots, the formation of late recombination intermediates is defective in Firrm cKO and Fignl1 cKO spermatocytes. Moreover, the FIGNL1-FIRRM complex limits RAD51 and DMC1 accumulation on intact chromatin, independently from the formation of SPO11-catalyzed DSBs. Purified human FIGNL1ΔN alters the RAD51/DMC1 nucleoprotein filament structure and inhibits strand invasion in vitro. Thus, this complex might regulate RAD51 and DMC1 association at sites of meiotic DSBs to promote proficient strand invasion and processing of recombination intermediates.

Abstract Liver fibrosis progressing to cirrhosis is a major risk factor for liver cancer, impacting surgical treatment and survival. Our study focuses on the role of extracellular nicotinamide adenine dinucleotide (eNAD+) in liver fibrosis, analyzing liver disease patients undergoing surgery. Additionally, we explore NAD+’s therapeutic potential in a mouse model of extended liver resection and in vitro using 3D hepatocyte spheroids. eNAD+ correlated with aspartate transaminase (AST) and bilirubin after liver resection (AST: r = 0.2828, p = 0.0087; Bilirubin: r = 0.2584, p = 0.0176). Concordantly, post-hepatectomy liver failure (PHLF) was associated with higher eNAD+ peaks (n = 10; p = 0.0063). Post-operative eNAD+ levels decreased significantly (p

Background Autoimmune encephalitis (AIE) is a group of inflammatory diseases characterized by the presence of antibodies against neuronal and glial antigens, leading to subacute psychiatric symptoms, memory complaints, and movement disorders. The patients are predominantly young, and delays in treatment are associated with worse prognosis.

Abstract Modern plant breeding, such as genomic selection and gene editing, is based on the knowledge of the genetic architecture of desired traits. Quantitative trait loci (QTL) analysis, which combines high throughput phenotyping and genotyping of segregating populations, is a powerful tool to identify these genetic determinants and to decipher the underlying mechanisms. However, meiotic recombination, which shuffles genetic information between generations, is limited: Typically only one to two exchange points, called crossovers, occur between a pair of homologous chromosomes. Here we test the effect on QTL analysis of boosting recombination, by mutating the anti-crossover factors RECQ4 and FIGL1 in Arabidopsis thaliana full hybrids and lines in which a single chromosome is hybrid. We show that increasing recombination ~6-fold empowers the detection and resolution of QTLs, reaching the gene scale with only a few hundred plants. Further, enhanced recombination unmasks some secondary QTLs undetected under normal recombination. These results show the benefits of enhanced recombination to decipher the genetic bases of traits.

This paper presents an evaluation of the hydrocarbon potential of the Cuvette Centrale basin in the Democratic Republic of Congo (DRC) using an integrated approach that combines seismic and geothermal data. The envelope attribute of seismic data was used to identify different rocks of the petroleum system, including potential gas-prone zones. The interpretation of seismic profiles helped to delineate geological units and determine their lithology. Isobath maps based on seismic data revealed the presence of grabens and anticlines, which are favorable geological structures for hydrocarbon accumulation. Analysis of the geothermal gradient and temperature evolution in the formations allowed us to establish source rock maturity maps, highlighting two distinct zones: an overmature zone favorable for gas and a mature zone favorable for oil. These results suggest a strong hydrocarbon potential in the Cuvette Centrale basin.

Abstract Chronic mountain sickness is a maladaptive syndrome that affects individuals living permanently at high altitude and is characterized primarily by excessive erythrocytosis (EE). Recent results concerning the impact of EE in Andean highlanders on clotting and the possible promotion of hypercoagulability, which can lead to thrombosis, were contradictory. We assessed the coagulation profiles of Andeans highlanders with and without excessive erythrocytosis (EE+ and EE−). Blood samples were collected from 30 EE+ and 15 EE− in La Rinconada (Peru, 5100–5300 m a.s.l.), with special attention given to the sampling pre‐analytical variables. Rotational thromboelastometry tests were performed at both native and normalized (40%) haematocrit using autologous platelet‐poor plasma. Thrombin generation, dosages of clotting factors and inhibitors were measured in plasma samples. Data were compared between groups and with measurements performed at native haematocrit in 10 lowlanders (LL) at sea level. At native haematocrit, in all rotational thromboelastometry assays, EE+ exhibited hypocoagulable profiles (prolonged clotting time and weaker clot strength) compared with EE− and LL (all P

