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Reply to Possenriede et al.: LDLR as a targetable HlyA receptor in <i>Escherichia coli</i> pyelonephritis

Influence of age and sex on the relative biological effectiveness of 13-keV/μm carbon ions for lifespan shortening of B6C3F1 Mice

Epidemiological studies of Japanese atomic bomb survivors indicate that the risk of cancer from radiation exposure is higher in individuals who are relatively young at the time of exposure, with women facing a more significant risk compared to men. However, this type of data is limited for other radiation types, such as particle radiations. Low linear energy transfer (LET) carbon ions are a type of particle radiation to which humans may be exposed as cosmic radiation during long-duration space missions and as radiation passing through healthy tissue during carbon ion radiotherapy. This raises concerns about the risk of late complications, including cancer development. To address these issues, we examined the lifespan of mice after exposure to γ rays or low-LET carbon-ion beams, assessed the effects of sex and age at the time of exposure, and calculated the RBE. Male and female B6C3F1 mice of various ages (embryonic days 3, 13, and 17, and postnatal weeks 1, 3, 7, and 15) were whole-body irradiated a single time with 137Cs γ rays (662 keV) or 290-MeV/u monoenergetic carbon ions (LET, ~ 13 keV/µm), and their lifespan was analyzed. For both γ rays and carbon ions, the hazard ratio for mortality increased in a dose-dependent manner, was higher for females than for males, and peaked at 1 week of age at the time of exposure. The RBE of low-LET carbon ions for lifespan shortening was 0.9–1.8 for females and 1.2–2.0 for males, regardless of the age at exposure. Thus, the risk associated with low-LET carbon ion exposure varied with age and sex, but RBE did not. These findings provide essential data for assessing the impacts of low-LET carbon ion exposure.

Weighted active space protocol for multireference machine-learned potentials

Multireference methods such as multiconfiguration pair-density functional theory accurately capture electronic correlation in systems with strong multiconfigurational character, but their cost precludes direct use in molecular dynamics. Combining these methods with machine-learned interatomic potentials (MLPs) can extend their reach. However, the sensitivity of multireference calculations to the choice of the active space complicates the consistent evaluation of energies and gradients across structurally diverse nuclear configurations. To overcome this limitation, we introduce the weighted active space protocol (WASP), a systematic approach to assign a consistent active space for a given system across uncorrelated configurations. By integrating WASP with MLPs and enhanced sampling techniques, we propose a data-efficient active learning cycle that enables the training of an MLP on multireference data. We demonstrated the approach on the TiC + -catalyzed C–H activation of methane, a reaction that poses challenges for Kohn–Sham density functional theory due to its significant multireference character. This framework enables accurate and efficient modeling of catalytic dynamics, establishing a paradigm for simulating complex reactive processes beyond the limits of conventional electronic-structure methods.

Distinct transcriptomic effects of intermittent and chronic caloric restriction in mammary fat pad of a breast cancer mouse model

Age-related dysfunction in neuroendocrine signaling, which influences adipose tissue homeostasis, has been implicated in numerous diseases, including breast cancer. Caloric restriction has been shown to improve metabolic health and prolong lifespan, yet the molecular mechanisms underlying its long-term effects are not fully understood. In this study, we investigated the impact of long-term chronic (CCR) and intermittent caloric restriction (ICR) on the whole transcriptome of mammary fat pad tissue (MFP) in a breast cancer mouse model. Transgenic female Mouse Mammary Tumor Virus-Transforming Growth Factor-Alpha (MMTV-TGF-ɑ) C57BL/6 mice were randomized into ad libitum (AL), CCR, and ICR groups. Total RNA was isolated from the samples collected at weeks 10 (baseline), 49/50 (adult), and 81/82 (old), were then subjected to RNA sequencing. Differential gene expression analysis identified significant age-related transcriptomic shifts. Specifically, Malat1 expression levels, a long non-coding RNA associated with cancer progression, were elevated with aging, suggesting increased tumorigenic susceptibility in this model. Pathways linked to neuroendocrine signaling were downregulated with age, reflecting a potential decline in neuro-adipose cross-talk. Remarkably, ICR appeared to mitigate this age-related decline in neuroendocrine signaling by upregulating genes involved in neurotransmitter support and downregulating extracellular matrix organization and positive regulation of angiogenesis. In contrast, CCR did not effectively alter the whole transcriptome profile, particularly in long-term. Our findings reveal that ICR mitigates age-related transcriptional shifts in MFP tissue, providing a novel insight into dietary strategies for maintaining adipose tissue function with potential implications for cancer susceptibility.

