Abstract For over 50 years, diffusion magnetic resonance (dMR) has been employed in numerous studies on characterizing chemical compounds, porous media, and biological tissues. These studies have almost exclusively employed the Stejskal-Tanner (ST) pulse sequence, which is sensitive to the ensemble average propagator (EAP). EAP is a compromised version of the true diffusion propagator---a quantity that fully describes the diffusion process in any system and holds exquisite information that can be used to characterize complex samples. Recently, a new diffusion sensitization method was proposed, here referred to as PROP, and was shown to be capable of acquiring the true diffusion propagator in closed pores. However, its adequate use requires a large number of measurements and (consequently) a long acquisition time. Thus, its translation to, e.g., the clinical field, is challenging. Here, we propose a reduced PROP pulse sequence (rPROP) which offers various advantages over the ST sequence. rPROP excels at isolating restricted diffusion thanks to its inherently high diffusion-weighting, yielding an efficient free diffusion filter. We employ rPROP to study different samples, and compare its performance to ST measurements in terms of estimation accuracy and gradient amplitude requirements. Furthermore, we study the capability of rPROP to detect anisotropic diffusion in samples which predominantly feature isotropic diffusion. Finally, we present a method capable of acquiring the mean position distribution (analogous to the EAP attainable via ST data) of particles via MR measurements. We highlight that all signals and images presented in this work were acquired using a benchtop MRI scanner.
Language change involves a complex interplay of selection and drift (or unbiased copying), shaping the popularity of words over time. This pre-registered study examines lexical evolution in the Ukrainian language using data from Slovotvir, a crowdsourcing platform where over 4,000 users proposed and ranked translations of foreign-origin words over 9 years. We rely on an agent-based model combined with novel generative inference methods to investigate the roles of frequency-dependent selection, selection for brevity, and random drift in shaping word popularity. Our results indicate that Slovotvir users exhibit a preference for shorter words, supporting Zipf's principle of least effort. However, the popularity of translations, which we approximate using likes on the platform, appears largely frequency-independent, suggesting that users do not disproportionately favor already popular words. However, this conclusion might be limited by the fact that our data consist of low-frequency neologisms that are still evolving in this population of speakers. These findings contribute to a broader understanding of language change by providing empirical evidence that selection for brevity, rather than frequency-dependent selection, drives lexical evolution in this grassroots language reform initiative, which reflects and shaped real-world language change.
Abstract Stress responses are triggered by diverse stressors and typically involve acute common physiological changes including increased heart rate and adrenocortical hormone secretion. In contrast, core body temperature (Tc) may either increase or decrease depending on the stressor. Although restraint is widely used to induce stress responses in laboratory animals, heterogeneous effects on Tc have been reported. To elucidate the central and peripheral mechanisms underlying restraint-induced hypothermia, a reliable model that consistently induces hypothermia is first required. In this study, we aimed to establish an experimental system using mice that can reliably induce hypothermia through physical restraint. Furthermore, we aimed to elucidate the primary factors contributing to hypothermia within the various elements constituting the restrained state and to simplify the restraint experimental system by eliminating unnecessary elements. Starting with conventional cylinder-shaped restraint equipment and modifying it in various ways, we finally found that the simple procedure of limb restraint reliably induces a rapid (within 15 min) and substantial (approximately 4 °C) decrease in rectal temperature, a good indicator of Tc. Limb restraint increased serum corticosterone concentration and activated the paraventricular hypothalamic nucleus, suggesting that a type of stress response involving Tc reduction was induced by limb restraint. The decrease in body temperature caused by limb restraint was attributed, at least in part, to reduced heat production in the brown adipose tissue (BAT) and increased heat loss from the tail. This simplified restraint paradigm provides a useful tool for elucidating the mechanisms underlying hypothermia induced by physical restraint.
Abstract It has been suggested that sexually dimorphic facial traits are related to competitive behavior and aggression, but empirical evidence remains inconsistent and is based on a small number of populations and culturally homogeneous samples. We have combined geometric morphometric analyses with hierarchical Bayesian modeling of sixteen culturally and geographically diverse but understudied ethnic groups in order to test whether self-reported aggression covaries with facial sexual shape dimorphism within and between populations. Across populations, we found no consistent association between the individual level of facial sexual dimorphism and self-reported aggression in either sex. Although populations did differ in mean aggression levels, mean self-reported aggression covaried neither with the magnitude of sexual dimorphism nor with overall facial masculinization. Finally, sex differences in self-reported aggression did not reflect morphological sex differences. These findings challenge the generalizability of claims that aggression is encoded in the sexually dimorphic facial structure.