Abstract Recent genetic and molecular classification of DLBCL has advanced our knowledge of disease biology, yet were not designed to predict early events and guide anticipatory selection of novel therapies. To address this unmet need, we used an integrative multiomic approach to identify a signature at diagnosis that will identify DLBCL at high risk of early clinical failure. Tumor biopsies from 444 newly diagnosed DLBCL were analyzed by WES and RNAseq. A combination of weighted gene correlation network analysis and differential gene expression analysis was used to identify a signature associated with high risk of early clinical failure independent of IPI and COO. Further analysis revealed the signature was associated with metabolic reprogramming and identified cases with a depleted immune microenvironment. Finally, WES data was integrated into the signature and we found that inclusion of ARID1A mutations resulted in identification of 45% of cases with an early clinical failure which was validated in external DLBCL cohorts. This novel and integrative approach is the first to identify a signature at diagnosis, in a real-world cohort of DLBCL, that identifies patients at high risk for early clinical failure and may have significant implications for design of therapeutic options.

Abstract Background Lifestyle and habits, cardiovascular risk factors (CRF), bone and mental health, dietary habits, physical activity, among others are developed in childhood and adolescence. Family environment has shown to play an important role in these outcomes. However, whether the parent-child relationship lifestyle habits and health parameters can be influenced by physical activity patterns still unclear. The objective of this study will be to monitor and investigate the associations between lifestyle habits between parents and their children longitudinally, as well as verify whether in more active parents, the possible associations with lifestyle habits are different from those of parents considered less active. Methods The sample will consist of parents (father, mother, or both) and their children /adolescents. The participants will be recruited through public call by flyers spread across all the regions of the city and also through social media. The health parameters will include cardiovascular (cardiac autonomic modulation, blood pressure and resting heart rate), bone mineral density, anthropometric indices, handgrip strength, mental health (quality of life, anxiety and depression symptoms and stress), self-reported morbidities and musculoskeletal pain. Lifestyle habits will include physical activity levels, sedentary behavior, sleep parameters, eating patterns, smoking and alcohol consumption. Sociodemographic variables of age, sex, ethnicity and socioeconomic status will be considered as covariates. The follow-up visits of data collection will be scheduled after a period of 12 months from the baseline assessment during every twelve months. Discussion The family environment has great potential to determine lifestyle habits in children and adolescents. Based on the results presented in the present study, we hope that health promotion actions can be better designed in the family environment.

Abstract Native amine dehydrogenases offer sustainable access to chiral amines, so the search for scaffolds capable of converting more diverse carbonyl compounds is required to reach the full potential of this alternative to conventional synthetic reductive aminations. Here we report a multidisciplinary strategy combining bioinformatics, chemoinformatics and biocatalysis to extensively screen billions of sequences in silico and to efficiently find native amine dehydrogenases features using computational approaches. In this way, we achieve a comprehensive overview of the initial native amine dehydrogenase family, extending it from 2,011 to 17,959 sequences, and identify native amine dehydrogenases with non-reported substrate spectra, including hindered carbonyls and ethyl ketones, and accepting methylamine and cyclopropylamine as amine donor. We also present preliminary model-based structural information to inform the design of potential (R)-selective amine dehydrogenases, as native amine dehydrogenases are mostly (S)-selective. This integrated strategy paves the way for expanding the resource of other enzyme families and in highlighting enzymes with original features.

Abstract Nutrient limitations play a key regulatory role in plant growth, thereby affecting ecosystem productivity and carbon uptake. Experimental observations identifying the most limiting nutrients are lacking, particularly in Afrotropical forests. We conducted an ecosystem-scale, full factorial nitrogen (N)-phosphorus (P)-potassium (K) addition experiment consisting 32 40 × 40 m plots (eight treatments × four replicates) in Uganda to investigate which (if any) nutrient limits fine root growth. After two years of observations, added N rapidly decreased fine root biomass by up to 36% in the first and second years of the experiment. Added K decreased fine root biomass by 27% and fine root production by 30% in the second year. These rapid reductions in fine root growth highlight a scaled-back carbon investment in the costly maintenance of large fine root network as N and K limitations become alleviated. No fine root growth response to P addition was observed. Fine root turnover rate was not significantly affected by nutrient additions but tended to be higher in N added than non-N added treatments. These results suggest that N and K availability may restrict the ecosystem’s capacity for CO2 assimilation, with implications for ecosystem productivity and resilience to climate change.