Tropical cyclones expand faster at warmer relative sea surface temperature

Tropical cyclones are expected to intensify more rapidly with warming, but relatively little work has examined whether they could expand more rapidly with warming, too. Recent theory predicts that peak expansion rate should increase with sea surface temperature (SST), and physical arguments suggest this dependence should be specifically on the relative SST, i.e. the SST difference from the tropical mean. We test this hypothesis with historical observational data, in which SST variations are primarily variations in relative SST. Both average and peak expansion rates are found to systematically increase with relative SST globally across the Northern Hemisphere (27.2 and 37.5 km/d/K) and within each individual basin. Results are robust across both reanalysis and Best Track observational datasets. Uniform-SST aquaplanet simulations show a much weaker dependence of maximum expansion rate on absolute SST, suggesting that the dominant dependence is on relative SST. Hence, mean global warming is not expected to strongly change storm size dynamics, but patterns of sea surface warming may play an important role in determining how storm size, and hence coastal risk, may change in the future. This work can also help improve forecasting of the wind field and its hazards and impacts at landfall.

Assessment of environmental risk factors for blastomycosis during a large outbreak at a Michigan paper mill

Background Blastomycosis is a rare, potentially fatal fungal infection caused by inhalation of Blastomyces spores, typically acquired outdoors in the midwestern and eastern United States. In 2023, the largest recorded U.S. blastomycosis outbreak occurred among workers at a paper mill in Michigan’s Upper Peninsula. Few data exist on occupational risk factors or indoor exposure to Blastomyces, limiting prevention efforts. Objectives We assessed workplace environments and conditions associated with blastomycosis risk through a cross-sectional medical survey and environmental sampling. Methods During April 22–28, 2023, we conducted a voluntary medical survey, including a work and health questionnaire and urine antigen testing, for 603 workers out of approximately 1,000 at the mill. We compared worker characteristics, work locations, and environmental exposures by blastomycosis case status and modeled disease risk using Poisson regression. We tested 533 environmental samples of outdoor soil, indoor surface dust, and raw materials for Blastomyces using polymerase chain reaction and culture-based methods. Results Twenty percent of workers were classified as blastomycosis cases based on positive urine antigen testing during the survey, self-reported provider diagnoses, or confirmed or probable case status reported by state or local health departments. Prevalence was highest among workers in paper machine line #1 (27%) and maintenance areas (25%). Adjusted analyses indicated a 40% [Prevalence Ratio (PR): 1.40; 95% confidence interval (CI): 1.00, 1.95] and 53% (PR: 1.53; 95% CI: 1.04, 2.25) higher risk for workers in these locations, respectively, compared to workers working elsewhere. Working in both locations doubled blastomycosis risk. Daily exposure to indoor pooling water was associated with a nearly two-fold higher prevalence of blastomycosis (PR: 1.79; 95% CI: 1.25, 2.57). All indoor and outdoor environmental samples were negative for Blastomyces. Discussion Blastomycosis was associated with specific indoor work locations and environmental conditions, suggesting the potential for occupational exposure to Blastomyces in indoor industrial settings. These findings may guide future outbreak investigations and occupational prevention strategies.

Did the vilca/tobacco snuff combination at Chavín aim for an “ayahuasca effect”?

