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Abstract Advances in theoretical understanding are frequently unlocked by access to large, diverse experimental datasets. Our understanding of olfactory neuroscience and psychophysics remain years behind the other senses, in part because rich datasets linking olfactory stimuli with their corresponding percepts, behaviors, and neural pathways remain scarce. Here we present a concerted effort to unlock and unify dozens of stimulus-linked olfactory datasets across species and modalities under a unified framework called Pyrfume. We present examples of how researchers might use Pyrfume to conduct novel analyses uncovering new principles, introduce trainees to the field, or construct benchmarks for machine olfaction.

Abstract It has been hypothesized that ultraviolet (UV) radiation can lead to depletion of plasma folate and B12 vitamin, but few studies have investigated effects of other parameters of solar and geomagnetic activity (SGA). We investigated the association between four SGA parameters—interplanetary magnetic field (IMF), sunspot number (SSN), Kp index, and ground shortwave solar radiation (SWR)—and three plasma B-complex vitamins—folate, B6, and B12—in 910 participants from the Normative Aging Study (NAS) between 1998 and 2017. Mixed-effects regression models were used for 1- to 28-moving day averages of SGA exposure, adjusted for covariates. We compared the impact of SGA in individuals under higher and lower B-complex supplementation (> or

Abstract Growing evidence suggests that long-term air pollution exposure is a risk factor for cardiovascular mortality and morbidity. However, few studies have investigated air pollution below current regulatory limits, and causal evidence is limited. We use a double negative control approach to examine the association between long-term exposure to air pollution at low concentration and cardiovascular hospitalizations among US Medicare beneficiaries aged ≥65 years between 2000 and 2016. The expected values of the negative outcome control (preceding-year hospitalizations) regressed on exposure and negative exposure control (subsequent-year exposure) are treated as a surrogate for omitted confounders. With analyses separately restricted to low-pollution areas (PM2.5

Abstract Human p97 ATPase is crucial in various cellular processes, making it a target for inhibitors to treat cancers, neurological, and infectious diseases. Triazole allosteric p97 inhibitors have been demonstrated to match the efficacy of CB-5083, an ATP-competitive inhibitor, in cellular models. However, the mechanism is not well understood. This study systematically investigates the structures of new triazole inhibitors bound to both wild-type and disease mutant forms of p97 and measures their effects on function. These inhibitors bind at the interface of the D1 and D2 domains of each p97 subunit, shifting surrounding helices and altering the loop structures near the C-terminal α2 G helix to modulate domain-domain communications. A key structural moiety of the inhibitor affects the rotameric conformations of interacting side chains, indirectly modulating the N-terminal domain conformation in p97 R155H mutant. The differential effects of inhibitor binding to wild-type and mutant p97 provide insights into drug design with enhanced specificity, particularly for oncology applications.

Background: Cardiovascular disease is a leading cause of death in Canada, but how the major cardiovascular risk factors vary across ethnicity and immigration status has yet to be examined. Methods: Using data from the Canadian Community Health Surveys, national trends in health conditions (hypertension, diabetes, high blood cholesterol level, and obesity) and health behaviours (smoking, activity levels, and alcohol consumption) were estimated for the period 2001-2018. In this cross-sectional study, the trends were then compared across sex, age, ethnicity, and immigration status. Results: A total of 1,065,391 respondents were examined, for the period 2001-2018. During the study period, the prevalence of the following risk factors increased in Canada over time, as follows: diabetes by 54.5%; hypertension by 23.4%; and obesity by 32.3%. For health behaviours, smoking prevalence decreased overall, especially in racialized populations. Heavy drinking was most prevalent for nonracialized and non-Indigenous Canadian-born populations, and was of lowest prevalence among racialized immigrants. Physical inactivity was most prevalent for racialized immigrant populations. The prevalence of self-reported heart disease decreased by 21.0%, except for racialized established immigrants (≥ 10 years since immigration to Canada), who had a 4.2% increase. Conclusions: During this study period, decreases occurred in the prevalences of smoking and physical inactivity, along with increases in obesity, diabetes, and hypertension prevalences. By migration-group status, established immigrants in Canada had a higher prevalence of cardiovascular disease risk factors compared to that among their Canadian-born counterparts. Migration gaps should be considered in future interventions targeted at reducing these cardiovascular risk factors in Canada. Résumé: Contexte: Les maladies cardiovasculaires sont une cause majeure de décès au Canada, mais la manière dont les principaux facteurs de risque cardiovasculaire varient en fonction de l’origine ethnique et du statut d’immigration n’a encore jamais été évaluée. Méthodologie: Des tendances nationales dans certains problèmes de santé (hypertension, diabète, hypercholestérolémie et obésité) et certains comportements liés à la santé (tabagisme, niveaux d’activité et consommation d’alcool) ont été dégagées à partir des données de l’Enquête sur la santé dans les collectivités canadiennes pour la période de 2001 à 2018. Ces tendances ont ensuite été comparées en fonction du sexe, de l’âge, de l’origine ethnique et du statut d’immigration dans le cadre de la présente étude transversale. Résultats: Au total, 1 065 391 répondants ont été examinés pour la période de 2001 à 2018. Durant la période de l’étude, la prévalence des facteurs de risque suivants a graduellement augmenté au Canada : diabète, de 54,5 %; hypertension, de 23,4 %; obésité, de 32,3 %. Dans le cas des comportements liés à la santé, la prévalence du tabagisme a globalement diminué, surtout dans les populations racialisées. La consommation excessive d’alcool était plus fréquente dans les populations non racialisées et non autochtones d’origine canadienne, et moins fréquente chez les immigrants racialisés. L’inactivité physique était particulièrement répandue dans les populations immigrantes racialisées. La prévalence des maladies cardiaques auto-déclarées a diminué de 21,0 %, sauf chez les immigrants établis racialisés (≥ 10 ans depuis l’arrivée au Canada), qui a connu une hausse de 4,2 %. Conclusions: Durant la période de l’étude, la prévalence du tabagisme et de l’inactivité physique a diminué tandis que celle de l’obésité, du diabète et de l’hypertension a augmenté. D’après le statut du groupe de migration, la prévalence des facteurs de risque de maladies cardiovasculaires était plus élevée chez les immigrants établis au Canada que chez leurs homologues nés au Canada. Il convient de prendre en considération les différences liées à la migration dans les interventions futures visant à réduire ces facteurs de risque cardiovasculaire au Canada.

Abstract While extensive research has explored the effects of plastic pollution, ecosystem responses remain poorly quantified, especially in field experiments. In this study, we investigated the impact of polyester pollution, a prevalent plastic type, on coastal sediment ecosystem function. Strips of polyester netting were buried into intertidal sediments, and effects on sediment oxygen consumption and polyester additive concentrations were monitored over 72-days. Our results revealed a rapid reduction in the magnitude and variability of sediment oxygen consumption, a crucial ecosystem process, potentially attributed to the loss of the additive di(2-ethylhexyl) phthalate (DEHP) from the polyester material. DEHP concentrations declined by 89% within the first seven days of deployment. However, effects on SOC dissipated after 22 days, indicating a short-term impact and a quick recovery by the ecosystem. Our study provides critical insights into the immediate consequences of plastic pollution on ecosystem metabolism in coastal sediments, contributing to a nuanced understanding of the temporal variation of plastic pollution’s multifaceted impacts. Additionally, our research sheds light on the urgent need for comprehensive mitigation strategies to preserve marine ecosystem functionality from plastic pollution impacts.