ABSTRACT Neuromuscular scoliosis usually involves patients in poor health conditions. In this context, minimizing intraoperative bleeding and length of hospital stay is essential while maintaining good clinical and radiological outcomes for the patient. Objective: The study aims to assess how variables such as age, weight, blood loss, and especially total surgical time influence the duration of hospital stay and identify a possible correlation between osteotomies and estimated blood loss. Method: This is a retrospective observational study where data was collected between January 2021 and December 2022. The inclusion criteria consisted of patients diagnosed with cerebral palsy GMFCS V suffering from neuromuscular scoliosis undergoing spine surgery for scoliosis correction, without age restrictions. Correlation analysis and linear regression were performed using the variables of interest, and p < .05 was accepted as a statistically significant difference. Results: A total of 26 patients were included, 14 males and 12 females. The median age was 13 years, and the median length of stay was 8 days. There was a significant, moderate, positive correlation between total surgical time and length of stay amongst class V surgically treated patients, r(24)= .39, p = .043. Conclusions: Prolonging the surgical procedure correlates with an extended hospital length of stay amongst surgically treated neuromuscular scoliosis GMFCS V patients with a pelvic obliquity of less than 20 degrees. Level of Evidence IV; Case-Control Study.

Resumo Avaliar a confiabilidade e a concordância intra-avaliador das avaliações da pressão arterial (PA), rigidez arterial e variabilidade da frequência cardíaca (VFC) em pacientes com doença de Parkinson (DP). Vinte pacientes com DP realizaram três visitas ao laboratório, durante as quais foram realizadas avaliações da PA braquial e central (tonometria de aplanação e auscultatório, respectivamente), rigidez arterial (velocidade da onda de pulso carotídeo-femoral e índice de aumento) e VFC em repouso. A PA sistólica braquial e central apresentou valores maiores na visita 1 quando comparada às visitas 2 e 3 (122±13 vs. 116±16 vs. 120±15, p=0,029). Não houve diferenças significativas (p>0,05) entre as visitas experimentais para outros parâmetros. A PA braquial e central apresentou um coeficiente de correlação intraclasse (CCI) acima de 0,842 e um erro padrão de medida (EPM) menor que 5,0%. Os gráficos de Bland–Altman indicaram baixa concordância entre as visitas 1 e 2 e boa concordância entre as visitas 2 e 3. Os índices de rigidez arterial exibiram valores de CCI entre 0,781 e 0,886, e o EPM variou de 7,3% a 25,2%. Os gráficos de Bland–Altman indicaram concordância moderada a boa entre as visitas para os parâmetros de rigidez arterial. Os índices de VFC apresentaram valores de CCI variando de 0,558 a 0,854 e valores de EPM que variam de 5,1% a 76,0%. Os gráficos de Bland–Altman indicaram concordância moderada entre as visitas para os parâmetros de VFC. Em pacientes com DP, a PA braquial e central apresenta baixa confiabilidade intra-avaliador e concordância entre as visitas 1 e 2 e boa confiabilidade intra-avaliador e concordância entre as visitas 2 e 3. Em geral, as avaliações de rigidez arterial e VFC apresentam confiabilidade intra-avaliador e concordância aceitáveis entre as visitas, exceto para o equilíbrio simpático-vagal cardíaco.

ABSTRACT In recent years, the diagnostic accuracy of Alzheimer’s disease has been enhanced by the development of different types of biomarkers that indicate the presence of neuropathological processes. In addition to improving patient selection for clinical trials, biomarkers can assess the effects of new treatments on pathological processes. However, there is concern about the indiscriminate and poorly supported use of biomarkers, especially in asymptomatic individuals or those with subjective cognitive decline. Difficulties interpreting these tests, high costs, and unequal access make this scenario even more challenging in healthcare. This article presents the recommendations from the Scientific Department of Cognitive Neurology and Aging of the Brazilian Academy of Neurology (Departamento Científico de Neurologia Cognitiva e Envelhecimento da Academia Brasileira de Neurologia) regarding the rational use and interpretation of Alzheimer’s disease biomarkers in clinical practice. The clinical diagnosis of cognitive-behavioral syndrome is recommended as the initial step to guide the request for biomarkers.

