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Abstract Gut microbiota affect transplantation outcomes; however, the influence of immunosuppression and cell therapy on the gut microbiota in cardiovascular care remains unexplored. We investigated gut microbiota dynamics in a nonhuman primate (NHP) cardiac ischemia/reperfusion model while under immunosuppression and receiving cell therapy with human induced pluripotent stem cell (hiPSC)-derived endothelial cells (EC) and cardiomyocytes (CM). Both immunosuppression and EC/CM co-treatment increased gut microbiota alpha diversity. Immunosuppression promoted anaerobes, such as Faecalibacterium, Streptococcus, Anaerovibrio and Dialister, and altered amino acid metabolism and nucleosides/nucleotides biosynthesis in host plasma. EC + CM cotreatment favors Phascolarctobacterium, Fusicatenibacter, Erysipelotrichaceae UCG-006, Veillonella and Mailhella. Remarkably, gut microbiota of the EC/CM co-treatment group resembled that of the pre-injury group, and the NHPs exhibited a metabolic shift towards amino acid and fatty acid/lipid biosynthesis in plasma following cell therapy. The interplay between shift in microbial community and host homeostasis during treatment suggests gut microbiome modulation could improve cell therapy outcomes.

Underground mine pillars provide natural stability to the mine area, allowing safe operations for workers and machinery. Extensive prior research has been conducted to understand pillar failure mechanics and design safe pillar layouts. However, limited studies (mostly based on empirical field observation and small-scale laboratory tests) have considered pillar-support interactions under monotonic loading conditions for the design of pillar-support systems. This study used a series of large-scale laboratory compression tests on porous limestone blocks to analyze rock and support behavior at a sufficiently large scale (specimens with edge length of 0.5 m) for incorporation of actual support elements, with consideration of different w/h ratios. Both unsupported and supported (grouted rebar rockbolt and wire mesh) tests were conducted, and the surface deformations of the specimens were monitored using three-dimensional (3D) digital image correlation (DIC). Rockbolts instrumented with distributed fiber optic strain sensors were used to study rockbolt strain distribution, load mobilization, and localized deformation at different w/h ratios. Both axial and bending strains were observed in the rockbolts, which became more prominent in the post-peak region of the stress-strain curve.

A Salmonella enterica serovar Abony outbreak occurred during January–April 2024 in Chile. Genomic evidence indicated that the outbreak strain was a clone of reference strain WDCM 00029, which is routinely used in microbiological quality control tests. When rare or unreported serovars cause human infections, clinicians and health authorities should request strain characterization.

Abstract Within ovarian cancer research, patient-derived xenograft (PDX) models recapitulate histologic features and genomic aberrations found in original tumors. However, conflicting data from published studies have demonstrated significant transcriptional differences between PDXs and original tumors, challenging the fidelity of these models. We employed a quantitative mass spectrometry-based proteomic approach coupled with generation of patient-specific databases using RNA-seq data to investigate the proteogenomic landscape of serially-passaged PDX models established from two patients with distinct subtypes of ovarian cancer. We demonstrate that the utilization of patient-specific databases guided by transcriptional profiles increases the depth of human protein identification in PDX models. Our data show that human proteomes of serially passaged PDXs differ significantly from their patient-derived tumor of origin. Analysis of differentially abundant proteins revealed enrichment of distinct biological pathways with major downregulated processes including extracellular matrix organization and the immune system. Finally, we investigated the relative abundances of ovarian cancer-related proteins identified from the Cancer Gene Census across serially passaged PDXs, and found their protein levels to be unstable across PDX models. Our findings highlight features of distinct and dynamic proteomes of serially-passaged PDX models of ovarian cancer.

Abstract Spinal cord injury (SCI) leads to permanent motor and sensory loss that is exacerbated by intraspinal inflammation and persists months to years after injury. After SCI, monocyte-derived macrophages (MDMs) infiltrate the lesion to aid in myelin-rich debris clearance. During debris clearance, MDMs adopt a proinflammatory phenotype that exacerbates neurodegeneration and hinders recovery. The underlying cause of the lipid-mediated MDM phenotype shift is unclear. Our previous work suggests that cytosolic phospholipase A2 (cPLA2) plays a role in the proinflammatory potentiating effect of myelin on macrophages in vitro. Cytosolic phospholipase A2 (cPLA2) frees arachidonic acid from phospholipids, generating eicosanoids that play an important role in inflammation, immunity, and host defense. cPLA2 is expressed in macrophages along with multiple other cell types after SCI, and cPLA2 inhibition has been reported to both reduce and exacerbate secondary injury pathology recovery. The role of cPLA2 in MDMs after SCI is not fully understood. We hypothesize that cPLA2 activation in MDMs after SCI contributes to secondary injury. Here, we report that cPLA2 plays an important role in the myelin-induced inflammatory macrophage phenotype in vitro using macrophages derived from cPLA2 knockout bone marrow. Furthermore, to investigate the role of cPLA2 in MDMs after SCI, we generated female bone marrow chimeras using cPLA2 knock-out donors and assessed locomotor recovery using the Basso Mouse Scale (BMS), CatWalk gait analysis system, and horizontal ladder task over six weeks. We also evaluated tissue sparing and intralesional axon density six weeks after injury. cPLA2 KO chimeras did not display altered locomotor recovery or tissue pathology after SCI compared to WT chimera controls. These data suggest that although cPLA2 plays a critical role in myelin-mediated potentiation of proinflammatory macrophage activation in vitro, it may not contribute to secondary injury pathology in vivo after SCI.

Abstract Protein/protein interactions (PPI) play crucial roles in neuronal functions. Yet, their potential as drug targets for brain disorders remains underexplored. The fibroblast growth factor 14 (FGF14)/voltage-gated Na+ channel 1.6 (Nav1.6) complex regulates excitability of medium spiny neurons (MSN) of the nucleus accumbens (NAc), a central hub of reward circuitry that controls motivated behaviors. Here, we identified compound 1028 (IUPAC: ethyl 3-(2-(3-(hydroxymethyl)-1H-indol-1-yl)acetamido)benzoate), a brain-permeable small molecule that targets FGF14R117, a critical residue located within a druggable pocket at the FGF14/Nav1.6 PPI interface. We found that 1028 modulates FGF14/Nav1.6 complex assembly and depolarizes the voltage-dependence of Nav1.6 channel inactivation with nanomolar potency by modulating the intramolecular interaction between the III-IV linker and C-terminal domain of the Nav1.6 channel. Consistent with the compound’s effects on Nav1.6 channel inactivation, 1028 enhances MSN excitability ex vivo and accumbal neuron firing rate in vivo in murine models. Systemic administration of 1028 maintains behavioral motivation preferentially during motivationally deficient conditions in murine models. These behavioral effects were abrogated by in vivo gene silencing of Fgf14 in the NAc and were accompanied by a selective reduction in accumbal dopamine levels during reward consumption in murine models. These findings underscore the potential to selectively regulate complex behaviors associated with neuropsychiatric disorders through targeting of PPIs in neurons.

Some microbes in the rumen form trans-10,cis-12 (t10,c12)-conjugated linoleic acid (CLA), a fatty acid that depresses synthesis of milk fat in dairy cattle and other lactating animals. Despite their importance to milk fat depression, the microbes responsible have been difficult to identify, and no laboratory strain is currently available for study. Here we describe the isolation of Cutibacterium acnes AP1, a bacterium that forms t10,c12-CLA at fast rates. It was isolated from rumen contents of a heifer by using medium containing lactate and metronidazole. It formed t10,c12-CLA from linoleic acid, a result confirmed by a combination of 3 methods (spectrophotometry, thin-layer chromatography, and GC). The initial rate of formation was 67% faster than for Cutibacterium acnes DSM 1897, the type strain from human skin. The availability of this isolate and its ability to rapidly form t10,c12-CLA make it a good subject for further study. Such study could help control formation of t10,c12-CLA in the rumen and alleviate milk fat depression in milk cows.

