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Predicting elemental cycles and maintaining water quality under increasing anthropogenic influence requires knowledge of the spatial drivers of river microbiomes. However, understanding of the core microbial processes governing river biogeochemistry is hindered by a lack of genome-resolved functional insights and sampling across multiple rivers. Here we used a community science effort to accelerate the sampling, sequencing and genome-resolved analyses of river microbiomes to create the Genome Resolved Open Watersheds database (GROWdb). GROWdb profiles the identity, distribution, function and expression of microbial genomes across river surface waters covering 90% of United States watersheds. Specifically, GROWdb encompasses microbial lineages from 27 phyla, including novel members from 10 families and 128 genera, and defines the core river microbiome at the genome level. GROWdb analyses coupled to extensive geospatial information reveals local and regional drivers of microbial community structuring, while also presenting foundational hypotheses about ecosystem function. Building on the previously conceived River Continuum Concept1, we layer on microbial functional trait expression, which suggests that the structure and function of river microbiomes is predictable. We make GROWdb available through various collaborative cyberinfrastructures2,3, so that it can be widely accessed across disciplines for watershed predictive modelling and microbiome-based management practices.

ObjectiveTo examine the effects of insulin-adjunctive therapy with a sodium-glucose cotransporter 2 (SGLT2) inhibitor and a glucagon receptor antagonist (GRA) on glycemia, insulin use, and ketogenesis during insulinopenia in type 1 diabetes.Research design and methodsIn a randomized, double-blind, placebo-controlled, crossover trial we assessed the effects of adjunctive SGLT2 inhibitor therapy (dapagliflozin 10 mg daily) alone and in combination with the GRA volagidemab (70 mg weekly) in 12 adults with type 1 diabetes. Continuous glucose monitoring, insulin dosing, and insulin withdrawal tests (IWT) for measurement of glucose and ketogenesis during insulinopenia were completed during insulin-only (Baseline), SGLT2 inhibitor, and combination (SGLT2 inhibitor + GRA) therapy periods.ResultsAverage glucose and percent time with glucose in range (70-180 mg/dL) improved with combination therapy versus Baseline and SGLT2 inhibitor (131 vs. 150 and 138 mg/dL [P < 0.001 and P = 0.01] and 86% vs. 70% and 78% [P < 0.001 and P = 0.03], respectively) without increased hypoglycemia. Total daily insulin use decreased with combination therapy versus Baseline and SGLT2 inhibitor (0.41 vs. 0.56 and 0.52 units/kg/day [P < 0.001 and P = 0.002]). Peak β-hydroxybutyrate levels during IWT were lower with combination therapy than with SGLT2 inhibitor (2.0 vs. 2.4 mmol/L; P = 0.048) and similar to levels reached during the Baseline testing period (2.1 mmol/L). Participants reported enhanced treatment acceptability and satisfaction with combination therapy.ConclusionsGlucagon antagonism enhances the therapeutic effects of SGLT2 inhibition in type 1 diabetes. Combination therapy improves glycemic control, reduces insulin dosing, and suggests a strategy to unlock the benefits of SGLT2 inhibitors while mitigating the risk of diabetic ketoacidosis.

Abstract Background Since older adults spend significant time in their neighborhood environment, environmental factors such as neighborhood socioeconomic disadvantage, high racial segregation, low healthy food availability, low access to recreation, and minimal social engagement may have adverse effects on cognitive function and increase susceptibility to dementia. DNA methylation, which is associated with neighborhood characteristics as well as cognitive function and white matter hyperintensity (WMH), may act as a mediator between neighborhood characteristics and neurocognitive outcomes. Methods In this study, we examined whether DNA methylation in peripheral blood leukocytes mediates the relationship between neighborhood characteristics and cognitive function (N = 542) or WMH (N = 466) in older African American (AA) participants without preliminary evidence of dementia from the Genetic Epidemiology Network of Arteriopathy (GENOA). Results For a 1-mile buffer around a participant’s residence, each additional fast food destination or unfavorable food store with alcohol per square mile was nominally associated with a 0.05 (95%CI: 0.01, 0.09) and a 0.04 (0.00, 0.08) second improvement in visual conceptual tracking score, respectively. Also, each additional alcohol drinking place per square mile was nominally associated with a 0.62 (0.05, 1.19) word increase in delayed recall score, indicating better memory function (all p

