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Identifying direct risk factors in UK Biobank via simultaneous Bayesian-frequentist model-averaged hypothesis testing using Doublethink
Big data approaches to discovering nongenetic risk factors have lagged behind genome-wide association studies that routinely uncover novel genetic risk factors for diverse diseases. Instead, epidemiology typically focuses on candidate risk factors. Since modern biobanks contain thousands of potential risk factors, candidate approaches may introduce bias, inadequately control for multiple testing, and overlook important signals. Doublethink, a model-averaged hypothesis testing approach, offers a solution that simultaneously controls the Bayesian false discovery rate (FDR) and frequentist familywise error rate (FWER) while accounting for uncertainty in variable selection. Here, we investigate direct risk factors for COVID-19 hospitalization from among 1,912 variables in 201,917 UK Biobank participants by implementing a Doublethink-based exposome-wide association study using Markov Chain Monte Carlo. Focusing on the 2020 outbreak, we find nine individual variables and seven groups of variables exposome-wide significant at 9% FDR and 0.05% FWER. We identify significant direct effects among relatively overlooked risk factors including aging, dementia, and prior infection, which we evaluate in relation to studies of other populations. We detect significant direct effects among some commonly reported risk factors like age, sex, and obesity, but not others like cardiovascular disease. The effects of hypertension, depression, and diabetes appeared to be mediated via general comorbidity. Doublethink produces interchangeable posterior odds and P -values for individual variables and arbitrary groups, facilitating flexible and powerful post hoc hypothesis testing. We discuss the potential for impact and limitations of joint Bayesian-frequentist hypothesis testing, including the benefits of an agnostic exposome-wide approach to discovery.
Impact of GC content on de novo gene birth
Hydrochemical and isotopic signatures of groundwater infiltration and legacy nitrogen discharge within Jeju Island aquaculture systems
Abstract The terrestrial aquaculture systems in Jeju Island have been increasingly threatened by the intrusion of deteriorated groundwater. In this study, we investigated spatiotemporal variations in hydrochemical properties and isotopic compositions (δ 13 C POC , δ 15 N PN , δ 15 N NO3 , and δ 18 O NO3 ) of influent waters from land-based fish farms to trace the sources of particulate organic matter (POM) and nitrate (NO₃⁻) pollution. During heavy summer precipitation (> 350 mm), hydrochemical and isotopic shifts revealed increased infiltration of terrestrial groundwater into fish farm systems. Based on discriminative isotopic values of POM and NO₃⁻ in aquaculture influents, source apportionment results after accumulated precipitation indicated that the contribution of anthropogenic POM (livestock; 39 ± 17%) was predominant than those of other sources (soil; 31 ± 16%, fertilizer; 24 ± 7%, septic waste; 6 ± 1%). In addition, the contribution of NO₃⁻ sources (soil; 67 ± 7%, livestock; 18 ± 10%, septic waste; 9 ± 4%, fertilizer; 5 ± 1%) were largely controlled by specific land-use types adjacent to aquaculture systems. These results suggest that variations in volcanic bedrock permeability and land-use patterns may lead to distinct infiltration pathways and delayed responses between the northern and southern sections of Jeju Island. Therefore, these findings demonstrated that legacy pollutants stored in both the unsaturated and saturated zones may continue to impair groundwater quality, thereby affecting aquaculture water quality, particularly during periods of accumulated precipitation. To effectively manage nutrient-driven degradation in aquaculture systems, we recommend integrating isotopic source-specific monitoring with hydrogeological zoning and the targeted pretreatment of saline groundwater. This approach can mitigate eutrophication risks and enhance the sustainability of fish farming operations in volcanic islands.