Abstract Background One factor considered essential to successful implementation is organizational readiness. The purpose of this study was to explore ways to improve the measurement of organizational readiness, and in particular to refine a preliminary measure based on the Readiness = Motivation x innovation Specific Capacity x General Capacity (R = MC2) heuristic. We assessed the experiences of staff in Federally Qualified Health Centers (FQHC) implementing evidence-based interventions (EBIs) designed to increase colorectal cancer screening (CRCS) who previously completed the survey and aimed to understand their perspectives on why our data were positively skewed. Methods We conducted a series of qualitative interviews with FQHC employees who had previously completed the readiness survey and/or been involved with the distribution of the readiness survey. Interviews were conducted via Zoom, recorded, transcribed. Data was analyzed using an inductive approach to identify key emergent themes. Results Analyses revealed numerous contributors to high organizational readiness assessment scores including concerns about confidentiality, social desirability bias, knowledge of respondents about the survey content, and the survey format. Specific to the survey format, we found that survey length and response scaling likely impacted scores and the overall survey experience. Lastly, some participants shared that the tendency for high scores may reflect actual perceptions because FQHC staff are passionate, work well in teams, and typically have already worked hard to improve CRCS rates through evidence-based interventions. Conclusion Study findings reinforce the importance of collaborative and community-engaged survey design and the need to address the common challenges dissemination and implementation surveys may be vulnerable to. Lessons learned can be applied to other measurement work and surveys conducted across public health research. The findings will inform continued organizational readiness measure development and have implications for measurement of other factors influencing implementation.

Abstract Uncertainty remains regarding the role of diet in colorectal cancer development. We examined associations of 97 dietary factors with colorectal cancer risk in 542,778 Million Women Study participants (12,251 incident cases over 16.6 years), and conducted a targeted genetic analysis in the ColoRectal Transdisciplinary Study, Colon Cancer Family Registry, and Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Alcohol (relative risk per 20 g/day=1.15, 95% confidence interval 1.09-1.20) and calcium (per 300 mg/day=0.83, 0.77–0.89) intakes had the strongest associations, followed by six dairy-related factors associated with calcium. We showed a positive association with red and processed meat intake and weaker inverse associations with breakfast cereal, fruit, wholegrains, carbohydrates, fibre, total sugars, folate, and vitamin C. Genetically predicted milk consumption was inversely associated with risk of colorectal, colon, and rectal cancers. We conclude that dairy products help protect against colorectal cancer, and that this is driven largely or wholly by calcium.

Abstract To extract information from NMR experiments, users need to identify the number of resonances in the spectrum, together with characteristic features such as chemical shifts and intensities. In many applications, particularly those involving biomolecules, this procedure is typically a manual and laborious process. While many algorithms are available to tackle this problem, their performance tends to be inferior to that of an experienced user. Here, we introduce UnidecNMR, which identifies resonances in NMR spectra using deconvolution. We demonstrate its favourable performance on 1 and 2D simulated spectra, strongly overlapped 1D spectra of oligosaccharides and 2D HSQC, 3D HNCO, 3D HNCA and 3/4D methyl-methyl NOE experimental spectra from a range of proteins. UnidecNMR outperforms a number of freely available algorithms and provides results comparable to those generated manually. Introducing additional restraints, such as a 2D peak list when analysing 3 and 4D data and incorporating reflection symmetry in NOE analysis further improves the results. UnidecNMR outputs a back-calculated spectrum and a peak list, both of which can be easily examined using the supplied GUI. The software allows interactive processing using nmrPipe, allowing users to go directly from raw data to processed spectra with picked peak lists.

Abstract Diffuse large B-cell lymphoma (DLBCL), the most common B-cell non-Hodgkin lymphoma rarely presents with circulating lymphoma cells (CL) at diagnosis. Previous studies were limited by small sample size precluding robust analysis. Hence, we evaluated the prognostic relevance of CL cells in newly diagnosed DLBCL patients. Based on peripheral blood (PB) immunophenotyping, patients were grouped into CL + and CL−. CL was defined as detectable clonally restricted B-cells that matched the actual or expected B-cell immunophenotype of DLBCL. The primary endpoint was progression-free survival (PFS), and secondary endpoints included overall survival (OS) and diagnosis-to-treatment interval (DTI). Among the 1266 patients with DLBCL, 621 had PB flow at diagnosis, and after excluding patients not meeting eligibility criteria, 588 cases remained. Among these, 85 (15%) were CL + and 503 were CL- (85%). Patients in CL + group were younger (67 vs. 70 years, p = 0.03) with a higher proportion of non-bulky disease (85% vs. 56%, p

Abstract Background Variation in stroke treatment metrics highlight a need for approaches to improve clinical processes. Training interventions can improve outcomes, but Australian physician trainees do not currently receive formal process-directed stroke training. Virtual reality (VR) stroke workflow training has proven acceptable, usable, useful and feasible in trial contexts, but how to integrate VR training into physician training remains unclear. The current study sought to document stroke staff perceptions of existing training and assess implementation of routine VR training at comprehensive stroke centres, outside of a trial context. Methods Training was delivered to physician trainees via individual sessions or facilitated group workshops depending on the hospital site. VR usage data was captured automatically via Wi-Fi. Survey responses from both trainees and training staff were collected, with statistical comparisons performed for matching questions in pre- and post-training surveys. Themes identified in open-ended survey responses were enumerated and reported. Results Forty-two TACTICS VR training sessions were logged at 2 hospitals between May 2022 and October 2023. Trainees reported receiving low amounts of prior formal stroke training; both trainees and training staff identified unmet needs and barriers to existing training. VR users (n = 30) provided positive feedback on VR hardware, software design, user experience, content, educational value and delivery approach (mean scores 3.9 to 4.7; 1 = strongly disagree, 5 = strongly agree). VR training improved confidence in: knowledge of acute stroke assessment / treatment (post-training vs. pre-training = 4.0±0.7 vs. 2.9±1.0; P

Abstract Background Genomic analysis has revealed extensive contamination among laboratory-maintained microbes including malaria parasites, Mycobacterium tuberculosis, and Salmonella spp. Here, we provide direct evidence for recent contamination of a laboratory schistosome parasite population, and we investigate its genomic consequences. The Brazilian Schistosoma mansoni population SmBRE has several distinctive phenotypes, showing poor infectivity, reduced sporocyst number, low levels of cercarial shedding and low virulence in the intermediate snail host, and low worm burden and low fecundity in the vertebrate rodent host. In 2021 we observed a rapid change in SmBRE parasite phenotypes, with a 10-fold increase in cercarial production and fourfold increase in worm burden. Methods To determine the underlying genomic cause of these changes, we sequenced pools of SmBRE adults collected during parasite maintenance between 2015 and 2023. We also sequenced another parasite population (SmLE) maintained alongside SmBRE without phenotypic changes. Results While SmLE allele frequencies remained stable over the 8-year period, we observed sudden changes in allele frequency across the genome in SmBRE between July 2021 and February 2023, consistent with expectations of laboratory contamination. (i) SmLE-specific alleles increased in the SmBRE population from 0 to 41–46% across the genome between September and October 2021, reflecting the timing and magnitude of the contamination event. (ii) After contamination, strong selection (s ≅0.23) drove the replacement of low-fitness SmBRE with high-fitness SmLE alleles. (iii) Allele frequency changed rapidly across the whole genome, except for a region on chromosome 4, where SmBRE alleles remained at high frequency. Conclusions We were able to detect contamination in this case because SmBRE shows distinctive phenotypes. However, this would likely have been missed with phenotypically similar parasites. These results provide a cautionary tale about the importance of tracking the identity of parasite populations, but also showcase a simple approach to monitor changes within populations using molecular profiling of pooled population samples to characterize single-nucleotide polymorphisms. We also show that genetic drift results in continuous change even in the absence of contamination, causing parasites maintained in different labs (or sampled from the same lab at different times) to diverge. Graphical Abstract