A protocol for an assessment of the health information system in Khomas region, Namibia

Introduction A robust and well-functioning Health Information System (HIS) is crucial for managing patient care, monitoring health system performance, and informing public health decisions. However, Namibia, like many developing countries, faces challenges in its HIS, such as limited financial and human resources, knowledge gaps, inadequate infrastructure, and behavioural barriers such as resistance to adopting new systems and a lack of supportive policies. Previous studies have not shown significant improvements since 2012. This study, conducted in Namibia’s Khomas region, aims to assess human factors affecting the HIS and evaluate progress made from 2012 to 2022. It draws on recommendations from a 2012 USAID assessment to provide insights and propose strategies to enhance healthcare delivery and resource allocation. Methods and analysis This study utilizes a cross-sectional design and a multi-method approach to evaluate the performance of the Health Information System (HIS). Qualitative component includes 17 in-depth interviews with key informants, a retrospective document review from the Ministry of Health and Social Services (MoHSS) headquarters in Windhoek, supplemented by a modified office/facility checklist from all 14 health facilities in the Khomas region. The quantitative component involves administering a questionnaire to 330 staff members, using an adapted version of the Performance of Routine Information System Management (PRISM)’s Organizational and Behavioural Assessment Tool (OBAT). Descriptive statistics will be applied to analyse the quantitative data, while a deductive interpretive approach will guide the qualitative data analysis. Ethics and dissemination Ethical approval was obtained from the Stellenbosch University Health Research Ethics Committee (Reference No: S23/05/119) and the Namibia Ministry of Health and Social Services (Reference No: 22/3/2/1). The study will be conducted in accordance to the principles of the Declaration of Helsinki (1964). The study seeks to identify barriers and facilitators for implementing recommendations across different levels of the Health Information System (HIS), with a focus on improving HIS functionality in the Khomas region. Dissemination plans include sharing findings with the study population, presenting at both local and international conferences, and publishing peer-reviewed journals.

The cost of banning TikTok: Implications for the digital advertising market

Social media platforms have become vital channels for businesses to reach consumers through advertising. But in the United States, the digital advertising market in which these platforms operate is dominated by a few major players, raising concerns for antitrust regulators. In such a concentrated market, the entry or exit of a single platform can reallocate billions in ad spending, affecting businesses and users. TikTok’s temporary suspension in the United States in January 2025 provides a unique natural experiment to examine how the removal of a major player would shift advertising demand and supply on competitors, specifically Facebook and Instagram, revealing the degree of substitutability across platforms and the intensity of competition. Using a difference-in-differences approach comparing advertising activity in the United States to other countries, we find that Meta ad volume and spend rose by 6.3% and 22.4%, as a result of the outage, without a corresponding increase in ad impressions. Consequently, Meta ad prices, as measured by cost per thousand impressions, jumped by 12.1%. Shifts in demand were three times greater for larger advertisers relative to smaller ones, suggesting that Meta platforms and TikTok are closer substitutes for larger firms and that a TikTok ban would therefore impose greater challenges on smaller businesses.

Dual efficacy-toxicity of Chelidonii Herba in chronic obstructive pulmonary disease: Integrated network pharmacology, immune profiling and molecular docking

