Browse Articles

The molecular mechanism of lipid uptake by membrane-anchored bridge-like lipid transfer proteins

Lipid transport by bridge-like lipid transfer proteins (BLTPs) is emerging as a key process in lipid and cellular metabolism in both physiological and pathological conditions. However, the precise mechanism of lipid transport by BLTPs has remained elusive. Here, we use extensive all-atom molecular dynamics simulations to characterize the precise mechanism of lipid transfer into the BLTP hydrophobic cavity from donor membranes. For multiple BLTPs, we observe the ability to extract and solubilize lipids without lipid selectivity, and we identify membrane destabilization as a critical parameter to achieve effective lipid desorption. We rationally design a mutant BLTP with altered ability to destabilize lipid bilayers, and we show that this abolishes lipid desorption in silico and protein function in vivo. Taken together, our data provide an atomic-level description of the mechanism of lipid transport by BLTPs, ultimately suggesting alternative strategies to interfere with their activity.

Correction: Trends and disparities in ischemic stroke mortality and location of death in the United States: A comprehensive analysis from 1999–2020

Therapeutic effects of IGF-2 on NMOSD by inhibiting astrocyte apoptosis through modulation of the IGF-1R/PI3K/AKT signaling pathway

Spatially regulated mRNA translation enables functional membrane protein integration in synthetic cells

Synthetic cells aim to emulate living systems by reconstituting essential cellular processes within lipid-bound architectures. However, their functional complexity remains constrained by a key challenge: the synthesis and correct integration of hydrophobic membrane proteins via cell-free approaches. Here, inspired by natural cells, we developed a spatially regulated translation strategy in which membrane-anchored mRNAs recruit ribosomes to drive the cotranslational insertion of membrane proteins into lipid bilayers. This design enables efficient in situ synthesis and integration of multiple transmembrane proteins within giant unilamellar vesicles, supporting selective small-molecule transport across membranes. Importantly, the method allows for precise stoichiometric control of membrane protein composition. Together, this work establishes a minimal yet versatile framework for the direct synthesis and integration of membrane proteins, advancing the construction of functional synthetic cells.

How audiences express emotions towards influencer short videos: Sentiment analysis of ‘my second uncle’

As short videos dominate digital communication, this study examines audience emotional expression in this evolving media landscape. Focusing on the popular Chinese video “My Second Uncle”, we collected bullet subtitles—user comments displayed on-screen—and related comments. Using Latent Dirichlet Allocation (LDA), we identified key themes, while SnowNLP and ChatGPT facilitated an in-depth emotional analysis. Findings show a nuanced audience “gaze” toward the protagonist, with a strong trend of embracing his inspirational story, which generated predominantly positive emotional responses. Unlike traditional “gaze” research, engagement here was active and voluntary, with viewers using innovative online language. The study also reveals that influencer-driven short videos can quickly foster positive group sentiments, underscoring their potential for emotional healing and mental well-being.

Advanced single-strut modelling of lightweight in-filled RC frames: validation and seismic performance assessment

Abstract Accurate numerical simulation of masonry-infilled reinforced concrete (RC) frames is essential for seismic performance assessment, particularly with modern lightweight infill systems like hollow clay bricks (HCB), gypsum blocks (GB), and autoclaved lightweight concrete (ALC) panels. This study presents an advanced single-strut macro-modeling framework, implemented in SAP2000, designed to overcome the limitations of conventional approaches in capturing the distinct nonlinear behavior of these systems. The core innovation involves the development of material-specific nonlinear axial hinges, meticulously calibrated against the full-scale experimental dataset from Cai et al. (J. Earthq. Eng. 23(9):1531-1559, 2019) to replicate crushing (HCB), shear-sliding (GB), and slip-hardening (ALC) mechanisms. The calibrated model demonstrates high predictive accuracy, with errors in lateral capacity and initial stiffness below 10% for all systems. Leveraging this validated model, a comprehensive comparative seismic performance analysis was conducted. The results quantify a critical performance trade-off: HCB infills increased initial stiffness by 471% but exhibited brittle failure, while ALC panels provided superior ductility (µ = 5.39) and stable energy dissipation up to 4.06% drift. The gypsum system confirmed its seismic inadequacy due to abrupt strength degradation. The study concludes that the proposed modeling strategy provides a reliable tool for performance-based design and analysis, enabling engineers to efficiently conduct parametric studies and evaluate the seismic viability of different infill systems at a fraction of the cost and time of full-scale testing.

