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Structure basis for C-C chemokine receptor 4 modulation by orthosteric and allosteric antagonists
The chemokine system, comprising a network of chemokines and their receptors, orchestrates leukocyte migration and plays a central role in immune surveillance and inflammation. Targeting this system has emerged as a promising strategy in cancer immunotherapy and the treatment of immune-related disorders. C-C chemokine receptor 4 (CCR4), the receptor for chemokines CCL17 and CCL22, is a clinically validated therapeutic target for adult T cell leukemia/lymphoma, cutaneous T cell lymphoma, and other malignancies; however, the molecular mechanisms underlying CCR4 inhibition remain poorly understood. Here, we report five cryoelectron microscopy structures of human CCR4 in its apo state and in complex with four inhibitors. Tivumecirnon (FLX475) and Zelnecirnon (RPT193), two clinical-stage investigational drugs, bind to the orthosteric site of CCR4, blocking the chemokine recognition site 1. In contrast, AZD2098 and GSK2239633A occupy an allosteric site near the TM7–H8 turn, presumably interfering with G-protein coupling. Further analyses reveal that the therapeutic antibody mogamulizumab binds to the N-terminal region of CCR4 without competing with CCL17, suggesting that its antagonistic effect is mediated exclusively through antibody-dependent cellular cytotoxicity. Together, these structural insights elucidate distinct modes of CCR4 inhibition and provide a framework for the rational design of next-generation therapeutics targeting chemokine receptors.
Human motion recognition based on progressive neural architecture search for efficient and interpretable spatiotemporal learning
From female to female: Communication via chemosignals
In many species, chemosensory cues convey important information about reproductive status, but their role in shaping social interactions among women is less understood. Here, we combined functional neuroimaging with behavioral measures to test how chemosignals from women at different reproductive stages [menstruation, ovulation (OV), and early pregnancy (PRG)] affect social perception in female recipients across their own menstrual cycle. Chemosignal donors were screened and tracked for cycle phase (n = 59) and pregnancy status (n = 36). Female functional MRI participants (n = 33) completed a single-blind within-subject crossover design with two sessions, one during menstruation and one during ovulation. The participants rated attractiveness, desired proximity, and pregnancy status of standardized female faces while being unknowingly exposed to the axillary chemosignals. Neuroimaging analyses showed OV chemosignals to elicit greater activation across frontal, parietal, temporal, and subcortical regions, including the temporoparietal junction, insula, hippocampus, hypothalamus, and basal ganglia. PRG chemosignals were associated with more circumscribed responses, particularly in the prefrontal and cingulate areas. These effects were modulated by the recipient’s own cycle phase, with broader networks being engaged during ovulation than menstruation. Behaviorally, the participants maintained a greater distance from faces paired with PRG but approached them more closely during their own ovulation. Attractiveness ratings and pregnancy categorizations were unaffected by chemosensory condition or cycle phase. Together, these findings demonstrate that subtle chemosensory signals shape female social cognition in a cycle-dependent manner, highlighting an adaptive mechanism by which chemosensory cues guide competition, vigilance, and affiliation without necessarily altering explicit judgments.
A retrospective analysis of chronic endometritis and antibiotic therapy in patients with endometriosis
Estimating returns to education using the genetic lottery
Does more schooling cause higher lifetime earnings? Social scientists have long sought to determine the economic returns to schooling given its importance to individual life chances and public policy. Prior estimates are limited by unobserved confounding in observational studies and the focus of popular quasi-experimental studies on increases in schooling at only one particular age. Genotyped data offer an opportunity to address unobserved confounding and to estimate the returns to an additional year of schooling at any age by using quasi-randomly assigned genetic variants related to education as instrumental variables [Mendelian randomization (MR)]. We analyze comprehensive Norwegian population registries with career-long earnings data and genotyped data from the Norwegian Mother, Father and Child Cohort Study (MoBa). We employ three identification strategies for triangulation: ordinary least squares (OLS) with covariate-adjustment, sibling and twin fixed-effects models, and MR. Estimated returns to schooling are 8.0% in MR (N = 109,800) and 6.3% in sibling-MR (N = 18,666). Extensive sensitivity analyses suggest that MR results are robust even to large potential violations of MR assumptions, including pleiotropy. MR estimates somewhat higher returns than OLS for the full population (5.9%, N = 1,255,604) and fixed-effects models for siblings (5.3%, N = 966,976) or monozygotic twins (3.2%, N = 2,630). The estimated internal rate of return to schooling exceeds opportunity costs of education as proxied by the market interest rate. The lifetime returns to schooling are positive and substantial across all models.
