Browse Articles

Structural rigidity of the I–II loop couples Ca _V β anchoring to Ca _V 2.2 gating modes

The auxiliary β subunits of voltage-gated Ca 2+ (Ca V ) channels are fundamental regulators of channel gating and neuronal excitability. While the subcellular localization of β subunits is known to influence current density and inactivation, the precise kinetic mechanism by which they differentially modulate channel opening and closing remains elusive. Here, we report a kinetic paradox in Ca V 2.2 channels: membrane-anchored β subunits decelerate current decay during depolarization yet accelerate tail deactivation upon repolarization, whereas cytosolic β subunits promote rapid decay but prolong deactivation. Using quantitative kinetic analysis and Markov state modeling, we demonstrate that macroscopic current decay is not solely a monolithic irreversible inactivation process but a composite of irreversible inactivation and a reversible transition to a nonconducting state. We reveal that membrane-anchored β subunits suppress the transition to this reversible nonconducting state, thereby maintaining the open state, while facilitating a rapid return from the nonconducting state to prevent kinetic trapping. Furthermore, by manipulating the linker length of β subunits and engineering the I–II loop hinge region (R370), we identify that the physical proximity of the β subunit to the plasma membrane, coupled with the structural rigidity of the I–II loop, acts as a mechanical determinant that governs this gating pathway selection. Our findings provide a unified gating model in which the β subunit fine-tunes the dynamic equilibrium between conducting and nonconducting states via mechanical constraint on the channel complex, offering a comprehensive resolution to the distinct regulation of Ca V 2.2 kinetics.

Disability status and expectations of disability services among individuals with chronic diseases

Background Disability is a multidimensional condition arising from impairment or chronic illness that limits individuals’ ability to perform age, gender, and socio-culturally expected activities. Many chronic diseases, including asthma, diabetes, cardiovascular diseases, cancer, and neurological disorders, fall within the scope of disability. Beyond functional limitations, barriers to social relationships and cultural participation further affect individuals’ lives, underscoring the importance of examining lived experiences and expectations. Objective This study aimed to examine in depth the disability status of individuals with chronic diseases and their expectations of disability services. Methods This qualitative study was conducted in Türkiye, and participant recruitment was carried out between 09/07/2024 and 07/01/2025. Semi-structured, in-depth interviews were conducted with 12 adults with chronic diseases who held official disability reports. Participants were recruited using purposive sampling combined with a snowball technique. Data were analyzed using inductive content analysis informed by a phenomenological perspective. Results Seventy percent of the participants were women, 50% had type 1 diabetes, and half reported limited awareness of disability services. Three main themes emerged: Impact of Disability on Daily Life, Awareness of Disability Services, and Accessibility of Disability Services. These findings highlight critical gaps between formal disability certification and effective access to services, indicating that informational and structural barriers persist despite legal entitlements. Conclusion Disability related to chronic illness affects multiple life domains, particularly social, cultural, educational, and professional areas. Although individuals with chronic diseases are entitled to disability services based on health board reports, limited awareness and accessibility hinder effective utilisation.

Comparative analysis of gut bacteria-associated enzymatic differentiation in honeybees Apis cerana and Apis mellifera

Deciphering the mechanism of protein aggregation and effects of inhibitors using single-molecule mass photometry

Aggregation of misfolded proteins is a prominent feature of many diseases and hence an attractive drug target. However, the small oligomers that are critical early species in the aggregation cascade are difficult to monitor directly owing to their heterogeneity and transience, complicating efforts to define aggregation mechanisms and target oligomers therapeutically. Here, we observe changes in oligomer populations directly using single-molecule mass photometry (MP). Studying the pathogenic P301L mutant of tau protein linked to frontotemporal dementia, we globally fit the growth/decay kinetics for every oligomer population observed by MP to microscopic models of aggregation. A simple extension to the best-fit model also accounts for amyloid fibril kinetics, as monitored by Thioflavin T fluorescence, providing a quantitative model of aggregation kinetics across all stages of the cascade based on direct observation. Crucially, we find that models fitting amyloid kinetics alone fail to capture oligomer behavior, implying that—contrary to standard practice—amyloid kinetics cannot be relied on to deduce aggregation mechanisms. Furthermore, there is no single rate-limiting nucleation step preceding rapid growth, as generally assumed, suggesting that standard models of aggregation are overly simplistic. Repeating the analysis in the presence of aggregation inhibitors allows identification of the discrete steps in the cascade affected by the inhibitors. This work presents a powerful approach for defining protein aggregation mechanisms and the mechanism of action of inhibitors, with applications to understanding many diseases and developing novel therapeutics.