Abstract Background All for Them is a theory-based and evidence-informed multilevel, multicomponent program delivered through schools to increase HPV vaccination among medically underserved youth across Texas. Given the potential logistical challenges of program implementation, understanding how to best support the implementation and sustainment of the program is critical. The overall goals of this study are twofold: 1) develop a multifaceted implementation strategy, Implementing All for Them (IM-AFT); and 2) evaluate the impact of IM-AFT on implementation outcomes for schools and healthcare providers to successfully implement All for Them in their respective settings. Methods This study is underpinned by a comprehensive and synergistic conceptual framework. We will use Social Cognitive Theory and the Interactive Systems Framework for Dissemination and Implementation to inform important individual and organizational factors to target as part of implementation strategy development. We will use this formative work and Implementation Mapping, a systematic, iterative process that guides the use of theories, models, and frameworks, to develop IM-AFT. The three core aims of the present study are connected to the five tasks of Implementation Mapping. For Aim 1, we will develop IM-AFT using a community-based participatory research-informed approach, including a qualitative assessment of needs and assets associated with program implementation and identification of behavioral and psychosocial objectives to determine implementation outcomes. For Aim 2, we will use a mixed-methods approach to assess user experience with the IM-AFT prototype to test its feasibility, usability, and acceptability. For Aim 3, we will use a descriptive checklist to assess the impact of IM-AFT on user fidelity of program implementation. Discussion This paper presents the detailed protocol for developing and evaluating IM-AFT to successfully implement All for Them, leveraging a systematic, community- and theory-based approach and user experience with the strategy prototype. This study will contribute to expanding limited scientific knowledge about using multiple sources to develop and evaluate specified implementation strategies for effective implementation of school-based vaccination programs. Theory-based IM-AFT will guide collaborations between schools and community health centers to improve HPV and other adolescent vaccination rates in underserved communities in Texas.

Abstract Background We have previously shown headache disorders to be prevalent in in the adult general population of Morocco, especially migraine (30.8%) and headache on ≥ 15 days/month (H15+; 10.5%). This study, collecting data from the same population-based sample, is the first to estimate headache-attributed burden not only in Morocco but, more widely, in the Maghreb countries of North Africa. Methods We used the standard methodology and questionnaire developed by the Global Campaign against Headache. Cluster-based random sampling generated a sample (N = 2,575) representative of the general population aged 18–65 years. Interviews conducted face-to-face enquired into symptom burden (headache frequency, usual duration and usual intensity), and impaired participation in paid work, household work and social or leisure activities during the preceding 3 months. Further enquiry was into headache yesterday (HY). We calculated population-level estimates by factoring in prevalence. Needs assessment estimated the population proportion in need of headache-related health care based on likelihood of benefit. Results Participants with headache of any type spent, on average, 12.5% of their time with headache of intensity rated 2.3 on a scale of 1–3. According to age- and gender-corrected estimates, 7.2–8.4% of all time in the population (calculated by two methods) was spent with headache, H15 + accounting for well over half of this. Impaired participation measured as lost time due to headache averaged 0.5 days from paid work, 1.6 days from household work and 0.3 days from social or leisure activities during the preceding 3 months. Of those with HY (17.8% of the sample), 24.1% of males and 50.9% of females could do nothing or less than half of their planned activity yesterday. At population level this diluted to 7.0% of all activity lost to headache. At least 30% of the population were estimated to need headache-related health care. Conclusion Headache disorders cause much ill health in the adult population of Morocco. While this will be of obvious concern to health policy in Morocco, the call for provision of health care for almost one third of this population is challenging. On the other hand, economic policy should recognise the lost-productivity costs of inadequately treated headache, especially migraine.

Introduction Streptococcus pneumoniae is a causative agent of pneumonia and acute otitis media (AOM), as well as invasive diseases such as meningitis and bacteremia. PCV15 (V114) is a new 15-valent pneumococcal conjugate vaccine (PCV) approved for use in individuals ≥6 weeks of age for the prevention of pneumonia, AOM, and invasive pneumococcal disease.Areas Covered This review summarizes the V114 Phase 3 development program leading to approval in infants and children, including pivotal studies, interchangeability and catch-up vaccination studies, and studies in at-risk populations. An integrated safety summary is presented in addition to immunogenicity and concomitant use of V114 with other routine pediatric vaccines.Expert Opinion Across the development program, V114 demonstrated a safety profile that is comparable to PCV13 in infants and children. Immunogenicity of V114 is comparable to PCV13 for all shared serotypes except serotype 3, where V114 demonstrated superior immunogenicity. Higher immune responses were demonstrated for V114 serotypes 22F and 33F. Results of the ongoing study to evaluate V114 efficacy against vaccine-type pneumococcal AOM and anticipated real-world evidence studies will support assessment of vaccine effectiveness and impact, with an additional question of whether higher serotype 3 immunogenicity translates to better protection against serotype 3 pneumococcal disease.

Abstract Purpose Tribal Nations disproportionately lack access to safe drinking water and can be adversely affected by other water quality and environmental concerns. Such conditions could lead to an increase in the transmission of waterborne, environmental and hygiene related infections. We collected saliva samples from attendees at two Tribal Nation annual festivals and tested them for salivary immunoglobulin G (IgG) responses to selected common infections using an in-house multiplex immunoassay. Antibody responses were compared to responses from a previously conducted study in the midwestern United States. Methods We collected and tested 531 samples from Tribal Nation sites and used data on 453 previously analyzed samples from the Midwest site. Logistic and linear regression models were used to model a binary classification of seropositivity and the intensity of the antibody response, respectively. Results Seroprevalence of chronic infections (Helicobacter pylori and Toxoplasma gondii) were generally consistent with estimates from population-based studies. Compared to the Midwest site, one of the Tribal Nation sites had consistently higher median antibody responses to several noroviruses. The Tribal Nation sites had a lower seroprevalence of hepatitis E virus antibodies. At the Tribal Nation sites, farm residents had higher antibody responses to Cryptosporidium spp., bottled water consumption was associated with lower responses to Cryptosporidium spp., animal contact was associated with T. gondii seropositivity, and recent diarrhea was associated with higher norovirus antibody responses. Helicobacter pylori seropositivity was associated with reduced odds of reporting allergies. Conclusion This study demonstrated the application of a multiplex salivary immunoassay in Tribal Nations to provide insights regarding selected common pathogens which are transmitted through different transmission pathways including person-to-person contacts, contaminated food, soil and drinking water.

Preliminary evidence has showed an emergent serotype O3 (SO3) strain of Vibrio anguillarum to cause mortality in pre-smolt Atlantic salmon (Salmo salar) by injection with >105 colony forming units (cfus). Here, we sought to identify the susceptibility of Atlantic salmon post-smolts to this emergent strain by both injection and cohabitation to better understand transmission risk within cultured salmon and possibly between salmon and Atlantic menhaden (Brevoortia tyrannus), where this strain was identified. We identified that although mortality could be induced with a high-dose (>106 cfus) intraperitoneal injection of the emergent SO3 strain (cumulative mortality of 40%), post-smolt Atlantic salmon were highly refractory to a low dose (6 cfus; cumulative mortality of 3%) or cohabitation exposure (no mortality). A qPCR assay targeting this strain was developed and analytically validated, revealing the limited presence of bacterial DNA in the spleen of low-dose-injected fish (2/36) and no detections in sampled cohabitants (0/70) across three timepoints during the 27-day challenge. These results suggest that although Atlantic salmon can succumb to high-dose artificial infections with V. anguillarum SO3, the risk of natural transmissibility and susceptibility of Atlantic salmon to this emergent strain is anticipated to be low.

