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BACKGROUND: Interpersonal violence is a leading cause of morbidity, with potentially severe adverse consequences for the mental health of the injured persons. The extent to which violent injury is associated with subsequent suicidal behavior, however, remains unclear. This study aimed to examine how violent injury was associated with subsequent deliberate self-harm and death by suicide. METHODS: This retrospective cohort study used nationwide longitudinal registry data from Norway to identify all individuals presenting to emergency services in 2010-2018 with a violence-related injury, along with sex- and age-matched control individuals from the general population. The primary outcomes were any emergency visit for deliberate self-harm (DSH) and suicide death, observed through 31 December 2018. Rates of each outcome were compared between violence-injured patients and comparison individuals using stratified multivariable Cox regression models, controlling for sociodemographic characteristics as well as history of psychiatric treatment and DSH. Secondary analyses tested for moderation by sex, age, and prior psychiatric treatment. FINDINGS: Violence-injured patients (n = 28,276) had substantially higher rates of DSH (946.7 per 100,000 person-years) and suicide death (74.5 per 100,000) when compared to controls (n = 282,760; 90.0 and 15.2 per 100,000, respectively). The hazard ratios (HRs) remained significantly higher even after accounting for covariates (HRadj for DSH: 5.11; 95% CI: 4.62, 5.66; HRadj for suicide: 2.40; 95% CI: 1.78, 3.24). Sex differences in this association were negligible, but the association between violence injury and DSH increased with age. Violence-injured patients with prior psychiatric treatment had the highest risk of suicidal behavior. INTERPRETATION: Violence-injured patients experience significantly excess rates of suicidal behavior, a finding with potential to inform both clinical intervention and population-level suicid

This paper wrestles with the concept of care and its role in the movement towards abolitionist education. I draw from my experiences as a teacher / ethnographer in an alternative high school, called FREE LA, that serves and was created by system-impacted young people who have been pushed out of or barred from, or otherwise refused to participate in, traditional schooling. Grounded in students’ perceptions of how this space departs from traditional schools and other carceral institutions, I grapple with their consistent emphasis on care. Students’ juxtaposition between the type of care they experienced in traditional schools, and a different type of care experienced at FREE LA, leads me to consider both the violent genealogies of conditional care as endemic to state schooling, and the potential for reclaiming old-new genealogies of unconditional care that map radically reimagined educational space(s). The juxtaposition between these two types of care opens broader questions about the limitations of educational reform and the possibilities for abolitionist departure.

This dissertation examines the relationships between schooling and carceral systems, and the ways system-impacted youth build abolitionist alternatives to punitive education, and criminalization more broadly. I conduct a two and a half-year ethnography of Fighting for the Revolution that will Educate and Empower Los Angeles (FREE LA) High School. FREE LA is a police-free, punishment-free alternative school in South LA, created for and by Black and Brown young people who were excluded from, or chose to leave, traditional schooling. FREE LA is rooted in abolition and transformative justice, each of which encompass a broad framework and set of everyday praxes for transforming the conditions, ideologies, and power relationships that make State and interpersonal violence continuous and inevitable. I also taught, substituted, and tutored at FREE LA for the past four years. Through a critical geographic frame, I use FREE LA’s model and students’ insights as a lens to explore the deeper entanglements between schooling and carceral regimes, beyond the focus on harsh “zero tolerance” discipline (e.g., suspension and expulsion) used in much current literature on schools and prisons. Likewise, by examining the numerous processes, praxes, and relationships through which FREE LA participants build an educational space where punishment is nowhere on the spectrum, I explore the possibilities for abolitionist alternatives beyond the “alternatives to discipline” (e.g., behavioral interventions and restorative practices) frequently proposed as solutions to the school-prison link. By viewing schools and prisons not as static ‘things’ linked through isolated policies, but dynamic sets of relationships, I analyze how carceral ideologies, modes of relationality, and forms of social organization flow into, out of, and across “school” in ways that entrench and normalize carceral regimes. I demonstrate how schooling and carceral systems are constitutively produced across numerous scales, to

The phenomenon of mixed/heterogenous treatment responses to cancer therapies within an individual patient presents a challenging clinical scenario. Furthermore, the molecular basis of mixed intra-patient tumor responses remains unclear. Here, we show that patients with metastatic lung adenocarcinoma harbouring co-mutations of EGFR and TP53, are more likely to have mixed intra-patient tumor responses to EGFR tyrosine kinase inhibition (TKI), compared to those with an EGFR mutation alone. The combined presence of whole genome doubling (WGD) and TP53 co-mutations leads to increased genome instability and genomic copy number aberrations in genes implicated in EGFR TKI resistance. Using mouse models and an in vitro isogenic p53-mutant model system, we provide evidence that WGD provides diverse routes to drug resistance by increasing the probability of acquiring copy-number gains or losses relative to non-WGD cells. These data provide a molecular basis for mixed tumor responses to targeted therapy, within an individual patient, with implications for therapeutic strategies.

The introduction of the International Association for the Study of Lung Cancer grading system has furthered interest in histopathological grading for risk stratification in lung adenocarcinoma. Complex morphology and high intratumoral heterogeneity present challenges to pathologists, prompting the development of artificial intelligence (AI) methods. Here we developed ANORAK (pyrAmid pooliNg crOss stReam Attention networK), encoding multiresolution inputs with an attention mechanism, to delineate growth patterns from hematoxylin and eosin-stained slides. In 1,372 lung adenocarcinomas across four independent cohorts, AI-based grading was prognostic of disease-free survival, and further assisted pathologists by consistently improving prognostication in stage I tumors. Tumors with discrepant patterns between AI and pathologists had notably higher intratumoral heterogeneity. Furthermore, ANORAK facilitates the morphological and spatial assessment of the acinar pattern, capturing acinus variations with pattern transition. Collectively, our AI method enabled the precision quantification and morphology investigation of growth patterns, reflecting intratumoral histological transitions in lung adenocarcinoma.

Will Americans stand up for democracy even when it works against their party?Seven years ago, two of the three authors of this report began a research study to understand American support for democracy and the potential appeal of authoritarian alternatives. Since then, we have surveyed thousands of Americans using multiple survey instruments. Over the course of this project, we have gone beyond an initial battery of questions and pursued multiple avenues to understand and explain what people really believe and why. To do so, we:re-interviewed the same individuals over time to check for consistency in responses to original questions,examined depth of support by asking respondents how strongly they felt about their answers and by testing alternative language to ensure that question wording is not being misunderstood,used focus groups and interviews to develop scenarios that are responsive to the reasons people give for supporting democratic alternatives, andcompared views about abstract principles with reactions to real-world circumstances.Our most recent survey in November 2022 offers us the chance to explore the most important uncertainty emerging from our earlier research. Namely, to what extent were responses to our previous questions an artifact of the Trump presidency? Are Republicans really more supportive of authoritarian actions than Democrats? Or, are Democrats just as willing to support abuses of power in a polarized environment when they control the executive branch?Following the 2020 election, we can understand how views shifted when control of the White House changed hands — even if we haven't yet emerged from an era in which Donald Trump is at the center of our politics. The results show that support for foundational principles of liberal democracy are discouragingly soft and inconsistent.

Wiskott-Aldrich syndrome (WAS) is a multifaceted monogenic disorder with a broad disease spectrum and variable disease severity and a variety of treatment options including allogeneic hematopoietic stem cell transplantation (HSCT) and gene therapy (GT). No reliable biomarker exists to predict disease course and outcome for individual patients. A total of 577 patients with a WAS variant from 26 countries and a median follow-up of 8.9 years (range, 0.3-71.1), totaling 6118 patient-years, were included in this international retrospective study. Overall survival (OS) of the cohort (censored at HSCT or GT) was 82% (95% confidence interval, 78-87) at age 15 years and 70% (61-80) at 30 years. The type of variant was predictive of outcome: patients with a missense variant in exons 1 or 2 or with the intronic hot spot variant c.559+5G>A (class I variants) had a 15-year OS of 93% (89-98) and a 30-year OS of 91% (86-97), compared with 71% (62-81) and 48% (34-68) in patients with any other variant (class II; P < .0001). The cumulative incidence rates of disease-related complications such as severe bleeding (P = .007), life-threatening infection (P < .0001), and autoimmunity (P = .004) occurred significantly later in patients with a class I variant. The cumulative incidence of malignancy (P = .6) was not different between classes I and II. It confirms the spectrum of disease severity and quantifies the risk for specific disease-related complications. The class of the variant is a biomarker to predict the outcome for patients with WAS.