Abstract Non-linearities in organic exciton-polariton microcavities represent an attractive platform for quantum devices. However, progress in this area hinges on the development of material platforms for high-performance polariton lasing, scalable and sustainable fabrication, and ultimately strategies for electrical pumping. Here, we show how introducing Schlieren texturing and a rough intra-cavity topography in a liquid crystalline conjugated polymer enables strong in-plane confinement of polaritons and drastic enhancement of the lasing properties. In high-Q distributed Bragg reflector microcavities, polariton lasing was observed at unprecedented thresholds of 136 fJ per pulse. Morphology tuning also permitted polariton lasing in more lossy metallic microcavities while maintaining a competitive lasing threshold. The facile fabrication of these cavities will drastically reduce the complexity of integrating polariton lasers with other structures and the high conductivity of metallic mirrors may provide a route to electrical pumping.

Abstract Pyruvate metabolism defects lead to severe neuropathies such as the Leigh syndrome (LS) but the molecular mechanisms underlying neuronal cell death remain poorly understood. Here, we unravel a connection between pyruvate metabolism and the regulation of the epitranscriptome that plays an essential role during brain development. Using genetically engineered mouse model and primary neuronal cells, we identify the transcription factor E4F1 as a key coordinator of AcetylCoenzyme A (AcCoA) production by the pyruvate dehydrogenase complex (PDC) and its utilization as an essential co-factor by the Elongator complex to acetylate tRNAs at the wobble position uridine 34 (U34). E4F1-mediated direct transcriptional regulation of Dlat and Elp3, two genes encoding key subunits of the PDC and of the Elongator complex, respectively, ensures proper translation fidelity and cell survival in the central nervous system (CNS) during mouse embryonic development. Furthermore, analysis of PDH-deficient cells highlight a crosstalk linking the PDC to ELP3 expression that is perturbed in LS patients.

Abstract Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death worldwide. Treating HCC is challenging because of the poor drug effectiveness and the lack of tools to predict patient responses. To resolve these issues, we established a patient-centric spheroid model using HepG2, TWNT-1, and THP-1 co-culture, that mimics HCC phenotype. We developed a target-independent cell killing (TICK) exclusion strategy to monitor the therapeutic response. We demonstrated that our model reproduced the Barcelona Clinic Liver Cancer (BCLC) molecular classification, displayed known alterations of epigenetic players, and responded to tyrosine kinase inhibitors (TKIs) such as sorafenib, cabozantinib, and lenvatinib in a patient-dependent manner. Importantly, we reported for the first time that our model correctly predicted 34 clinical outcomes to TKIs out of 37 case studies on 32 HCC patients confirming that patient-centric spheroids, combined with our TICK exclusion strategy, are valuable models for drug discovery and opening a near perspective to personalized care.

Societal Impact Statement Bananas are nutritious fruits of major importance worldwide. Characterizing their diversity is essential to ensure their conservation and use. A catalog showcasing cultivated bananas genomic diversity was compiled and is to be used as a tool to support the classification of banana cultivars. This research revealed that cultivated banana groups are not all made of identical clones. Materials from recent collecting missions indicated that more banana diversity is expected to be found as the exploration of the banana gene pool continues. These discoveries will drive dynamic conservation strategies for banana genetic resources and should increase their use. Summary Banana is an important food crop cultivated in many tropical and subtropical regions around the world. Because banana cultivars often have low fertility, they are typically propagated clonally, which maintains desirable traits across generations. However, different factors, such as synonymy, incomplete passport data, and environmental effects, complicate the morphological‐based assignment of banana cultivars to specific clones or cultivar groups. In this study, we applied a previously developed genomic‐based tool for fine‐scale characterization of banana ancestry, known as in silico chromosome painting, to high‐throughput genotyping data from 317 banana accessions. This dataset covers most of the globally conserved, studied, and cultivated cultivar groups and includes both genebanks and new, uncharacterized materials. By comparing curated morphological assignation to the genomic patterns resulting from in silico chromosome painting, we compiled a diversity catalog referencing curated passport data, pictures, and chromosome painting patterns of the cultivar groups. Examining the genomic patterns obtained, intra‐cultivar group variability was discovered. In some cultivar groups, mitotic recombination or deletions accumulated clonally. In addition, at least four cultivar groups encompassed cultivars from distinct sexual events co‐existing, notably Pisang Awak with five distinct patterns across two ploidy levels. Finally, additional patterns were discovered in the newest materials of the set, showing that a wider diversity of clones still exists on farm.