Genetic associations with education have increased and are patterned by socioeconomic context: Evidence from 3 studies born 1946–1970

Social scientists have long sought to investigate whether the predictors of educational attainment (EA) have changed across time. Here, we provide insights by incorporating genetic predictors of education in three nationally representative British birth cohorts born in 1946, 1958, and 1970. We investigated whether individual characteristics as proxied by polygenic indexes (PGIs) for EA and cognition have become more relevant to educational success over time and whether returns to genetic predisposition were moderated by early life socioeconomic background. We present three findings. First, associations between the EA PGI and attainment increased over time, with increasing incremental variance explained by the EA PGI. Second, associations between the cognition PGI and attainment were broadly consistent across cohorts, and there was no clear change in explained variance. Since the EA PGI captures multiple traits related to educational success, factors other than those related to cognition may have become more relevant over time. Third, we observed strong evidence of interaction: Associations between the EA PGI and EA were disproportionately larger among those from more advantaged socioeconomic backgrounds. The strength and pattern of associations varied when using EA PGIs that were less conservatively filtered for SNPs. Our findings suggest EA is influenced by social and genetic factors both independently and jointly. Genetic liability and social background could be considered as two forms of inherited advantage which synergistically influence education attainment.

Peer support after clinical incidents in veterinary care: Adopting the RISE (Resilience In Stressful Events) program

Veterinary professionals often experience emotional distress after clinical incidents, affecting well-being and job performance. This study explores the adaptation and implementation of the Resilience In Stressful Events (RISE) program, originally developed for human healthcare, to support veterinary clinicians. RISE provides peer support through trained responders, focusing on emotional care rather than event details. Findings indicate that the RISE program is both acceptable and feasible for veterinary settings, with minor adaptations, such as including veterinary examples, to fit veterinary specific needs. The study highlights the importance of structured support systems in improving the mental health and retention of veterinary professionals, suggesting that programs like RISE could play a crucial role in enhancing clinician wellbeing and care quality.

Unveiling economic and humanistic burden of hematologic malignancies in Japan with personal health record data

Abstract To characterize the economic and humanistic burden of patients with hematologic malignancies in Japan using real-world data. Patients with a claim record for a hematologic malignancy who responded to a survey regarding productivity loss and quality of life (QoL) were analyzed to assess their direct medical cost, productivity loss, and QoL along with their levels of comorbidity. This study identified a main cohort of 122 patients with a hematologic malignancy who responded to Work Productivity and Activity Impairment (WPAI) and EQ-5D-5 L questionnaires. Median patient age was 54.5 years (range 25–71 years), with median Charlson Comorbidity Score (CCI) of 2. Most of the mean total cost (USD 12,836.14; JPY 1,670,624) was attributed to productivity loss (mean USD 8,106.39; JPY 1,055,046) rather than direct medical cost (mean USD 4,729.76; JPY 615,578). Presenteeism (mean USD 5,117.84; JPY 666,086) accounted for a greater proportion of productivity loss than absenteeism (mean USD 2,988.55; JPY 388,960). Deterioration in QoL (-0.045) was observed in comparison to the general population in Japan. The results point to the need for a social security policy to provide appropriate support such as better therapies or access for patients who must receive treatment while still working.

Quantifying the compressibility of the human brain

In the human brain, the allowed patterns of activity are constrained by the correlations between brain regions. Yet it remains unclear which correlations—and how many—are needed to predict large-scale neural activity. Here, we present an information-theoretic framework to identify the most important correlations, which provide the most accurate predictions of neural states. Applying our framework to cortical activity in humans, we find that the vast majority of variance in activity is explained by a small number of correlations. This means that the brain is highly compressible: Only a sparse network of correlations is needed to predict large-scale activity. We find that this compressibility is strikingly consistent across different individuals and cognitive tasks and that, counterintuitively, the most important correlations are not necessarily the strongest. Together, these results suggest that nearly all correlations are not needed to predict neural activity, and we provide the tools to uncover the key correlations that are.

Gendered activities: Men farm, women trade, or is it less clear-cut?