The BYOND study evaluated the efficacy and safety of bosutinib 500 mg once daily in patients with chronic myeloid leukemia (CML) resistant/intolerant to prior tyrosine kinase inhibitors (TKIs). These post-hoc analyses assessed the efficacy and safety of bosutinib by resistance or intolerance to prior TKIs (imatinib-resistant vs dasatinib/nilotinib-resistant vs TKI-intolerant), and cross-intolerance between bosutinib and prior TKIs (imatinib, dasatinib, nilotinib), in patients with Philadelphia chromosome–positive chronic phase CML. Data are reported after ≥3 years’ follow-up. Of 156 patients with Philadelphia chromosome–positive chronic phase CML, 53 were imatinib-resistant, 29 dasatinib/nilotinib-resistant, and 74 intolerant to all prior TKIs; cumulative complete cytogenetic response rates at any time were 83.7%, 61.5%, and 86.8%, and cumulative major molecular response rates at any time were 72.9%, 40.7%, and 82.4%, respectively. Of 141, 95, and 79 patients who received prior imatinib, dasatinib, and nilotinib, 64 (45.4%), 71 (74.7%), and 60 (75.9%) discontinued the respective TKI due to intolerance; of these, 2 (3.1%), 5 (7.0%), and 0 had cross-intolerance with bosutinib. The response rates observed in TKI-resistant and TKI-intolerant patients, and low cross-intolerance between bosutinib and prior TKIs, further support bosutinib use for patients with Philadelphia chromosome–positive chronic phase CML resistant/intolerant to prior TKIs.

Autoimmune diseases disproportionately affect females more than males. The XX sex chromosome complement is strongly associated with susceptibility to autoimmunity. Xist long non-coding RNA (lncRNA) is expressed only in females to randomly inactivate one of the two X chromosomes to achieve gene dosage compensation. Here, we show that the Xist ribonucleoprotein (RNP) complex comprising numerous autoantigenic components is an important driver of sex-biased autoimmunity. Inducible transgenic expression of a non-silencing form of Xist in male mice introduced Xist RNP complexes and sufficed to produce autoantibodies. Male SJL/J mice expressing transgenic Xist developed more severe multi-organ pathology in a pristane-induced lupus model than wild-type males. Xist expression in males reprogrammed T and B cell populations and chromatin states to more resemble wild-type females. Human patients with autoimmune diseases displayed significant autoantibodies to multiple components of XIST RNP. Thus, a sex-specific lncRNA scaffolds ubiquitous RNP components to drive sex-biased immunity., QC 20240209

We study a family of excitonic quantum phase transitions describing the evolution of a bilayer metallic state to an inter-layer coherent state where excitons condense. We argue that such transitions can be continuous and exhibit a non-Fermi liquid counterflow response ${\rho_{\mathrm{counterflow}}(\omega)\sim\omega^{2/z}}$ that directly encodes the dynamical critical exponent $z$. Our calculations are performed within a controlled expansion around $z = 2$. This physics is relevant to any system with spin, valley, or layer degrees of freedom. We consider two contexts for excitonic quantum criticality: (1) a weakly interacting graphene bilayer, and (2) a system of two narrow, half-filled Chern bands at zero external magnetic field, with total Chern number $C_{\mathrm{tot}}=0$, which may soon be realizable in moir\'{e} materials. The latter system hosts a time-reversed pair of composite Fermi liquid states, and the condensation of excitons of the composite fermions leads to an exotic exciton insulator* state with a charge neutral Fermi surface. Our work sheds new light on the physics of inter-layer coherence transitions in 2D materials., Comment: 30 pages + 26 pages appendices, 8 figures. (v2) Includes the effect of momentum dependence in the fermion self energy, which was neglected in (v1). Appendix A has been expanded to clarify the relationship between this work and the existing literature on ferromagnetic transitions in metals

Football both impacts, and is impacted by, climate change and environmental decline. The sport’s position as the ‘global game’ makes this particularly noteworthy and there is the potential for it to play a leading role in how society responds. The current reaction of football organisations is, however, insufficient for the magnitude of the problem, and undermined by attempts to expand activity: bigger tournaments, more matches, increased travel. There is no co-ordinated strategy to tackle an issue that could overwhelm the game, instead it is left to individuals to voice concerns and try to mobilise action. This must change.

IntroductionFederal policies and guidelines have expanded the return of individual results to participants and expectations for data sharing between investigators and through repositories. Here, we report investigators' and study participants' views and experiences with data stewardship practices within frontotemporal lobal degeneration (FTLD) research, which reveal unique ethical challenges.MethodsSemi-structured interviews with (1) investigators conducting FTLD research that includes genetic data collection and/or analysis and (2) participants enrolled in a single site longitudinal FTLD study.ResultsAnalysis of the interviews identified three meta themes: perspectives on data sharing, experiences with enrollment and participation, and data management and security as mechanisms for participant protections.DiscussionThis study identified a set of preliminary gaps and needs regarding data stewardship within FTLD research. The results offer initial insights on ethical challenges to data stewardship aimed at informing future guidelines and policies.

Lupus nephritis (LN) is a pathologically heterogenous autoimmune disease linked to end-stage kidney disease and mortality. Better therapeutic strategies are needed as only 30%-40% of patients completely respond to treatment. Noninvasive biomarkers of intrarenal inflammation may guide more precise approaches. Because urine collects the byproducts of kidney inflammation, we studied the urine proteomic profiles of 225 patients with LN (573 samples) in the longitudinal Accelerating Medicines Partnership in RA/SLE cohort. Urinary biomarkers of monocyte/neutrophil degranulation (i.e., PR3, S100A8, azurocidin, catalase, cathepsins, MMP8), macrophage activation (i.e., CD163, CD206, galectin-1), wound healing/matrix degradation (i.e., nidogen-1, decorin), and IL-16 characterized the aggressive proliferative LN classes and significantly correlated with histological activity. A decline of these biomarkers after 3 months of treatment predicted the 1-year response more robustly than proteinuria, the standard of care (AUC: CD206 0.91, EGFR 0.9, CD163 0.89, proteinuria 0.8). Candidate biomarkers were validated and provide potentially treatable targets. We propose these biomarkers of intrarenal immunological activity as noninvasive tools to diagnose LN and guide treatment and as surrogate endpoints for clinical trials. These findings provide insights into the processes involved in LN activity. This data set is a public resource to generate and test hypotheses and validate biomarkers.