Objective To investigate the pharmacodynamic material basis, multi-target mechanisms of Chelidonii Herba in treating chronic obstructive pulmonary disease (COPD), and its hepatotoxicity pathways using network pharmacology, network toxicology, and molecular docking. Methods Active components and targets of Chelidonii Herba were screened via Traditional Chinese Medicine Systems Pharmacology (TCMSP), SwissTargetPrediction (STP), and PharmMapper databases. COPD and hepatotoxicity targets were obtained from GeneCards and OMIM. Venn diagrams identified shared targets. Protein-protein interaction (PPI) networks were constructed using STRING, with core targets filtered via CytoNCA. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed in Metascape. Molecular docking was validated by AutoDock Vina, and immune infiltration was analyzed using the GSE55962 dataset. Results Twenty active components and 108 potential targets of Chelidonii Herba were identified. Eighty shared targets intersected with COPD, and 96 with hepatotoxicity. Seven core targets for COPD treatment (CASP3, PPARG, PTGS2, CDK2, ALB, HSP90AA1, ESR1) and hepatotoxicity (PPARG, ESR1, CASP3, PTGS2, ESR2, CALM3, ALB) were determined. KEGG enrichment revealed COPD mechanisms involving PI3K-Akt, VEGF, and cGMP-PKG pathways, while hepatotoxicity implicated VEGF, PI3K-Akt, and estrogen signaling. Core components (e.g., dihydrochelerythrine, oxysanguinarine) exhibited strong binding to targets (binding energy ≤ −5.0 kcal/mol, partial ≤ −7.0 kcal/mol). Immune infiltration analysis linked core targets to macrophages M2 and γδ T cells. Conclusion Chelidonii Herba treats COPD primarily through alkaloids modulating shared targets (CASP3, PPARG, PTGS2) via PI3K-Akt pathways, while concurrently inducing hepatotoxicity through VEGF and estrogen signaling. This dual efficacy-toxicity profile necessitates cautious clinical application and experimental validation to define safe therapeutic windows.

Parametrically guided design of beta barrels and transmembrane nanopores using deep learning

Francis Crick’s global parameterization of coiled coil geometry has been widely useful for guiding design of new protein structures and functions. However, design guided by similar global parameterization of beta barrel structures has been less successful, likely due to the deviations from ideal barrel geometry required to maintain interstrand hydrogen bonding without introducing backbone strain. Instead, beta barrels have been designed using two-dimensional structural blueprints; while this approach has successfully generated new fluorescent proteins, transmembrane nanopores, and other structures, it requires expert knowledge and provides only indirect control over the global shape. Here, we show that the simplicity and control over shape and structure provided by parametric representations can be generalized beyond coiled coils by taking advantage of the rich sequence–structure relationships implicit in RoseTTAFold-based design methods. Starting from parametrically generated barrel backbones, both RFjoint inpainting and RFdiffusion readily incorporate backbone irregularities necessary for proper folding with minimal deviation from the idealized barrel geometries. We show that for beta barrels across a broad range of beta sheet parameterizations, these methods achieve high in silico and experimental success rates, with atomic accuracy confirmed by an X-ray crystal structure of a rare barrel topology, and de novo designed transmembrane nanopores with conductances ranging from 200 to 500 pS. By combining the simplicity and control of parametric generation with the high success rates of deep learning–based protein design methods, our approach makes the design of proteins where global shape confers function, such as beta barrel nanopores, more precisely specifiable and accessible.

Correction: Risk factors for, metrics of, and consequences of access to veterinary care for companion animals: A scoping review

A reanalysis of population dynamics in the Casas Grandes region of Northern Mexico using mitochondrial DNA

The Casas Grandes region in northwest Chihuahua, Mexico, is ideally situated to explore the notion of contact between the US Southwest/Northwest Mexico and Mesoamerica, as it lies geographically in a region where cultural traditions were combined in unique ways. In order to explain these dynamics, past researchers have suggested that the primary catalyst for the flourishing Casas Grandes population in the thirteenth century A.D. was caused by migrants from Mesoamerica or from larger populations to the north. We analyzed mitochondrial genetic data from individuals interred at sites that date to earlier (A.D. 700–1200) and later (A.D. 1200–1450) time periods, which allowed us to examine changes in gene pools over time and to test these migration hypotheses. Comparing the full mitogenomes from 114 individuals, we show that low levels of migration occurred diachronically, although they still may have contributed to hybridized cultural practices. These data counter the long-standing assumption that widescale population replacement was the cause for the rise of Paquimé, the center of the Casas Grandes world in the thirteenth-century A.D.