Abstract Background Biological control is a promising alternative or complementary approach for controlling vector populations in response to the spread of insecticide resistance in malaria vectors. This study evaluated the efficacy of three selected potential predators on the density and fitness parameters of Anopheles funestus larvae in rural Tanzania. Methods Common predator families Aeshnidae (dragonflies), Coenagrionidae (damselflies), and Notonectidae (backswimmers) and An. funestus group larvae were collected from natural aquatic habitats in rural south-eastern Tanzania. Predators were starved for 12-h while An. funestus larvae were given fish food before starting the experiment. Anopheles funestus larvae were placed into artificial habitats containing predators, exposing them to potential predation. The number of surviving An. funestus larvae were counted every 24-h. An emergence traps were placed at the top of artificial habitats to capture emerging mosquitoes. Emerged mosquitoes were monitored until they died. Female wings were measured and used as a proxy for body size. Generalized linear mixed models (GLMM) with binomial variates at 95% CI and Cox proportional hazard models were used to assess the proportion of dead mosquitoes and the daily survival determined. Results There were significant differences in the number of emerged mosquitoes between the treatment and control groups (P

Abstract Immunodominance of antibodies targeting non-neutralizing epitopes and the high level of somatic hypermutation within germinal centers (GCs) required for most HIV broadly neutralizing antibodies (bnAbs) are major impediments to the development of an effective HIV vaccine. Rational protein vaccine design and non-conventional immunization strategies are potential avenues to overcome these hurdles. Here, we report using implantable osmotic pumps to continuously deliver a series of epitope-targeted immunogens to rhesus macaques over the course of six months to prime and elicit antibody responses against the conserved fusion peptide (FP). GC responses and antibody specificities were tracked longitudinally using lymph node fine-needle aspirates and electron microscopy polyclonal epitope mapping (EMPEM), respectively, to show antibody responses to the FP/N611 glycan hole region were primed, although exhibited limited neutralization breadth. Application of cryoEMPEM delineated key residues for on-target and off-target responses that can drive the next round of structure-based vaccine design.

Abstract Background Studies of animal habitat selection are important to identify and preserve the resources species depend on, yet often little attention is paid to how habitat needs vary depending on behavioral state. Fishers (Pekania pennanti) are known to be dependent on large, mature trees for resting and denning, but less is known about their habitat use when foraging or moving within a home range. Methods We used GPS locations collected during the energetically costly pre-denning season from 12 female fishers to determine fisher habitat selection during two critical behavioral activities: foraging (moving) or resting, with a focus on response to forest structure related to past forest management actions since this is a primary driver of fisher habitat configuration. We characterized behavior based on high-resolution GPS and collar accelerometer data and modeled fisher selection for these two behaviors within a home range (third-order selection). Additionally, we investigated whether fisher use of elements of forest structure or other important environmental characteristics changed as their availability changed, i.e., a functional response, for each behavior type. Results We found that fishers exhibited specialist selection when resting and generalist selection when moving, with resting habitat characterized by riparian drainages with dense canopy cover and moving habitat primarily influenced by the presence of mesic montane mixed conifer forest. Fishers were more tolerant of forest openings and other early succession elements when moving than resting. Conclusions Our results emphasize the importance of considering the differing habitat needs of animals based on their movement behavior when performing habitat selection analyses. We found that resting fishers are more specialist in their habitat needs, while foraging fishers are more generalist and will tolerate greater forest heterogeneity from past disturbance.

Introduction Air pollution presents a major public health threat to India, affecting more than three quarters of the country’s population. In the current project, GEOHealth Health Effects of Selected Environmental Exposomes Across the Life CourSe–India, we aim to study the effect of environmental exposomes—fine particulate matter (PM2.5), nitrogen dioxide (NO2), ozone (O3) and extremes of temperature—on multiple health outcomes using a modified life course approach. The associated training grant aims to build capacity in India to address the unique environmental health problems.Methods and analysis The project aims to (A) Develop exposure assessments in seven cities, namely Delhi, Chennai, Sonipat, Vizag, Pune, Hyderabad and Bikaner, for: (1) A fine-scale spatiotemporal model for multiple pollutants (PM2.5, NO2, O3, temperature); (2) Combined ground monitoring and modelling for major chemical species of ambient PM2.5 at seven cities; and (3) Personal exposure assessment in a subsample from the six cities, except Pune, and (B) Conduct health association studies covering a range of chronic non-communicable diseases and their risk factors leveraging a unique approach using interdigitating cohorts. We have assembled existing pregnancy, child, adolescent, adult and older adult cohorts across India to explore health effects of exposomes using causal analyses. We propose to use Bayesian kernel machine regression to assess the effects of mixtures of all pollutants including species of PM2.5 on health while accounting for potential non-linearities and interactions between exposures. This builds on earlier work that constructed a fine spatiotemporal model for PM2.5 exposure to study health outcomes in two Indian cities.Ethics and dissemination Ethical clearance for conduct of the study was obtained from the Institutional Ethics Committee (IEC) of the Centre for Chronic Disease Control, and all the participating institutes and organisations. National-level permission was provided by the Indian Council of Medical Research. The research findings will be disseminated through peer-reviewed publications, policy briefs, print and social media, and communicating with the participating communities and stakeholders. Training of Indian scientists will build the capacity to undertake research on selected adverse environmental exposures on population health in India.

Abstract BackgroundYoung men who have sex with men and young transgender women (YMSM-YTW) use online spaces to meet sexual partners with increasing regularity, and research shows that experiences of racism online mimics the real world. ObjectiveWe analyzed differences by race and ethnicity in web-based and mobile apps used to meet sexual partners as reported by Chicago-based YMSM-YTW in 2016‐2017. MethodsA racially and ethnically diverse sample of 643 YMSM-YTW aged 16‐29 years were asked to name websites or mobile apps used to seek a sexual partner in the prior 6 months, as well as provide information about sexual partnerships from the same period. We used logistic regression to assess the adjusted association of race and ethnicity with (1) use of any website or mobile apps to find a sexual partner, (2) use of a “social network” to find a sexual partner compared to websites or mobile apps predominantly used for dating or hookups, (3) use of specific websites or mobile apps, and (4) reporting successfully meeting a sexual partner online among website or mobile app users. ResultsWhile most YMSM-YTW (454/643, 70.6%) used websites or mobile apps to find sexual partners, we found that Black non-Hispanic YMSM-YTW were significantly less likely to report doing so (comparing White non-Hispanic to Black non-Hispanic: adjusted odds ratio [aOR] 1.74, 95% CI 1.10‐2.76). Black non-Hispanic YMSM-YTW were more likely to have used a social network site to find a sexual partner (comparing White non-Hispanic to Black non-Hispanic: aOR 0.20, 95% CI 0.11‐0.37), though this was only reported by one-third (149/454, 32.8%) of all app-using participants. Individual apps used varied by race and ethnicity, with Grindr, Tinder, and Scruff being more common among White non-Hispanic YMSM-YTW (93/123, 75.6%; 72/123, 58.5%; and 30/123, 24.4%, respectively) than among Black non-Hispanic YMSM-YTW (65/178, 36.5%; 25/178, 14%; and 4/178, 2.2%, respectively) and Jack’d and Facebook being more common among Black non-Hispanic YMSM-YTW (105/178, 59% and 64/178, 36%, respectively) than among White non-Hispanic YMSM-YTW (6/123, 4.9% and 8/123, 6.5%, respectively). Finally, we found that while half (230/454, 50.7%) of YMSM-YTW app users reported successfully meeting a new sexual partner on an app, Black non-Hispanic YMSM-YTW app users were less likely to have done so than White non-Hispanic app users (comparing White non-Hispanic to Black non-Hispanic: aOR 2.46, 95% CI 1.50‐4.05). ConclusionsWe found that Black non-Hispanic YMSM-YTW engaged with websites or mobile apps and found sexual partners systematically differently than White non-Hispanic YMSM-YTW. Our findings give a deeper understanding of how racial and ethnic sexual mixing patterns arise and have implications for the spread of sexually transmitted infections among Chicago’s YMSM-YTW.