The study explores gender participation in agricultural value chains, showing how roles are differentiated across genders and regions. The study fills an important gap in the literature which takes gender disparities as uniform and ignores subnational differences in farming and trading activities, with a focus on Africa’s most populous country, Nigeria. We estimated gender differences in participation, and compared welfare outcomes, using a combination of logit regression models, and instrumental variable estimation, that control for unobserved factors in the model. Household consumption expenditure is used as a proxy for welfare in the data, the most recent General Household Survey, covering more than 32,000 individuals. We find that men dominate farming, while women tend to dominate retail and wholesale trade, but with large regional differences that blur these distinctions. Being a woman implies a lower probability of farming, but almost doubles the likelihood of being engaged in wholesale and about triples that of retailing compared to being a man. The regional differences matter. In the southern regions of the country, women are more diversified across farming and trade activities relative to the north. In assessing the impact of the allocation of activities by gender, we show that farming households spend the least, while households with wholesalers have significantly higher expenditures.

Normal force in natural active touch correlates with fingertip stiffness

α2-macroglobulin function of thioester-containing proteins guards <i>Drosophila</i> from a bacterial protease via two immune-induced peptides

RNAseq analysis of the Drosophila genome has revealed further immune-induced genes. Two genes initially annotated as lncRNAs, CG44404 ( yulü ) and CG45045 ( shenshu ), are strongly induced. We report here that these two genes actually encode highly related secreted peptides found in the Sophophora subgenus of Drosophila species. We have generated single and double null mutants of these loci and found that the double mutant line did not display any enhanced susceptibility to an immune challenge with a panel of bacterial and fungal pathogens, except for Pseudomonas aeruginosa . We did not observe any increased P. aeruginosa burden in yulü-shenshu mutants, suggesting that the two peptides may not be required for resistance to infection. Rather, we find that they provide a level of protection against Outer Membrane Vesicles (OMVs) purified from either P. aeruginosa or Serratia marcescens culture supernatants. We have recently reported that S. marcescens OMVs induce the paralysis of flies through the induction of apoptosis in at least some neurons. Much of the virulence of these OMVs is mediated by the metalloprotease PrtA. While Yulü/Shenshu do not display any protease inhibition activity, the detection of an association between Yulü and the Drosophila complement thioester-containing protein 2 (Tep2) led to the finding that both Tep2 and Tep4 mutants are sensitive to the injection of PrtA while their overexpression significantly protects wild-type flies from the effects of this protease. Both Tep2 and Tep4 are able to inhibit the activity of PrtA in a thioester- and yulü/shenshu -dependent manner. Thus, these Teps may also function as α2-macroglobulins.

The impact of training on farmers’ human capital accumulation in rural China

Training represents a crucial pathway for enhancing farmers’ human capital. China currently invests over 2 billion CNY (310 million USD) annually to train nearly a million professional farmers. While previous studies have primarily focused on the direct effects of training on production and income, there is no consensus on how training specifically contributes to farmers’ human capital accumulation. This study employs panel survey data from 753 farmers across four Chinese provinces collected in 2016 and 2019, utilizing Propensity Score Matching-Difference in Differences (PSM-DID) methodology to examine the impact of farmer training on participants’ human capital. The empirical analysis reveals that farmers who participated in professional training programs experienced significant improvements in their explicit human capital, demonstrated by increases of 6.76% and 13.30% in obtaining national vocational qualification certificates and farmer technical staff titles, respectively. Additionally, their internalized human capital showed marked enhancement, with increases of 21.03% and 11.29% in utilizing digital platforms such as WeChat groups and Douyin (or Kuaishou) for agricultural knowledge and skill acquisition. These findings suggest that China should continue prioritizing farmers’ human capital development, particularly through professional training programs, as a key strategy for promoting agricultural transformation and rural revitalization.