Death by incarceration: Detention duration, overdose, and COVID-19 in Los Angeles County Jails, 2008–2023

Importance Jail mortality in the United States has risen sharply in recent years, yet deaths in custody—especially those related to substance use—remain underexamined. The COVID-19 pandemic and the opioid crisis compounded pre-existing carceral health issues, necessitating a closer examination of their combined impact and aftermath. Previous reports suggest that incarcerated people—particularly those who overdose on drugs—die early in their confinement. This article indicates that the dual health threats of the COVID-19 pandemic and the opioid crisis have changed this relationship, substantially extending the time from arrest to death. Objective To investigate how duration of confinement, manners and causes of death (e.g., COVID-19, substance use), and pandemic mitigation policies impacted mortality in Los Angeles (LA) County Jail from 2008–2023. Design A retrospective, observational study utilizing linked datasets to identify mortality trends and associated factors. Setting LA County Jail, the largest jail system in the United States. Participants We created three data sets: 1) LA County Jail deaths from 2008–2023, N = 509, 2) City Jail deaths within LA County, encompassing LA City Jail deaths 2008–2023, N = 42 and Non-LA City Jail deaths, 2008–2023, N = 30, and 3) all bookings from 2010–2022, N = 1,435,479. Main outcome(s) and Measure(s) Mortality trends over time, duration of incarceration prior to death, duration of incarceration for those released or transferred, and cause-specific mortality including direct standardized rates and standardized mortality ratios. Statistical models assessed the impact of confinement duration and pandemic and opioid crisis years on mortality. Results Jail mortality broadly, and substance-related deaths specifically, increased from 2008 to 2023, peaking during the pandemic. The median time from arrest to death was over five times as long (59 days) as the median duration of stay for all bookings (11 days). COVID-19 infection, prolonged confinement, and restrictive pandemic policies were associated with elevated mortality rates. Conclusions and Relevance Findings highlight the urgent need for reforms, including reduced incarceration; reduced incarceration duration; expanded access to substance use disorder treatment; decreased influx of drugs into jails; increased programming, visits, and out-of-cell time; and improved health safeguards.

Walking-induced fatigue does not increase the risk of falling during physiological aging

Cell division sets a universal flow geometry in cell layers

Collective flows in epithelial tissues contain a geometric backbone of vortical interfaces whose statistics exhibit hallmarks of critical percolation and conformal invariance. Yet how fundamental cellular processes govern the breakdown of such symmetry-rich flow geometry remains unclear. Here we show that cell division plays a central physical role in regulating this universal flow organization by controlling both the geometric and mechanical flexibility of the cell–cell network. Using pharmacological perturbations, we find that when proliferation is suppressed through two independent interventions, coherent flows persist but neighbor exchanges decline and conformally invariant geometry is lost. Blocking apoptosis does not affect universality, isolating division as the key control. A vertex model with tunable division quantitatively reproduces these effects and restores conformal invariance when division is allowed. We further trace this effect to changes in both the geometric and mechanical organization of the cell layer: Divisions act as intermittent topological renewals that loosen constraints, preserving the network’s flexibility and capacity to rearrange across scales. Thus, beyond its canonical role in growth, cell division acts as a structural and mechanical regulator of collective self-organization. These findings establish a direct connection between fundamental biological processes and emergent physical symmetries.