Introduction: Community pharmacies, as unique and accessible healthcare venues, are ideal locations to implement interventions aiming to improve patient care. However, these interventions may increase workload or disrupt workflow for community pharmacists, technicians, and other staff members, threatening long-term sustainment. There are growing calls from the field of implementation science to design for intervention sustainment and maintenance by maximizing innovation fit. Senior Safe™, an intervention to facilitate safer over-the-counter (OTC) product selection by older adults, serves as a case study to examine the congruence between Innovation Factors and community pharmacy Inner Context constructs and their implications for workload and sustainment.Methods: Using the Exploration, Preparation, Implementation, Sustainment (EPIS) framework, this qualitative study identified factors surrounding Senior Safe implementation. Semi-structured interviews were conducted with staff from pharmacies where Senior Safe was implemented. Two coders independently analyzed interview transcripts using deductive analysis based on EPIS constructs. Thematic analysis was used to generate three themes that encapsulated innovation fit.Results: Nineteen pharmacy staff members participated, with the majority reporting no significant change in their workload or workflow due to Senior Safe. Interview feedback supported a pre-existing culture of the healthcare system to engage patients, of leadership commitment to patient safety initiatives, and of an amplified role of pharmacy technicians.Discussion and Conclusion: Pharmacy staff interviews revealed congruence between Innovation Factors and Inner Context that likely yielded intervention workload neutrality. This study highlighted the importance for researchers to consider maintenance and sustainability when designing and implementing an intervention and the critical influence of culture and leadership support during this process.

The endoplasmic reticulum (ER) regulates protein folding and maintains proteostasis in cells. We observed that the ER transcriptome is impaired during chronic reductive stress (RS) in cardiomyocytes. Here, we hypothesized that a prolonged moderate treadmill exercise mitigates the RS-induced ER dysfunction and cardiac remodeling in cardiac-specific constitutively active Nrf2 mice (CaNrf2-TG). RNA sequencing showed notable alterations in the ER transcriptome of TG hearts at 4, 12, and 24 weeks (16, 28, and 35 genes, respectively). Notably, the downregulation of ER genes was significant at 12 weeks, and further pronounced at 24 weeks, at which the cardiac pathology is evident. We also observed increased levels of ubiquitinated proteins in CaNrf2-TG hearts across all ages, along with VCP, a marker of ERAD function, at 24 weeks. These findings indicate that constitutive Nrf2 activation and RS impair protein-folding activity and augments ERAD function over time. Exercise intervention for 20 weeks (beginning at 6 weeks of age), reduced cardiomyocyte hypertrophy (from 448 μm2 to 280 μm2) in TG mice, through adaptive remodeling, and preserved the cardiac function. However, while exercise did not influence antioxidants or ER stress protein levels, it significantly improved ERAD function and autophagy flux (LC-I to LC-II) in the TG-EXE hearts. Collectively, our findings underscore the prophylactic potential of exercise in mitigating RS-associated pathology, highlighting its essential role in maintaining cellular proteostasis through ER-independent mechanisms.

Choroidal detachment (CD) is a rare and potentially vision-threatening complication of glaucoma surgery. Inflammation and prolonged ocular hypotony can promote fluid accumulation between the choroid and sclera. Risk factors include trauma, advanced age, use of anticoagulant medications, systemic hypertension, atherosclerosis, and diabetes. CD ultrasound findings will show 2 layers, detaching as far anteriorly as the ciliary bodies, that protrude convexly into the vitreous without extending to the optic disc, often described as the appositional or kissing choroidal sign. In contrast, retinal detachments will show a distinct “V” shape due to the retina's fixation to the optic nerve head posteriorly. In the case of hemorrhagic CD, therapy should be targeted at reducing intraocular pressure.In this case, the patient was started on atropine and prednisolone drops and discontinued on all glaucoma medications in the left eye. While serous choroidal detachments are usually benign, persistent choroidal effusions may cause significant morbidity with hemorrhagic CD having a worse prognosis. Point of care ultrasound can help emergency physicians quickly distinguish between choroidal and retinal detachments and thus guide management in a safe and timely manner.

Abstract Objectives To examine whether long-term air pollution exposure is associated with central hemodynamic and brachial artery stiffness parameters. Methods We assessed central hemodynamic parameters including central blood pressure, cardiac parameters, systemic vascular compliance and resistance, and brachial artery stiffness measures [including brachial artery distensibility (BAD), compliance (BAC), and resistance (BAR)] using waveform analysis of the arterial pressure signals obtained from a standard cuff sphygmomanometer (DynaPulse2000A, San Diego, CA). The long-term exposures to particles with an aerodynamic diameter

Abstract Social networks are a mathematical representation of interactions among individuals which are prevalent across various animal species. Studies of human populations have shown the breadth of what can spread throughout a social network: obesity, smoking cessation, happiness, drug use and divorce. ‘Betweenness centrality’ is a key property of social networks that indicates an individual’s importance in facilitating communication and cohesion within the network. Heritability of betweenness centrality has been suggested in several species, however the genetic regulation of this property remains enigmatic. Here, we demonstrate that the gene CG14109, referred to as degrees of kevin bacon (dokb), influences betweenness centrality in Drosophila melanogaster. We identify strain-specific alleles of dokb with distinct amino acid sequences and when the dokb allele is exchanged between strains, flies exhibit the betweenness centrality pattern dictated by the donor allele. By inserting a GAL4 reporter into the dokb locus, we confirm that dokb is expressed in the central nervous system. These findings define a novel genetic entry point to study social network structure and thereby establish gene-to-social structure relationships. While dokb sequence homology is exclusive to Diptera, we anticipate that dokb-associated molecular pathways could unveil convergent neural mechanisms of social behaviour that apply in diverse animal species.

Abstract Luminescence constitutes a unique source of insight into hot carrier processes in metals, including those in plasmonic nanostructures used for sensing and energy applications. However, being weak in nature, metal luminescence remains poorly understood, its microscopic origin strongly debated, and its potential for unraveling nanoscale carrier dynamics largely unexploited. Here, we reveal quantum-mechanical effects in the luminescence emanating from thin monocrystalline gold flakes. Specifically, we present experimental evidence, supported by first-principles simulations, to demonstrate its photoluminescence origin (i.e., radiative emission from electron/hole recombination) when exciting in the interband regime. Our model allows us to identify changes to the measured gold luminescence due to quantum-mechanical effects as the gold film thickness is reduced. Excitingly, such effects are observable in the luminescence signal from flakes up to 40 nm in thickness, associated with the out-of-plane discreteness of the electronic band structure near the Fermi level. We qualitatively reproduce the observations with first-principles modeling, thus establishing a unified description of luminescence in gold monocrystalline flakes and enabling its widespread application as a probe of carrier dynamics and light-matter interactions in this material. Our study paves the way for future explorations of hot carriers and charge-transfer dynamics in a multitude of material systems.

Abstract Recombinant native-like HIV-1 envelope glycoprotein (Env) trimers are used in candidate vaccines aimed at inducing broadly neutralizing antibodies. While state-of-the-art SOSIP or single-chain Env designs can be expressed as native-like trimers, undesired monomers, dimers and malformed trimers that elicit non-neutralizing antibodies are also formed, implying that these designs could benefit from further modifications for gene-based vaccination approaches. Here, we describe the triple tandem trimer (TTT) design, in which three Env protomers are genetically linked in a single open reading frame and express as native-like trimers. Viral vectored Env TTT induced similar neutralization titers but with a higher proportion of trimer-specific responses. The TTT design was also applied to generate influenza hemagglutinin (HA) trimers without the need for trimerization domains. Additionally, we used TTT to generate well-folded chimeric Env and HA trimers that harbor protomers from three different strains. In summary, the TTT design is a useful platform for the design of HIV-1 Env and influenza HA immunogens for a multitude of vaccination strategies.