E2 variants for probing E3 ubiquitin ligase activities
E3 ligases partner with E2 enzymes to regulate vast eukaryotic biology. The hierarchical nature of these pairings, with >600 E3s and ~40 E2s in humans, necessitates that E2s cofunction with numerous different E3s. Here, focusing on E3s in the RING-between-RING (RBR) family and their partner UBE2L3 and UBE2D-family E2s, we report an approach to interrogate selected pathways. We screened phage-displayed libraries of structure-based E2 variants (E2Vs) to discover enzymes with enhanced affinity and specificity toward half of all RBR E3 ligases (ARIH1, ARIH2, ANKIB1, CUL9, HOIL1, HOIP, and RNF14). Collectively, these E2Vs allowed distinguishing actions of different cofunctioning E3s, obtaining high-resolution cryogenic Electron Microscopy (cryo-EM) structures of an RBR E3 in the context of a substrate-bound multiprotein complex, and profiling an endogenous RBR E3 response to an extracellular stimulus. Overall, we anticipate that E2V technology will be a generalizable tool to enable in-depth mechanistic and structural analysis of E3 ligase functions, and mapping their activity states and protein partners in cellular signaling cascades.
Unlocking efficient electrocatalytic removal of trace emerging contaminants via synchronized pollutant enrichment and electron delivery
Occult hepatitis B virus infection among hepatitis B surface antigen negative vaccinated healthcare workers in East Gojjam zone hospitals
Sticky interactions govern sequence-dependent dynamics in biomolecular condensates
Intrinsically disordered proteins (IDPs) play a central role in shaping the dynamics and material properties of biomolecular condensates. Understanding how sequence features determine these properties is critical for elucidating physiological function and guiding the rational design of synthetic condensates. Here, we use molecular dynamics simulations to investigate condensates formed by model IDPs with systematically varied chain length and charge patterning, two features characteristic of natural IDPs. Our results show that chain relaxation times, governed by sequence-dependent electrostatic interactions, quantitatively predict condensate viscosity and diffusivity. These condensates exhibit dynamics consistent with a crossover regime between Rouse and reptation behavior. While the Rouse model with idealized friction fails to capture sequence effects, a sticky Rouse-like framework, which incorporates transient interchain contact lifetimes, accurately predicts chain reconfiguration times and, consequently, macroscopic material properties. This work establishes a predictive, sequence-resolved framework that links molecular interactions to condensate dynamics across length and time scales.
Breaking immiscibility barriers: ultrafast sintering of interlocked Cu-Fe-based composites
On urban maladaptation in times of epidemics
Abstract Epidemics are long-lasting and transboundary crises that challenge traditional approaches. Given the complexity and interconnectedness of modern cities, interventions can lead to unintended consequences or maladaptation. Although adaptation is central to resilience, crisis management often focuses on short-term response, leaving a gap in understanding urban adaptation and maladaptation. This study examines the impacts of uniform interventions across diverse urban districts to assess this (mal)adaptive process. We use the COVID-19 pandemic in The Hague, Netherlands, as a case study, employing a large-scale agent-based model. We find that without an intervention, the high-contact city centre becomes an infection hotspot due to the transient population it attracts. Conversely, the outer residential district, with fewer amenities, experiences infections primarily among its residents. A uniform lockdown policy significantly reduces infections in the city centre by limiting mobility and social interactions, but inadvertently increases risk in the outer residential district. Using the Urban Adaptation Index (UAI), we demonstrate that these uncontextualised policies can constitute maladaptation, confirming the unintended consequences of ’one-size-fits-all’ approaches. Our results underscore this need, leading us to propose an updated, equity-oriented crisis management framework that accounts for the heterogeneous nature of modern cities.