Machine learning-based prediction of fever among under-five children in Ethiopia: A national-level study

Fever remains a leading cause of morbidity and mortality among children under the age of five, particularly in low-resource settings like Ethiopia. Most existing studies in Ethiopia have relied predominantly on traditional statistical techniques, which may not fully capture complex patterns and nonlinear relationships within the data. To address this gap, the present study applies multiple machine learning algorithms to determine the most accurate model for predicting fever among under-five children in Ethiopia. This study utilized a total of 8,592 weighted child samples from the 2016 EDHS. After preprocessing, the dataset was randomly split into 70% training and 30% testing sets. Five machine learning algorithms; LR, RF, SVM, GNB, and DT were developed to predict fever. SMOTE was applied to address class imbalance in the training data. Model performance was assessed using accuracy, AUC, sensitivity, specificity, precision, F1-score, and balanced accuracy. Association rule mining via the Apriori algorithm was used to identify frequent patterns associated with fever. The overall prevalence of fever among under-five children was 14% (n = 1,197). Among the algorithms tested, the RF classifier achieved the best performance (accuracy: 92.2%, AUC: 0.958, sensitivity: 98.7%, specificity: 85.6%, F1-score: 0.8761). RF Gini importance and SHAP values ranked region, diarrhea & maternal factors as top predictors. Association rule mining revealed ten strong rules linking predictor variables with fever occurrence. The RF classifier demonstrated superior performance in predicting fever and identifying key features among under-five children. The results confirm that machine learning algorithms can serve as effective tools for accurately predicting childhood fever. These findings provide valuable insights for policymakers and public health stakeholders, supporting data-driven decision-making for targeted fever prevention strategies in Ethiopia.

A CT-based radiomics nomogram for predicting intrahepatic recurrence of HCC after radiofrequency ablation

Parabrachial <i>Ntsr1</i> neurons modulate food intake and anxiety through a projection to the ventromedial hypothalamus

The parabrachial nucleus (PBN) is an important hub located in the pons that relays sensory signals from peripheral regions. It is genetically diverse and contains many populations that modulate feeding and responses to threatening situations. A small Ntsr1 -expressing population of neurons was identified that projects selectively to the ventromedial hypothalamus (VMH). The Ntsr1 neurons are scattered throughout the lateral PBN with a cluster of cells along the border to the nucleus of the lateral lemniscus that overlap with Cck and Foxp2 expression. Chemogenetic activation of PBN Ntsr1 neurons results in Fos induction in Nr5a1 (SF1) and Bdnf neurons in the VMH. Activation of PBN Ntsr1 neurons or their terminals in the VMH reduces food intake after fasting and increases anxiety-like behaviors. In anxiogenic feeding assays, activation of PBN Ntsr1 neurons increases latency to feed as well as reducing food intake. Photometry showed that PBN Ntsr1 -neuronal activity increases during anxiogenic situations but is suppressed during food consumption, suggesting a role in threat-induced suppression of feeding. Silencing PBN Ntsr1 neurons with tetanus toxin light-chain increased food intake and reduced anxiety. These findings reveal a genetically defined PBN to VMH circuit that responds to threats and suppresses feeding behavior.

“… Infections are not confined in labs…”: Community engagement for Controlled Human Infection Studies: Opinions of researchers, bioethicists and research regulators in Uganda

Controlled human infection studies play a critical role in advancing our knowledge of infectious diseases and developing therapeutics. However, these studies involve knowingly exposing research participants to pathogens, raising significant ethical, social, environmental and logistical concerns. Controlled human infection studies are being conducted in settings where individuals are economically disadvantaged and may have limited access to healthcare, education, and basic social amenities, making community engagement a central element in ensuring the ethical conduct of controlled human infection studies and the protection of participants’ rights. In a cross-sectional qualitative study, we explored the views of research stakeholders on how to effectively engage local communities on controlled human infection studies. Twenty-seven key informant interviews were conducted with researchers, bioethics experts, research ethics committee members, and staff at national research regulatory bodies in Uganda between September 2023 – March 2024. A systematic inductive analysis approach was used. Due to the complexity and sensitivity of controlled human infection studies, findings reveal the necessity for early planning, adequate budgets and broad-based engagement using multiple approaches and activities. Research participants viewed the bottom-up approach as more appropriate for engaging communities. They also argued that meaningful community engagement should be a continuous process grounded in respect, justice and partnership, rather than merely a procedural or regulatory obligation. The acceptability and success of controlled human infection studies in low resource settings largely depends on effective intentional community engagement in the entire research process.