Abstract Skeletal development depends on coordinated angiogenesis and osteogenesis. Bone morphogenetic proteins direct bone formation in part by activating SMAD1/5 signaling in osteoblasts. However, the role of SMAD1/5 in skeletal endothelium is unknown. Here, we found that endothelial cell-conditional SMAD1/5 depletion in juvenile mice caused metaphyseal and diaphyseal hypervascularity, resulting in altered trabecular and cortical bone formation. SMAD1/5 depletion induced excessive sprouting and disrupting the morphology of the metaphyseal vessels, with impaired anastomotic loop formation at the chondro-osseous junction. Endothelial SMAD1/5 depletion impaired growth plate resorption and, upon long-term depletion, abrogated osteoprogenitor recruitment to the primary spongiosa. Finally, in the diaphysis, endothelial SMAD1/5 activity was necessary to maintain the sinusoidal phenotype, with SMAD1/5 depletion inducing formation of large vascular loops and elevated vascular permeability. Together, endothelial SMAD1/5 activity sustains skeletal vascular morphogenesis and function and coordinates growth plate remodeling and osteoprogenitor recruitment dynamics in juvenile mouse bone.

Abstract Induction programs have been promoted as a potential solution for alleviating aspects of job dissatisfaction that lead to attrition of beginning science teachers. We can meet the immediate concerns of beginning teachers that impact job satisfaction while simultaneously helping them improve their practices by better understanding the particular challenges they face. This qualitative study examines challenges as expressed within an online induction program for non-tenured Science educators with data from synchronous chat room sessions between mentors and beginning teachers. The results indicate that there is a more diverse and nuanced set of challenges that beginning in-service science teachers face than previously indicated by literature. The content-specific nature of these challenges supports the call for content-specific induction.

Background & Aims: Metabolic-dysfunction associated steatohepatitis (MASH) is associated with obesity and diabetes, and is linked to liver fibrosis and cardiovascular disease. Identification of patients who have MASH is challenging and the development of non-invasive strategies to diagnose and follow this condition is an important unmet need. Recent studies in mouse and humans have identified that significant changes occur in liver macrophage composition during MASH progression; namely, resident Kupffer cells decrease in number while recruited monocyte-derived macrophages increase. Methods: We developed peptide radiotracers targeted to C–C motif chemokine receptor 2 (CCR2) and CD163 to conduct positron emission tomography (PET) imaging of recruited vs. resident macrophages, respectively. Mice were placed on a MASH-inducing diet and non-invasive PET imaging of the liver was performed with tissue confirmation studies using flow cytometry and immunofluorescence. Statistical analyses were conducted using Student’s t tests, Pearson correlational analysis, and linear regression. Results: Using a mouse model of MASH, we found that the liver uptake of both CCR2 and CD163 radiotracers detected an increase in recruited cells and a decrease in resident macrophages. These findings correlated well with tissue macrophage content assessed by flow cytometry with an r value of 0.77 (p = 0.002) and 0.78 (p = 0.001) for CCR2 and CD163, respectively. Serial imaging with these radiotracers at several time points during MASH progression and regression revealed good correlation between liver macrophage composition and PET signal intensity. Conclusion: We demonstrate that novel PET radiotracers targeting CCR2 and CD163 can be used to image macrophage composition in MASH. Non-invasive molecular imaging of inflammation has the potential for diagnosis and monitoring of disease activity in humans with MASH. Impact and implications:: Macrophage-mediated inflammation contributes to MASH progression and fibrosis; however, liver biopsy is currently the only tool to assess this response. Thus, the development of non-invasive imaging modalities to identify and follow inflammatory activation is an area of need for patient care. In this study, we leverage molecular imaging using PET radiotracers to follow changes in macrophage composition that are related to MASH disease activity. The results in our preclinical model provide important proof of concept evidence that this approach can be used to diagnose MASH and to follow disease activity in response to intervention. Ongoing studies will evaluate the utility of this modality in humans with MASH.

Subconcussive, repetitive head impacts sustained in collision sports may negatively affect brain health. American football practices are controlled environments amenable to intervention. Engaging community members is essential for successful development, implementation, and sustainability of viable interventions. The objective of this study is to develop and pilot test an evidence-based intervention to reduce head impact exposure in youth American football (i.e., football), using a community-engaged approach. This manuscript describes the co-design of the intervention and associated implementation plan and the study protocol for evaluating the effectiveness and feasibility of the intervention and implementation plan. In the first part of this study, focus groups with parents and coaches, and individual interviews with organizational leaders associated with two teams at the middle school level were conducted. An anonymous survey assessing beliefs and perceptions of non-concussive head impacts was given to parents, coaches, and organizational leaders within the local youth football league. Following the football season, qualitative and quantitative data describing determinants of head acceleration events in football were shared with 12 stakeholders of coaches, league and school administrators, parents, an athletic trainer, and local university player development director. Together, we co-designed COACH (COmmunities Aligned to reduce Concussion and Head impact exposure) and implementation plan using a strategic planning approach. The preliminary effectiveness and feasibility were assessed in the second part of this study. Youth football players participating on the teams in year 1 (control teams) were fitted with mouthpiece-based head kinematic sensors which measure head acceleration events (HAEs). HAEs were collected and quantified during team activities. Preliminary effectiveness of the intervention to reduce HAEs was measured among two new teams pilot testing COACH with mouthpiece-based sensors, while simultaneously monitoring implementation of the intervention. We report our study design and evaluation, and opportunities and challenges with our approach. The results will inform a future full-scale pragmatic trial to assess the implementation and effectiveness of the intervention program.NCT04908930.

The regulation of inflammatory responses and pulmonary disease during SARS-CoV-2 infection is incompletely understood. Here we examine the roles of the prototypic pro- and anti-inflammatory cytokines IFNγ and IL-10 using the rhesus macaque model of mild COVID-19. We find that IFNγ drives the development of 18fluorodeoxyglucose (FDG)-avid lesions in the lungs as measured by PET/CT imaging but is not required for suppression of viral replication. In contrast, IL-10 limits the duration of acute pulmonary lesions, serum markers of inflammation and the magnitude of virus-specific T cell expansion but does not impair viral clearance. We also show that IL-10 induces the subsequent differentiation of virus-specific effector T cells into CD69+CD103+ tissue resident memory cells (Trm) in the airways and maintains Trm cells in nasal mucosal surfaces, highlighting an unexpected role for IL-10 in promoting airway memory T cells during SARS-CoV-2 infection of macaques.

Chitosan nanofiber membranes manufactured via electrospinning are attractive for drug delivery applications due to their increased surface area. The as-spun fibers contain trifluoroacetate (TFA)-salts that cause swelling and loss of nanofiber structure in physiological solutions and are cytotoxic. Here, a post-electrospinning treatment has been reported using fatty acyl chlorides and pyridine to O-acylate the membranes with different acyl chain-length (C6, C8, C10, and C12). The O-acylation reactions were carried out with acyl chlorides in a basic environment for 2 hr, 3 hr, 4 hr and, 5 hr. The effects of the acyl chain length and the reaction time were assessed using various physio-chemical characterization techniques including FTIR, NMR, Contact Angle, XPS, and SEM. The acylated nanofibers displayed hydrophobic properties and allowed the removal of the cytotoxic TFA salts without compromising the nanofibrous structure. The fiber diameter increased with the increasing length of the substituted acyl chain. The degree of substitution of the acyl chains did not change significantly when reacted for a longer period indicating the completion of the reaction within 2 hr. This could allow the faster modification of the membranes for potential application in the delivery of hydrophobic drugs.