This dissertation delves into the rich intersection of machine learning (ML) and biology, a field marked by significant progress yet full of opportunities for further breakthroughs. The work presented here is divided into three main parts. The first two focus on employing ML to investigate reward-based learning in animals and to study protein-protein interactions within viruses. The third part shifts focus to explore the development of robust computer vision models, drawing inspiration from biological insights. In the first part, we apply the reinforcement learning (RL) framework to gain insights into reward-based learning in animals. We explore how key neural circuits and neurotransmitter systems, specifically the prefrontal cortex, ventral striatum, and the dopaminergic pathways, contribute to the implementation of RL algorithms to learn the association of actions with delayed outcomes, known as the credit assignment problem. We first identify a distinct pattern of neural activity in the prefrontal cortical inputs to the ventral striatum: activity that is sequential over time and selective to a given choice. We then use computational modeling to show how these inputs provide an effective state representation for the ventral striatum, enabling it to calculate accurate value signals for each choice at any given time point. This is demonstrated through the implementation of two neural circuit models of reinforcement learning, where reward prediction error drives learning either by inducing rapid synaptic plasticity or by altering neural dynamics. Additionally, we test and confirm our circuit model predictions experimentally through direct manipulation of the input neurons to the ventral striatum.In the second part, we conduct two computational studies of SARS-CoV-2 to understand its spike protein interactions and its implications in viral transmission and immune response evasion. To achieve this we employ two key computational tools: molecular dynamic simulations and

The phase III double-blind PROPEL study compared the novel two-component therapy cipaglucosidase alfa + miglustat (cipa + mig) with alglucosidase alfa + placebo (alg + pbo) in adults with late-onset Pompe disease (LOPD). This ongoing open-label extension (OLE; NCT04138277) evaluates long-term safety and efficacy of cipa + mig. Outcomes include 6-min walk distance (6MWD), forced vital capacity (FVC), creatine kinase (CK) and hexose tetrasaccharide (Hex4) levels, patient-reported outcomes and safety. Data are reported as change from PROPEL baseline to OLE week 52 (104 weeks post-PROPEL baseline). Of 118 patients treated in the OLE, 81 continued cipa + mig treatment from PROPEL (cipa + mig group; 61 enzyme replacement therapy [ERT] experienced prior to PROPEL; 20 ERT naïve) and 37 switched from alg + pbo to cipa + mig (switch group; 29 ERT experienced; 8 ERT naive). Mean (standard deviation [SD]) change in % predicted 6MWD from baseline to week 104 was + 3.1 (8.1) for cipa + mig and - 0.5 (7.8) for the ERT-experienced switch group, and + 8.6 (8.6) for cipa + mig and + 8.9 (11.7) for the ERT-naïve switch group. Mean (SD) change in % predicted FVC was - 0.6 (7.5) for cipa + mig and - 3.8 (6.2) for the ERT-experienced switch group, and - 4.8 (6.5) and - 3.1 (6.7), respectively, in ERT-naïve patients. CK and Hex4 levels improved in both treatment groups by week 104 with cipa + mig treatment. Three patients discontinued the OLE due to infusion-associated reactions. No new safety signals were identified. Cipa + mig treatment up to 104 weeks was associated with overall maintained improvements (6MWD, biomarkers) or stabilization (FVC) from baseline with continued durability, and was well tolerated, supporting long-term benefits for patients with LOPD.Trial registration number: NCT04138277; trial start date: December 18, 2019.

America’s juvenile justice system was founded on the notion that the juvenile court would serve as the “ultimate parent” for youth. Yet, the history of youth punishment challenges the promise of juvenile “justice.” To offer a more comprehensive account of the family systems in juvenile court, this study draws from the insights of historical research on youth punishment and family criminalization to examine juvenile court outcomes in Arizona. Combining a historical lens with insights from attribution theory, we use quantitative and qualitative methods to examine the relationship between diverse family systems, including single mothers, single fathers, extended families, and foster care families, and juvenile court outcomes (i.e., diversion, preadjudication detention, petition, and judicial dismissal). Our findings suggest the need for more complex understandings of both family and punishment, and more expansive theorizations of the sorts of solutions that match the scope and scale of the problem.

BACKGROUND: The penetrance of common genetic risk variants for Parkinsons disease (PD) is low. Pesticide exposure increases PD risk, but how exposure affects penetrance is not well understood. OBJECTIVE: To determine the relationship between occupational pesticide exposure and PD in people with LRRK2 and GBA risk variants. METHODS: Participants of the Parkinsons Progression Markers Initiative (PPMI) with a LRRK2-G2019 S or GBA risk variant provided information about occupational pesticide exposure. We compared exposure in carriers with and without PD. Among carriers with PD, we used Cox proportional hazard models to compare time-to impairment in balance, cognition, and activities of daily living (ADLs) between participants with and without prior occupational pesticide exposure. RESULTS: 378 participants with a risk variant provided exposure information; 176 with LRRK2-G2019 S (54 with and 122 without PD) and 202 with GBA variants (47 with and 155 without PD). Twenty-six participants reported pesticide exposure. People with a GBA variant and occupational pesticide exposure had much higher odds of PD (aOR: 5.4, 95% CI 1.7-18.5, p < 0.01). People with a LRRK2 variant and a history of occupational pesticide exposure had non-significantly elevated odds of PD (aOR 1.3, 95% CI 0.4-4.6, p = 0.7). Among those with PD, pesticide exposure was associated with a higher risk of balance problems and cognitive impairment in LRRK2-PD and functional impairment in GBA-PD, although associations were not statistically significant. CONCLUSIONS: Occupational pesticide exposure may increase penetrance of GBA-PD and may be associated with faster symptom progression. Further studies in larger cohorts are necessary.

BACKGROUND: Patients with telomere biology disorders (TBD) develop hepatic disease, including hepatitis, cirrhosis, and hepatopulmonary syndrome. No specific treatment exists for TBD-related liver disease, and the role of liver transplantation (LT) remains controversial. Our study objectives were to describe the clinical characteristics, management, and outcomes in patients with TBD-related liver disease, and their LT outcomes. METHODS: Data from 83 patients with TBD-associated liver disease were obtained from 17 participating centers in the Clinical Care Consortium of Telomere-Associated Ailments and by self-report for our retrospective, multicenter, international cohort study. RESULTS: Group A (Advanced) included 40 patients with advanced liver disease. Of these, 20 underwent LT (Group AT). Group M (Mild) included 43 patients not warranting LT evaluation, none of whom were felt to be medically unfit for liver transplantation. Supplemental oxygen requirement, pulmonary arteriovenous malformation, hepatopulmonary syndrome, and higher bilirubin and international normalized ratio values were associated with Group A. Other demographics, clinical manifestations, and laboratory findings were similar between groups. Six group A patients were declined for LT; 3 died on the waitlist. Median follow-up post-LT was 2.9 years (range 0.6-13.2 y). One-year survival post-LT was 73%. Median survival post-LT has not been reached. Group AT patients had improved survival by age compared to all nontransplant patients (log-rank test p = 0.02). Of 14 patients with pretransplant hypoxemia, 8 (57%) had improved oxygenation after transplant. CONCLUSIONS: LT recipients with TBD do not exhibit excessive posttransplant mortality, and LT improved respiratory status in 57%. A TBD diagnosis should not exclude LT consideration.

UNLABELLED: Cryptococcus neoformans causes cryptococcosis, one of the most prevalent fungal diseases, generally characterized by meningitis. There is a limited and not very effective number of drugs available to combat this disease. In this manuscript, we show the host defense peptide mimetic brilacidin (BRI) as a promising antifungal drug against C. neoformans. BRI can affect the organization of the cell membrane, increasing the fungal cell permeability. We also investigated the effects of BRI against the model system Saccharomyces cerevisiae by analyzing libraries of mutants grown in the presence of BRI. In S. cerevisiae, BRI also affects the cell membrane organization, but in addition the cell wall integrity pathway and calcium metabolism. In vivo experiments show BRI significantly reduces C. neoformans survival inside macrophages and partially clears C. neoformans lung infection in an immunocompetent murine model of invasive pulmonary cryptococcosis. We also observed that BRI interacts with caspofungin (CAS) and amphotericin (AmB), potentiating their mechanism of action against C. neoformans. BRI + CAS affects endocytic movement, calcineurin, and mitogen-activated protein kinases. Our results indicate that BRI is a novel antifungal drug against cryptococcosis. IMPORTANCE: Invasive fungal infections have a high mortality rate causing more deaths annually than tuberculosis or malaria. Cryptococcosis, one of the most prevalent fungal diseases, is generally characterized by meningitis and is mainly caused by two closely related species of basidiomycetous yeasts, Cryptococcus neoformans and Cryptococcus gattii. There are few therapeutic options for treating cryptococcosis, and searching for new antifungal agents against this disease is very important. Here, we present brilacidin (BRI) as a potential antifungal agent against C. neoformans. BRI is a small molecule host defense peptide mimetic that has previously exhibited broad-spectrum immunomodulatory/anti-inflammato