Background/Objectives: Glioblastomas (GBMs) are dreadful brain tumors with abysmal survival outcomes. GBM extracellular vesicles (EVs) dramatically affect normal brain cells (largely astrocytes) constituting the tumor microenvironment (TME). We asked if EVs from different GBM patient-derived spheroid lines would differentially alter recipient brain cell phenotypes. This turned out to be the case, with the net outcome of treatment with GBM EVs nonetheless converging on increased tumorigenicity. Methods: GBM spheroids and brain slices were derived from neurosurgical patient tissues following informed consent. Astrocytes were commercially obtained. EVs were isolated from conditioned culture media by ultrafiltration, concentration, and ultracentrifugation. EVs were characterized by nanoparticle tracking analysis, electron microscopy, biochemical markers, and proteomics. Astrocytes/brain tissues were treated with GBM EVs before downstream analyses. Results: EVs from different GBMs induced brain cells to alter secretomes with pro-inflammatory or TME-modifying (proteolytic) effects. Astrocyte responses ranged from anti-viral gene/protein expression and cytokine release to altered extracellular signal-regulated protein kinase (ERK1/2) signaling pathways, and conditioned media from EV-treated cells increased GBM cell proliferation. Conclusions: Astrocytes/brain slices treated with different GBM EVs underwent non-identical changes in various omics readouts and other assays, indicating “personalized” tumor-specific GBM EV effects on the TME. This raises concern regarding reliance on “model” systems as a sole basis for translational direction. Nonetheless, net downstream impacts from differential cellular and TME effects still led to increased tumorigenic capacities for the different GBMs.

Abstract A novel, optimized, polysaccharide and biochar-based, compostable hydrogel horticultural growing substrate for use in hydroponics and vertical farming was created based upon empirical methods and statistical design of experiments. A 15-run D-optimal mixture design of experiments was completed that increased the 14-day plant growing ability of a five-component hydrogel nearly ten-fold from 4.3695 g to 41.2623 g per 100 plants. The data were analyzed using a standard least squares method with an effect screening emphasis, and a model was created that maximized the signal to noise ratio. There was a good correlation between the measured and predicted values of the model, with an r-squared value of 0.90. The predictions of efficacy and compostability were confirmed with subsequent experiments that showed the hydrogel was composted in less than 84 days and that the plant growth predicted by the model differed from the experimental growth by 0.65%. The resulting optimized formulation had a high fertilizer content for a growth medium. We therefore suggest that an empirical approach to formulation research can produce superior outcomes with a statistically designed study.

Abstract Background We have previously found that almost two thirds (64.6%) of adults in Peru have an active headache disorder. Here, using data from the same sample, we present attributed burden at individual and population levels. We use these data to assess need for headache-related health care among this population. Methods We used the standard methodology of the Global Campaign against Headache. Cluster-sampling from five geographical regions of Peru (Cajamarca, Lima, Piura, Puno, San Martín) generated a sample representative of the population aged 18–65 years. At unannounced visits to households, we interviewed one adult from each using the HARDSHIP questionnaire. We assessed symptom burden in terms of headache frequency and usual duration and intensity, and impaired participation in paid work, household work and social or leisure activities using the HALT index. To assess need for health care, we counted all those with headache on ≥ 15 days/month (H15+), those with migraine on ≥ 3 days/month, and those with migraine or tension-type headache meeting either of two criteria: a) proportion of time in ictal state (pTIS) > 3.3% and intensity ≥ 2 (moderate-to-severe); b) ≥ 3 lost days from paid and/or household work during the preceding 3 months. We derived population-level estimates by factoring in prevalences. Results The sample size was N = 2,149. From individual data, we estimated population-level pTIS at 1.9–2.5%, this proportion of all time among adults in Peru being spent with headache, with migraine the greatest contributor (1.2%). At population level, headache was responsible for 0.5 days lost from paid work and 1.0 days from household work per person per 3 months, with migraine again the biggest contributor (0.2 and 0.5 days). However, at individual level, H15 + was associated with greatest burden (pTIS 14.9–24.9%; 2.3–4.5 lost workdays/3 months). A quarter of the sample (n = 590; 27.5%) fulfilled one or more of our health-care need criteria. Conclusion Headache disorders are responsible for high levels of ill health and economic burden in Peru, with a substantial requirement for health care. Health and economic policies balancing health benefits against the cost of providing care should take account of the productivity losses that might be recovered, and the expected cost-offset.

Abstract Despite antiretroviral therapy (ART), HIV persists in latently-infected cells (the HIV reservoir) which decay slowly over time. Here, leveraging >500 longitudinal samples from 67 people living with HIV (PLWH) treated during acute infection, we developed a mathematical model to predict reservoir decay from peripheral CD4 + T cells. Nonlinear generalized additive models demonstrated rapid biphasic decay of intact DNA (week 0-5: t1/2 ~ 2.83 weeks; week 5-24: t1/2 ~ 15.4 weeks) that extended out to 1 year. These estimates were ~5-fold faster than prior decay estimates among chronic treated PLWH. Defective DNA had a similar biphasic pattern, but data were more variable. Predicted intact and defective decay rates were faster for PLWH with earlier timing of ART initiation, higher initial CD4 + T cell count, and lower pre-ART viral load. In this study, we advanced our limited understanding of HIV reservoir decay at the time of ART initiation, informing future curative strategies targeting this critical time.

Abstract Neuroinflammation in the central nervous system (CNS), driven largely by resident phagocytes, has been proposed as a significant contributor to disability accumulation in multiple sclerosis (MS) but has not been addressed therapeutically. Bruton’s tyrosine kinase (BTK) is expressed in both B-lymphocytes and innate immune cells, including microglia, where its role is poorly understood. BTK inhibition may provide therapeutic benefit within the CNS by targeting adaptive and innate immunity-mediated disease progression in MS. Using a CNS-penetrant BTK inhibitor (BTKi), we demonstrate robust in vivo effects in mouse models of MS. We further identify a BTK-dependent transcriptional signature in vitro, using the BTKi tolebrutinib, in mouse microglia, human induced pluripotent stem cell (hiPSC)-derived microglia, and a complex hiPSC-derived tri-culture system composed of neurons, astrocytes, and microglia, revealing modulation of neuroinflammatory pathways relevant to MS. Finally, we demonstrate that in MS tissue BTK is expressed in B-cells and microglia, with increased levels in lesions. Our data provide rationale for targeting BTK in the CNS to diminish neuroinflammation and disability accumulation.

Abstract Objective This study examined the effect of cognitive status, education, and sex on the association between subjective cognitive decline (SCD) and Alzheimer's disease (AD) biomarkers in non‐demented older adults. Methods Vanderbilt Memory and Aging Project participants (n = 129), dementia or stroke free, completed fasting lumbar puncture, SCD assessment, and cognitive assessment. Cerebrospinal fluid (CSF) biomarkers for AD were analyzed. Linear regression models related SCD to CSF AD biomarkers and follow‐up models assessed interactions of SCD × cognitive status, sex, reading level, and education on AD biomarkers. Results In main effect models, higher SCD was associated with more amyloidosis (p‐values 0.38). SCD score interacted with cognitive status (p 0.51) though SCD related to amyloid markers in the higher reading‐level group (p‐values

Abstract Natural killer (NK) cell function is regulated by a balance of activating and inhibitory signals. Tumor necrosis factor (TNF) is an inflammatory cytokine ubiquitous across homeostasis and disease, yet its role in regulation of NK cells remains unclear. Here, we find upregulation of the immune checkpoint protein, T cell immunoglobulin and mucin domain 3 (Tim3), is a biomarker of TNF signaling in NK cells during Salmonella Typhimurium infection. In mice with conditional deficiency of either TNF receptor 1 (TNFR1) or TNF receptor 2 (TNFR2) in NK cells, we find TNFR1 limits bacterial clearance whereas TNFR2 promotes it. Mechanistically, via single cell RNA sequencing we find that both TNFR1 and TNFR2 induce the upregulation of Tim3, while TNFR1 accelerates NK cell death but TNFR2 promotes NK cell accumulation and effector function. Our study thus highlights the complex interplay of TNF-based regulation of NK cells by the two TNF receptors during inflammation.