Sensitivity analysis of cluster cable current-carrying capacity correction factor

Long-range magnetoelectricity in type-II multiferroic NiI ₂

Type-II multiferroics, where spin order induces ferroelectricity, exhibit strong magnetoelectric coupling. However, for the typical 2D type-II multiferroic NiI 2 , the underlying magnetoelectric mechanism remains unclear. Here, applying generalized spin-current model, together with first-principles calculations and a tight-binding approach, we build a comprehensive magnetoelectric model for spin-induced polarization. Such model reveals that third-nearest-neighbor spin pairs provide an unexpectedly strong contribution to the electric polarization, which rivals that of the first-nearest neighbors. Adopting such model, both experimental-detectable bound charge induced by spin-induced polarization at the spiral domain boundary, as well as polar vortex lattice induced by magnetic skyrmion lattice under moderate magnetic field, are predicted. Furthermore, by analyzing the orbital-resolved contributions to polarization, our tight-binding model reveals that the long-range magnetoelectric coupling is enabled by the strong e g - p hopping of NiI 2 . These findings can guide the identification and design of strongly magnetoelectric multiferroics.

Synergetic effect of bioslurry and charcoal co – composted fertilizers on soil properties and tomato (Solanum lycopersicum) productivity

Tomato ( Solanum lycopersicum ) is one of the most widely cultivated and economically important vegetable crops worldwide, contributing significantly to food security. However, its low productivity remains a substantial concern in Ethiopia due to mainly poor soil quality and limited use of inorganic fertilizers. On the contrary, improper disposal of recyclable charcoal and anaerobic cow dung bioslurry (ACDB) wastes poses environmental pollution challenges. Hence, this study aimed to evaluate the synergetic effects of ACDB and charcoal co-composted fertilizers (ACDBCFs) on tomato productivity and soil properties. A pot experiment consisting of eight treatments (T1 - T8) was arranged in a randomized complete block design with three replications. Characterization of the five formulated ACDBCFs revealed good physico-chemical properties of pH, organic carbon, ammonium, nitrate, and orthophosphate, fluctuated from 8.9 to 9.63, 26.8 to 65.6%, 2.5 to 4.6 mgL ⁻  1 , 11.9 to 18.2 mgL ⁻  1 , and 0.74 to 3.1 mgL ⁻  1 , respectively. Significant differences (p &lt; 0.05) were observed in tomato fruit yield with relatively higher values of 2.87 and 2.73 kgpot ⁻  1 for T6 and T8 under ACDB + charcoal (+10%) and inorganic fertilizers amendments, respectively. Principal component analysis (PCA) demonstrated strong associations between nutrient availability and tomato growth and yield component parameters. Heat map visualization further confirmed that ACDBCFs application improved soil background nutrient and carbon contents. Overall, the findings from this short-term study indicate that ACDBCFs can enhance tomato productivity while improving soil organic matter and nutrient availability. However, further long-term studies on field level validation in real soil conditions and nutrient dynamics are recommended to support large-scale adoption of this resource-recovery approach, contributing to sustainable agriculture, environmental protection, and socio-economic development.

Effect of polyethylene and glass fiber reinforcement on the mechanical strength, fracture behavior, and elastic modulus of notched dentin

Mechanisms of von Willebrand factor activation driving no reflow in ischemic stroke