Uranium-based materials are an important research topic in material science due to numerous industrial and scientific applications. However, hydrogen embrittlement of uranium, which arises due to the formation of a structurally weak pyrophoric hydride, poses a major safety risk in material applications. Relatively little is known about the hydriding initiation mechanism in pure uranium, in part due to the material’s highly reactive nature and toxicity. Future hydriding studies would thus greatly benefit from atomic-level simulations of the hydriding process, which can provide microscopic details about the hydrogen-uranium reaction and help guide future experimentation. Kohn-Sham Density Functional Theory (DFT) is a well-established quantum mechanical technique that can be used to elucidate many aspects of the onset of hydride formation. DFT is used in chemistry, physics, and materials science for accurate prediction of physical and chemical properties, such as material equations of state, heats of formation, and the energetics of bond forming/breaking under reactive conditions. However, molecular dynamics (MD) simulations run with DFT are generally limited to time scales on the order of picoseconds and system sizes of a few hundred atoms. In contrast, many processes related to hydriding, such as initiation, nucleation, and growth, probe significantly longer time and length scales, and can require simulation cells of thousands of atoms run for nanosecond timescales or longer. In this regard, the Chebyshev Interaction Model for Efficient Simulation (ChIMES) approach is a method for rapid creation of reactive MD models. Briefly, ChIMES is optimized through determination of linear combinations many-body Chebyshev polynomials by fitting to DFT simulation data, such atomic forces, system energies, and stress tensor components. ChIMES has been shown to yield similar accuracy to DFT while yielding linear scaling and orders of magnitude improvement in computational efficienc

The Sigatoka disease complex (SDC), caused by Mycosphaerella fijiensis (Mf) and M. musicola (Mm), comprises the most destructive fungal leaf streak and spot diseases of commercial banana crops worldwide. In Brazil, the site-specific succinate dehydrogenase inhibitor (SDHI) fungicides labeled for SDC management since 2014 present a high risk for the emergence of resistance if deployed intensively and solo. Our study determined the levels of sensitivity to boscalid and fluxapyroxad in four populations of the SDC pathogens sampled in 2020 from three distinct geographical regions under contrasting fungicide programs. Resistance, defined as EC50 values exceeding 20 µg mL−1, was prevalent at 59.7% for fluxapyroxad and 94.0% for boscalid. Only 1.5% of isolates exhibited sensitivity to both fungicides. We also assessed the changes in the corresponding fungicide target protein-encoding genes (SdhB, C, and D). None of the target site alterations detected were associated with reduced sensitivity. A second SdhC paralog was also analyzed, but target alterations were not found. However, MDR (multidrug resistance) was detected in a selection of isolates. Further monitoring for Sdh target mutations will be important, but an important role for other resistance mechanisms such as the presence of additional Sdh paralogs and MDR cannot be ruled out. These results highlight the importance of implementing sound anti-resistance management strategies when SDHI fungicides are deployed for the management of SDC.

Cerebrovascular Reactivity (CVR) refers to the ability of cerebral blood vessels to dilate or constrict under the effect of vasoactive substances and can be estimated using functional Magnetic Resonance Imaging (fMRI). Computation of CVR maps is relevant in various brain diseases and requires specialized data processing. We introduce CVRmap, an opensource software that automates the computation of CVR map. The toolbox complies with the Brain Imaging Data Structure (BIDS) standards., SCOPUS: ar.j, info:eu-repo/semantics/published

To investigate cortical oscillations during a sentence completion task (SC) using magnetoencephalography (MEG), focusing on the semantic control network (SCN), its leftward asymmetry, and the effects of semantic control load., SCOPUS: ar.j, info:eu-repo/semantics/published

Football both impacts, and is impacted by, climate change and environmental decline. The sport’s position as the ‘global game’ makes this particularly noteworthy and there is the potential for it to play a leading role in how society responds. The current reaction of football organisations is, however, insufficient for the magnitude of the problem, and undermined by attempts to expand activity: bigger tournaments, more matches, increased travel. There is no co-ordinated strategy to tackle an issue that could overwhelm the game, instead it is left to individuals to voice concerns and try to mobilise action. This must change.

‘Open schooling’ has become in recent years a burgeoning theme in the discourse on how to rethink education for the 21st century. This paper addresses a gap between calls for implementing an open schooling approach in policy papers and international reports and the scarcity of rigorous academic discourse on what open schooling theoretically means and practically entails in terms of school organization and curriculum. To this end, the paper presents an ecological model of school openness that is composed of eight interrelated dimensions: shared governance, ‘open’ curriculum, inner-school communities, learning communities, student participation, social engagement, parental involvement, and community collaborations. These dimensions are organized into three categories, accounting for organizational, pedagogical and communal aspects of school openness. The multidimensional nature of the model presented here provides a more intricate and nuanced account of open schooling that acknowledges the complexities and challenges that the movement towards greater openness yields for school communities. From an educational research perspective, this model functions to inform the understanding and examination of the multidimensionality of opening schools to their community. From an educational practice perspective, it can instigate in-depth and meaningful dialogue within school teams on what open schooling is and its ensuing merits.

‘Open schooling’ has become in recent years a burgeoning theme in the discourse on how to rethink education for the 21st century. This paper addresses a gap between calls for implementing an open schooling approach in policy papers and international reports and the scarcity of rigorous academic discourse on what open schooling theoretically means and practically entails in terms of school organization and curriculum. To this end, the paper presents an ecological model of school openness that is composed of eight interrelated dimensions: shared governance, ‘open’ curriculum, inner-school communities, learning communities, student participation, social engagement, parental involvement, and community collaborations. These dimensions are organized into three categories, accounting for organizational, pedagogical and communal aspects of school openness. The multidimensional nature of the model presented here provides a more intricate and nuanced account of open schooling that acknowledges the complexities and challenges that the movement towards greater openness yields for school communities. From an educational research perspective, this model functions to inform the understanding and examination of the multidimensionality of opening schools to their community. From an educational practice perspective, it can instigate in-depth and meaningful dialogue within school teams on what open schooling is and its ensuing merits.

‘Open schooling’ has become in recent years a burgeoning theme in the discourse on how to rethink education for the 21st century. This paper addresses a gap between calls for implementing an open schooling approach in policy papers and international reports and the scarcity of rigorous academic discourse on what open schooling theoretically means and practically entails in terms of school organization and curriculum. To this end, the paper presents an ecological model of school openness that is composed of eight interrelated dimensions: shared governance, ‘open’ curriculum, inner-school communities, learning communities, student participation, social engagement, parental involvement, and community collaborations. These dimensions are organized into three categories, accounting for organizational, pedagogical and communal aspects of school openness. The multidimensional nature of the model presented here provides a more intricate and nuanced account of open schooling that acknowledges the complexities and challenges that the movement towards greater openness yields for school communities. From an educational research perspective, this model functions to inform the understanding and examination of the multidimensionality of opening schools to their community. From an educational practice perspective, it can instigate in-depth and meaningful dialogue within school teams on what open schooling is and its ensuing merits.

‘Open schooling’ has become in recent years a burgeoning theme in the discourse on how to rethink education for the 21st century. This paper addresses a gap between calls for implementing an open schooling approach in policy papers and international reports and the scarcity of rigorous academic discourse on what open schooling theoretically means and practically entails in terms of school organization and curriculum. To this end, the paper presents an ecological model of school openness that is composed of eight interrelated dimensions: shared governance, ‘open’ curriculum, inner-school communities, learning communities, student participation, social engagement, parental involvement, and community collaborations. These dimensions are organized into three categories, accounting for organizational, pedagogical and communal aspects of school openness. The multidimensional nature of the model presented here provides a more intricate and nuanced account of open schooling that acknowledges the complexities and challenges that the movement towards greater openness yields for school communities. From an educational research perspective, this model functions to inform the understanding and examination of the multidimensionality of opening schools to their community. From an educational practice perspective, it can instigate in-depth and meaningful dialogue within school teams on what open schooling is and its ensuing merits.