ABSTRACT Novel therapies for Alzheimer’s disease, particularly anti-amyloid drugs like lecanemab and donanemab, have shown modest clinical benefits but also significant risks. The present paper highlights the challenges of access to diagnosis, cost-effectiveness, safety, and the need for more representation of diverse populations in clinical trials. Recommendations include careful patient selection, risk-benefit analysis, and the importance of proven amyloid pathology for treatment. Future work involves further research on anti-amyloid therapies in Brazil and the development of more effective treatments for Alzheimer’s disease.

IntroductionCitrus is an important fruit crop for human health. The sensitivity of citrus trees to a wide range of abiotic stresses is a major challenge for their overall growth and productivity. Among these abiotic stresses, salinity results in a significant loss of global citrus yield. In order to find straightforward and sustainable solutions for the future and to ensure citrus productivity, it is of paramount importance to decipher the mechanisms responsible for salinity stress tolerance. Thisstudy aimed to investigate how ploidy levels influence salt stress tolerance in citrus by comparing the transcriptomic responses of diploid and tetraploid genotypes. In a previous article we investigated the physiological and biochemical response of four genotypes with different ploidy levels: diploid trifoliate orange (Poncirus trifoliata [L.] Raf.) (PO2x) and Cleopatra mandarin (Citrus reshni Hort. Ex Tan.) (CL2x) and their respective tetraploids (PO4x, CL4x).MethodsIn this study, we useda multifactorial gene selection and gene clustering approach to finely dissect the influence of ploidy level on the salt stress response of each genotype. Following transcriptome sequencing, differentially expressed genes (DEGs) were identified in response to salt stress in leaves and roots of the different citrus genotypes.Result and discussionGene expression profiles and functional characterization of genes involved in the response to salt stress, as a function of ploidy level and the interaction between stress response and ploidy level, have enabled us to highlight the mechanisms involved in the varieties tested. Saltstress induced overexpression of carbohydrate biosynthesis and cell wall remodelling- related genes specifically in CL4x Ploidy level enhanced oxidative stress response in PO and ion management capacity in both genotypes. Results further highlighted that under stress conditions, only the CL4x genotype up- regulated genes involved in sugar biosynthesis, transport management, cell wall remodelling, hormone signalling, enzyme regulation and antioxidant metabolism. These findings provide crucial insights that could inform breeding strategies for developing salt-tolerant citrus varieties.

ABSTRACT Dictyostelium discoideum is a phagocytic amoeba continuously eating, killing, and digesting bacteria. Previous studies have detected in D. discoideum cell extracts a bacteriolytic activity effective against Klebsiella pneumoniae bacteria. In this study, we characterized bacteriolytic activities found in D. discoideum cell extracts against five different bacteria (K. pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Bacillus subtilis). We first analyzed the bacteriolytic activity against these five bacteria in parallel over a range of pH values. We then measured the remaining bacteriolytic activity in D. discoideum kil1 and modA knockout mutants. We also performed partial fractionation of D. discoideum extracts and assessed activity against different bacteria. Together our results indicate that optimal bacteriolytic activity against different bacteria results from the action of different effectors. Proteomic analysis allowed us to propose a list of potential bacteriolytic effectors.IMPORTANCEMany antibacterial effectors have been characterized over the past decades, and their biological importance, mode of action, and specificity are often still under study. Here we characterized in vitro bacteriolytic activity in D. discoideum extracts against five species of Gram-negative and Gram-positive bacteria. Our results reveal that optimal lysis of different bacteria mobilizes different effectors. Proteomic analysis generated a list of potential bacteriolytic effectors. This work opens the way for future analysis of the role of individual effectors in living D. discoideum cells.