ABSTRACT Aims/Hypothesis In diabetes haptoglobin (Hp) 2 vs Hp 1 allelic product is associated with cardiac and renal complications. Few studies report both Hp phenotype and Hp levels. In a Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial substudy we evaluated the Hp phenotype, Hp levels, and fenofibrate effects. Materials and Methods In 480 adults with type 2 diabetes (T2D) the Hp phenotype was assessed and the Hp level quantified (both using ELISAs assays) in plasma from baseline, after 6 weeks of fenofibrate, and (in n = 200) at 2 years post‐randomization to fenofibrate or placebo. Results The Hp phenotypes 1‐1, 2‐1, and 2‐2 frequencies were 15%, 49%, and 36%, respectively. Baseline Hp levels differed by phenotype (P

Abstract Low-abundance members of microbial communities are difficult to study in their native habitats, including Escherichia coli, a minor but common inhabitant of the gastrointestinal tract, and key opportunistic pathogen of the urinary tract. While multi-omic analyses have detailed interactions between uropathogenic Escherichia coli (UPEC) and the bladder mediating urinary tract infection (UTI), little is known about UPEC in its pre-infection reservoir, the gastrointestinal tract, partly due to its low relative abundance (

Abstract We describe the geographical variation in tree species composition across Amazonian forests and show how environmental conditions are associated with species turnover. Our analyses are based on 2023 forest inventory plots (1 ha) that provide abundance data for a total of 5188 tree species. Within-plot species composition reflected both local environmental conditions (especially soil nutrients and hydrology) and geographical regions. A broader-scale view of species turnover was obtained by interpolating the relative tree species abundances over Amazonia into 47,441 0.1-degree grid cells. Two main dimensions of spatial change in tree species composition were identified. The first was a gradient between western Amazonia at the Andean forelands (with young geology and relatively nutrient-rich soils) and central–eastern Amazonia associated with the Guiana and Brazilian Shields (with more ancient geology and poor soils). The second gradient was between the wet forests of the northwest and the drier forests in southern Amazonia. Isolines linking cells of similar composition crossed major Amazonian rivers, suggesting that tree species distributions are not limited by rivers. Even though some areas of relatively sharp species turnover were identified, mostly the tree species composition changed gradually over large extents, which does not support delimiting clear discrete biogeographic regions within Amazonia.

Abstract Alzheimer’s disease (AD) is associated with heterogeneous atrophy patterns. We employed a semi-supervised representation learning technique known as Surreal-GAN, through which we identified two latent dimensional representations of brain atrophy in symptomatic mild cognitive impairment (MCI) and AD patients: the “diffuse-AD” (R1) dimension shows widespread brain atrophy, and the “MTL-AD” (R2) dimension displays focal medial temporal lobe (MTL) atrophy. Critically, only R2 was associated with widely known sporadic AD genetic risk factors (e.g., APOE ε4) in MCI and AD patients at baseline. We then independently detected the presence of the two dimensions in the early stages by deploying the trained model in the general population and two cognitively unimpaired cohorts of asymptomatic participants. In the general population, genome-wide association studies found 77 genes unrelated to APOE differentially associated with R1 and R2. Functional analyses revealed that these genes were overrepresented in differentially expressed gene sets in organs beyond the brain (R1 and R2), including the heart (R1) and the pituitary gland, muscle, and kidney (R2). These genes were enriched in biological pathways implicated in dendritic cells (R2), macrophage functions (R1), and cancer (R1 and R2). Several of them were “druggable genes” for cancer (R1), inflammation (R1), cardiovascular diseases (R1), and diseases of the nervous system (R2). The longitudinal progression showed that APOE ε4, amyloid, and tau were associated with R2 at early asymptomatic stages, but this longitudinal association occurs only at late symptomatic stages in R1. Our findings deepen our understanding of the multifaceted pathogenesis of AD beyond the brain. In early asymptomatic stages, the two dimensions are associated with diverse pathological mechanisms, including cardiovascular diseases, inflammation, and hormonal dysfunction—driven by genes different from APOE—which may collectively contribute to the early pathogenesis of AD. All results are publicly available at https://labs-laboratory.com/medicine/ .

Abstract Although abdominal aortic aneurysms (AAA) are more common in men, women are at greater risk for AAA growth/rupture. Vascular deformation mapping (VDM) utilizes deformable image registration to qualify and quantify 3D-AAA growth using computed tomography angiograms (CTA). In this study we leveraged VDM to investigate sex differences in AAA growth patterns. Patients with infra-renal AAA and ≥ 2 CTA were identified. Males and females were matched for age, hypertension, and smoking history. Patient characteristics, maximum diameter (Dmax), and AAA volume were obtained. CTA images were segmented, and VDM was conducted to quantify 3D AAA growth rate per year (GR, cm/year). Statistical shape modeling was utilized to compute mean aneurysm shapes and 3D GR. Average GR was evaluated at specific regions of the aortic surface for males and females. Seventeen males and 17 females were matched. At the individual level, there were no sex differences in changes in Dmax or AAA volume. However, females had larger GR across the anterior and right lateral AAA (1.33 vs 0.89 and 1.56 vs 0.74 cm/year, respectively), despite no difference in posterior or left lateral AAA GR. Despite comparable changes in Dmax, AAA volume, and GR magnitude, women demonstrated a more eccentric, anterior-predominant, AAA growth pattern.

Abstract Background Current acute healthcare service metrics are not meaningful for older people living with frailty. Healthcare knowledge, situational security, and physical and psychosocial function are important outcomes typically not collected. The use of patient-reported outcome measures (PROMs) could support these assessments. Existing instruments are not comprehensive as they typically consider function, while older people with frailty also value enablement (self-determination and security in health and healthcare). This study field-tested and validated a PROM for older people with frailty receiving acute care (PROM-OPAC) to measure enablement. Methods People aged 65+ with Clinical Frailty Scale 5–8 were recruited within seventy-two hours of an emergency attendance. Iterations of the novel instrument were administered over three stages: (1) preliminary field-testing for reliability (response distribution and internal consistency) and structure (exploratory factor analysis, EFA); (2) intermediate field-testing of an improved instrument for reliability and structure; (3) final draft validation assessing reliability, structure (confirmatory factor analysis, CFA), and construct validity based on a priori hypotheses. Feasibility was appraised throughout using data completeness and response rates and times. Results 241 people participated. Three items of a preliminary seven-item measure had poor response distribution or loading and were accordingly improved. The intermediate instrument had interpretability issues and three items required further improvement. The final eight-item draft had acceptable reliability (Cronbach’s alpha: 0.71), structure (two factors for self-determination and security; RMSEA: 0.065; TLI: 0.917; CFI: 0.944), and construct validity (lower scores from respondents waiting longer and requiring admission). Feasibility was promising (response rate 39%; 98% responses complete; median completion time 11 (IQR: 12) minutes). Conclusions Administration of the PROM-OPAC appeared feasible and the instrument had acceptable psychometric properties. Further evaluation is required to assess generalisability.