Modern taxonomic classification is often based on phylogenetic analyses of a few molecular markers, although single-gene studies are still common. Here, we leverage genome-scale molecular phylogenetics (phylogenomics) of species and populations to reconstruct evolutionary relationships in a dense data set of 710 fungal genomes from the biomedically and technologically important genus Aspergillus. To do so, we generated a novel set of 1,362 high-quality molecular markers specific for Aspergillus and provided profile Hidden Markov Models for each, facilitating their use by others. Examining the resulting phylogeny helped resolve ongoing taxonomic controversies, identified new ones, and revealed extensive strain misidentification (7.59% of strains were previously misidentified), underscoring the importance of population-level sampling in species classification. These findings were corroborated using the current standard, taxonomically informative loci. These findings suggest that phylogenomics of species and populations can facilitate accurate taxonomic classifications and reconstructions of the Tree of Life.

OBJECTIVE: HER2 mutations are associated with poor prognosis and are detected in 3-6% of cervical cancers. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, had activity in several HER2-mutant cancer types in the phase 2 SUMMIT basket study. We present updated and final results from the cervical cancer cohort of SUMMIT. METHODS: Eligible patients had HER2-mutant, metastatic or recurrent cervical cancer progressing after platinum-based treatment for advanced/recurrent disease. Patients received neratinib 240 mg/day; loperamide was mandatory during cycle 1. Confirmed objective response rate (ORR) was the primary endpoint. Duration of response (DoR), clinical benefit rate (CBR), progression-free survival (PFS), and safety were secondary endpoints. RESULTS: Twenty-two patients were enrolled; 18 (81.8%) had endocervical adenocarcinoma; median two prior systemic chemotherapy regimens (range 1-4). The most common HER2 variant was S310F/Y mutation (n = 13; 59.1%). Four patients had confirmed partial responses (ORR 18.2%; 95% CI 5.2-40.3); 6 had stable disease ≥16 weeks (CBR 45.5%; 95% CI 24.4-67.8). Median DoR was 7.6 months (95% CI 5.6-12.3). Median PFS was 5.1 months (95% CI 1.7-7.2). All-grade diarrhea (90.9%), nausea (54.5%), and constipation (54.5%) were the most common adverse events. Five patients (22.7%) reported grade 3 diarrhea. There were no grade 4 adverse events, no diarrhea-related treatment discontinuations, and two grade 5 adverse events, unrelated to neratinib: dyspnea (n = 1) and embolism (n = 1). CONCLUSIONS: Neratinib resulted in durable responses and disease control in patients with HER2-mutant metastatic/recurrent cervical cancer in SUMMIT. These findings support next-generation sequencing and tailored therapy for select patients with advanced cervical cancer. All responses occurred in patients with endocervical adenocarcinoma. Further assessment of neratinib in this setting is warranted. TRIAL REGISTRATION NUMBER: NCT01953926 (ClinicalTria

‘Open schooling’ has become in recent years a burgeoning theme in the discourse on how to rethink education for the 21st century. This paper addresses a gap between calls for implementing an open schooling approach in policy papers and international reports and the scarcity of rigorous academic discourse on what open schooling theoretically means and practically entails in terms of school organization and curriculum. To this end, the paper presents an ecological model of school openness that is composed of eight interrelated dimensions: shared governance, ‘open’ curriculum, inner-school communities, learning communities, student participation, social engagement, parental involvement, and community collaborations. These dimensions are organized into three categories, accounting for organizational, pedagogical and communal aspects of school openness. The multidimensional nature of the model presented here provides a more intricate and nuanced account of open schooling that acknowledges the complexities and challenges that the movement towards greater openness yields for school communities. From an educational research perspective, this model functions to inform the understanding and examination of the multidimensionality of opening schools to their community. From an educational practice perspective, it can instigate in-depth and meaningful dialogue within school teams on what open schooling is and its ensuing merits.

Some marine sculpins (Psychrolutidae) exhibit an unusual reproductive mode called internal gametic association (IGA), in which sperm transfer between the sexes occurs during copulation, but fertilization is delayed until the eggs are released in seawater. IGA is suggested in many internally inseminating marine sculpins, but experimental evidence of IGA is limited to a few species. The Fluffy Sculpin (Oligocottus snyderi) and its sister species, the Rosy Sculpin (O. rubellio), occur in sympatry in intertidal zones along the central California coast. Although these species likely exhibit internal insemination, their reproductive strategy is not well understood. Here, we investigate reproductive mode, mating season, egg-laying season, and sperm morphology and activity in Fluffy and Rosy Sculpins near Pillar Point, California. Delayed embryonic development was observed for one clutch of eggs of the Rosy Sculpin after exposure to seawater, indicating IGA in this species. We were unable to demonstrate IGA by initiation of development in the Fluffy Sculpin because we were unable to collect females with ovulated oocytes. Nevertheless, we found that sperm morphology with elongated head and high motility in isotonic solution while immotile in seawater in both species represent characteristics associated with IGA. Seasonal changes in gonadosomatic index (GSI) of both sexes revealed asynchronous gonadal maturation between the sexes in the Fluffy Sculpin and suggest a similar pattern in the Rosy Sculpin; however, the latter was affected by small sample size. These patterns indicate that males copulate with females before egg maturation, and females store sperm for several months. Our study supports the generality of IGA across marine sculpins and provides an understanding of its relationship to asynchrony in GSI between the sexes. Further, while Fluffy and Rosy Sculpins are similar in body morphology, habitat, and reproductive mode, the slight difference in mating season (pre-ma

Dynamic Task Scheduling is an enticing programming model aiming to ease the development of parallel programs with intrinsically irregular or data-dependent parallelism. The performance of such solutions relies on the ability of the Task Scheduling HW/SW stack to efficiently evaluate dependencies at runtime and schedule work to available cores. Traditional SW-only systems implicate scheduling overheads of around 30K processor cycles per task, which severely limit the ( core count , task granularity ) combinations that they might adequately handle. Previous work on HW-accelerated Task Scheduling has shown that such systems might support high performance scheduling on processors with up to eight cores, but questions remained regarding the viability of such solutions to support the greater number of cores now frequently found in high-end SMP systems. The present work presents an FPGA-proven, tightly-integrated, Linux-capable, 30-core RISC-V system with hardware accelerated Task Scheduling. We use this implementation to show that HW Task Scheduling can still offer competitive performance at such high core count, and describe how this organization includes hardware and software optimizations that make it even more scalable than previous solutions. Finally, we outline ways in which this architecture could be augmented to overcome inter-core communication bottlenecks, mitigating the cache-degradation effects usually involved in the parallelization of highly optimized serial code., This work is supported by the TEXTAROSSA project G.A. n.956831, as part of the EuroHPC initiative, by the Spanish Government (grants PCI2021-121964, TEXTAROSSA; PDC2022-133323-I00, Multi-Ka; PID2019-107255GB-C21 MCIN/AEI/10.13039/501100011033; and CEX2021-001148-S), by Generalitat de Catalunya (2021 SGR 01007), and FAPESP (grant 2019/26702-8)., Peer Reviewed, Postprint (published version)

BACKGROUND: The Outcome Measures in Rheumatology (OMERACT) Systemic Lupus Erythematosus (SLE) Working Group held a Special Interest Group (SIG) at the OMERACT 2023 conference in Colorado Springs where SLE collaborators reviewed domain sub-themes generated through qualitative research and literature review. OBJECTIVE: The objective of the SIG and the subsequent meetings of the SLE Working Group was to begin the winnowing and binning of candidate domain sub-themes into a preliminary list of candidate domains that will proceed to the consensus Delphi exercise for the SLE COS. METHODS: Four breakout groups at the SLE SIG in Colorado Springs winnowed and binned 132 domain sub-themes into candidate domains, which was continued with a series of virtual meetings by an advisory group of SLE patient research partners (PRPs), members of the OMERACT SLE Working Group Steering Committee, and other collaborators. RESULTS: The 132 domain sub-themes were reduced to a preliminary list of 20 candidate domains based on their clinical and research relevance for clinical trials and research studies. CONCLUSION: A meaningful and substantial winnowing and binning of candidate domains for the SLE COS was achieved resulting in a preliminary list of 20 candidate domains.

