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Targeting VGLL4 maintains extracellular matrix homeostasis and mitigates osteoarthritis in a preclinical model
A matter of size: Comparing IV and OLS estimates
Sizeable differences between OLS (Ordinary Least Squares) and IV (Instrumental Variables) estimates might be interpreted in the literature as evidence that the instrument is not valid. Yet, to the best of our knowledge, this comparison is carried out using only the OLS coefficient as a benchmark and does not account for statistical measures or information from the OLS regression. This paper establishes a framework where [1]’s methodology might be used to compare objectively OLS and IV estimates. This methodology offers evidence to support or discard IV estimates with respect to the OLS regression.
Genome-wide association study of childhood B-cell acute lymphoblastic leukemia reveals novel African ancestry-specific susceptibility loci
Abstract B-cell acute lymphoblastic leukemia (B-ALL) is the most common pediatric malignancy. Given racial/ethnic differences in incidence and outcomes, B-ALL genome-wide association studies among children of African ancestry are needed. Leveraging multi-institutional datasets with 840 African American children with B-ALL and 3360 controls, nine loci achieved genome-wide significance ( P < 5 × 10 −8 ) after meta-analysis. Two loci were established trans-ancestral susceptibility regions ( IKZF1 , ARID5B ), while the remaining novel loci were specific to African populations. Five-year overall survival among children carrying novel risk alleles was significantly worse (83% versus 96% in non-carriers, P = 4.8 × 10 −3 ). Novel risk variants were also associated with subtype-specific disease ( P < 0.05), including higher susceptibility for a subtype overrepresented in African American children ( TCF3-PBX1 ) and lower susceptibility for a subtype with excellent prognosis ( ETV6-RUNX1 ). Functional experiments revealed novel B-ALL risk variants had allele-specific differences in transcriptional activity ( P < 0.05) in B-cell and leukemia cell lines. These findings shed insights into ancestry-related differences in leukemogenesis and prognosis.
Design, simulation, and experimental study of hydrostatic drive system for wide-span farming platform
A versatile, robotic, and multi-functional wide-span farming platform, commonly known as a gantry tractor, can reduce soil compaction and enhance field production efficiency. In order to meet the functional requirements of wide-span farming platforms to achieve various steering modes in both transverse and longitudinal driving modes, while also improving the flexibility and stability of the platform’s movement, a hydrostatic drive system was designed in this study based on an X-type dual-pump and four-motor system. The platform drive system adopts two variable pumps to drive four hydraulic motors, and the two pump–motor systems are distributed diagonally along the chassis. Each pump–motor system uses a flow diverter to prevent track slippage when the platform is driving. Mechanical analysis of the tracked platform while driving was first carried out. Based on the analysis results, the parameters of the main hydraulic components of the hydraulic drive system were calculated and selected. Then, the hydraulic drive system was modeled and simulated using the AMESim software. Finally, experiments were conducted under different driving conditions, including road tests in longitudinal mode and farmland tests in transverse mode. The experimental results showed that the hydraulic drive system exhibited a stable and synchronized performance. The average deviation rate of platform in longitudinal mode on cement roads was 5.0%. The deviation of the platform in transverse mode on dry and wet soil at the maximum driving speed were 6% and 2.1%, respectively. The test results demonstrated that the designed wide-span platform exhibited good driving stability, which validated the rationality of the design. These findings provide a reference for the improvement and optimization of wide-span farming platforms.
Targeted volume imaging reveals early vascular interactions of Lyme disease pathogen in skin
Abstract Although the contours of the dissemination pathways of human pathogenic spirochetes in the vertebrate hosts are known, detailed high-resolution information on these processes remain lacking. In this study, we establish an efficient serial block-face scanning electron microscopy workflow incorporating semi-automatic AI-driven segmentation to investigate the architecture of early events following the deposition of Borrelia burgdorferi at the tick bite site in mice. We capture evidence of Borrelia penetrating the lymphatic endothelium via both transcellular and paracellular routes and observe its early presence within the lumen of the lymphatic vessel. The multistep process of transcellular migration is documented in detail, showing sequential invagination and encasement of shorter Borrelia segments by the lymphatic endothelial cells during intravasation. Our findings reveal that the first contact of B. burgdorferi and blood vessels is not random but involves close interactions with pericytes. We also capture the infiltration of immune cells in the skin and their interactions with invading bacteria. Altogether, these observations suggest that Borrelia strategically targets vascular regions with lower mechanical resistance to breach the endothelial barrier, thereby enhancing its dissemination.
Designing a deposit-refund system for cigarette butts: What do smokers care about?