Abstract We consider the problem of computing semi-classical Rényi entropies of CFT on AdS2 backgrounds in JT gravity with nongravitating baths, for general replica number n. Away from the n → 1 limit, the backreaction of the CFT twist fields on the geometry is nontrivial. For one twist field insertion and general n, we show that the quantum extremal surface (QES) condition involves extremisation of the generalised modular entropy, consistent with Dong’s generalisation of the Ryu-Takayanagi formula for general n. For multiple QES we describe replica wormhole geometries using the theory of Fuchsian uniformisation, explicitly working out the analytically tractable case of the n = 2 double trumpet wormhole geometry. We determine the off-shell dependence of the gravitational action on the QES locations and boundary map. In a factorisation limit, corresponding to late times, we are able to relate this action functional to area terms given by the value of the JT dilaton at the (off-shell) QES locations, with computable corrections. Applied to the two-sided eternal black hole, we find the n-dependent Page times for Rényi enropies in the high temperature limit.

Abstract Moral injury has emerged as a construct of interest in healthcare workers’ (HCW) occupational stress and health. We conducted one of the first multidisciplinary, longitudinal studies evaluating the relationship between exposure to potentially morally injurious events (PMIEs), burnout, and turnover intentions. HCWs (N = 473) completed surveys in May of 2020 (T1) and again in May of 2021 (T2). Generalized Linear Models (robust Poisson regression) were used to test relative risk of turnover intentions, and burnout at T2 associated with PMIE exposure, controlling for T1 covariates. At T1, 17.67% reported they had participated in a PMIE, 41.44% reported they witnessed a PMIE and 76.61% reported feeling betrayed by healthcare or a public health organization. In models including all T1 PMIE exposures and covariates, T2 turnover intentions were increased for those who witnessed a PMIE at T1 (Relative Risk [RR] = 1.66, 95% Confidence Interval [CI] 1.17–2.34) but not those that participated or felt betrayed. T2 burnout was increased for those who participated in PMIE at T1 (RR = 1.38, 95%CI 1.03–1.85) but not those that witnessed or felt betrayed. PMIE exposure is highly prevalent among HCWs, with specific PMIEs associated with turnover intentions and burnout. Organizational interventions to reduce and facilitate recovery from moral injury should account for differences in the type of PMIE exposures that occur in healthcare work environments.

Abstract Metabolic disorder significantly contributes to diabetic vascular complications, including diabetic retinopathy, the leading cause of blindness in the working-age population. However, the molecular mechanisms by which disturbed metabolic homeostasis causes vascular dysfunction in diabetic retinopathy remain unclear. O-GlcNAcylation modification acts as a nutrient sensor particularly sensitive to ambient glucose. Here, we observe pronounced O-GlcNAc elevation in retina endothelial cells of diabetic retinopathy patients and mouse models. Endothelial-specific depletion or pharmacological inhibition of O-GlcNAc transferase effectively mitigates vascular dysfunction. Mechanistically, we find that Yes-associated protein (YAP) and Transcriptional co-activator with PDZ-binding motif (TAZ), key effectors of the Hippo pathway, are O-GlcNAcylated in diabetic retinopathy. We identify threonine 383 as an O-GlcNAc site on YAP, which inhibits its phosphorylation at serine 397, leading to its stabilization and activation, thereby promoting vascular dysfunction by inducing a pro-angiogenic and glucose metabolic transcriptional program. This work emphasizes the critical role of the O-GlcNAc-Hippo axis in the pathogenesis of diabetic retinopathy and suggests its potential as a therapeutic target.

Abstract Alternative cleavage and polyadenylation within introns (intronic APA) generate shorter mRNA isoforms; however, their physiological significance remains elusive. In this study, we developed a comprehensive workflow to analyze intronic APA profiles using the mammalian target of rapamycin (mTOR)-regulated transcriptome as a model system. Our investigation revealed two contrasting effects within the transcriptome in response to fluctuations in cellular mTOR activity: an increase in intronic APA for a subset of genes and a decrease for another subset of genes. The application of this workflow to RNA-seq data from The Cancer Genome Atlas demonstrated that this dichotomous intronic APA pattern is a consistent feature in transcriptomes across both normal tissues and various cancer types. Notably, our analyses of protein length changes resulting from intronic APA events revealed two distinct phenomena in proteome programming: a loss of functional domains due to significant changes in protein length or minimal alterations in C-terminal protein sequences within unstructured regions. Focusing on conserved intronic APA events across 10 different cancer types highlighted the prevalence of the latter cases in cancer transcriptomes, whereas the former cases were relatively enriched in normal tissue transcriptomes. These observations suggest potential, yet distinct, roles for intronic APA events during pathogenic processes and emphasize the abundance of protein isoforms with similar lengths in the cancer proteome. Furthermore, our investigation into the isoform-specific functions of JMJD6 intronic APA events supported the hypothesis that alterations in unstructured C-terminal protein regions lead to functional differences. Collectively, our findings underscore intronic APA events as a discrete molecular signature present in both normal tissues and cancer transcriptomes, highlighting the contribution of APA to the multifaceted functionality of the cancer proteome.

Abstract Infections caused by Gram-negative bacteria are leading causes of mortality worldwide. Due to the rise in antibiotic resistant strains, there is a desperate need for alternative strategies to control infections caused by these organisms. One such approach is the prevention of infection through vaccination. While live attenuated and heat-killed bacterial vaccines are effective, they can lead to adverse reactions. Newer vaccine technologies focus on utilizing polysaccharide or protein subunits for safer and more targeted vaccination approaches. One promising avenue in this regard is the use of proteins released by the Type 5 secretion system (T5SS). This system is the most prevalent secretion system in Gram-negative bacteria. These proteins are compelling vaccine candidates due to their demonstrated protective role in current licensed vaccines. Notably, Pertactin, FHA, and NadA are integral components of licensed vaccines designed to prevent infections caused by Bordetella pertussis or Neisseria meningitidis. In this review, we delve into the significance of incorporating T5SS proteins into licensed vaccines, their contributions to virulence, conserved structural motifs, and the protective immune responses elicited by these proteins.

Abstract Background Clostridium autoethanogenum is an acetogenic bacterium that autotrophically converts carbon monoxide (CO) and carbon dioxide (CO2) gases into bioproducts and fuels via the Wood–Ljungdahl pathway (WLP). To facilitate overall carbon capture efficiency, the reaction stoichiometry requires supplementation of hydrogen at an increased ratio of H2:CO to maximize CO2 utilization; however, the molecular details and thus the ability to understand the mechanism of this supplementation are largely unknown. Results In order to elucidate the microbial physiology and fermentation where at least 75% of the carbon in ethanol comes from CO2, we established controlled chemostats that facilitated a novel and high (11:1) H2:CO uptake ratio. We compared and contrasted proteomic and metabolomics profiles to replicate continuous stirred tank reactors (CSTRs) at the same growth rate from a lower (5:1) H2:CO condition where ~ 50% of the carbon in ethanol is derived from CO2. Our hypothesis was that major changes would be observed in the hydrogenases and/or redox-related proteins and the WLP to compensate for the elevated hydrogen feed gas. Our analyses did reveal protein abundance differences between the two conditions largely related to reduction–oxidation (redox) pathways and cofactor biosynthesis, but the changes were more minor than we would have expected. While the Wood–Ljungdahl pathway proteins remained consistent across the conditions, other post-translational regulatory processes, such as lysine-acetylation, were observed and appeared to be more important for fine-tuning this carbon metabolism pathway. Metabolomic analyses showed that the increase in H2:CO ratio drives the organism to higher carbon dioxide utilization resulting in lower carbon storages and accumulated fatty acid metabolite levels. Conclusions This research delves into the intricate dynamics of carbon fixation in C. autoethanogenum, examining the influence of highly elevated H2:CO ratios on metabolic processes and product outcomes. The study underscores the significance of optimizing gas feed composition for enhanced industrial efficiency, shedding light on potential mechanisms, such as post-translational modifications (PTMs), to fine-tune enzymatic activities and improve desired product yields.