Cipaglucosidase alfa plus miglustat (cipa + mig) is a novel, two-component therapy for Pompe disease. We report data from the Phase I/II ATB200-02 study for up to 48 months of treatment. Four adult cohorts, including one non-ambulatory ERT-experienced (n = 6) and three ambulatory cohorts, (two enzyme replacement therapy [ERT]-experienced cohorts [2–6 years (n = 11) and ≥ 7 years (n = 6)]), one ERT-naïve cohort (n = 6), received 20 mg/kg intravenous-infused cipa plus 260 mg oral mig biweekly. Change from baseline (CFBL) for multiple efficacy endpoints at 12, 24, 36, and 48 months, pharmacodynamics, pharmacokinetics, safety, and immunogenicity data were assessed. Six-minute walking distance (% predicted) improved at 12, 24, 36, and 48 months: pooled ambulatory ERT-experienced cohorts, mean(± standard deviation [SD]) CFBL: 6.1(± 7.84), n = 16; 5.4(± 10.56), n = 13; 3.4(± 14.66), n = 12; 5.9(± 17.36), n = 9, respectively; ERT-naïve cohort: 10.7(± 3.93), n = 6; 11.0(± 5.06), n = 6; 9.0(± 7.98), n = 5; 11.7(± 7.69), n = 4, respectively. Percent predicted forced vital capacity was generally stable in ERT-experienced cohorts, mean(± SD) CFBL − 1.2(± 5.95), n = 16; 1.0(± 7.96), n = 13; − 0.3(± 6.68), n = 10; 1.0(± 6.42), n = 6, respectively, and improved in the ERT-naïve cohort: 3.2(± 8.42), n = 6; 4.7(± 5.09), n = 6; 6.2(± 3.35), n = 5; 8.3(± 4.50), n = 4, respectively. Over 48 months, CK and Hex4 biomarkers improved in ambulatory cohorts. Overall, cipa + mig was well tolerated with a safety profile like alglucosidase alfa. ATB200-02 results show the potential benefits of cipa + mig as a long-term treatment option for Pompe disease. Trial registration number: NCT02675465 January 26, 2016.

Cipaglucosidase alfa plus miglustat (cipa + mig) is a novel, two-component therapy for Pompe disease. We report data from the Phase I/II ATB200-02 study for up to 48 months of treatment. Four adult cohorts, including one non-ambulatory ERT-experienced (n = 6) and three ambulatory cohorts, (two enzyme replacement therapy [ERT]-experienced cohorts [2-6 years (n = 11) and ≥ 7 years (n = 6)]), one ERT-naïve cohort (n = 6), received 20 mg/kg intravenous-infused cipa plus 260 mg oral mig biweekly. Change from baseline (CFBL) for multiple efficacy endpoints at 12, 24, 36, and 48 months, pharmacodynamics, pharmacokinetics, safety, and immunogenicity data were assessed. Six-minute walking distance (% predicted) improved at 12, 24, 36, and 48 months: pooled ambulatory ERT-experienced cohorts, mean(± standard deviation [SD]) CFBL: 6.1(± 7.84), n = 16; 5.4(± 10.56), n = 13; 3.4(± 14.66), n = 12; 5.9(± 17.36), n = 9, respectively; ERT-naïve cohort: 10.7(± 3.93), n = 6; 11.0(± 5.06), n = 6; 9.0(± 7.98), n = 5; 11.7(± 7.69), n = 4, respectively. Percent predicted forced vital capacity was generally stable in ERT-experienced cohorts, mean(± SD) CFBL - 1.2(± 5.95), n = 16; 1.0(± 7.96), n = 13; - 0.3(± 6.68), n = 10; 1.0(± 6.42), n = 6, respectively, and improved in the ERT-naïve cohort: 3.2(± 8.42), n = 6; 4.7(± 5.09), n = 6; 6.2(± 3.35), n = 5; 8.3(± 4.50), n = 4, respectively. Over 48 months, CK and Hex4 biomarkers improved in ambulatory cohorts. Overall, cipa + mig was well tolerated with a safety profile like alglucosidase alfa. ATB200-02 results show the potential benefits of cipa + mig as a long-term treatment option for Pompe disease. Trial registration number: NCT02675465 January 26, 2016.

Infection, autoimmunity, and cancer are principal human health challenges of the 21st century. Often regarded as distinct ends of the immunological spectrum, recent studies hint at potential overlap between these diseases. For example, inflammation can be pathogenic in infection and autoimmunity. T resident memory (TRM) cells can be beneficial in infection and cancer. However, these findings are limited by size and scope; exact immunological factors shared across diseases remain elusive. Here, we integrate large-scale deeply clinically and biologically phenotyped human cohorts of 526 patients with infection, 162 with lupus, and 11,180 with cancer. We identify an NKG2A+ immune bias as associative with protection against disease severity, mortality, and autoimmune/post-acute chronic disease. We reveal that NKG2A+ CD8+ T cells correlate with reduced inflammation and increased humoral immunity and that they resemble TRM cells. Our results suggest NKG2A+ biases as a cross-disease factor of protection, supporting suggestions of immunological overlap between infection, autoimmunity, and cancer.

BackgroundNon-enhancing (NE) infiltrating tumor cells beyond the contrast-enhancing (CE) bulk of tumor are potential propagators of recurrence after gross total resection of high-grade glioma.MethodsWe leveraged single-nucleus RNA sequencing on 15 specimens from recurrent high-grade gliomas (n = 5) to compare prospectively identified biopsy specimens acquired from CE and NE regions. Additionally, 24 CE and 22 NE biopsies had immunohistochemical staining to validate RNA findings.ResultsTumor cells in NE regions are enriched in neural progenitor cell-like cellular states, while CE regions are enriched in mesenchymal-like states. NE glioma cells have similar proportions of proliferative and putative glioma stem cells relative to CE regions, without significant differences in % Ki-67 staining. Tumor cells in NE regions exhibit upregulation of genes previously associated with lower grade gliomas. Our findings in recurrent GBM paralleled some of the findings in a re-analysis of a dataset from primary GBM. Cell-, gene-, and pathway-level analyses of the tumor microenvironment in the NE region reveal relative downregulation of tumor-mediated neovascularization and cell-mediated immune response, but increased glioma-to-nonpathological cell interactions.ConclusionsThis comprehensive analysis illustrates differing tumor and nontumor landscapes of CE and NE regions in high-grade gliomas, highlighting the NE region as an area harboring likely initiators of recurrence in a pro-tumor microenvironment and identifying possible targets for future design of NE-specific adjuvant therapy. These findings also support the aggressive approach to resection of tumor-bearing NE regions.

BACKGROUND: Cranial neuropathies (CN) are a rare neuropsychiatric SLE (NPSLE) manifestation. Previous studies reported that antibodies to the kinesin family member 20B (KIF20B) (anti-KIF20B) protein were associated with idiopathic ataxia and CN. We assessed anti-KIF20B as a potential biomarker for NPSLE in an international SLE inception cohort. METHODS: Individuals fulfilling the revised 1997 American College of Rheumatology (ACR) SLE classification criteria were enrolled from 31 centres from 1999 to 2011 and followed annually in the Systemic Lupus Erythematosus International Collaborating Clinics inception cohort. Anti-KIF20B testing was performed on baseline (within 15 months of diagnosis or first annual visit) samples using an addressable laser bead immunoassay. Logistic regression (penalised maximum likelihood and adjusting for confounding variables) examined the association between anti-KIF20B and NPSLE manifestations (1999 ACR case definitions), including CN, occurring over the first 5 years of follow-up. RESULTS: Of the 1827 enrolled cohort members, baseline serum and 5 years of follow-up data were available on 795 patients who were included in this study: 29.8% were anti-KIF20B-positive, 88.7% female, and 52.1% White. The frequency of anti-KIF20B positivity differed only for those with CN (n=10) versus without CN (n=785) (70.0% vs 29.3%; OR 5.2, 95% CI 1.4, 18.5). Compared with patients without CN, patients with CN were more likely to fulfil the ACR haematological (90.0% vs 66.1%; difference 23.9%, 95% CI 5.0%, 42.8%) and ANA (100% vs 95.7%; difference 4.3%, 95% CI 2.9%, 5.8%) criteria. In the multivariate analysis adjusting for age at baseline, female, White race and ethnicity, and ACR haematological and ANA criteria, anti-KIF20B positivity remained associated with CN (OR 5.2, 95% CI 1.4, 19.1). CONCLUSION: Anti-KIF20B is a potential biomarker for SLE-related CN. Further studies are needed to examine how autoantibodies against KIF20B, which is variably expr