In recent times, the global population explosion and growing depletion of fossil fuels have compelled academics and scientists to do extensive research on alternate energy sources and energy storage techniques. A hydrothermal approach was used to create Copper (II) oxide (Cu2O), Manganese oxide (MnO2), Nickel oxide (NiO), and Copper@Manganese@Nickel (Cu2O@MnO2@NiO) oxide composite electrodes. Sarcophrynium Brachystachys leaves extract was used equally as a bolstering mediator. According to the Debye-Scherer equation, the crystallites size of different nanoparticles (NPs) were established to be 29.45, 24.22, 26.33 and 20.24 nm for Cu2O, MnO2, NiO, and Cu2O@MnO2@NiO, respectively, based on X-ray diffraction (XRD) experiments. According to electrochemical examinations, assessed specific capacitances for Cu2O, MnO2, NiO, and Cu2O@MnO2@NiO obtained by cyclic voltammetry (CV) using 1.00 mV/s scan rates are 785, 955, 825 and 1092 F/g, respectively. The obtained results clearly showed that separate metallic oxides specific capacitances compared with composites specific capacitance using Sarcophrynium Brachystachys leaves extract, a biological and natural constituent stands superior. Sarcophrynium Brachystachys leaves extract enhanced the synergistic impact between constituents’ ions via lowering electrode resistances, raising electrode conductivity and improving electrode characteristics.

ABSTRACT Objective: To analyze the association between the time spent in sedentary behavior and physical activity of different intensities with cardiovascular health in men and women with peripheral artery disease. Methods: Two hundred and sixty patients with peripheral artery disease and claudication symptoms (65.7% men; 66±1 years; ankle brachial index 0.57±0.18) were evaluated. Physical activity and sedentary behavior were assessed using an accelerometer. Physical activity was classified into light and moderate-vigorous intensities. The cardiovascular outcomes included blood pressure (oscillometric method), cardiac autonomic modulation (heart rate variability), and arterial stiffness (pulse wave velocity). Results: Women spent more time engaged in light physical activity than men (341±14 min/day versus 306±9 min/day; p=0.040, respectively). There was no significant difference in the time spent on sedentary behavior and moderate-vigorous physical activity. Women had a higher systolic blood pressure (p=0.025), higher augmentation index (p

ABSTRACT Objective: This study aimed at investigating the extent to which COVID-19-induced fatalities affect the duration of palliative care among patients with advanced cancer. Methods: A retrospective cohort study was conducted at the Palliative Care Unit of the Brazilian Instituto Nacional de Câncer in Rio de Janeiro, Brazil, on 1,104 advanced cancer patients who died under exclusive palliative care between March 11, 2020, and March 31, 2021. Wilcoxon rank-sum (Mann-Whitney U) and log-rank tests were performed to examine statistical differences between the medians of time, and the Kaplan-Meier estimator was used to graphically illustrate survival over time under exclusive palliative care contingent upon the underlying causes of death of the two experimental groups (cancer versus COVID-19). Results: A total of 133 (12.05%) patients succumbed to COVID-19. In both groups, the median time under exclusive palliative care was less than one month. The exclusive palliative care survival curves did not exhibit any statistically significant difference between the groups. Conclusion: Death due to COVID-19 did not modify the duration of exclusive palliative care among patients with advanced cancer.

Abstract The aim of this work was to evaluate the use of shrimp waste as a bioavailable source of nutrients for the growth of Salicornia europaea, before and after a cavitation process and either in combination with or without commercial fertilizer. Fecal wastes were collected from the drum filter in a recirculating system for shrimp Penaeus vannamei culture. The two-factorial experimental design was pretreatment of fecal waste with cavitation (and control without cavitation) and nutrient source (commercial nutrient media (NM) or fecal waste (FW)) at different concentration ratios (100%/0%; 65%/35%; 35%/65% and 0%/100% of nutrient media or fecal waste respectively). The growth experiment lasted 62 days. Media composition had a significant effect on final biomass, and yields ranged from 0.29 to 0.62 kg m-2 at 0%/100% and 65%/35%, respectively. The commercial media evaluated does not appear to be well suited for cultivation of Salicornia, and performance can be significantly increased if the commercial media is partially replaced with fecal waste (65%/35% ratio). However, whether pretreatment of fecal sludge is necessary to make nutrients available to Salicornia cannot be answered because it had no significant effect on the final biomass.