Nonalcoholic steatohepatitis (NASH) is characterized by hepatocyte injury and lobular inflammation driven by lipid accumulation, oxidative stress, and apoptosis. Low testosterone levels are associated with increased steatosis risk, particularly in transgender women undergoing feminization. To investigate the effects of estradiol supplementation and its mechanisms involving lipid metabolism, oxidative stress, apoptosis, and mitogen-activated protein kinase (MAPK) signaling (ERK, JNK, and p38) in testosterone-deficient rats fed a high-fat, high-fructose (HFHF) diet. Twenty-one male Sprague-Dawley rats were randomized into three groups (n = 7/group): (i) control (standard diet), (ii) ORX + HFHF (bilateral orchidectomy plus HFHF diet), and (iii) ORX + HFHF + E2 (ORX + HFHF plus oral estradiol, 1.6 mg/kg/day). After 6 weeks, the ORX + HFHF group exhibited the greatest hepatic steatosis, lobular inflammation, hepatocyte ballooning, NAS scores, and Oil Red O staining. Lipid accumulation markers (PLIN2 and Foxa1), oxidative stress markers (MDA, 4-hydroxynonenal, HO-1, and iNOS), and Nrf2 expression were significantly increased versus controls. Testosterone deficiency combined with HFHF feeding induced apoptosis primarily through the intrinsic pathway, evidenced by increased Bax, Bcl-2, caspase-3, and caspase-9, while caspase-8 showed an increasing trend. Estradiol supplementation significantly attenuated NASH pathology by reducing lipogenesis, oxidative stress, and apoptosis, with these effects strongly associated with suppression of all MAPK subtypes. Estradiol mitigates NASH progression in testosterone-deficient rats by modulating lipid metabolism, restoring antioxidant defenses, suppressing intrinsic apoptosis, and inhibiting MAPK signaling. These findings provide mechanistic insight into hormone therapy in transgender women and identify GPER/MAPK signaling as a potential therapeutic target.
Cities across the United States are experimenting with civilian-led alternatives to policing, yet rigorous evidence of their effectiveness remains scarce. This study evaluates a large-scale civilianized public safety program in San Francisco that deploys unarmed "safety practitioners" to high-crime intersections to provide consistent presence, de-escalation, and service referrals in place of traditional law enforcement. Using a generalized synthetic control design covering 624 intersections from 2018 to 2023, we estimate the causal impact of practitioner deployment on reported crime. We find that deployments significantly reduced total and behavioral health-related crimes, with smaller yet meaningful reductions in drug and violent crimes, and no change in property crime. These effects persisted across robustness checks comparing daytime (operating) to nighttime (nonoperating) hours, suggesting that observed declines are attributable to practitioner presence rather than secular trends. The findings indicate that civilianized safety practitioners-drawn largely from communities affected by incarceration, addiction, and homelessness-can function as capable guardians who lower public disorder without relying on coercive authority. By embedding trusted, nonpolice actors in high-need public spaces, cities may improve safety while reducing harmful police contact and expanding workforce opportunities for people historically excluded from the formal economy.
The persistent threat of influenza pandemics and seasonal outbreaks, coupled with rising resistance to existing antiviral drugs targeting influenza viruses, necessitates the development of new therapeutics. This study investigated the antiviral potential of cell-penetrating peptide-conjugated host nucleolin (NCL)-binding peptide drugs, AGM-380d (dimeric) and AGM-380t (tetrameric), as innovative, broad-spectrum host-directed anti-influenza therapies. Infection with both influenza A and B viruses (IAVs and IBVs) significantly increased NCL expression and colocalization with viral nucleoprotein (NP), a core component of viral ribonucleoprotein complexes, in both in vitro and in vivo settings. The peptide drugs rapidly localized to the nucleolus and specifically bound to NCL. This targeted binding successfully disrupted the interaction between NCL and the NP of IAV and IBV, effectively blocking nuclear NP trafficking and inhibiting the replication of both pandemic and seasonal strains. Importantly, AGM-380d and AGM-380t protected mice from lethal IAV challenge by markedly reducing lung viral replication and pathology. The combination of AGM-380t with oseltamivir resulted in 100% protection from mortality following the deadly IAV challenge. In conclusion, AGM-380d and AGM-380t are highly promising as novel, broad-spectrum host-directed antivirals for the management of seasonal and pandemic influenza.