Abstract Background Green space exposures may promote child mental health and well-being across multiple domains and stages of development. The aim of this study was to investigate associations between residential green space exposures and child mental and behavioral health at age 4–6 years. Methods Children’s internalizing and externalizing behaviors in the Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE) cohort in Shelby County, Tennessee, were parent-reported on the Child Behavior Checklist (CBCL). We examined three exposures—residential surrounding greenness calculated as the Normalized Difference Vegetation Index (NDVI), tree cover, and park proximity—averaged across the residential history for the year prior to outcome assessment. Linear regression models were adjusted for individual, household, and neighborhood-level confounders across multiple domains. Effect modification by neighborhood socioeconomic conditions was explored using multiplicative interaction terms. Results Children were on average 4.2 years (range 3.8-6.0) at outcome assessment. Among CANDLE mothers, 65% self-identified as Black, 29% as White, and 6% as another or multiple races; 41% had at least a college degree. Higher residential surrounding greenness was associated with lower internalizing behavior scores (-0.66 per 0.1 unit higher NDVI; 95% CI: -1.26, -0.07) in fully-adjusted models. The association between tree cover and internalizing behavior was in the hypothesized direction but confidence intervals included the null (-0.29 per 10% higher tree cover; 95% CI: -0.62, 0.04). No associations were observed between park proximity and internalizing behavior. We did not find any associations with externalizing behaviors or the attention problems subscale. Estimates were larger in neighborhoods with lower socioeconomic opportunity, but interaction terms were not statistically significant. Conclusions Our findings add to the accumulating evidence of the importance of residential green space for the prevention of internalizing problems among young children. This research suggests the prioritization of urban green spaces as a resource for child mental health.

Several countries have encouraged the installation of photovoltaic (PV) systems in urban areas to contribute to the decarbonization goals of the electric power system. At the same time, consumers have adopted PV systems to reduce their electricity bills. While grid-following PV inverters offset active power demand, they can decrease the power factor at the point of interconnection with the grid, subsequently leading to financial penalties imposed by distribution utilities. Additionally, utilities must maintain power factor values above a predefined threshold to maintain acceptable levels of power losses at the transmission level. This paper examines low power factor penalty schemes for distribution utilities and consumers with PV systems. In such an analysis, an optimization approach is used to minimize the costs of penalties associated with low power factor during a consumer’s billing period. This approach makes it possible to reduce the number of low power factor penalties, thus reducing the amount of electricity bills to be paid by consumers. The decision variable in this context is the power factor of the PV inverters. A case study is presented that considers the financial penalties in a city in the metropolitan area of Sao Paulo, Brazil, with various levels of PV penetration in the distribution system. The results show that while the penalties for consumers are low, distribution utilities would incur more significant penalties or require additional investments to maintain the power factor at the values imposed by electric transmission companies. This analysis aims to help regulatory agencies evaluate penalty schemes to reduce electrical losses in the distribution system.

Urban planning must coordinate expanding public electric vehicle charging infrastructure (EV-CI) with energy distribution companies to satisfy growing demand. To this end, measurements and charger load curves are indispensable to execute appropriate operational studies and expansion planning. However, the necessary databases are small in cities with low EV penetration, and may not adequately characterize future consumption patterns. This article proposes an “Extensive Method for Demand Estimation in Charging Infrastructures” (X-Modeci) to fill this gap, which is especially beneficial for large metropolitan areas. The method employs statistical regressions to model the different phases of EV adoption, using traffic simulations to incorporate new travel dynamics that may arise due to increased charging and new EV battery range values. The proposal result is a spatial database that shows EV-CI load curves for typical urban traffic days in locations that would be more appropriate for installing new chargers. This results class can help energy companies identify the best connection locations and necessary reinforcements in the distribution grid to meet electromobility demand. The method was applied in the most significant capital in the Northeast of Brazil, showing that the estimated load curves tend to reach their maximum point between the end of the afternoon and the beginning of the night, following the high rate of vehicle circulation during this period. The case study clarified that the characterization of EV-CI use provided a 10% gain in the EV-CI usage rate about the national average, respecting regulated levels. In this way, the results of the proposed method can help the agents involved better understand the energy demand within the scope of electromobility plans with high spatial resolution at the location of the main avenues in urban areas.

Abstract Background The uptake of Intermittent Preventive Treatment of malaria in pregnancy using Sulfadoxine-Pyrimethamine (IPTp-SP) remains unacceptably low, with more than two-thirds of pregnant women in sub-Saharan Africa still not accessing the three or more doses recommended by the World Health Organisation (WHO). In contrast, the coverage of Seasonal Malaria Chemoprevention (SMC), a more recent strategy recommended by the WHO for malaria prevention in children under five years living in Sahelian countries with seasonal transmission, including Mali and Burkina-Faso, is high (up to 90%). We hypothesized that IPTp-SP delivery to pregnant women through SMC alongside antenatal care (ANC) will increase IPTp-SP coverage, boost ANC attendance, and increase public health impact. This protocol describes the approach to assess acceptability, feasibility, effectiveness, and cost-effectiveness of the integrated strategy. Methods and analysis This is a multicentre, cluster-randomized, implementation trial of IPTp-SP delivery through ANC + SMC vs ANC alone in 40 health facilities and their catchment populations (20 clusters per arm). The intervention will consist of monthly administration of IPTp-SP through four monthly rounds of SMC during the malaria transmission season (July to October), for two consecutive years. Effectiveness of the strategy to increase coverage of three or more doses of IPTp-SP (IPTp3 +) will be assessed using household surveys and ANC exit interviews. Statistical analysis of IPT3 + and four or more ANC uptake will use a generalized linear mixed model. Feasibility and acceptability will be assessed through in-depth interviews and focus group discussions with health workers, pregnant women, and women with a child

The present paper proposes a new methodology to solve a problem in the literature in which a consumer becomes eligible for reactive power excess charging (RPEC) after installing a photovoltaic (PV) system, even if its reactive demand has not changed. This problem mainly affects this kind of consumer, which is known as PV prosumers, in countries where the power factor at the point of common coupling (PCC) is used as the main parameter in calculating reactive power excess charges instead of directly pricing the surplus reactive energy delivered from the distribution network. The classical approaches to reducing or eliminating RPEC are based on providing reactive power within the consumer’s installations from their PV inverters and their capacitor banks. However, the solutions presented require optimization studies since the costs of producing reactive energy can be even higher than the penalties involved. In this context, we developed a new hourly-based optimization model for the RPEC problem based on the variable neighborhood search meta-heuristic and the Fibonacci search method. In addition, we apply the proposed methodology to two medium voltage prosumers in Santo André, Brazil. The results showed the proposal’s effectiveness, mitigating RPEC and minimizing the prosumers’ electricity bills without installing new equipment to supply their reactive demand. The best results were found when reactive power was delivered by the capacitor bank and PV inverters simultaneously rather than applying these solutions separately. The proposed hourly-based correction method can help in day-ahead energy management, avoiding premature wear from switching the consumer’s reactive power compensation equipment switches. Also, the methodology proposal improved the power factor at the utility substation, which benefits the power distribution systems.