Objective To examine the course of interstitial lung disease associated with rheumatoid arthritis (RA-ILD) in France on treatment with Janus kinase inhibitors (JAKis) using the MAJIK-SFR registry.Methods Prospective national multicentre observational study identifying patients with RA-ILD from the MAJIK-SFR registry. Pulmonary assessment data were collected at JAKi initiation and follow-up visits (6 months, 12 months and a median of 21 months postinclusion), including chest high-resolution CT (HRCT), pulmonary function tests (forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide (DLCO)), acute exacerbations of ILD, respiratory infections and lung cancers.Results We enrolled 42 patients (26 women, 62%) with RA-ILD with a mean age of 61±13 years and a mean disease duration of 16±10 years. Compared with the 778 RA patients without ILD from the MAJIK registry, RA-ILD patients were older, displayed more severe and active disease and had more prevalent comorbidities. Non-specific interstitial pneumonia and usual interstitial pneumonia accounted for 46% and 43% of the chest HRCT ILD patterns, respectively. No significant changes in FVC and DLCO were observed during the follow-up period. Chest HRCT lesions remained stable in 69% of patients. Progressive ILD was identified in 8 patients (19%). 16 (38%) respiratory tract infections were observed. Only one acute regressive exacerbation of ILD was noted, and no lung cancer was diagnosed. No deaths occurred. JAKi was discontinued in 17 patients including 8 for inefficacy on joint involvement and 5 for intolerance.Conclusion The analysis indicates stability of RA-ILD in patients treated with JAKi. The tolerance profile of JAKi in this higher risk population did not reveal new safety signal.

This article provides a comprehensive analysis of knee strengthening post-surgery, focusing on key performance indicators (KPIs) essential for recovery and performance enhancement. The study delves into the importance of range of motion (ROM), load management through repetitions maximum (RM) and velocity-based training (VBT), speed variations, repetition schemes for hypertrophy and strength, and the assessment of pain, inflammation, and effusion. Emphasis is placed on dynamic alignment, muscle activation, and rate of perceived exertion (RPE) to tailor individualized rehabilitation programs. The integration of these KPIs ensures a balanced approach, enhancing muscle strength and joint integrity while minimizing injury risk. Regular monitoring and adjustments based on these indicators are recommended to optimize outcomes and ensure sustained progress in knee function and overall mobility.

ABSTRACT BACKGROUND: Multimodal protocols such as Acceleration of Total Postoperative Recovery and Enhanced Recovery After Surgery propose a set of pre- and post-operative care to accelerate the recovery of surgical patients. However, in clinical practice, simple care such as early refeeding and use of drains are often neglected by multidisciplinary teams. AIMS: Investigate whether early postoperative refeeding determines benefits in colorectal oncological surgery; whether the patients’ clinical conditions preoperatively and the use of a nasogastric tube and abdominal drain delay their recovery. METHODS: Retrospective cohort carried out at the Cascavel Uopeccan Cancer Hospital, including adult cancer patients (age ≥18 years), from the Unified Health System (SUS), who underwent colorectal surgeries from January 2018 to December 2021. RESULTS: 275 patients were evaluated. Of these, 199 (75.4%) were refed early. Late refeeding (odds ratio — OR=2.1; p=0.024), the use of nasogastric tube (OR=2.72; p=0.038) and intra-abdominal drain (OR=1.95; p=0.054) increased the chance of infectious complication. Multivariate analysis showed that receiving a late postoperative diet is an independent risk factor for infectious complications. Late refeeding (p=0.006) after the operation and the placement of an intra-abdominal drain (p=0.007) are independent risk factors for remaining hospitalized for more than five days postoperatively. CONCLUSIONS: Refeeding early in the postoperative period reduces the risk of infectious complications. Using abdominal drains and refeeding late (>48h) for cancer patients undergoing colorectal surgery are risk factors for hospital stays longer than five days.