Online assessment of medical students’ communication competence in patient encounters: Validation of the VA-MeCo situational judgement test

Background Medical communication is a core task of physicians, and its quality affects both patients and physicians. Hence, the teaching and measurement of medical communication competence (MCC) are crucial during medical studies. This study aims to explore the factorial and construct validity of the Video-Based Assessment of Medical Communication Competence (VA-MeCo), an online-situational judgement test (SJT) designed to measure three aspects of medical students’ communication competence in patient encounters: advancing content, providing structure, and building relationship. Methods We conducted an online survey with N = 395 medical students. Factorial validity was tested by confirmatory factor analysis (CFA). To investigate convergent and discriminant aspects of construct validity, we tested correlations of participants’ VA-MeCo sub-test scores with scores in relevant cognitive variables, patient-interaction, and general personality traits. Results The CFA confirmed the expected three-dimensional factorial structure showing good model fit and highly correlated dimensions. A McDonald’s Ω of.94 for the complete test and &gt;.81 for the sub-scales indicated high reliability. Regarding construct validity, the directions of the correlations were in line with the theoretically assumed associations; correlation sizes partly deviated from our expectations. Conclusions The results support that MCC can be validly measured using the VA-MeCo. The CFA results align with theory and previous studies that proposed three distinguishable dimensions of MCC. The findings on convergent and discriminant validity demonstrate that the test measures MCC as a specific construct that is positively related to patient-interaction; moreover, it can be distinguished from related but more generic constructs (e.g., social competence) and is not overly confounded with construct-irrelevant traits (e.g., intelligence). Notwithstanding the need for further validation, the results indicate that the VA-MeCo is a useful test for assessing MCC in medical education.

Reply to Quillien: Intuitive preferences and interpretive humility in intentionality judgments

Motivation matters: How enrollment motives shape doctoral experiences and career aspirations

This study examines the motivational profiles of Russian doctoral students and their implications for academic success, satisfaction, and career aspirations. We employ data from a nationwide survey of doctoral students at Russian universities (N = 1,267). Using latent class analysis we identify four distinct motivational profiles: Academic Orientation, Unconscious Motives, Topic Devoted, and Everything Everywhere All at Once. Our findings reveal that students with academic orientations exhibit higher satisfaction, greater confidence in successfully defending their dissertations, and a stronger intention to pursue research careers. In contrast, students with unconscious motives demonstrate lower satisfaction, reduced confidence, and a weaker inclination toward research career paths. These findings highlight the role of unclear enrollment goals or non-academic motivations, such as military service deferment, in shaping doctoral outcomes. Additionally, our analysis shows that engagement in research is the only aspect of the doctoral experience that fosters research career aspirations among students with initially non-academic motivations. These findings emphasize the need for Russian universities to reconsider admission policies, doctoral program structures, and academic support mechanisms to better accommodate the increasingly diverse expectations of doctoral students. The study contributes to the broader discourse on doctoral education by providing empirical insights into the relationship between motivation, institutional factors, and career trajectories.

Tubular ACSM3 deficiency impairs medium-chain fatty acid metabolism and aggravates kidney fibrosis

Kidney fibrosis is driven by multiple factors, among which impaired fatty acid oxidation has emerged as a critical determinant. Acyl-Coenzyme A (CoA) synthetase medium-chain family member 3 (ACSM3), a key enzyme of medium-chain fatty acid (MCFA) metabolism, has been implicated in metabolic syndrome, but its function in fibrotic kidney remains unexplored. Here, we found that tubular epithelial ACSM3 expression was downregulated in kidney fibrotic mice and patients and inversely correlated with disease severity. Systemic and tubular-specific knockout of ACSM3 both exacerbated renal fibrosis, whereas adeno-associated virus (AAV)-mediated ACSM3 overexpression alleviated fibrotic kidneys in mice. Mechanistically, ACSM3 deficiency disrupted MCFA metabolism and resulted in abnormal mitochondrial homeostasis. Notably, we identified that dodecanoic acid (C12:0) could improve kidney fibrosis, which was primarily utilized via ACSM3 in kidneys. Furthermore, C12:0 oxidation impairment caused by tubular ACSM3 deficiency aggravated fibrotic kidney. Together, ACSM3-regulated MCFA metabolism played a pivotal role in kidney fibrosis, highlighting a potent drug target of ACSM3 and a potential supplementary therapy of MCFA against chronic kidney disease.