Constitutive relations-functions linking a local state variable to a material or system property such as thermal conductivity, hydraulic permeability, or reaction rate constant-appear across the physical, engineering, and life sciences. They must often be inferred from sparse, indirect observations of the field they govern rather than from direct assays. Unlike the well-studied spatially varying parameter ϕ ( x ) , the scalar state-dependent function ϕ ( u ) : R → R + of a single local state variable has received no systematic Bayesian treatment, and a basic question remains open: how much can sparse indirect observations actually inform ϕ ( u ) ? We show the answer is governed by a two-factor attenuation: information must pass first through the inverse of the linearized partial differential equation (PDE) Jacobian and then through the sparse observation mask. The product of these factors lies far below unity for practical configurations, leaving the posterior structurally prior-dominated regardless of the number of indirect observations of the same type and configuration. The primary determinant is not the PDE class but the coupling mechanism-whether ϕ ( u ) enters the residual through a spatial gradient (as for diffusion coefficients) or pointwise (as for source terms). We instantiate the analysis in a sparse variational Gaussian process with an explicit, checkable prior and a closed-form Laplace posterior, and validate it across four PDE classes, four constitutive shapes, and two prior conditions. A small number of direct constitutive measurements at well-placed state values, bypassing the PDE entirely, collapse the posterior where arbitrarily many indirect observations of the same type cannot.
The rising incidence of antimicrobial resistance (AMR) has threatened global public health with a high mortality rate. In parallel, the de-incentivization for further investment, regulatory constraints, and overuse/misuse of antibiotics have accelerated the progression of AMR. Together, these factors have contributed to the declining efficacy of a wide spectrum of antibiotics and the increasing prevalence of drug resistance that outpaced AMR-specific drug development. More importantly, even with substantial historical investments in antibiotic discovery over several decades, the development of clinically actionable, novel antibiotics has remained limited. In this article, we present the challenges of addressing AMR and outline emerging strategies that may reduce its burden. While advanced therapies, including bacteriophage therapy, have demonstrated promising results, complementary strategies that integrate emerging technologies and engage diverse stakeholders are needed. Building on this vision, we propose the potential role of AI-powered platforms in supporting and accelerating AMR-specific drug development alongside a community-driven approach that engages scientists, policymakers, health economists, clinicians, and patients to help address existing scientific and translational challenges. Furthermore, this article offers an inclusive strategy with key considerations, including educational and public health interventions, government-led programs, and health economics, which together could potentially tackle the threat of AMR along with AI-powered solutions.
A substantial body of evidence documents misperceptions among natives regarding the number of migrants and their integration. Using two experimental studies, we show that these misperceptions are context-dependent rather than universal. The first study examines whether the accuracy of natives' perceptions varies with the spatial scale at which they are elicited. People consistently overestimate the share of migrants, and this misperception does not depend on scale. In contrast, perceptions of migrant integration improve at more localized levels: natives underestimate integration at the national scale but estimates become more accurate at the district and neighborhood levels. The second study shows that perceptions of labor market integration for both natives and migrants are generally inaccurate and vary across different migrant groups. Overall, our findings suggest that researchers studying (mis)perceptions about migrants should carefully consider the spatial context of their data. Misperceptions are more nuanced than previously recognized.
People are often prompted to donate to charities through subtle cues rather than purely noble intentions. While previous studies have identified various factors that promote prosocial behavior, these factors have not been fully tested in designing effective donation advertisements. Here, focusing on advertisements for the nongovernmental organization WaterAid Japan, we conducted an online nudge experiment (n = 6,232) that revealed emphasizing "society's expectation" is most effective at soliciting donations without adverse psychological effects. We then tested messages with this emphasis in real-world advertisements on a commercial online platform (Yahoo Ads), comparing them to alternative framings that emphasized "inequity aversion," "sense of control," or "warm glow." The "society's expectation" message achieved the highest number of impressions and clicks to the final donation page, suggesting its strong effect in activating prosocial instincts in real-world social decision-making.