Despite much literature on operations research applied to various healthcare problems, impactful implementation in public healthcare is limited, which often results in allocative inefficiency. This article uses a mobile clinic routing and scheduling problem in the Witzenberg region of South Africa as a case study to demonstrate the improvement of implementation success through cross-disciplinary collaboration, and also to propose a new three-stage approach for modelling a mobile clinic problem that incorporates continuity of care, fairness, and minimisation of distance travelled. Mobile clinics are used in many countries to improve access to healthcare for rural communities. Decision makers must assign farms or villages to mobile clinics, and determine their monthly visit schedules. To improve implementation success, we follow a collaborative three-phased mixed-methods approach with healthcare professionals to improve workload balance, fairness, and transportation cost. During phase 1, qualitative and quantitative data are gathered through qualitative research methods. In phase 2, fairly distributed optimal routes and schedules are designed using a three-stage model that incorporates a multi-vehicle routing problem to determine daily routes, a knapsack problem to establish a fair allocation of these daily routes between different clinics, and another variation on the vehicle routing problem to determine the monthly visit schedule that minimises the distance between the last farm visited on each consecutive day in the case of having to return to a farm the next day. Different input parameter estimations result in different routes and schedules. In phase 3, AHP is performed with main decision makers to determine their preferred solution. Final routes and schedules are designed based on model results, AHP results, and contextual input from decision makers. In our case study, an improved workload balance, a 23% reduction in total distance travelled, and buy-in to implement the changes, were obtained.

Summary: Background: The Bari-SolidAct randomized controlled trial compared baricitinib with placebo in patients with severe COVID-19. A post hoc analysis revealed a higher incidence of serious adverse events (SAEs) among SARS-CoV-2-vaccinated participants who had received baricitinib. This sub-study aimed to investigate whether vaccination influences the safety profile of baricitinib in patients with severe COVID-19. Methods: Biobanked samples from 146 participants (55 vaccinated vs. 91 unvaccinated) were analysed longitudinally for inflammation markers, humoral responses, tissue viral loads, and plasma viral antigens on days 1, 3, and 8. High-dimensional analyses, including RNA sequencing and flow cytometry, were performed on available samples. Mediation analyses were used to assess relationships between SAEs, baseline-adjusted biomarkers, and treatment-vaccination status. Findings: Vaccinated participants were older, more frequently hospitalized, had more comorbidities, and exhibited higher nasopharyngeal viral loads. Baricitinib treatment did not affect antibody responses or viral clearance, but reduced markers of T-cell and monocyte activation compared to placebo (sCD25, sCD14, sCD163, sTIM-3). Age, baseline levels of plasma viral antigen, and several inflammatory markers, as well as IL-2, IL-6, Neopterin, CXCL16, sCD14, and suPAR on day 8 were associated with the occurrence of SAEs. However, mediation analyses of markers linked to SAEs, baricitinib treatment, or vaccination status did not reveal statistically significant interactions between vaccination status and SAEs. Interpretation: This sub-study did not identify any virus- or host-related biomarkers significantly associated with the interaction between SARS-CoV-2 vaccination status and the safety of baricitinib. However, caution should be exercised due to the moderate sample size. Funding: EU Horizon 2020 (grant number 101015736).