Cigarette butts (CBs) are the world’s most littered item and significantly contribute to environmental pollution. A deposit-refund system (DRS) has been proposed to reduce CB littering, but its effective design remains underexplored. This study addressed this gap by investigating smokers’ perceptions and preferences in hypothetical DRS scenarios for CBs. We conducted a discrete choice experiment in Japan (n = 1,865) and Indonesia (n = 2,000). Respondents were divided into treatment and control groups, with the treatment group receiving information on CB environmental impact aligned with the WHO’s campaign. Our results revealed that a DRS for CBs was preferred to the status quo, with higher preferences in Indonesia (90.33%) than in Japan (63.92%). The information treatment further increased DRS preferences (Indonesia: 91.82%; Japan: 69.83%) and willingness to endure cost to support DRS operations. Cost simulations showed participation probabilities remained above 55% with a cost of up to 5% of a cigarette’s price in Japan, and above 80% with a cost of up to 10% in Indonesia. Our findings underscore the importance of environmental information in DRS adoption. Both countries preferred a producer-managed system to a government-managed one, highlighting an opportunity for tobacco producers to fulfill extended producer responsibility through a DRS. Furthermore, DRS design should be country-specific. Notably, Japanese respondents’ familiarity with heat-not-burn cigarettes influenced their preference for a tailored DRS to those products, whereas Indonesian respondents preferred a DRS for CBs. Japanese respondents also emphasized accessibility more than their Indonesian counterparts.
Neurocomputational basis of learning when choices simultaneously affect both oneself and others
Sex difference in the burden of rheumatic heart disease: Insights from the Global Burden of Disease Study 2021
Introduction Rheumatic heart disease (RHD) shows significant sex differences in disease burden. This study assesses these differences using data from the Global Burden of Disease Study 2021 (GBD 2021). Methods We extracted sex-specific indicators for RHD from the GBD database, including disability-adjusted life years (DALYs), mortality, and prevalence. Trends were analyzed using estimated annual percentage change (EAPC), and sex differences were assessed via female-by-male ratios. Results From 1990 to 2021, females consistently had higher age-standardized DALYs (ASDR), mortality (ASMR), and prevalence rates (ASPR) than males. These differences were particularly pronounced in specific regions and age groups. In 2021, female ASDR and ASMR in Andorra were over three times higher than males, while in the Cook Islands, they were less than half of males’ rates. In the United States Virgin Islands, females aged 10–19 had an ASMR only 0.01 times that of males, whereas in the United Arab Emirates, females aged 70–89 had ASDR and ASMR five times higher than males. Overall, the female-by-male ratios in ASDR, ASMR, and ASPR have shown a yearly decline. However, these ratios are positively correlated with the Sociodemographic Index (SDI), with correlation coefficients of 0.1 for ASDR, 0.22 for ASMR, and 0.47 for ASPR. Conclusion Our study reveals a persistent global sex disparity in RHD burden from 1990 to 2021, with females generally experiencing a heavier burden. These findings underscore the need for sex-specific approaches in RHD prevention and treatment and further research into the underlying factors driving these disparities.
Accessing acute care hospitals in the San Francisco Bay Area after a major hayward earthquake
Abstract Earthquakes can severely disrupt healthcare access, especially in dense cities. Here, we provide a comprehensive assessment of how a magnitude 7.25 earthquake on the Hayward Fault would impact access to acute care hospitals in the San Francisco Bay Area. By integrating seismic hazard with hospital and transportation infrastructure’s vulnerability and connectivity data, we analyze 76 hospitals (426 buildings with 16,639 beds) and 5163 bridges within a vast network of ~1.5 million edges and ~0.5 million nodes. We leverage the rich data to formulate a coupled risk-network model to quantify simultaneous failures and cascading disruptions across the healthcare and transportation systems. Our results revealed that hospital bed capacity could drop to 51%, with Alameda County retaining only 20%. Widespread transportation failures further restrict access, increasing regional travel times by 177% and exceeding 1000% in parts of East Bay, potentially fully isolating a hospital and an entire urban community. These findings underscore the urgent need for resilient healthcare and transportation infrastructure to mitigate life-threatening disruptions following major earthquakes.