Understanding landfill-related groundwater contamination is challenging in heterogeneous hydrogeological settings characterized by sparse monitoring networks and limited subsurface information, constraints common to many environmental and earth-science systems. Based on our previous investigations, we present an interpretive framework that synthesizes machine learning (ML), hydrogeochemistry, and subsurface geoelectrical imaging to characterize leachate plume dynamics and surface methane emissions. We examine two Canadian case studies: a closed, nonengineered municipal landfill and an industrial bark dump near an Indigenous community. At both sites, direct-current electrical resistivity (ER) and induced polarization (IP) surveys were conducted, and the resulting data were inverted to produce 2D and pseudo-3D tomographic images of leachate-related anomalies. In the municipal landfill, a supervised Adaptive Neuro-Fuzzy Inference System employed geoelectrical proxies of waste stabilization to infer landfill-scale methane-emission trends, with localized misfits attributed to near-surface biogas attenuation and metallic-waste-related high-IP responses. Gaussian Mixture Modeling (GMM) and stacked pollution index mapping of hydrogeochemical data delineated contamination zones used to validate low-ER anomalies at well-screening depth. For the industrial landfill, hydrogeochemical facies were identified from water-quality parameters using unsupervised ML methods (GMM, Hierarchical Agglomerative Clustering, and Self-Organizing Maps + K-means), supporting the interpretation of ER and IP anomalies associated with plume migration, mixing interfaces, and matrix-controlled attenuation. These studies illustrate a methodological framework in which ML links geophysical proxies and environmental processes. By integrating geophysical and hydrogeochemical information and evaluating cross-domain consistency using multiple ML methods, this framework reduces interpretive ambiguity and strengthens process-based conceptual models in data-limited settings.
Scaling up microvessel culture systems is essential for producing clinically relevant vascularized tissues, yet conventional microphysiological platforms offer limited insight into how to maintain flow conditions during scale-up. Here, we present a computational-experimental framework using computational fluid dynamics (CFD) to guide the design and scaling of microvessel bioreactors. Interstitial flow (IF) distributions were predicted in two perfusion-based platforms-a permeable well-plate insert and a rhomboidal microfluidic chamber-across multiple scaling factors and hydrostatic pressures. CFD identified IF ranges conducive to microvessel network formation and quantified how geometry and pressure modulate the flow field. IF-preserving scale-up in permeable well-plate inserts generated microvessel networks with consistent morphology metrics across a more than 30-fold increase in culture volume. In microfluidic rhomboidal chambers, regions with distinct CFD-predicted IF velocity fields showed significant differences in average lumen diameter and total vessel length per area under otherwise matched experimental conditions, supporting an association between local IF environment and regional morphology. Together, these results show that CFD can predict and compare IF environments during scale-up, that preserving IF conditions during scale-up can result in similar morphology metrics, and that IF distributions inside a device can correlate with regional network morphology.
Neuropathic pain encompasses a spectrum of conditions that significantly impact quality of life. In case of nerve injuries, when regenerating axons fail to reach their target organs, they can form painful neuromas, yet the mechanisms underlying their formation remain unclear. In this exploratory study, we analyzed the neural components of painful neuromas by examining the expression patterns of key nociceptor markers. Neural components within neuromas exhibited up-regulated growth-associated protein 43, indicating their regenerative potential. Calcitonin gene-related peptide was expressed in 84% of axons, versus 3% in healthy nerves, suggesting a phenotypic shift toward a nociceptive profile. We also observed increased expression of the mechanosensitive channel Piezo2 in 78% of axons and up-regulation of the low-threshold sodium channel Nav1.3, consistent with heightened mechanosensitivity and hyperexcitability. These observations identify candidate molecular alterations in painful neuromas and may provide a guide for future development of targeted therapies for neuroma-related pain.