Researching violence, especially within homes, families or closed community spaces, is often challenging. PhotoVOICE 2.0 is an innovative technology-assisted adaptation of the participatory arts-based research (PABR) method, Photovoice. It was developed and piloted in 2018 by the authors to conduct research on the ways the Anglican Mothers’ Union in Zambia contributes to and/or resists violence against women and violence against children. This article discusses the methodological underpinnings and origins of this method and offers an overview of its implementation in Zambia. Several key insights emerge regarding how PhotoVOICE 2.0 enables feminist, participatory arts-based research, including that it empowers local community co-researchers and amplifies the voices of insiders to the specific institution being researched in ways that can support feminist research aims for social transformation. The technological component of the method centers PABR methods throughout the whole research process. The article concludes by emphasizing the extraordinary disruptive power of the PhotoVOICE 2.0 method in subverting existing hierarchies of knowledge and control and highlighting its continued evolution in new settings.

ABSTRACT The post-transcriptional process of RNA polyadenylation sits at the crossroads of energy metabolism and RNA metabolism. RNA polyadenylation is catalyzed by poly(A) polymerases, which use ATP as a substrate to add adenine to the 3′ end of RNAs, which can alter their stability. In Escherichia coli, RNA polyadenylation mediated by the major poly(A) polymerase was previously shown to facilitate degradation of individual RNAs. In this study, we performed the first genome-wide study of RNA stability in the absence of PAP I. Inactivation of the pcnB gene coding for PAP I led to the stabilization of more than a thousand of E. coli RNAs in the form of full-length functional molecules or non-functional fragments. The absence of PAP I altered the energy metabolism, with an almost 20% reduction in ATP levels. To better understand how RNA and energy metabolisms are interconnected, we investigated the role of ATP levels in regulating RNA stability. When we lowered intracellular ATP levels below 0.5 mM, many RNAs were stabilized, demonstrating the causal link between ATP levels and RNA stability for the first time in E. coli. Above this concentration, changes in ATP levels had no impact on RNA stability. We also demonstrated that some RNAs were stabilized when PAP I was inactivated by low ATP availability. These results clearly demonstrate that PAP I mediates an energy-dependent RNA stabilization, which may contribute to cell energy homeostasis under energy-limited conditions.IMPORTANCEPoly(A) polymerases are prime targets for understanding the interactions between RNA polyadenylation, RNA stability, and cellular energy. These enzymes catalyze the process of RNA polyadenylation, which involves ATP hydrolysis and addition of poly(A) tails to the 3′ end of RNAs. 3′ end poly(A) extensions potentially facilitate RNA degradation in bacteria. In this study, we inactivated the pcnB gene encoding PAP I, the major poly(A) polymerase in E. coli, and investigated the effects on RNA stability and energy levels. Our results show for the first time in E. coli a genome-wide RNA stabilization in the absence of PAP I associated with a decrease in ATP levels. We provide the first evidence in E. coli of a link between ATP levels and RNA stabilization and demonstrate that this is mediated in some cases by PAP I. PAP I-mediated RNA stabilization at low ATP levels could be a means of energy conservation under energy-limited conditions.

Wild animals can modulate ecosystem-climate feedbacks, e.g. through impacts on vegetation and associated carbon dynamics. However, vegetation cover and composition also affect land surface albedo, which is an important component of the global energy budget. We currently know very little about the influence of wild animals on land surface albedo and the resulting climate forcing of these albedo changes. Leveraging a unique, ecosystem-scale, semi-experimental approach, we study how the local removals of the world’s largest, terrestrial grazer, white rhinoceros ( Ceratotherium simum ), affected the coupling between fire dynamics, woody encroachment and surface albedo in Hluhluwe–iMfolozi Park (HiP), South Africa. Our path analysis revealed that areas in the park where more rhinos had been removed showed a stronger increase in burnt area and woody encroachment compared to areas with fewer rhinos removed, which were both related to a decrease in surface albedo. Increasing burnt area was further associated with higher rates of woody encroachment, indirectly reinforcing the negative effect of rhino loss on albedo. Our study demonstrates that removals of megagrazers in HiP were related to complex ecosystem-wide cascades with measurable impacts on land cover and surface albedo and consequences on climate forcing. This highlights the importance of restoring functional ecosystems by reinstating trophic processes.