Social patterns underlying a new group formation in olive baboons
In group-living animals, social and ecological challenges can push groups to fission into two or more ‘daughter’ groups. Here, we describe the demographic and social behavioral changes that were associated with the formation of a new group of olive baboons ( Papio anubis ) in Laikipia, Kenya. The process began when a high-ranking natal male transferred into a nearby study group, which coincided with the dispersal of several adult females. The dispersing females had close social ties with this male, and he had sired most of their current offspring. After a stint in the neighboring group, these animals eventually budded off to form a new, separate group. Throughout the fission process, female-female grooming was strongly predicted by eventual fission outcomes. In other words, females groomed most with the females they would remain with after the fission. By contrast, female-male grooming was prevalent in co-resident dyads but less strictly predicted by eventual fission outcomes. Although rates of aggression were elevated during periods when females dispersed, females who moved between groups were not targeted for eviction. Intergroup grooming remained elevated throughout the fission process, particularly between mixed-sex dyads, suggesting that group boundaries may have remained somewhat blurred. Taken together, the formation of this new group appears to have been a product of social factors including elevated levels of female-female aggression and females’ affinity for particular males.
Cerium Dimer Anion and the Contribution of 4f Electrons to Lanthanide Metal–Metal Bonds
A multimodal cross-species comparison of pancreas development
Abstract Human pancreas development remains incompletely characterized due to restricted sample access. We investigate whether pigs resemble humans in pancreas development, offering a complementary large-animal model. As pig pancreas organogenesis is unexplored, we first annotate developmental hallmarks throughout its 114-day gestation. Building on this, we construct a pig single-cell multiome pancreas atlas across all trimesters. Cross-species comparisons reveal pigs resemble humans more closely than mice in developmental tempo, epigenetic and transcriptional regulation, and gene regulatory networks. This further extends to progenitor dynamics and endocrine fate acquisition. Transcription factors regulated by NEUROG3, the endocrine master regulator, are over 50% conserved between pig and human, many being validated in human stem cell models. Notably, we uncover that during embryonic development, emerging beta-cell heterogeneity coincides with a species-conserved primed endocrine cell (PEC) population alongside NEUROG3-expressing cells. Overall, our work lays the foundation for comparative investigations and offers unprecedented insights into evolutionarily conserved pancreas organogenesis mechanisms across animal models.
Discovery of C-12 dithiocarbamate andrographolide analogue as a novel antioxidant and α-glucosidase inhibitors: In vitro and in silico studies
Type 2 diabetes mellitus (T2DM) is a global health issue associated with oxidative stress, inflammation, and insulin resistance. Even though α-glucosidase inhibitors such as acarbose are used in treatment, their efficacy is limited by gastrointestinal side effects. In this study, we evaluated the antioxidant properties and α-glucosidase inhibition of C-12 dithiocarbamate andrographolide analogues compared to the parent compound, andrographolide. Among all analogues, compound 3f exhibited strong antioxidant activity, achieving 84% DPPH inhibition and a reducing antioxidant power activity of 254 μM ascorbic acid equivalent (AAE) at 500 μM. Additionally, molecular docking suggested a favorable binding to both yeast and human α-glucosidase at a comparable level as andrographolide, verified by the surface plasmon resonance (SPR) detection system, indicating a strong binding affinity with a dissociation constant ( K D ) of 12.86 μM. It also retains favorable physicochemical properties that align with drug-likeness based on Lipinski’s Rule. Functional assay confirmed its inhibitory activity with an IC 50 of 411 μM against the yeast α-glucosidase enzyme model, which was greater than both andrographolide and acarbose. Further molecular dynamics (MD) simulation analysis revealed that compound 3f exhibited stable and thermodynamically favorable binding to human α-glucosidase as well as interacting with key amino acids similar to those of andrographolide, providing a preliminary understanding of its potential relevance in a human enzyme context. Altogether, these findings highlight the significant potential of compound 3f as a novel α-glucosidase inhibitor, offering a potential therapeutic alternative and paving the way for further anti-diabetic drug development.
Computational design and evaluation of optimal bait sets for scalable proximity proteomics
A randomized trial of grant writing coaching groups: Baseline analysis of early-career scientists’ research background, demographics, and mentorship variables
Introduction Racial, ethnic, and gender disparities in academic career advancement persist in biomedical disciplines. One approach to addressing this problem is systematizing access to mentorship in critical skills such as grant writing. This report summarizes the baseline characteristics of early-career investigators who enrolled in a randomized trial of a group coaching intervention focused on National Institutes of Health (NIH) grant application development. Methods Surveys assessed participants’ demographic characteristics, research focus, prior publications and grant submissions, self-efficacy for grantsmanship and career advancement, and access to mentorship. Two-sided t-test and Fisher’s exact test were performed to compare baseline variables by gender identity (male/female) and by background from a racial or ethnic population that is an underrepresented minority group in biomedical research (non-URM/URM). Results The study sample includes 271 faculty and 96 postdoctoral fellows. Sixty-two percent of faculty and 76.0% of postdoctoral fellows identified as female. Nearly half (45.4% of faculty, 49.0% of postdocs) were from URM populations in biomedical research. At baseline, most were conducting clinical and translational research at institutions with high levels of research activity. Past submission of NIH R-series applications was limited; 29.9% of faculty had submitted K applications. On average, participants had moderate levels of self-efficacy (in grantsmanship and career advancement) and research-related mentoring support. Male and non-URM participants had a higher mean number of previous publications. For the remaining variables, there were no or minimal differences by gender identity and URM status. Conclusions Early-career investigators from diverse backgrounds are motivated to engage in external grant writing coaching programs regardless of existing mentorship and other supports at their home institutions, suggesting that grant coaching can provide complementary value.