Abstract Inferring the 3D structure and conformation of disordered biomolecules, e.g., single stranded nucleic acids (ssNAs), remains challenging due to their conformational heterogeneity in solution. Here, we use escape-time electrometry (ETe) to measure with sub elementary-charge precision the effective electrical charge in solution of short to medium chain length ssNAs in the range of 5–60 bases. We compare measurements of molecular effective charge with theoretically calculated values for simulated molecular conformations obtained from Molecular Dynamics simulations using a variety of forcefield descriptions. We demonstrate that the measured effective charge captures subtle differences in molecular structure in various nucleic acid homopolymers of identical length, and also that the experimental measurements can find agreement with computed values derived from coarse-grained molecular structure descriptions such as oxDNA, as well next generation ssNA force fields. We further show that comparing the measured effective charge with calculations for a rigid, charged rod—the simplest model of a nucleic acid—yields estimates of molecular structural dimensions such as linear charge spacings that capture molecular structural trends observed using high resolution structural analysis methods such as X-ray scattering. By sensitively probing the effective charge of a molecule, electrometry provides a powerful dimension supporting inferences of molecular structural and conformational properties, as well as the validation of biomolecular structural models. The overall approach holds promise for a high throughput, microscopy-based biomolecular analytical approach offering rapid screening and inference of molecular 3D conformation, and operating at the single molecule level in solution.

Abstract The role of the cerebral cortex in self-initiated versus sensory-driven movements is central to understanding volitional action. Whether the differences in these two movement classes are due to specific cortical areas versus more cortex-wide engagement is debated. Using wide-field Ca2+ imaging, we compared neural dynamics during spontaneous and motorized treadmill locomotion, determining the similarities and differences in cortex-wide activation and functional connectivity (FC). During motorized locomotion, the cortex exhibits greater activation globally prior to and during locomotion starting compared to spontaneous and less during steady-state walking, during stopping, and after termination. Both conditions are characterized by FC increases in anterior secondary motor cortex (M2) nodes and decreases in all other regions. There are also cortex-wide differences; most notably, M2 decreases in FC with all other nodes during motorized stopping and after termination. Therefore, both internally- and externally-generated movements widely engage the cortex, with differences represented in cortex-wide activation and FC patterns.

Abstract The physical characterization of proteins in terms of their sizes, interactions, and assembly states is key to understanding their biological function and dysfunction. However, this has remained a difficult task because proteins are often highly polydisperse and present as multicomponent mixtures. Here, we address this challenge by introducing single-molecule microfluidic diffusional sizing (smMDS). This approach measures the hydrodynamic radius of single proteins and protein assemblies in microchannels using single-molecule fluorescence detection. smMDS allows for ultrasensitive sizing of proteins down to femtomolar concentrations and enables affinity profiling of protein interactions at the single-molecule level. We show that smMDS is effective in resolving the assembly states of protein oligomers and in characterizing the size of protein species within complex mixtures, including fibrillar protein aggregates and nanoscale condensate clusters. Overall, smMDS is a highly sensitive method for the analysis of proteins in solution, with wide-ranging applications in drug discovery, diagnostics, and nanobiotechnology.

Knowledge of the factors influencing nutrient-limited subtropical maize yield and subsequent prediction is crucial for effective nutrient management, maximizing profitability, ensuring food security, and promoting environmental sustainability. We analyzed data from nutrient omission plot trials (NOPTs) conducted in 324 farmers' fields across ten agroecological zones (AEZs) in the Eastern Indo-Gangetic Plains (EIGP) of Bangladesh to explain maize yield variability and identify variables controlling nutrient-limited yields. An additive main effect and multiplicative interaction (AMMI) model was used to explain maize yield variability with nutrient addition. Interpretable machine learning (ML) algorithms in automatic machine learning (AutoML) frameworks were subsequently used to predict attainable yield relative nutrient-limited yield (RY) and to rank variables that control RY. The stack-ensemble model was identified as the best-performing model for predicting RYs of N, P, and Zn. In contrast, deep learning outperformed all base learners for predicting RYK. The best model's square errors (RMSEs) were 0.122, 0.105, 0.123, and 0.104 for RYN, RYP, RYK, and RYZn, respectively. The permutation-based feature importance technique identified soil pH as the most critical variable controlling RYN and RYP. The RYK showed lower in the eastern longitudinal direction. Soil N and Zn were associated with RYZn. The predicted median RY of N, P, K, and Zn, representing average soil fertility, was 0.51, 0.84, 0.87, and 0.97, accounting for 44, 54, 54, and 48% upland dry season crop area of Bangladesh, respectively. Efforts are needed to update databases cataloging variability in land type inundation classes, soil characteristics, and INS and combine them with farmers' crop management information to develop more precise nutrient guidelines for maize in the EIGP.

Abstract Background Having previously shown headache disorders to be prevalent in Mongolia, here we elaborate on headache as a public-health concern in this country, reporting symptom burden and headache-attributed impaired participation at individual and societal levels, and conducting a health-care needs assessment. Methods The study followed the standardized methodology developed by the Global Campaign against Headache, generating a representative general-population sample through multi-level randomized cluster sampling. Participants aged 18–65 years were interviewed at unannounced household visits by interviewers administering the HARDSHIP questionnaire. Symptom burden was established through questions on frequency, duration and intensity of headache, with proportion of time in ictal state calculated from frequency and duration. Individual impaired participation was established through the HALT questionnaire, enquiring into lost time from paid and household work and from leisure activities. Symptom burden and impaired participation yesterday were also assessed in those reporting headache yesterday. Population-level estimates were derived by factoring in prevalence. Results The total sample included 2,043 participants. Those reporting any headache in the last year (n = 1,351) spent, on average, 9.7% of all their time with headache, losing 1.3 workdays and 2.4 household days/3 months. These losses were considerably higher among those with probable medication-overuse headache (37.5%, 3.5 workdays, 6.7 household days) or other headache on ≥ 15 days/month (H15+) (21.9%, 2.4 workdays, 5.1 household days). At population-level (including those with and without headache), 6.2–7.4% of all time was spent with headache, 3.1% with H15+; 0.8 workdays and 1.4 household days/person/3 months were lost to headache, 0.3 workdays and 0.6 household days to migraine (the biggest contributor of all headache types). Our needs assessment estimated that one third (33.2%) of the adult population of Mongolia have headache (mostly migraine or H15+) likely to benefit from health care. Conclusion This first population-based study on headache burden in Mongolia shows high levels of individual and societal burden, with H15 + the cause of greater burden at population level than migraine and TTH combined. Migraine, however, has the biggest impact on the nation’s productivity. From a purely economic perspective, Mongolia, with limited health resources, would probably be best served by focusing on mitigating migraine-attributed burden.