Abstract Camera traps deployed with olfactory attractants are used to survey rare and elusive carnivores. Study areas with deep snowpack and rugged terrain present challenges and risks to field personnel, who traditionally must revisit camera stations regularly to refresh attractants. In such locations, alternative overwinter survey protocols that include a persistent attractant would improve both the safety and efficiency of camera‐trap surveys. We present a protocol for installing camera traps and automated scent dispensers on trees at above‐average maximum snow depth to eliminate the need for interim service visits and to enable standardized surveys to be conducted throughout the year. Our protocol proved to be effective at attracting and detecting numerous and repeated visits by wolverines, fishers, and other carnivores in two montane regions of the western contiguous United States. The volume, timing, and composition of liquid scent lure released by automated scent dispensers can be varied to target multiple species of interest, and the dispenser can be used in situations where bait rewards may influence the behavior of target species and/or pose human safety concerns.

Mycobacterium tuberculosis (Mtb) infects lung myeloid cells, but the specific Mtb-permissive cells and host mechanisms supporting Mtb persistence during chronic infection are incompletely characterized. We report that after the development of T cell responses, CD11clo monocyte-derived cells harbor more live Mtb than alveolar macrophages (AM), neutrophils, and CD11chi monocyte-derived cells. Transcriptomic and functional studies revealed that the lysosome pathway is underexpressed in this highly permissive subset, characterized by less lysosome content, acidification, and proteolytic activity than AM, along with less nuclear TFEB, a regulator of lysosome biogenesis. Mtb infection does not drive lysosome deficiency in CD11clo monocyte-derived cells but promotes recruitment of monocytes that develop into permissive lung cells, mediated by the Mtb ESX-1 secretion system. The c-Abl tyrosine kinase inhibitor nilotinib activates TFEB and enhances lysosome functions of macrophages in vitro and in vivo, improving control of Mtb infection. Our results suggest that Mtb exploits lysosome-poor lung cells for persistence and targeting lysosome biogenesis is a potential host-directed therapy for tuberculosis.

Background: Fine particulate matter (PM2.5) exposure has been associated with liver cancer incidence and mortality in a limited number of studies. We sought to evaluate this relationship for the first time in a U.S. cohort with historical exposure assessment. Methods: We used spatiotemporal prediction models to estimate annual average historical PM2.5 concentrations (1980–2015) at residential addresses of 499,729 participants in the NIH-AARP Diet and Health Study, a cohort in 6 states (California, Florida, Louisiana, New Jersey, North Carolina, and Pennsylvania) and 2 metropolitan areas (Atlanta, Georgia, and Detroit, Michigan) enrolled in 1995–1996 and followed up through 2017. We used a time-varying Cox model to estimate the association for liver cancer and the predominant histologic type, hepatocellular carcinoma (HCC), per 5 µg/m3 increase in estimated outdoor PM2.5 levels, incorporating a 5-year average, lagged 10 years prior to cancer diagnosis and adjusting for age, sex, race/ethnicity, education level and catchment state. We also evaluated PM2.5 interactions with hypothesized effect modifiers. Results: We observed a non-significantly increased risk of liver cancer associated with estimated PM2.5 exposure (Hazard ratio [HR] = 1.05 [0.96–1.14], N = 1,625); associations were slightly stronger for HCC, (84 % of cases; HR = 1.08 [0.98–1.18]). Participants aged 70 or older at enrollment had an increased risk of liver cancer versus other age groups (HR = 1.50 [1.01–2.23]); p-interaction = 0.01) and risk was elevated among participants who did not exercise (HR = 1.81 [1.22–2.70]; p-interaction = 0.01). We found no evidence of effect modification by sex, smoking status, body mass index, diabetes status, or alcohol consumption (p-interaction > 0.05). Conclusions: Our findings in this large cohort suggest that residential ambient PM2.5 levels may be associated with liver cancer risk. Further exploration of the variation in associations by age and physical activity are important areas for future research.

BackgroundInterleukin-17–producing CD4 T cells contribute to the control of Mycobacterium tuberculosis (Mtb) infection in humans; whether infection with human immunodeficiency virus (HIV) disproportionately affects distinct Th17-cell subsets that respond to Mtb is incompletely defined.MethodsWe performed high-definition characterization of circulating Mtb-specific Th17 cells by spectral flow cytometry in people with latent TB and treated HIV (HIV-ART). We also measured kynurenine pathway activity by liquid chromatography-mass spectrometry (LC/MS) on plasma and tested the hypothesis that tryptophan catabolism influences Th17-cell frequencies in this context.ResultsWe identified two subsets of Th17 cells: subset 1 defined as CD4+Vα7.2−CD161+CD26+and subset 2 defined as CD4+Vα7.2−CCR6+CXCR3−cells of which subset 1 was significantly reduced in latent tuberculosis infection (LTBI) with HIV-ART, yet Mtb-responsive IL-17–producing CD4 T cells were preserved; we found that IL-17–producing CD4 T cells dominate the response to Mtb antigen but not cytomegalovirus (CMV) antigen or staphylococcal enterotoxin B (SEB), and tryptophan catabolism negatively correlates with both subset 1 and subset 2 Th17-cell frequencies.ConclusionsWe found differential effects of ART-suppressed HIV on distinct subsets of Th17 cells, that IL-17–producing CD4 T cells dominate responses to Mtb but not CMV antigen or SEB, and that kynurenine pathway activity is associated with decreases of circulating Th17 cells that may contribute to tuberculosis immunity.

Mesenchymal stromal cells (MSCs) are widely used in cell-based therapies and tissue regeneration for their potent secretome, which promotes host cell recruitment and modulates inflammation. Compared to monodisperse cells, MSC spheroids exhibit improved viability and increased secretion of immunomodulatory cytokines. While mechanical stimulation of monodisperse cells can increase cytokine production, the influence of mechanical loading on MSC spheroids is unknown. Here, we evaluated the effect of controlled, uniaxial cyclic compression on the secretion of immunomodulatory cytokines by human MSC spheroids and tested the influence of load-induced gene expression on MSC mechanoresponsiveness. We exposed MSC spheroids, entrapped in alginate hydrogels, to three cyclic compressive regimes with varying stress (L) magnitudes (i.e., 5 and 10 kPa) and hold (H) durations (i.e., 30 and 250 s) L5H30, L10H30, and L10H250. We observed changes in cytokine and chemokine expression dependent on the loading regime, where higher stress regimes tended to result in more exaggerated changes. However, only MSC spheroids exposed to L10H30 induced human THP-1 macrophage polarization toward an M2 phenotype compared to static conditions. Static and L10H30 loading facilitated a strong, interlinked F-actin arrangement, while L5H30 and L10H250 disrupted the structure of actin filaments. This was further examined when the actin cytoskeleton was disrupted via Y-27632. We observed downregulation of YAP-related genes, and the levels of secreted inflammatory cytokines were globally decreased. These findings emphasize the essential role of mechanosignaling in mediating the immunomodulatory potential of MSC spheroids.

Abstract Background Attention-deficit hyperactivity disorder (ADHD) affects around 1 in 20 children and is associated with life-long sequelae. Previous studies of the association between Apgar score and ADHD have reported inconsistent findings. Methods Record linkage of maternity, prescribing and school pupil census databases was used to conduct a population e-cohort study of singleton children born in Scotland and attending school in Scotland at any point between 2009 and 2013. Binary logistic regression analysis was used to investigate the association between 5-min Apgar score and treated ADHD adjusting for sociodemographic and maternity confounders. Results Of the 758,423 children, 7,292 (0.96%) received ADHD medication. The results suggested a potential dose–response relationship between Apgar score and treated ADHD independent of confounders. Referent to an Apgar score of 10, risk of treated ADHD was higher for scores of 0–3 (adjusted OR 1.76, 95% CI 1.32–2.34), 4–6 (adjusted OR 1.50, 95% CI 1.21–1.86) and even 7–9 (adjusted OR 1.26, 95% CI 1.18–1.36) which are traditionally considered within the normal range. Conclusions In addition to reinforcing the need to maximise Apgar score through good obstetric practice, the findings suggest that Apgar score may be useful in predicting future risk of ADHD and therefore facilitating early diagnosis and treatment.