An automated skeleton extraction method for 3D point-cloud phenotyping of Schima Superba seedlings

Aiming to address the issues of low efficiency and large errors in the manual measurement process of phenotypic parameters in Schima Superba seedlings, an automated non-destructive method for acquiring phenotypic parameters based on three-dimensional point clouds is proposed, which includes the main steps of alignment, skeleton extraction, and automatic phenotypic calculation. Aiming to overcome the technical challenges of stem and leaf separation in Schima Superba, a density-weighted voxel centroid method is proposed to extract skeleton points, combined with minimum spanning tree (MST) and principal component analysis (PCA) techniques to accurately identify the stem skeleton point cloud, effectively addressing the problem of stem-leaf separation. The separation process encounters difficulties at the stem-leaf junction, resulting in suboptimal separation accuracy. An improved K-means++ algorithm is proposed to initially estimate the number of adhering leaves based on coarse segmentation, followed by fine segmentation to achieve higher precision in leaf segmentation, effectively improving the accuracy and efficiency of the segmentation process. Following the completion of stem and leaf segmentation, a fully automated phenotypic characterization method based on the segmented point cloud is proposed for the first time. The method automatically outputs relevant phenotypic parameters, including plant height, stem length, stem diameter, and leaf area. The predicted correlation coefficients for the experimental phenotypes were 0.994, 0.992, 0.938, and 0.873, meeting the requirements for on-site measurement of phenotypic parameters in Schima Superba and providing strong technical support for plantation management and cultivar improvement.

Earliest evidence of smoke-dried mummification: More than 10,000 years ago in southern China and Southeast Asia

In southern China and Southeast Asia (collectively, Southeastern Asia), Terminal Pleistocene and Early to Middle Holocene (ca. 12,000 to 4,000 cal. BP) hunter-gatherer burials feature tightly crouched or squatting postures, sometimes with indications of post-mortem dismemberment. Such burials contrast strongly with the extended supine burial postures typical of subsequent Neolithic inhumations in these regions. Their contorted postures, often with traces of burning, present interpretive challenges. This study uses multiple techniques, including X-ray diffraction and Fourier-transform infrared spectroscopy, to investigate 54 pre-Neolithic burials from 11 archaeological sites located across Southeastern Asia. The findings confirm that many of these pre-Neolithic flexed and squatting burials were treated by an extended period of smoke-drying over fire, a process of mummification similar to that recorded ethnographically in some Australian and Highland New Guinea societies. Some of the analyzed archaeological samples represent the oldest known instances of such artificial mummification in the world.

Loneliness is not associated with attention interference of negative social information: Evidence from four studies

Extended experiences of loneliness, defined as perceived social isolation, are associated with lasting impacts on health outcomes. One proposed mechanism through which loneliness contributes to health risk is heightened vigilance to cues of social threat resulting in extended activation of stress responses systems. This heightened vigilance is thought to be driven by loneliness-related shifts in a variety of cognitive and affective processes, though the differential effects of loneliness on specific stages of processing remain unclear. The present study examined four datasets using individual participant data meta-analytical techniques to test the link between loneliness and attention interference to social threat cues in an Emotional Stroop task. Despite existing theoretical frameworks predicting heightened attentional interference for negative social information in lonely individuals, we found no support for this effect across the four samples. These findings highlight the need for further work delving into the complex interplay between distinct perceptual processes associated with loneliness and how they contribute to the maintenance of loneliness states over time.