Abstract Background Obstructive lung disease (OLD) is increasingly prevalent among persons living with HIV (PLWH). However, the role of proteases in HIV-associated OLD remains unclear. Methods We combined proteomics and peptidomics to comprehensively characterize protease activities. We combined mass spectrometry (MS) analysis on bronchoalveolar lavage fluid (BALF) peptides and proteins from PLWH with OLD (n = 25) and without OLD (n = 26) with a targeted Somascan aptamer-based proteomic approach to quantify individual proteases and assess their correlation with lung function. Endogenous peptidomics mapped peptides to native proteins to identify substrates of protease activity. Using the MEROPS database, we identified candidate proteases linked to peptide generation based on binding site affinities which were assessed via z-scores. We used t-tests to compare average forced expiratory volume in 1 s per predicted value (FEV1pp) between samples with and without detection of each cleaved protein and adjusted for multiple comparisons by controlling the false discovery rate (FDR). Findings We identified 101 proteases, of which 95 had functional network associations and 22 correlated with FEV1pp. These included cathepsins, metalloproteinases (MMP), caspases and neutrophil elastase. We discovered 31 proteins subject to proteolytic cleavage that associate with FEV1pp, with the top pathways involved in small ubiquitin-like modifier mediated modification (SUMOylation). Proteases linked to protein cleavage included neutrophil elastase, granzyme, and cathepsin D. Interpretations In HIV-associated OLD, a significant number of proteases are up-regulated, many of which are involved in protein degradation. These proteases degrade proteins involved in cell cycle and protein stability, thereby disrupting critical biological functions.

Abstract Determining the genetic architecture of Alzheimer’s disease pathologies can enhance mechanistic understanding and inform precision medicine strategies. Here, we perform a genome-wide association study of cortical tau quantified by positron emission tomography in 3046 participants from 12 independent studies. The CYP1B1-RMDN2 locus is associated with tau deposition. The most significant signal is at rs2113389, explaining 4.3% of the variation in cortical tau, while APOE4 rs429358 accounts for 3.6%. rs2113389 is associated with higher tau and faster cognitive decline. Additive effects, but no interactions, are observed between rs2113389 and diagnosis, APOE4, and amyloid beta positivity. CYP1B1 expression is upregulated in AD. rs2113389 is associated with higher CYP1B1 expression and methylation levels. Mouse model studies provide additional functional evidence for a relationship between CYP1B1 and tau deposition but not amyloid beta. These results provide insight into the genetic basis of cerebral tau deposition and support novel pathways for therapeutic development in AD.

Citizen science is a rapidly growing field, particularly among young scientists. In this case study, we review a year-long citizen science initiative hosted at Western University, Canada, which aimed to document and highlight biodiversity on campus while simultaneously seeking to improve community engagement with the environment. Using the popular citizen science platform iNaturalist, we facilitated data collection and community engagement through a combination of informal field surveys, undergraduate-level course assignments, social media, and passive data submission. Throughout the first year of the initiative, nearly 300 community members submitted 3716 observations of 1225 species, including observations of 103 species documented on iNaturalist for the first time in the region, and other species of ecological significance. This citizen science project underscores the strengths and utility of citizen science and provides a framework for other higher education institutions to develop similar initiatives.

Summary: Cell-intrinsic antiviral gene expression by intestinal epithelial cells (IECs) limits infection by enteric viral pathogens. Here, we find that neonatal IECs express antiviral genes at homeostasis that depend on interferon lambda (IFN-λ) and are required for early control of mouse rotavirus (mRV) infection. Neonatal homeostatic IFN-λ responses are independent of microbiota and pervasively distributed among IECs, distinguishing them from the homeostatic responses of adult mice. Developmental differences in homeostatic IFN-stimulated gene signatures of the intestine are regulated by maturation during the suckling-to-weanling transition, which includes reduced expression of Prdm1 by mature IECs. These studies identify developmental regulation of the homeostatic IFN-λ response, which is present in the neonatal intestine from birth, stimulated independent of microbiota, and preemptively protects IECs from viral infection. This intrinsically programmed antiviral response in early life is particularly important due to the absence of a robust microbiota or protective immune memory at birth, when the risk of enteric infection is high.

The growing frequency, extent and severity of wildfire is destabilizing carbon sinks in western North America, underscoring an urgent need to better understand fire impacts on soil carbon stocks, carbon stability, and fungi that regulate soil carbon cycling. Here, we examined the effects of wildfire two years post-burn on soil carbon and fungal communities across a fire severity gradient in Douglas-fir forests in central British Columbia, Canada. We observed no significant differences in soil carbon or fungal community composition between low-severity and unburned stands. In contrast, high-severity wildfire resulted in a 49 % reduction in belowground carbon stocks (20.7 Mg C·ha−1), a 91 % decline in ectomycorrhizal fungi, 5- to 27-fold increases in pathogenic fungi, and a proliferation of pyrophilous taxa compared to unburned stands. Carbon was lost primarily as light particulate organic matter, whereas impacts to mineral-associated carbon were muted. Pyrogenic carbon preferentially associated with the mineral fraction, modestly increasing (∼0.15 Mg C·ha−1) the proportion of carbon resistant to decay in this stable fraction. Select helotialean (e.g. Phialocephala fortinii) and other pyrophilous taxa were well-correlated with pyrogenic carbon, suggesting this consortium is well-adapted to decompose persistent carbon and will likely continue to mineralize soil carbon even after high severity wildfire. The markedly higher abundance of pathogenic fungi and reduced ectomycorrhizal abundance in stands affected by high-severity fires pose risks to post-fire recovery, particularly if pathogen proliferation reduces conifer fitness. These results highlight that low-severity wildfires have comparatively muted impacts on soil carbon and fungal communities relative to high-severity wildfires, underscoring the importance of management strategies such as thinning and prescribed burns to mitigate the catastrophic effects of high-severity wildfires.

Coastal embayments are dynamic ecosystems facing environmental and anthropogenic pressures, including bivalve aquaculture and climate change. Mesozooplankton, essential for transferring energy from primary producers to higher trophic levels, serve as indicators of habitat changes. Size structure is a critical trait that reflects local community dynamics, trophic interactions, and ecosystem conditions, offering insights into the functioning and resilience of aquatic environments. This study examines the spatio-temporal variation in mesozooplankton size structure across nine bivalve aquaculture embayments in Atlantic and Pacific Canada from 2020 to 2022. Using high-resolution imaging (FlowCam®) to measure individual zooplankton, we assessed the effects of location, tide, sampling day, season, and aquaculture pressure on the size distribution variation among and within bays. Results indicate that bays with similar size distributions tend to have larger mesozooplankton, while those with more variable distributions are dominated by medium-sized individuals. Significant associations between environmental factors and size variation were observed in four of eleven sampling events. Notably, St. Peters Bay, with the highest aquaculture pressure, showed significant variation associated with station location and sampling day. However, the tide effect was significant only in two sampling events. Seasonal analysis revealed that colder months generally exhibited larger median sizes, with some exceptions influenced by local conditions. Despite high levels of aquaculture pressure in some bays, no consistent association between aquaculture pressure and size variation was found, highlighting the influence of local environmental factors. This study underscores the importance of monitoring mesozooplankton size structure as a bioindicator for effective ecosystem management and targeted conservation strategies.

The function of abscission zones (AZs) determines the timing of fleshy fruit abscission, with important consequences not only for the optimal fruit harvest, but also on the overall final fruit quality. In this context, chemical treatments are commonly used at different stages of fruit development to control fruit abscission, which can also have positive or negative effects on fruit quality. In the current review, we examine commonly used chemicals that affect the metabolic activity in the AZs of fleshy fruit, in addition to their effects on fruit quality characteristics. The main hormone metabolism and signaling in the AZ include that of ethylene, auxin, abscisic acid and jasmonates, and the molecular components that are involved are covered and discussed, in addition to how these hormones work together to regulate AZ activity and hence, affect fruit quality. We focus on studies that have provided new insight into possible protein complexes that function in the AZ, including multiple MADS-box transcription factors, with potential overlapping regulatory roles which exist between AZ development, ethylene production, AZ activation, fruit ripening and overall fruit quality. The view of the AZ as a cross roads where multiple pathways and signals are integrated is discussed.