Abstract The purpose of this study was to evaluate the cleanliness of Interstitial Free (IF) steels produced in a Ruhrstahl Heraeus (RH) vacuum degasser by determining the level of Al2O3 and Al-Ti-O inclusion types generated in three different process conditions: i) steel processed without thermal intervention; ii) steel processed with chemical heating and iii) steel processed with cooling by the scrap addition. The inclusion formation and remotion during these processes were analyzed. The influence of homogenization time was also studied. The content of inclusions was measured by a Scanning Electron Microscope (SEM) with an automated counting system denoted as Automated Steel Cleanliness Analysis Tool (ASCAT). This method can provide the size and composition of non-metallic compounds. The results have shown that the Ruhrstahl Heraeus (RH) process can improve the remotion efficiency of the inclusions, such as those larger than 2.5 mm, which is due to the molten steel circulating in RH vessel. For some inclusion types, higher concentrations were detected, but their size was smaller. For a heat where it was necessary to apply chemical heating using Al addition and O injection, there was detected a higher concentration of inclusions when compared with that cooled by scrap addition. In cooling heats, there is a strong generation of small and thin inclusions (

Abstract Myelodysplastic syndromes (MDS) with mutated SF3B1 gene present features including a favourable outcome distinct from MDS with mutations in other splicing factor genes SRSF2 or U2AF1. Molecular bases of these divergences are poorly understood. Here we find that SF3B1-mutated MDS show reduced R-loop formation predominating in gene bodies associated with intron retention reduction, not found in U2AF1- or SRSF2-mutated MDS. Compared to erythroblasts from SRSF2- or U2AF1-mutated patients, SF3B1-mutated erythroblasts exhibit augmented DNA synthesis, accelerated replication forks, and single-stranded DNA exposure upon differentiation. Importantly, histone deacetylase inhibition using vorinostat restores R-loop formation, slows down DNA replication forks and improves SF3B1-mutated erythroblast differentiation. In conclusion, loss of R-loops with associated DNA replication stress represents a hallmark of SF3B1-mutated MDS ineffective erythropoiesis, which could be used as a therapeutic target.

Abstract Ocean spring phytoplankton blooms are dynamic periods important to global primary production. We document vertical patterns of a diverse suite of eukaryotic algae, the prasinophytes, in the North Atlantic Subtropical Gyre with monthly sampling over four years at the Bermuda Atlantic Time-series Study site. Water column structure was used to delineate seasonal stability periods more ecologically relevant than seasons defined by calendar dates. During winter mixing, tiny prasinophytes dominated by Class II comprise 46 ± 24% of eukaryotic algal (plastid-derived) 16S rRNA V1-V2 amplicons, specifically Ostreococcus Clade OII, Micromonas commoda, and Bathycoccus calidus. In contrast, Class VII are rare and Classes I and VI peak during warm stratified periods when surface eukaryotic phytoplankton abundances are low. Seasonality underpins a reservoir of genetic diversity from multiple prasinophyte classes during warm periods that harbor ephemeral taxa. Persistent Class II sub-species dominating the winter/spring bloom period retreat to the deep chlorophyll maximum in summer, poised to seed the mixed layer upon winter convection, exposing a mechanism for initiating high abundances at bloom onset. Comparisons to tropical oceans reveal broad distributions of the dominant sub-species herein. This unparalleled window into temporal and spatial niche partitioning of picoeukaryotic primary producers demonstrates how key prasinophytes prevail in warm oceans.

This study focuses on N'Djili River catchment, a vital water source in Kinshasa that undergoes anthropogenic pressure and land use changes. The lower course of the river is particularly affected by uncontrolled urbanization, informal settlements, improper waste management practices, and vegetation degradation. The aim of this study is to determine the relationship between land use and river water quality in this catchment. Water samples were collected for physico-chemical and bacteriological analysis from 10 sampling sites along the river course. Land use categories were determined using Sentinel-2 land cover imageries and buffer scaling techniques. A redundancy analysis (RDA) was conducted to determine the relationship between land use categories and water quality variables. The laboratory analysis revealed physical, chemical, and biological pollution of the river waters. The RDA results showed that 70% of water quality parameters were explained by the studied land use categories. The urbanized area was the most significant explanatory variable at all buffer scales, negatively impacting water quality parameters. Conversely, trees and range lands had a positive impact on water quality. The study concludes that further research is needed to assess the extent of water pollution and develop integrated management strategies for minimizing pollution in this catchment. HIGHLIGHTS N'Djili River water quality is affected by point and non-point pollution sources.; Esri-Sentinel-2 10 m resolution land cover imageries were used to generate land use categories.; Buffer zone approach and redundancy analysis were used to determine the relationship between land use and water quality.; Land use indicators at multiple scales were related to water quality.;