It has been suggested recently that the Hubble tension could be eliminated by a sharp, $\sim 10\%$ increase of the effective gravitational constant at $z \sim 0.01$. This would decrease the luminosities of type 1a supernovae in just the needed amount to explain the larger value of the Hubble parameter. In the present paper we call attention to a dramatic effect of such transition on neutron stars. A neutron star that existed at $z=0.01$ would contract, conserving the baryon mass but undergoing a mass reduction. We computed neutron star models, with a realistic equation of state, and obtained that this reduction is typically $ 0.04 M_{\odot}$. This amounts to an energy of $7 \times 10^{52}$ erg. The transition will affect {\it all} neutron stars that formed along the history of each galaxy prior to the transition. Given the large number of neutron stars per galaxy, the liberated energy is huge. An estimate of the expected fluxes of neutrinos and x-rays yields values exceeding observational upper limits, thus rendering the late G transition scenario non-viable., Comment: 5 pages. Submitted to Physics Letters B. Comments welcomed

We investigate experimentally and theoretically a system ruled by an intricate interplay between topology, nonlinearity, and spontaneous symmetry breaking. The experiment is based on a two-mode coherently-driven optical resonator where photons interact through the Kerr nonlinearity. In presence of a phase defect, the modal structure acquires a synthetic Möbius topology enabling the realization of spontaneous symmetry breaking in inherently bias-free conditions without fine tuning of parameters. Rigorous statistical tests confirm the robustness of the underlying symmetry protection, which manifests itself by a periodic alternation of the modes reminiscent of period-doubling. This dynamic also confers long term stability to various localized structures including domain walls, solitons, and breathers. Our findings are supported by an effective Hamiltonian model and have relevance to other systems of interacting bosons and to the Floquet engineering of quantum matter. They could also be beneficial to the implementation of coherent Ising machines., SCOPUS: ar.j, info:eu-repo/semantics/published

Progressive neuronal loss is a hallmark feature distinguishing neurodegenerative diseases from normal ageing. However, the underlying mechanisms remain unknown. Extracellular K+ homeostasis is a potential mediator of neuronal injury as K+ elevations increase excitatory activity. The dysregulation of extracellular K+ and potassium channel expressions during neurodegeneration could contribute to this distinction. Here we measured the cortical extracellular K+ concentration ([K+]e) in awake wild-type mice as well as murine models of neurodegeneration using K+-sensitive microelectrodes. Unexpectedly, aged wild-type mice exhibited significantly lower cortical [K+]e than young mice. In contrast, cortical [K+]e was consistently elevated in Alzheimer’s disease (APP/PS1), amyotrophic lateral sclerosis (ALS) (SOD1G93A) and Huntington’s disease (R6/2) models. Cortical resting [K+]e correlated inversely with neuronal density and the [K+]e buffering rate but correlated positively with the predicted neuronal firing rate. Screening of astrocyte-selective genomic datasets revealed a number of potassium channel genes that were downregulated in these disease models but not in normal ageing. In particular, the inwardly rectifying potassium channel Kcnj10 was downregulated in ALS and Huntington’s disease models but not in normal ageing, while Fxyd1 and Slc1a3, each of which acts as a negative regulator of potassium uptake, were each upregulated by astrocytes in both Alzheimer’s disease and ALS models. Chronic elevation of [K+]e in response to changes in gene expression and the attendant neuronal hyperexcitability may drive the neuronal loss characteristic of these neurodegenerative diseases. These observations suggest that the dysregulation of extracellular K+ homeostasis in a number of neurodegenerative diseases could be due to aberrant astrocytic K+ buffering and as such, highlight a fundamental role for glial dysfunction in neurodegeneration., Progressive neuronal loss is a hallmark feature distinguishing neurodegenerative diseases from normal ageing. However, the underlying mechanisms remain unknown. Extracellular K+ homeostasis is a potential mediator of neuronal injury as K+ elevations increase excitatory activity. The dysregulation of extracellular K+ and potassium channel expressions during neurodegeneration could contribute to this distinction. Here we measured the cortical extracellular K+ concentration ([K+]e) in awake wild-Type mice as well as murine models of neurodegeneration using K+-sensitive microelectrodes. Unexpectedly, aged wild-Type mice exhibited significantly lower cortical [K+]e than young mice. In contrast, cortical [K+]e was consistently elevated in Alzheimer's disease (APP/PS1), amyotrophic lateral sclerosis (ALS) (SOD1G93A) and Huntington's disease (R6/2) models. Cortical resting [K+]e correlated inversely with neuronal density and the [K+]e buffering rate but correlated positively with the predicted neuronal firing rate. Screening of astrocyte-selective genomic datasets revealed a number of potassium channel genes that were downregulated in these disease models but not in normal ageing. In particular, the inwardly rectifying potassium channel Kcnj10 was downregulated in ALS and Huntington's disease models but not in normal ageing, while Fxyd1 and Slc1a3, each of which acts as a negative regulator of potassium uptake, were each upregulated by astrocytes in both Alzheimer's disease and ALS models. Chronic elevation of [K+]e in response to changes in gene expression and the attendant neuronal hyperexcitability may drive the neuronal loss characteristic of these neurodegenerative diseases. These observations suggest that the dysregulation of extracellular K+ homeostasis in a number of neurodegenerative diseases could be due to aberrant astrocytic K+ buffering and as such, highlight a fundamental role for glial dysfunction in neurodegeneration.

Human glial progenitor cells (hGPCs) exhibit diminished expansion competence with age, as well as after recurrent demyelination. Using RNA-sequencing to compare the gene expression of fetal and adult hGPCs, we identify age-related changes in transcription consistent with the repression of genes enabling mitotic expansion, concurrent with the onset of aging-associated transcriptional programs. Adult hGPCs develop a repressive transcription factor network centered on MYC, and regulated by ZNF274, MAX, IKZF3, and E2F6. Individual over-expression of these factors in iPSC-derived hGPCs lead to a loss of proliferative gene expression and an induction of mitotic senescence, replicating the transcriptional changes incurred during glial aging. miRNA profiling identifies the appearance of an adult-selective miRNA signature, imposing further constraints on the expansion competence of aged GPCs. hGPC aging is thus associated with acquisition of a MYC-repressive environment, suggesting that suppression of these repressors of glial expansion may permit the rejuvenation of aged hGPCs., Human glial progenitor cells (hGPCs) exhibit diminished expansion competence with age, as well as after recurrent demyelination. Using RNA-sequencing to compare the gene expression of fetal and adult hGPCs, we identify age-related changes in transcription consistent with the repression of genes enabling mitotic expansion, concurrent with the onset of aging-associated transcriptional programs. Adult hGPCs develop a repressive transcription factor network centered on MYC, and regulated by ZNF274, MAX, IKZF3, and E2F6. Individual over-expression of these factors in iPSC-derived hGPCs lead to a loss of proliferative gene expression and an induction of mitotic senescence, replicating the transcriptional changes incurred during glial aging. miRNA profiling identifies the appearance of an adult-selective miRNA signature, imposing further constraints on the expansion competence of aged GPCs. hGPC aging is thus associated with acquisition of a MYC-repressive environment, suggesting that suppression of these repressors of glial expansion may permit the rejuvenation of aged hGPCs.