Recent empirical literature has documented that men and women differ systematically in measures of patience, risk-taking, trust, and prosociality in many countries throughout the world. These gender gaps have been associated with variation in economic and social development. However, little is known about how these gender gaps evolve and whether they systematically vary across age cohorts. To examine this question, we analyze how within-country gender gaps in patience, risk-taking, trust, and prosociality have evolved. We compare gender gaps across country-period-cohort cells using two survey datasets covering 460,000 people in more than 100 countries. Our results document that gender gaps in patience, risk-taking, trust, and prosociality are smaller among younger cohorts, and suggest that this decline can be attributed to variation across birth cohorts rather than age groups. These findings challenge the conjecture that gender gaps widen as countries develop and instead point to an ongoing decline in the differences between men and women.
Light pollution, an increasingly recognized environmental hazard, disrupts urban ecosystems, including plant phenology, such as leaf-out and senescence. In recent years, municipalities have enacted legislation to reduce artificial light at night (ALAN) at city levels. However, the effectiveness of these mitigation strategies on reducing ALAN and their impacts on urban ecosystems remain underexplored. Here, we present a proof of concept analysis to explore the potential of ALAN-mitigation policies on changes in intensity and spectrum composition of ALAN and consequent changes in plant phenology using Sustainable Development Science Satellite 1 data for 2022-2024 in paired US cities-one with mitigation policies and one without. Results suggest that ALAN declined in cities with ALAN-mitigation policies (New York City and Washington DC), with the largest decline in blue band. In contrast, ALAN increased in cities without policies (Newark and Philadelphia). The reduction in shifts of spring and autumn phenology observed in cities with mitigation was consistent with declines in ALAN exposure. These findings highlight the potential of multispectral nighttime light data in quantitatively assessing the efficacy of ALAN-mitigation policies in reducing light pollution and its ecological impacts.
The Asian longhorned tick (Haemaphysalis longicornis) impacts the health of humans, livestock, and wildlife, both as a parasite and a vector. Over more than a century, H. longicornis has become a widespread invasive species across much of the Asia-Pacific region, with a recent emergence in North America. This dispersal success could be associated with the ability of certain lineages of H. longicornis to reproduce via parthenogenesis. We analyzed complete mitochondrial genomes and genome-wide single-nucleotide polymorphisms (SNPs) from ticks collected within the native range of H. longicornis (Japan), invasive populations in the Asia-Pacific (Australia, Fiji, and New Caledonia), and laboratory-maintained parthenogenetic and bisexual strains. We also compared our data with DNA sequences in GenBank from invasive populations in other countries (e.g., United States). Two distinct clades (Mt-Clade 1 and Mt-Clade 2) were observed in the phylogenetic tree based on mitochondrial genomes. All specimens from the bisexual laboratory strains were assigned to Mt-Clade 1 and those from the parthenogenetic laboratory strains were assigned to Mt-Clade 2, whereas the field-collected male specimens were included in both clades. No geographical cline associated with the phylogenetic characteristics was observed. In contrast, analyses based on genome-wide SNPs demonstrated a cluster composed of Oceanian samples apart from Japanese samples and detected gene flow between the two mitogenomic clades. Our results suggest that parthenogenesis may have evolved multiple times within H. longicornis rather than originating from a single evolutionary event.
Urban segregation challenges the sustainable and inclusive development of cities, yet little is known about how to address it effectively. This study examines how restaurants in Chengdu, China, a city renowned for its vibrant food culture, shape social interactions in daily life, aiming to uncover ways to promote greater social mixing. Drawing on 1.52 million cell phone records and information on 5,347 restaurants from Dianping.com, social isolation indices were measured across residential contexts and dining-out activities. The results show that the social isolation index during dining-out activities is, on average, 47.3% lower than in residential settings. Community restaurants with dense service coverage within 5.76 km demonstrate substantial potential to reduce social isolation. However, restaurant visits are highly unevenly distributed and concentrated in a limited number of neighborhoods in central and newly developed districts. Regression analyses reveal that restaurant-level social segregation is strongly negatively associated with customer flows, while service radius has a positive effect, in contrast, price level and cuisine type show no significant impact. These findings from Chengdu, China, provide a motivation and an analytical framework for future research in other contexts to examine how the food service industry may relate to social integration, including through factors such as affordability and transport accessibility.