Rapid restoration of cerebral blood flow is the cornerstone of acute ischemic stroke treatment. Endovascular thrombectomy achieves substantial reperfusion in 90% of patients with large-vessel occlusion stroke; however, almost half of treated patients continue to have significant disability despite successful thrombus removal. Transient periods of ischemia can trigger microvascular thrombosis resulting in the no-reflow phenomenon. Yet the molecular and hemodynamic triggers underlying no reflow remain poorly defined. Using a murine model of transient ischemic stroke combined with intravital imaging, we visualized platelet-von Willebrand factor (VWF) thrombi forming in penumbral tissue where blood flow dynamics were altered in response to the original ischemic insult. In silico modeling based on our intravital observations indicated that the altered, converging blood flow in these vessels increases local elongational flow, a condition that can favor VWF unfolding. The activity of VWF is controlled by ADAMTS13, which cleaves VWF. We further identified that in the acute phase of stroke, locally released IL-6 suppresses ADAMTS13-mediated cleavage of VWF, creating a prothrombotic imbalance that promotes microvascular thrombosis and worsens outcomes in mice. In ischemic stroke patients, we observed an acute increase in IL-6 that correlated strongly with increased VWF activity. VWF activity was highest in patients experiencing worse outcomes. Inhibition of IL-6 in ex vivo stroke patient plasma restored ADAMTS13 activity. Together, these findings reveal how hemodynamic and inflammatory factors converge to favor VWF activation in the reperfused brain and contribute to the development of no reflow in ischemic stroke.

Editorial Note: NOXA-Induced Alterations in the Bax/Smac Axis Enhance Sensitivity of Ovarian Cancer Cells to Cisplatin

Evaluating Artificial Intelligence enabled teaching reform in higher education using the generalized orthopair fuzzy RANCOM FUCA decision framework

Why shear adhesion is not monotonically enhanced by stiffening

Interfaces between dissimilar elastic materials are ubiquitous in biological and engineered systems and often span orders of magnitude in stiffness. Yet it remains unclear whether stiffening an adhesive system strengthens or weakens shear adhesion, as conflicting trends have been widely reported and the underlying physics has remained unresolved. Here we provide a mechanistic explanation by developing a unified framework for shear adhesion across broad modulus contrasts. We derive an analytical solution for a finite-height elastic adhesive bonded to an elastic substrate and validate the theory using systematic experiments and finite element simulations. We show that, despite global shear loading for the typical geometries encountered, interfacial failure is governed by edge-initiated separation dominated by opening-mode fracture within a finite cohesive zone, rather than by interfacial sliding. Across more than six orders of magnitude in shear modulus contrast, shear adhesion exhibits a pronounced nonmonotonic dependence on stiffness, characterized by well-defined local maxima and minima that delineate attachment- and detachment-favorable regimes. This behavior arises from a competition between a modulus-contrast–dependent corner stress singularity, which promotes separation initiation, and elastic deformation, which controls interfacial opening. Building on this mechanism, we construct parameterized adhesion maps that identify optimal modulus ratios for robust attachment and on-demand release. These results reconcile disparate experimental observations by revealing their common physical origin, establish modulus contrast as an independent design variable for shear adhesion, and provide predictive guidelines for designing bioinspired, wearable, and robotic adhesive systems.

Presence of a home cage running wheel, but not wheel running per se, decreases social motivation in adult C57BL/6J female mice

Physical activity offers myriad benefits to health and well-being, in humans and other animals as well. In rodents, voluntary wheel running can attenuate the effects of both physical and social stressors on rodent social behavior. Whether wheel running affects rodent social behaviors per se remains less well understood. We conducted the current study to test whether home cage access to running wheels impacts the social behaviors of adult, group-housed C57BL/6J female mice during same-sex interactions with novel females. Group-housed females were either given continuous home cage running wheel access or a standard paper hut starting at weaning, and as adults, social behaviors were measured during interactions with novel females. In two cohorts, we found that 5 weeks of running wheel access during adolescence reduced the time that subject females spent investigating a novel female and also tended to reduce total ultrasonic vocalizations produced during interactions. These effects were not reversed by a 2-week period of running wheel removal but were recapitulated in a different cohort by 2 weeks of running wheel access in adulthood. Unexpectedly, we found that these effects on female social behavior were not due to wheel running per se, because females raised from weaning with ‘immobile’ running wheels also showed low rates of social behaviors during same-sex interactions in adulthood. Overall, we find that the presence of a running wheel in the home cage has an enduring inhibitory influence on female social behavior during same-sex interactions, a finding that has implications for the design of studies that include same-sex interactions between female mice.