Overweight &amp; obesity epidemic, temporal trends and regional disparities in physical growth of Vietnamese children

A cytokine receptor–targeting chimera toolbox for expanding extracellular targeted protein degradation

Extracellular targeted protein degradation (eTPD) is an important new modality for manipulating the extracellular proteome. However, most eTPD receptors are expressed broadly or are restricted to the liver, limiting specific degradation in other tissues. Cytokine receptor–targeting chimeras (kineTACs) are genetically encoded bispecifics for eTPD that fuse a natural ligand like CXCL12 to an antibody, directing soluble or membrane proteins for lysosomal degradation using the widely expressed chemokine receptor CXCR7 (K. Pance et al. , Nat. Biotechnol. 41 , 273–281 (2023)]. Here, we dramatically expand the kineTAC toolbox by constructing 81 different kineTACs based on an unbiased list of cytokines, chemokines, and growth factors. Remarkably, 55 of these expressed at suitable levels for analysis without any optimization. Many of these kineTACs bind receptors that have unique cell-type expression profiles, allowing for eTPD in specific cells and tissues, and some were more potent than the original CXCL12-based kineTAC against specific targets. We further show the internalizing capability of a kineTAC can enhance the performance of antibody drug conjugates. We believe these simple, genetically encoded tools will be useful for expanding the applications for optimized or cell type–selective eTPD.

Machine learning-based prediction of mortality risk from air pollution-induced acute coronary syndrome in the Western Pacific region

Structural basis for iterative methylation by a cobalamin-dependent radical <i>S</i> -adenosylmethionine enzyme in cystobactamids biosynthesis

Cystobactamids are nonribosomal peptide natural products that function as DNA gyrase inhibitors, exhibiting significant antibacterial activity. They are isolated from Cystobacter sp. Cbv34 and contain various alkoxy groups on para-aminobenzoic acid moieties, which are believed to play a crucial role in antibacterial functions. The alkoxy groups are generated by iterative methylations on a methoxy group by the cobalamin (Cbl)-dependent radical S -adenosylmethionine (SAM) enzyme CysS. CysS catalyzes up to three methylations to give ethoxy, isopropoxy, sec-butoxy, and tert-butoxy groups. For each methylation, CysS uses a ping–pong mechanism in which two molecules of SAM are consumed. One SAM is used to methylate cob(I)alamin, while another generates a 5′-deoxyadenosyl 5′-radical to initiate substrate methylation. However, little is known about how the enzyme promotes both Cbl methylation and iterative substrate methylation, which occur by polar S N 2 and radical processes, respectively. Here, we report three X-ray crystal structures of a homolog of CysS from Corallococcus sp. CA054B . Two were determined in the presence of methoxy- and ethoxy-containing substrates, showing how CysS accommodates substrates and products during iterative methylation. The third structure, determined in the absence of a substrate, exhibits structural changes that reorient the SAM’s conformation to allow for the methylation of cob(I)alamin.

Deep learning-based system to predict hepatocellular carcinoma resection volume using contrast-enhanced CT

Selective targeting of NRF2-high pancreatic ductal adenocarcinoma with an NQO1-activatable prodrug

Activation of transcription factor NRF2 in pancreatic ductal adenocarcinoma (PDAC) promotes aggressive tumor phenotype and protection from therapy-induced oxidative stress. We postulated that NRF2 high PDAC can be selectively targeted by C29h, a prodrug that is activated by the NRF2-induced enzyme NAD(P)H:quinone oxidoreductase-1 (NQO1), which is elevated in human pancreatic tumors. Initial evaluations of C29h alone or together with the standard-of-care chemotherapeutic drug gemcitabine were conducted on NQO1 high human and mouse PDAC cell lines and patient-derived organoids. As PDAC is enriched in collagen-containing extracellular matrix (ECM) that activates NRF2 and induces NQO1 expression, we examined the ECM effect on the response to C29h, as well as in vivo tumor control in IKKα-deficient Kras G12D /Ikkα ΔPEC mice in which NRF2 is strongly activated, immunocompromised Nu/Nu mice orthotopically transplanted with human PDAC cells and C57BL/6n and NOD/SCID mice transplanted with mouse PDAC. C29h led to NQO1-dependent killing of human and mouse PDAC cell lines and organoids and acted additively with gemcitabine. Furthermore, ECM-plated PDAC cells were more susceptible to C29h cytotoxicity than cells grown on plastic. Importantly, C29h treatment induced tumor regression and increased the survival of PDAC-bearing mice and optimal C29h-induced tumor regression was dependent on CD8 + T lymphocytes whose tumoral recruitment was enhanced by drug treatment. This study supports the use of C29h alone or as part of a drug combination as an effective and promising strategy for selective eradication of NRF2 high PDAC.