Titanium has a long history of clinical use, but the naturally forming oxide is not ideal for bacterial resistance. Anodization processes can modify the crystallinity, surface topography, and surface chemistry of titanium oxides. Anatase, rutile, and mixed phase oxides are known to exhibit photocatalytic activity (PCA)-driven bacterial resistance under UVA irradiation. Silver additions are reported to enhance PCA and reduce bacterial attachment. This study investigated the effects of silver-doping additions to three established anodization processes. Silver doping showed no significant influence on oxide crystallinity, surface topography, or surface wettability. Oxides from a sulfuric acid anodization process exhibited significantly enhanced PCA after silver doping, but silver-doped oxides produced from phosphoric-acid-containing electrolytes did not. Staphylococcus aureus attachment was also assessed under dark and UVA-irradiated conditions on each oxide. Each oxide exhibited a photocatalytic antimicrobial effect as indicated by significantly decreased bacterial attachment under UVA irradiation compared to dark conditions. However, only the phosphorus-doped mixed anatase and rutile phase oxide exhibited an additional significant reduction in bacteria attachment under UVA irradiation as a result of silver doping. The antimicrobial success of this oxide was attributed to the combination of the mixed phase oxide and higher silver-doping uptake levels.

Abstract Background Epigenome-wide association studies of ambient fine particulate matter (PM2.5) have been reported. However, few have examined PM2.5 components (PMCs) and sources or included repeated measures. The lack of high-resolution exposure measurements is the key limitation. We hypothesized that significant changes in DNA methylation might vary by PMCs and the sources. Methods We predicted the annual average of 14 PMCs using novel high-resolution exposure models across the contiguous U.S., between 2000–2018. The resolution was 50 m × 50 m in the Greater Boston Area. We also identified PM2.5 sources using positive matrix factorization. We repeatedly collected blood samples and measured leukocyte DNAm with the Illumina HumanMethylation450K BeadChip in the Normative Aging Study. We then used median regression with subject-specific intercepts to estimate the associations between long-term (one-year) exposure to PMCs / PM2.5 sources and DNA methylation at individual cytosine-phosphate-guanine CpG sites. Significant probes were identified by the number of independent degrees of freedom approach, using the number of principal components explaining > 95% of the variation of the DNA methylation data. We also performed regional and pathway analyses to identify significant regions and pathways. Results We included 669 men with 1,178 visits between 2000–2013. The subjects had a mean age of 75 years. The identified probes, regions, and pathways varied by PMCs and their sources. For example, iron was associated with 6 probes and 6 regions, whereas nitrate was associated with 15 probes and 3 regions. The identified pathways from biomass burning, coal burning, and heavy fuel oil combustion sources were associated with cancer, inflammation, and cardiovascular diseases, whereas there were no pathways associated with all traffic. Conclusions Our findings showed that the effects of PM2.5 on DNAm varied by its PMCs and sources.

Introducción: La cetoacidosis diabética (CAD) es la emergencia hiperglucémica aguda más común en pacientes diabéticos y junto con el estado hiperosmolar hiperglucémico son las complicaciones agudas más graves en pacientes diabéticos. Esto está condicionado por diversos factores de riesgo. Objetivo: Este estudio identificó los factores de riesgo principales asociados al desarrollo de CAD en pacientes con diabetes mellitus (DM) y se llevó a cabo en el área de urgencias del Hospital General de Chihuahua Dr. Salvador Zubirán Anchondo. Método: Estudio observacional, exploratorio y prospectivo que incluyó un total de 50 pacientes diabéticos tipo 1 o 2 que ingresaron con diagnóstico de CAD durante el periodo de julio a diciembre de 2020. Se aplicaron los cuestionarios DSMQ y MARS-5 para valorar automanejo y adherencia al tratamiento. Resultados: En cuanto a la etiología se observó que el mal apego al tratamiento es el principal factor de riesgo desencadenante para el desarrollo de la CAD en el 94% de los casos, seguido de infecciones, con un 64% (IVU 22%, SARS-CoV-2 18%, neumonía 14% y otras infecciones 10%), transgresión dietética (44%), ingesta aguda de alcohol (22%), DM de inicio (16%) y otras causas (5%). Conclusiones: No existe un apego al tratamiento en la población estudiada y este es el factor de riesgo principal para desencadenar una CAD.

IntroductionInsecticide-treated nets (ITNs), specifically long-lasting insecticidal nets (LLINs), are the most commonly used, scalable, and cost-effective tools for controlling malaria transmission in sub-Saharan Africa. However, the multiple alternative uses of retired LLINs have been associated with poor disposal practices. The World Health Organization (WHO) has provided guidelines and recommendations for the proper management of worn-out LLINs. This study assessed the existing alternative uses and disposal practices of old LLINs.MethodsAn explanatory sequential mixed-methods approach was used to assess LLINs existing alternative uses, disposal practices, knowledge, and perceptions regarding WHO recommendations on proper disposal of old LLINs among stakeholders in Kilombero and Ulanga districts, south-eastern Tanzania. A survey questionnaire was administered to 384 participants. Furthermore, the study employed focus group discussions (FGD) and key informant interviews (KII) to elucidate responses regarding existing disposal practices, associated challenges, and alternative uses of LLINs. The insights derived from both study components were subsequently used for inferential analysis.ResultsThe major challenge influencing the proper disposal of LLINs was limited awareness of how to properly dispose of them. Of the 384 people surveyed, 97.0% were not aware of the WHO recommendations for the proper disposal of old LLINs. All key informants were unaware of the WHO guidelines for proper disposal of old LLINs. The common methods used to dispose of LLINs were burning (30.7%), disposing them into garbage pits (14.8%), and alternative uses (12.2%). Of the 239 respondents with LLINs, 41.0% had alternative use, while 59.0% had no alternative use. The common alternative uses were ropes for tying or covering items (20.9%), garden fencing (7.5%), chicken coops (5.0%), and 7.5% for other minor alternative uses.ConclusionStrengthening awareness and education on proper LLIN disposal practices among community members and key stakeholders is essential for enhancing malaria control efforts and preventing environmental pollution.

Background: While epidemiologic evidence links higher levels of exposure to fine particulate matter (PM2.5) to decreased cognitive function, fewer studies have investigated links with traffic-related air pollution (TRAP), and none have examined ultrafine particles (UFP, ≤100 nm) and late-life dementia incidence. Objective: To evaluate associations between TRAP exposures (UFP, black carbon [BC], and nitrogen dioxide [NO2]) and late-life dementia incidence. Methods: We ascertained dementia incidence in the Seattle-based Adult Changes in Thought (ACT) prospective cohort study (beginning in 1994) and assessed ten-year average TRAP exposures for each participant based on prediction models derived from an extensive mobile monitoring campaign. We applied Cox proportional hazards models to investigate TRAP exposure and dementia incidence using age as the time axis and further adjusting for sex, self-reported race, calendar year, education, socioeconomic status, PM2.5, and APOE genotype. We ran sensitivity analyses where we did not adjust for PM2.5 and other sensitivity and secondary analyses where we adjusted for multiple pollutants, applied alternative exposure models (including total and size-specific UFP), modified the adjustment covariates, used calendar year as the time axis, assessed different exposure periods, dementia subtypes, and others. Results: We identified 1,041 incident all-cause dementia cases in 4,283 participants over 37,102 person-years of follow-up. We did not find evidence of a greater hazard of late-life dementia incidence with elevated levels of long-term TRAP exposures. The estimated hazard ratio of all-cause dementia was 0.98 (95 % CI: 0.92–1.05) for every 2000 pt/cm3 increment in UFP, 0.95 (0.89–1.01) for every 100 ng/m3 increment in BC, and 0.96 (0.91–1.02) for every 2 ppb increment in NO2. These findings were consistent across sensitivity and secondary analyses. Discussion: We did not find evidence of a greater hazard of late-life dementia risk with elevated long-term TRAP exposures in this population-based prospective cohort study.