M2 type macrophages promote OSCC progress via conferring resistance to Erastin-induced ferroptosis
A scalable embryonic stem cell–based platform for efficient generation of mitochondrial DNA mutant mice
Mitochondria are central to energy metabolism and cellular signaling, and mutations in mitochondrial DNA (mtDNA) can disrupt these processes and contribute to human disease. However, progress in defining how mtDNA variation influences adaptation, pathophysiology, and disease susceptibility has been limited by the lack of suitable animal models. Although recent base-editing approaches enable direct mtDNA modification, their low efficiency restricts the generation of diverse models reflecting human mtDNA variation. Here, we develop a scalable embryonic stem (ES) cell–based platform for efficient production of mtDNA mutant mice. Random mutagenesis using an error-prone mtDNA polymerase generates a broad spectrum of mtDNA mutations, which are transferred into ES cells via a multiplexed cybrid fusion strategy coupled with sensitive mutation detection. Optimized ES cell–embryo aggregation enables robust contribution of mtDNA mutant ES cells to host embryos, producing chimeric mice with germline transmission. Using this platform, we generate a library of 155 donor fibroblast lines carrying distinct homoplasmic single-nucleotide mtDNA mutations that produce diverse mitochondrial phenotypes, including impaired oxidative phosphorylation, increased reactive oxygen species, and altered mitochondrial membrane potential. We further generate 34 female C57BL/6 ES cell lines harboring 18 mtDNA mutations across a range of heteroplasmy levels, yielding multiple chimeric mice and achieving germline transmission for one mutation. These data reveal a strong correlation between mitochondrial function and early embryonic development, suggesting a minimal energetic threshold required for normal development. This scalable resource enables systematic investigation of mtDNA variation in physiology, adaptation, disease mechanisms, and therapeutic development.
Strength and resilient performance of expansive subgrades stabilized with apricot kernel shell ash
Loss of FoxO in skeletal muscle leads to disrupted muscle metabolism and exacerbates starvation-induced hepatic steatosis
Up to a third of the global population is afflicted by metabolic dysfunction-associated steatotic liver disease with excessive triglyceride accumulation in the liver. Prolonged fasting rapidly causes hepatic steatosis via excessive influx of free fatty acids from adipose tissue. However, it is unclear whether skeletal muscle is involved in the etiology of hepatic steatosis during starvation. Here, we demonstrate a critical connection between the liver and skeletal muscle via FoxO transcription factors. During prolonged fasting, hepatic steatosis was exacerbated in skeletal muscle–specific FoxO-deficient mice (mFoxO1,3,4 −/− ) despite preventing skeletal muscle wasting, suggesting that skeletal muscle FoxOs prevent hepatic steatosis during energy deprivation. FoxO deficiency in skeletal muscle weakened fatty acid oxidation and induced abnormal glycogen accumulation in skeletal muscle during fasting. Mechanistically, the starvation-induced transcriptional regulation of triglyceride lipase was attenuated in skeletal muscle of FoxO-deficient mice. Conversely, skeletal muscle–specific FOXO1 overexpression was sufficient to increase triglyceride lipase in vivo and protected the liver from Western diet–induced metabolic dysfunction–associated steatohepatitis-like phenotype. Taken together, our results demonstrate the physiological importance of skeletal muscle FoxO signaling on the liver pathophysiology.
Exploration of m7G-related immune genes and construction of a prognostic risk model in gastric cancer
Selective reuse of prior ensemble data improves the latest air temperature forecast over North America
Accurate subseasonal to seasonal (S2S) weather forecasts are critical for managing risks to society, yet improving forecast skill remains challenging. Ensemble forecasting mitigates atmospheric chaos but is limited by computational cost and by declining accuracy at longer lead times. Previous attempts to incorporate previous ensemble forecasts have yielded little improvement in the accuracy of the latest forecast because members from earlier initializations tend to degrade forecast quality. Here, we introduce a simple yet powerful postprocessing approach, lagged ensemble analog subselection (LEAS), which selectively chooses previous ensemble members that best predicted the most recent conditions. Using hindcasts of daily maximum 2-m air temperature over North America from four state-of-the-art S2S weather forecast models, we show that LEAS enhances both deterministic and probabilistic skill across multiple weeks, including for extreme heat events. The method reduces systematic bias as well as variance error, outperforming conventional lagged ensembles without requiring additional simulations or changes to model initialization. The improvement arises from filtering out poorly performing members and effectively emulating enhanced initialization of both atmospheric and land–surface states. LEAS combines principles of analog forecasting with lagged ensembles, extending their impact from short-term to multiweek predictions. Its simplicity and generality suggest broad applicability, not only to machine-learning–based weather forecasting but also to other predictive systems that rely on repeated initialization, such as hydrological, climate, and Earth system models. By extracting more value from existing forecast data, LEAS advances toward the upper limit of forecast skill achievable within current model frameworks while avoiding added computational burden.