Tidewater cycle drives alpine glacial sediment plume geochemistry
Abstract Sediments transported by glacial meltwaters are important sources of trace-metal micronutrients for coastal microbial communities, linking cryospheric processes with ocean fertilization and biogeochemical cycles. Tidewater glacier advance-retreat cycles drive sediment fluxes and influence fjord geochemistry. Here, we used a chemical extraction method to determine the iron and manganese fertilization potential of suspended sediment-plume and iceberg-laden particulate matter from two adjacent, yet geomorphologically distinct, fjords in Southcentral Alaska. We found that the glacier retreat status underpinned the fraction of labile trace-metals within fjord surface plumes, with distinctly lower lability of metals associated with recent and rapid retreat coincident with enhanced erosion and chemical weathering. Particle size did not affect chemical lability, resulting in a well-mixed particle assemblage transported to the coastal ocean. With global tidewater glacier retreat, these results provide implications for future ecosystem fertilization via cryospheric processes and the interpretation of fjord sediment archives.
In silico and in vivo assessment of the immunostimulatory activity of palmitic acid derived from Vernonia amygdalina
The experience and impact of living with idiopathic hypersomnia: A qualitative study of patient perspectives shared in online media
Introduction Understanding the experience and impact of idiopathic hypersomnia (IH) is critical for improving diagnosis, treatment, research, drug development, and policy awareness. Currently, physician and researcher perspectives dominate the discourse on IH, often overlooking the lived experiences of those with the condition. Objective To understand the lived experience of IH from the patient perspective by analyzing spontaneously generated online patient-experience data. Methods Publicly available data were collected through iterative Google searches, manually coded, and thematically analyzed using inductive and deductive approaches to qualitative content analysis. Concept saturation was reached, ensuring comprehensive theme exploration. Results Searches identified 346 social media posts, community forums, blogs, videos, and podcasts created by 123 people with self-identified IH between 2012 and 2022. Most were female, 16–60 years old, and lived in the United States, Australia, Europe, and Canada. Symptom experiences were grouped under 10 themes: prolonged sleep, never feeling fully awake, relentless sleepiness, non-restorative sleep, difficulty in waking, automatic behavior, microsleeps and prolonged naps, cognitive difficulties, limited physical energy, and vivid dreams and hypnogogic hallucinations. Life impacts were identified and grouped under seven domains: psychological and emotional well-being, activities of daily living, injuries, relationships, work and school, physical health, and healthcare and treatment burden. Discussion This study expands the understanding of IH beyond clinician and researcher-driven perspectives and clinical descriptions and illuminates its profound impact on all aspects of life from patients’ point of view. These insights can help clinicians provide better care, drive patient-centered drug development, and raise awareness of this devastating disorder.
Hierarchical incremental learning deciphers molecular arrangements in multi-component materials
Abstract Identifying meaningful patterns of atomic and molecular arrangements from molecular simulations is crucial for revealing microscopic mechanisms in materials. Unraveling these patterns is challenging for the multi-component systems frequently encountered in advanced materials, energy and environmental applications. This limits the understanding of the microscopic mechanisms that ultimately govern the performance of devices based on these systems. Here, we propose a hierarchical incremental learning research protocol named HiDiscover to systematically expedite the mechanistic exploration in multi-component materials. As illustrations, we study Li-ion transport and gas adsorption in nanoporous framework materials, as well as molecular packing in organic active layers for photovoltaics. The HiDiscover protocol enables the detailed differentiation and facile extraction of ionic and molecular arrangements, and reveals quantitative microscopic features that are difficult to discern through conventional molecular simulations, thereby informing materials design. Our approach is seen to improve the reliability of mechanistic descriptions for three different processes in three different classes of materials.