A MAPK cascade regulates nuclear migration during female gametogenesis to establish specific cell identity and rice female fertility
During the development of the rice female gametophyte (FG, embryo sac), there exists a free-nuclear stage wherein eight nuclei, originating from the same mother cell nucleus, respectively migrate to specific positions to acquire distinct cell identities after cellularization and develop into the egg cell, central cell, or accessory cells. Therefore, this nuclear migration stage is essential for fertilization and rice fertility. How these nuclei can find their own way to exactly move to different predetermined positions and how the two polar nuclei are selected have been intriguing questions for decades. Here, we show that a mitogen-activated protein kinase cascade, composed of OsMEKK2/OsMEKK21, OsMKK6, and OsMPK4, precisely regulates free-nuclear migration and determines the number and identities of polar nuclei. Specifically, OsMKK6 phosphorylates OsMPK4 to restrict nuclear migration at the chalazal pole, ensuring the accurate number and positioning of antipodal cells and polar nuclei. Loss-of-function mutations in OsMKK6 and OsMPK4 result in an excess of polar nuclei at the expense of antipodal cells. Additionally, OsMEKK2 and OsMEKK21 function as upstream regulators, phosphorylating and modulating downstream substrates to control nuclear migration at both poles. This regulation is essential for FG fertility and seed production. Our findings reveal a hierarchical model for the regulation of nuclear migration during embryo sac development and provide valuable insights into how an embryo sac orchestrates the migration of eight nuclei in response to different positional cues, thereby establishing female fertility in rice.
Individual and population-level risk factors for new HIV infections among adults in Eastern and Southern Africa
Abstract Despite substantial recent declines, general population HIV incidence in sub-Saharan Africa remains above international targets. Better description of risk factors for new infections would improve prioritisation of interventions. Using data from population-based cohorts in Kenya, Malawi, Tanzania, South Africa, Uganda, Zimbabwe we described the prevalence of risk factors for men and women aged 15-24 and 25-49 and estimated the association between individual and community-level risk factors and HIV acquisition between 2005 and 2016. Among 43,434 men and 55,919 women aged 15 to 49 there were 4,612 seroconversions. Education, marital status, male circumcision, new sexual partners, types of partner, prevalence of untreated HIV infection in the community and community partner acquisition rates were associated with HIV incidence. Only the prevalence of untreated HIV was a risk for both sexes and apparent at all ages. The prevalence of risk factors varied by age, sex and study. HIV incidence was higher in people aged 25-49 living in communities where men had high partner acquisition rates. Our results show potential for improved prevention through changed timing of prevention interventions relative to behaviour and the utility of using community characteristics to target prevention.
The red cell distribution width to albumin ratio as a novel predictor of 180-day mortality in lung cancer patients
Distinct macronutrient ratios optimize offspring survival, growth, and maternal glucose tolerance across mouse reproduction
Pregnancy and lactation are reproductive periods that require major energy and nutrient investment by the mother. Dietary perturbations over reproduction can impair offspring development and increase the risk of metabolic disease for the mother. However, how the intake of specific macronutrients, independent of total calorie intake, influence maternal reproductive investment and metabolic health remains poorly understood. To understand the role of protein, carbohydrate, and fat intake in influencing these parameters, we fed mice one of ten isocaloric diets that differed systematically in their macronutrient make-up. We allowed females to breed and observed striking effects of different macronutrients on fetal development, with protein intake having strong positive effects on offspring survival, accompanied by major shifts in the morphological structure of the placenta and placental lactogen production. However, maternal glucose tolerance was strongly impaired by high protein intake during pregnancy, with reproductive females more susceptible to the effects of these macronutrients than nonpregnant animals. Strikingly, metabolic effects were reversed after lactation, with mothers developing a resilience to the chronic effects of protein and fat intake on glucose tolerance observed in virgin animals. During lactation, we also observed that offspring development was optimized by a different ratio of macronutrients compared to during pregnancy. These results highlight the importance of optimizing macronutrient, particularly protein, intake to specific levels during pregnancy, ensuring a balance that maintains maternal glucose tolerance while providing sufficient nutrients to ensure healthy offspring growth and survival.