The mediating role of gaslighting as a psychological violence between self-silencing and psychological distress
Nanocondensate bioadhesive delivery via metal–halogenated catechol coordination in tunicate rhizoid holdfasts
The root-like holdfast of the tunicate Halocynthia roretzi provides strong underwater adhesion. However, the biological processing and biochemical composition underlying its adhesive remain largely unknown. Here, we identify a nanocondensate-based transport system in which halogenated 3,4-dihydroxyphenylalanine (DOPA)-containing peptides coordinate with metal ions such as iron, chromium, and vanadium to form stable nanocondensates within dense-granular cells. These nanocondensates are secreted into the extracellular matrix and rapidly incorporated into the cuticular layer, where the proteins cross-link oxidatively to form the adhesive interface, releasing the metals upon solidification. This process establishes a previously unrecognized solid-state adhesive delivery mechanism regulated by coordination chemistry between metal ions and halogenated catechols. Indeed, while other systems (e.g., mussels) use DOPA-containing proteins to transport metal ions during glue formation, the current system is distinctive in that metal coordination is transient and used ostensibly to deliver the adhesive protein cargo—findings relevant for design of next-generation underwater glues.
Correction: A comparative SWOT analysis of urban green infrastructure in the Global South
China’s demographic dividend has moved from age-based labor supply to skill-based productivity
Accelerated global population aging challenges conventional economic growth paths. Yet, the mechanisms underlying the transition from the age-based demographic dividend, derived from a favorable age support ratio (ASR), to a skill-based dividend, driven by human capital accumulation, remain insufficiently understood. Using population census data for 336 Chinese cities from 2000 to 2020, we develop a task-based skill ratio (TSR) index to quantify the skill composition of local labor markets, capturing the relative intensity of high- and low-skill tasks within city-level employment structures. We identify a divergence trend where the ASR peaked around 2010 and has since declined, while the TSR has continued to rise and diffuse geographically. We further examine a synergistic effect between ASR and TSR on economic growth and project the compensatory TSR required under alternative demographic scenarios to 2100. It shows that both ASR and TSR positively affect the per capita GDP of a city, but the latter plays a dominant role. A higher ASR amplifies the economic returns to TSR, with the old-age support ratio (OSR) as the binding constraint. Projections indicate that delayed retirement can partly alleviate the effects of the ASR decline, but cannot reverse the long-term trend. Continued improvement in the TSR is therefore necessary to offset this structural demographic shift. Economic growth relies less on favorable age structures and increasingly depends on the skill composition of the workforce, making skill upgrading central to sustained prosperity.
Exploring the mechanical and thermal properties of sustainable epoxy composites reinforced with Ethiopian false banana fiber
Reconstruction of human metabolic models with large language models
Genome-scale metabolic models (GEMs) have become essential tools for understanding human metabolism. Here, we introduce Human2, a consensus human GEM with enhanced precision and biological relevance, which leverages large language models (LLMs) and GitHub Action checks to streamline automated, efficient, and collaborative curation. Human2 supports the reconstruction of tissue- and organ-specific models tailored to sex- and age-specific human groups. By integrating transcriptomic, proteomic, and kinetic data, we reveal distinct metabolic features across these groups, such as significant differences in arachidonic acid and leukotriene metabolism. The specific models were integrated into a dynamic whole-body framework, marking an enzyme-constrained dynamic model that simulates interorgan metabolite exchanges under varying nutritional states, from feeding to fasting. Our work highlights the transformative role of LLMs in GEM reconstruction and introduces a whole-body dynamic simulation that integrates kinetic data, offering a powerful resource for multiscale human metabolism modeling.
Dynamical behavior of analytic solutions of the generalized derivative nonlinear Schrödinger equation under stochastic perturbations in fiber communication systems
Offspring chemical control of adult reproductive transitions in a social insect
Parental care enhances offspring survival and growth but often entails a trade-off in which caregivers temporarily suppress their own reproduction to invest in existing young. In vertebrates, these parental reproductive cycles are controlled by offspring-derived cues that reduce or suppress parental fertility. While many insects display obligate parental care, the role of offspring cues in regulating adult reproduction remains unresolved outside advanced eusocial taxa, where reproductive cycles have largely been lost. Here, we investigate reproductive cycles in the clonal raider ant Ooceraea biroi , in which totipotent females alternate between caring for larvae and laying eggs. Using custom behavioral assays, we show that larvae inhibit adult reproduction without physical contact, implicating volatile cues. Chemical analyses identified a previously undescribed larva-specific compound, methyl 3-ethyl-2-hydroxy-4-methylpentanoate (MEHMP), which is absent from other developmental stages and ant species. Exposure to synthetic MEHMP recapitulated the inhibitory effect of larval volatiles, confirming its role as a pheromone that suppresses adult egg laying. Our findings demonstrate that ant larvae produce a pheromone that suppresses adult reproduction, providing a direct chemical link between offspring presence and parental reproductive suppression, and underscoring the central role of offspring signals in mediating parental reproductive investment in animals that care for their young.