Abstract Mutations in chromatin regulators are widespread in cancer. Among them, the histone H3 lysine 27 methyltransferase Polycomb Repressive Complex 2 (PRC2) shows distinct alterations according to tumor type. This specificity is poorly understood. Here, we model several PRC2 alterations in one isogenic system to reveal their comparative effects. Focusing then on lymphoma-associated EZH2 mutations, we show that Ezh2 Y641F induces aberrant H3K27 methylation patterns even without wild-type Ezh2, which are alleviated by partial PRC2 inhibition. Remarkably, Ezh2 Y641F rewires the response to PRC2 inhibition, leading to induction of antigen presentation genes. Using a unique longitudinal follicular lymphoma cohort, we further link EZH2 status to abnormal H3K27 methylation. We also uncover unexpected variability in the mutational landscape of successive biopsies, pointing to frequent co-existence of different clones and cautioning against stratifying patients based on single sampling. Our results clarify how oncogenic PRC2 mutations disrupt chromatin and transcription, and the therapeutic vulnerabilities this creates.

Abstract Background Practicing sports during childhood and adolescence provides benefits to cardiac autonomic modulation (CAM) at these stages of life. However, it is not known whether these benefits to CAM persist into adulthood. Therefore, the objective of this study was to analyze the association of early sports practice (sports practice in childhood and/or adolescence) with CAM in adult life, regardless of habitual moderate-to-vigorous PA. Methods The sample of the present study consisted of 242 adults (141 women and 101 men; age: 41.99 ± 16.24). The assessment of CAM was performed using heart rate variability indices. Sports practice in childhood and adolescence was assessed using a questionnaire. The intensity of physical activity was assessed using accelerometry. To analyze the association between previous sports practice (childhood and/or adolescence) and CAM, the Generalized Linear Model was adopted, considering CAM indices as continuous variables and early sports practice as a 3-fold factor (no sports practice; sports practice in childhood or adolescence; and sports practice in both childhood and adolescence) adjusted by sex, age, socioeconomic condition, and moderate to vigorous PA. Results Sports practice in childhood was associated with the average standard deviation of all normal RR intervals expressed in milliseconds (SDNN): β = 5.89; 95%CI: 0.25;11.52, and the standard deviation of the long-term intervals between consecutive heartbeats (SD2): β = 7.63; 95%CI:1.04; 14.23 indices. Sports practice in adolescence was associated in adulthood with the SD2 index: β = 7.37; 95%CI: 0.71;14.04. Sports practice in at least one of the periods (childhood or adolescence) was significantly associated with the square root of the mean square of the differences between adjacent normal RR intervals for a period of time expressed in milliseconds (RMSSD) (β = 8.86; 95%CI = 0.71;17.01), and the standard deviation of the instantaneous beat to beat variability (SD1) (β = 6.21; 95%CI = 0.45;11.97). Sports practice at both stages of life was significantly associated with better SDNN (β = 7.70; 95%CI = 1.16;14.23) and SD2 (β = 10.18; 95%CI = 2.51;17.85). Conclusion Early sports practice was associated with better CAM in adulthood, independently of the current physical activity level. Based on these findings, sports practice is encouraged from childhood and adolescence, for benefits to CAM in adult life.