Highly efficient exciton-exciton annihilation in single conjugated polymer chains
Abstract The number of excitons that conjugated polymers can support at any one time underpins their optoelectronic performance in light-emitting diodes and as laser gain media, as it sets a natural limit on exciton density. Here we have measured the time-resolved photon statistics of single, isolated chains of polyfluorene to extract the absolute number of independent emitting sites present and its time dependence by studying the intramolecular exciton-exciton annihilation. We find that after 100 ps each chain can only support 1 or 2 independent excitons, and that even at the earliest times this number rises only to 4, suggesting a high degree of electronic coupling between chromophores that facilitates efficient exciton-exciton annihilation. In circumstances where a low density of low-energy sites is present, annihilation between them still dominates. The results indicate that achieving high exciton densities in conjugated polymers is difficult, and in applications where it is desirable new strategies should be devised to control exciton-exciton annihilation.
Multiparameter design optimisation of a mud-based natural draft biomass cookstove using response surface methodology and desirability function
Memory B cell development in response to mRNA SARS-CoV-2 and nanoparticle immunization in mice
Nanoparticle immunogens excel at rapidly inducing high levels of circulating antibodies and are being deployed as part of several novel vaccines. However, their ability to elicit memory B cell responses is less well understood. Here, we compared serologic and memory B cell responses after prime boost vaccination with either SARS-CoV-2 Wuhan-Hu-1 mRNA vaccine, or protein nanoparticles: SARS-CoV-2 B.1.351 homotypic containing a single receptor binding domain (RBD); (homotypic beta) or a combination of different Sarbecovirus RBDs (mosaic 8b), respectively. The memory B cells elicited by the 3 vaccine regimens showed closely related antibody sequences, similar levels of somatic mutation, and clonal diversity. The breadth of serologic responses elicited by the mosaic nanoparticles was comparable to the homotypic nanoparticle and superior to the mRNA vaccine for some mismatched strains. However, serum neutralizing titers to SARS-CoV-2 were highest after mRNA vaccination. The three vaccines elicited memory B cells that produced antibodies specific to a broad range of epitopes on the RBD that differed in a way that may reflect epitope masking. Monoclonal antibodies derived from memory B cells elicited by the mosaic 8b nanoparticle showed greater breadth against a panel of SARS-CoV-2 variants and SARS-CoV.
Stress-trained microalgae robots with probiotics backpack and intestinal brake for inflammatory bowel disease management
Cancer cells surviving cisplatin chemotherapy increase stress-induced OMA1 activity and mitochondrial fragmentation
Abstract Cancer is one of the leading causes of deaths worldwide. Once cancer cells acquire therapy resistance, they become the main driver of cancer lethality in patients. Thus, mechanisms of therapy resistance must be investigated to improve patient outcomes. Mitochondria are critical organelles in the cellular stress responses, undergoing dynamic morphological and functional changes in response to external stimuli. We and others have identified a chemotherapy-resistant cancer cell state where cells that survive treatment exhibit a dramatic increase in cell size and remain non-proliferative for weeks. In this study, we demonstrate that cancer cells that enter this resistant cell state in response to cisplatin increase OMA1 activity and decrease mitochondrial fusion and function to combat oxidative stress. These findings contribute to further understanding the role of the mitochondrial stress responses in therapy resistance in cancer and provide a potential therapeutic avenue to targeting cancer cells that enter this chemotherapy-resistant cell state.
Self-adaptive dislocation morphing ductilizes a refractory high-entropy alloy across an ultrawide temperature spectrum
Metals usually fracture catastrophically at cryogenic temperatures and soften rapidly at high temperatures. This dilemma arises from the incompatibility of strengthening mechanisms across vast temperature regimes. Here, this work unveils a self-adaptive dislocation morphing mechanism in a model NbTaTi-based refractory high-entropy alloy (RHEA) that enables exceptional strength and ductility from 4 K to 1673 K. At cryogenic temperatures, dislocation kinking coupled with deformation twinning suppresses the ductile-to-brittle transition. At ambient conditions, the sequential activation of edge and screw dislocations sustains work hardening. At elevated temperatures, enhanced dislocation interactions generate jogs, multijunctions, and helical dislocations, promoting superplasticity up to 250%. This intrinsic, temperature-responsive evolution of dislocation modes offers a defect engineering strategy for designing RHEAs capable of enduring extreme environments.