Fragile X syndrome (FXS) is a neurodevelopmental disorder that is often modeled in Fmr1 knockout mice where the RNA-binding protein FMRP is absent. Here, we show that in Fmr1-deficient mice, RNA mis-splicing occurs in several brain regions and peripheral tissues. To assess molecular mechanisms of splicing mis-regulation, we employed N2A cells depleted of Fmr1. In the absence of FMRP, RNA-specific exon skipping events are linked to the splicing factors hnRNPF, PTBP1, and MBNL1. FMRP regulates the translation of Mbnl1 mRNA as well as Mbnl1 RNA auto-splicing. Elevated Mbnl1 auto-splicing in FMRP-deficient cells results in the loss of a nuclear localization signal (NLS)-containing exon. This in turn alters the nucleus-to-cytoplasm ratio of MBNL1. This redistribution of MBNL1 isoforms in Fmr1-deficient cells could result in downstream splicing changes in other RNAs. Indeed, further investigation revealed that splicing disruptions resulting from Fmr1 depletion could be rescued by overexpression of nuclear MBNL1. Altered Mbnl1 auto-splicing also occurs in human FXS postmortem brain. These data suggest that FMRP-controlled translation and RNA processing may cascade into a general dys-regulation of splicing in Fmr1-deficient cells.

Insufficient bone fracture repair represents a major clinical and societal burden and novel strategies are needed to address it. Our data reveal that the transforming growth factor-β superfamily member Activin A became very abundant during mouse and human bone fracture healing but was minimally detectable in intact bones. Single-cell RNA-sequencing revealed that the Activin A-encoding gene Inhba was highly expressed in a unique, highly proliferative progenitor cell (PPC) population with a myofibroblast character that quickly emerged after fracture and represented the center of a developmental trajectory bifurcation producing cartilage and bone cells within callus. Systemic administration of neutralizing Activin A antibody inhibited bone healing. In contrast, a single recombinant Activin A implantation at fracture site in young and aged mice boosted: PPC numbers; phosphorylated SMAD2 signaling levels; and bone repair and mechanical properties in endochondral and intramembranous healing models. Activin A directly stimulated myofibroblastic differentiation, chondrogenesis and osteogenesis in periosteal mesenchymal progenitor culture. Our data identify a distinct population of Activin A-expressing PPCs central to fracture healing and establish Activin A as a potential new therapeutic tool.

Abstract Background There are a variety of costs associated with publication of scientific findings. The purpose of this work was to estimate the cost of peer review in scientific publishing per reviewer, per year and for the entire scientific community. Methods Internet-based self-report, cross-sectional survey, live between June 28, 2021 and August 2, 2021 was used. Participants were recruited via snowball sampling. No restrictions were placed on geographic location or field of study. Respondents who were asked to act as a peer-reviewer for at least one manuscript submitted to a scientific journal in 2020 were eligible. The primary outcome measure was the cost of peer review per person, per year (calculated as wage-cost x number of initial reviews and number of re-reviews per year). The secondary outcome was the cost of peer review globally (calculated as the number of peer-reviewed papers in Scopus x median wage-cost of initial review and re-review). Results A total of 354 participants completed at least one question of the survey, and information necessary to calculate the cost of peer-review was available for 308 participants from 33 countries (44% from Canada). The cost of peer review was estimated at $US1,272 per person, per year ($US1,015 for initial review and $US256 for re-review), or US$1.1–1.7 billion for the scientific community per year. The global cost of peer-review was estimated at US$6 billion in 2020 when relying on the Dimensions database and taking into account reviewed-but-rejected manuscripts. Conclusions Peer review represents an important financial piece of scientific publishing. Our results may not represent all countries or fields of study, but are consistent with previous estimates and provide additional context from peer reviewers themselves. Researchers and scientists have long provided peer review as a contribution to the scientific community. Recognizing the importance of peer-review, institutions should acknowledge these costs in job descriptions, performance measurement, promotion packages, and funding applications. Journals should develop methods to compensate reviewers for their time and improve transparency while maintaining the integrity of the peer-review process.

Abstract Uncleaved prefusion-optimized (UFO) design can stabilize diverse HIV-1 envelope glycoproteins (Envs). Single-component, self-assembling protein nanoparticles (1c-SApNP) can display 8 or 20 native-like Env trimers as vaccine candidates. We characterize the biophysical, structural, and antigenic properties of 1c-SApNPs that present the BG505 UFO trimer with wildtype and modified glycans. For 1c-SApNPs, glycan trimming improves recognition of the CD4 binding site without affecting broadly neutralizing antibodies (bNAbs) to major glycan epitopes. In mice, rabbits, and nonhuman primates, glycan trimming increases the frequency of vaccine responders (FVR) and steers antibody responses away from immunodominant glycan holes and glycan patches. The mechanism of vaccine-induced immunity is examined in mice. Compared with the UFO trimer, the multilayered E2p and I3-01v9 1c-SApNPs show 420 times longer retention in lymph node follicles, 20-32 times greater presentation on follicular dendritic cell dendrites, and up-to-4 times stronger germinal center reactions. These findings can inform future HIV-1 vaccine development.

Singlet fission is recognized as an enabling process for next-generation solar cells. Here the authors design a molecular system where specific spin sub-levels can be initialized to produce a highly entangled state and demonstrate that the coherence between magnetic sub-levels of that state is preserved at higher temperatures than those encountered in conventional superconducting quantum hardware.

Diagnosis of rare, unpredictable, drug-induced liver injury (DILI) is a significant challenge for patients, clinicians, and drug development. Here, the authors discover, evaluate, and validate potential blood biomarkers to diagnose DILI and distinguish it from alternative causes of liver injury.

Desirable characteristics of electrospun chitosan membranes (ESCM) for guided bone regeneration are their nanofiber structure that mimics the extracellular fiber matrix and porosity for the exchange of signals between bone and soft tissue compartments. However, ESCM are susceptible to swelling and loss of nanofiber and porous structure in physiological environments. A novel post-electrospinning method using di-tert-butyl dicarbonate (tBOC) prevents swelling and loss of nanofibrous structure better than sodium carbonate treatments. This study aimed to evaluate the hypothesis that retention of nanofiber morphology and high porosity of tBOC-modified ESCM (tBOC-ESCM) would support more bone mineralization in osteoblast-fibroblast co-cultures compared to Na2CO3 treated membranes (Na2CO3-ESCM) and solution-cast chitosan solid films (CM-film). The results showed that only the tBOC-ESCM retained the nanofibrous structure and had approximately 14 times more pore volume than Na2CO3-ESCM and thousands of times more pore volume than CM-films, respectively. In co-cultures, the tBOC-ESCM resulted in a significantly greater calcium-phosphate deposition by osteoblasts than either the Na2CO3-ESCM or CM-film (p < 0.05). This work supports the study hypothesis that tBOC-ESCM with nanofiber structure and high porosity promotes the exchange of signals between osteoblasts and fibroblasts, leading to improved mineralization in vitro and thus potentially improved bone healing and regeneration in guided bone regeneration applications