This review will focus on the contribution of glial pathology to HD, particularly so with regard to diseased glial progenitor cells and their derived astrocytes and oligodendrocytes. It will briefly discuss the body of data identifying the contribution of glial dysfunction to disease phenotype in rodent models of HD, and will then focus on recent studies of cell-intrinsic glial transcriptional dysregulation in HD. The review will emphasize recent studies of diseased human cells and humanized models of HD glial pathology, and on the contributions of that glial pathology to neuronal and synaptic dysfunction in HD., This review will focus on the contribution of glial pathology to HD, particularly so with regard to diseased glial progenitor cells and their derived astrocytes and oligodendrocytes. It will briefly discuss the body of data identifying the contribution of glial dysfunction to disease phenotype in rodent models of HD, and will then focus on recent studies of cell-intrinsic glial transcriptional dysregulation in HD. The review will emphasize recent studies of diseased human cells and humanized models of HD glial pathology, and on the contributions of that glial pathology to neuronal and synaptic dysfunction in HD.

The inability of the mammalian central nervous system (CNS) to undergo spontaneous regeneration has long been regarded as a central tenet of neurobiology. However, while this is largely true of the neuronal elements of the adult mammalian CNS, save for discrete populations of granule neurons, the same is not true of its glial elements. In particular, the loss of oligodendrocytes, which results in demyelination, triggers a spontaneous and often highly efficient regenerative response, remyelination, in which new oligodendrocytes are generated and myelin sheaths are restored to denuded axons. Yet remyelination in humans is not without limitation, and a variety of demyelinating conditions are associated with sustained and disabling myelin loss. In this work, we will (1) review the biology of remyelination, including the cells and signals involved; (2) describe when remyelination occurs and when and why it fails, including the consequences of its failure; and (3) discuss approaches for therapeutically enhancing remyelination in demyelinating diseases of both children and adults, both by stimulating endogenous oligodendrocyte progenitor cells and by transplanting these cells into demyelinated brain., The inability of the mammalian central nervous system (CNS) to undergo spontaneous regeneration has long been regarded as a central tenet of neurobiology. However, while this is largely true of the neuronal elements of the adult mammalian CNS, save for discrete populations of granule neurons, the same is not true of its glial elements. In particular, the loss of oligodendrocytes, which results in demyelination, triggers a spontaneous and often highly efficient regenerative response, remyelination, in which new oligodendrocytes are generated and myelin sheaths are restored to denuded axons. Yet remyelination in humans is not without limitation, and a variety of demyelinating conditions are associated with sustained and disabling myelin loss. In this work, we will (1) review the biology of remyelination, including the cells and signals involved; (2) describe when remyelination occurs and when and why it fails, including the consequences of its failure; and (3) discuss approaches for therapeutically enhancing remyelination in demyelinating diseases of both children and adults, both by stimulating endogenous oligodendrocyte progenitor cells and by transplanting these cells into demyelinated brain.

Background Non-enhancing (NE) infiltrating tumor cells beyond the contrast-enhancing (CE) bulk of tumor are potential propagators of recurrence after gross total resection of high-grade glioma. Methods We leveraged single-nucleus RNA sequencing on 15 specimens from recurrent high-grade gliomas (n = 5) to compare prospectively identified biopsy specimens acquired from CE and NE regions. Additionally, 24 CE and 22 NE biopsies had immunohistochemical staining to validate RNA findings. Results Tumor cells in NE regions are enriched in neural progenitor cell-like cellular states, while CE regions are enriched in mesenchymal-like states. NE glioma cells have similar proportions of proliferative and putative glioma stem cells relative to CE regions, without significant differences in % Ki-67 staining. Tumor cells in NE regions exhibit upregulation of genes previously associated with lower grade gliomas. Our findings in recurrent GBM paralleled some of the findings in a re-analysis of a dataset from primary GBM. Cell-, gene-, and pathway-level analyses of the tumor microenvironment in the NE region reveal relative downregulation of tumor-mediated neovascularization and cell-mediated immune response, but increased glioma-to-nonpathological cell interactions. Conclusions This comprehensive analysis illustrates differing tumor and nontumor landscapes of CE and NE regions in high-grade gliomas, highlighting the NE region as an area harboring likely initiators of recurrence in a pro-tumor microenvironment and identifying possible targets for future design of NE-specific adjuvant therapy. These findings also support the aggressive approach to resection of tumor-bearing NE regions., Background. Non-enhancing (NE) infiltrating tumor cells beyond the contrast-enhancing (CE) bulk of tumor are potential propagators of recurrence after gross total resection of high-grade glioma. Methods. We leveraged single-nucleus RNA sequencing on 15 specimens from recurrent high-grade gliomas (n = 5) to compare prospectively identified biopsy specimens acquired from CE and NE regions. Additionally, 24 CE and 22 NE biopsies had immunohistochemical staining to validate RNA findings. Results. Tumor cells in NE regions are enriched in neural progenitor cell-like cellular states, while CE regions are enriched in mesenchymal-like states. NE glioma cells have similar proportions of proliferative and putative glioma stem cells relative to CE regions, without significant differences in % Ki-67 staining.Tumor cells in NE regions exhibit upregulation of genes previously associated with lower grade gliomas. Our findings in recurrent GBM paralleled some of the findings in a re-analysis of a dataset from primary GBM. Cell-, gene-, and pathway-level analyses of the tumor microenvironment in the NE region reveal relative downregulation of tumor-mediated neovascularization and cell-mediated immune response, but increased glioma-to-nonpathological cell interactions. Conclusions. This comprehensive analysis illustrates differing tumor and nontumor landscapes of CE and NE regions in high-grade gliomas, highlighting the NE region as an area harboring likely initiators of recurrence in a pro-tumor microenvironment and identifying possible targets for future design of NE-specific adjuvant therapy. These findings also support the aggressive approach to resection of tumor-bearing NE regions.

Objective To explore the efficacy and safety of semaglutide 2.4 mg in people with overweight/obesity who were also being treated with antidepressants (ADs). Methods Across the Semaglutide Treatment Effect for People with obesity (STEP) 1–3 and 5 trials, adults with overweight/obesity and type 2 diabetes (STEP 2 only) were enrolled. People with severe major depressive disorder within 2 years prior to screening or with a patient health questionnaire-9 score ≥15 at screening were excluded. Participants were categorized into subgroups according to baseline AD status (on/off ADs) in this post hoc exploratory analysis of the STEP trials. Results Of 3683 participants randomized, 539 were on ADs at baseline. Mean body weight change from baseline to week 68 was greater for semaglutide versus placebo, regardless of baseline AD use. In STEP 1, for participants on ADs at baseline, mean change from baseline was −15.7% with semaglutide versus −0.2% with placebo and −14.7% versus −2.8% for those not on ADs at baseline. Similar patterns were seen in STEP 2, 3, and 5. The prevalence of adverse events (AEs) was generally similar between semaglutide and placebo in participants on ADs at baseline. Conclusions In adults with overweight/obesity, semaglutide provided clinically meaningful weight loss regardless of baseline AD use, with an AE profile consistent with previous studies., Objective: To explore the efficacy and safety of semaglutide 2.4 mg in people with overweight/obesity who were also being treated with antidepressants (ADs). Methods: Across the Semaglutide Treatment Effect for People with obesity (STEP) 1–3 and 5 trials, adults with overweight/obesity and type 2 diabetes (STEP 2 only) were enrolled. People with severe major depressive disorder within 2 years prior to screening or with a patient health questionnaire-9 score ≥15 at screening were excluded. Participants were categorized into subgroups according to baseline AD status (on/off ADs) in this post hoc exploratory analysis of the STEP trials. Results: Of 3683 participants randomized, 539 were on ADs at baseline. Mean body weight change from baseline to week 68 was greater for semaglutide versus placebo, regardless of baseline AD use. In STEP 1, for participants on ADs at baseline, mean change from baseline was −15.7% with semaglutide versus −0.2% with placebo and −14.7% versus −2.8% for those not on ADs at baseline. Similar patterns were seen in STEP 2, 3, and 5. The prevalence of adverse events (AEs) was generally similar between semaglutide and placebo in participants on ADs at baseline. Conclusions: In adults with overweight/obesity, semaglutide provided clinically meaningful weight loss regardless of baseline AD use, with an AE profile consistent with previous studies.