Abstract Background Adaptive radiation therapy (ART) offers a dynamic approach to address structural and spatial changes that occur during radiotherapy (RT) for locally advanced head and neck cancers. The integration of daily ART with Cone-Beam CT (CBCT) imaging presents a solution to enhance the therapeutic ratio by addressing inter-fractional changes. Methods We evaluated the initial clinical experience of daily ART for patients with head and neck cancer using an online adaptive platform with intelligence-assisted workflows on daily CBCT. Treatment included auto-contour and structure deformation of Organs at Risk (OARs) and target structures, with adjustments by the treating physician. Two plans were generated: one based on the initial CT simulation with the edited structures (scheduled) and a re-optimized plan (adaptive). Both plans were evaluated and the superior one approved and delivered. Clinical and dosimetric outcomes were reviewed. Results Twenty two patients with head and neck cancers (7 Nasopharynx, 6 Oropharynx, 1 oral cavity, 8 larynx) stages I-IVA were treated with daily ART. 770 adaptive and scheduled radiotherapy plans were generated. 703 (91.3%) adaptive plans were chosen. Median time to deliver ART was 20 minutes (range: 18-23). Adaptive compared to scheduled plans demonstrated improved mean V95 values for the PTV70, PTV59.5, and PTV56 by 1.2%, 7.2%, and 6.0% respectively and a mean 1.4% lower maximum dose in PTV70. Fourteen of 17 OARs demonstrated improved dosimetry with adaptation, with select OARs reaching statistical significance. At a median follow up of 14.1 months, local control was 95.5%, two patients developed metastatic disease and four patients died. 9.1% of patients had acute grade 3 dysphagia and 13.6% had grade 2 chronic xerostomia. Discussion These findings provide real world evidence of the feasibility and dosimetric benefit of incorporating daily ART on CBCT in the treatment of head and neck cancer. Prospective study is needed to determine if these dosimetric improvements translate into improved outcomes.

Objective: To develop and validate a robust risk prediction model for stroke and systemic embolism (SSE) in adult patients with congenital heart disease (ACHD), using artificial intelligence. Patients and Methods: Deidentified insurance claims from the Optum Labs Data Warehouse, including enrollment records and medical and pharmacy claims for commercial and Medicare Advantage enrollees, were used to identify 49,276 patients with ACHD, followed between January 1, 2009, and December 31, 2014. The group was randomly divided into development (70%) and validation (30%) cohorts. The development cohort was used to train 2 machine learning (ML) algorithms, regularized Cox regression (RegCox), and extreme gradient boosting (XGBoost) to predict SSE at 1, 2, and 5 years. The Shapley additive explanations (SHAP) model was used to identify the variables particularly driving the SSE risk. Results: Within this large and diverse cohort of patients with ACHD (mean age, 59 ± 19 years; 25,390 (51.5%) female, 35,766 [77.6%]) white), 1756 (3.6%) patients experienced SSE during follow-up. In the Validation cohort, CHA2DS2-VASC had an area under the receiver operating characteristics curve (AUC) of 0.66 for predicting SSE at 1-,2, and 5-years. RegCox had the best predictive performance, with AUCs of 0.82,.81, and.80 at 1-, 2, and 5-years. XGBoost had AUCs of 0.81, 0.80, and 0.79 respectively. Atrial septal defect (ASD) emerged as an important predictor for SSE uncovered by the unbiased ML algorithms. A new clinical risk score, the CHA2DS2-VASC-ASD2 score, provides improved SSE prediction in ACHD. Yet, the ML models still outperformed this. Conclusion: ML models significantly outperformed the clinical risk scores in patients with ACHD.

Mastitis is highly prevalent and causes significant economic loss in the Ethiopian dairy industry. An important aspect of monitoring dairy cow health and milk quality is understanding somatic cell count (SCC), composition and milk yield. This study aimed to evaluate milk SCC, composition, yield, and factors associated with the quality traits of Ethiopian dairy farms. A total of 3269 milk samples were collected from 1719 cows across 201 herds. The overall means and standard deviations of loge-transformed somatic cell score (SCS), fat, protein, lactose, and test day milk yield were 12.39 ± 1.61 cells/mL, 2.68 ± 1.71%, 3.17 ± 0.24%, 4.75 ± 0.36%, and 10.45 ± 5.04 litres, respectively. The results showed that 40.7% of the analysed milk samples had the SCC class ≤ 200x103 cells/mL. SCS was negatively correlated with milk yield and composition but moderately positively correlated with electrical conductivity (r = 0.41). Lactation stage, breed, parity, herd size and altitude significantly influenced most milk parameters, except fat content, which was unaffected by parity (p > 0.05). In conclusion, the highest SCS was recorded in this study. An increase in SCS negatively affects both milk yield and composition. Therefore, breed selection and herd management should focus on reducing the SCC to improve milk yield and quality.