eLife最新文献

Investigation of the bacterial pathogen Neisseria gonorrhoeae is complicated by extensive horizontal gene transfer: a process which disrupts phylogenetic signals and impedes our understanding of population structure. The ability to consistently identify N. gonorrhoeae lineages is important for surveillance of this increasingly antimicrobial resistant organism, facilitating efficient communication regarding its epidemiology; however, conventional typing systems fail to reflect N. gonorrhoeae strain taxonomy in a reliable and stable manner. Here, a N. gonorrhoeae genomic lineage nomenclature, based on the barcoding system of Life Identification Number (LIN) codes, was developed using a refined 1430 core gene MLST (cgMLST). This hierarchical LIN code nomenclature conveys lineage information at multiple levels of resolution within one code, enabling it to provide immediate context to an isolate's ancestry, and to relate to familiar, previously used typing schemes such as Ng cgMLST v1, 7-locus MLST, or NG-STAR clonal complex (CC). Clustering with LIN codes accurately reflects gonococcal diversity and population structure, providing insight into associations between genotype and phenotype for traits such as antibiotic resistance. These codes are automatically assigned and publicly accessible via the https://pubmlst.org/organisms/neisseria-spp database.

Decision-making stems from a sequence of information processing steps between the onset of the stimulus and the response. Despite extensive research, uncertainty remains about the actual cognitive sequence involved that leads to the reaction time. Using the hidden multivariate pattern method, we modeled the single-trial electroencephalogram of participants performing a decision task as a sequence of an unknown number of events estimated as trial-recurrent, time-varying, stable topographies. We provide evidence for five events occurring during participants' decision-making with two visual encoding events and three events capturing respectively attention orientation, decision, and motor execution. This interpretation is supported by the observation that a targeted manipulation of stimulus intensity yields Piéron's law in the interval between encoding and attention orientation, and Fechner's law in the interval between attention orientation and decision commitment. The final decision-related event is represented in the brain as a ramping signal in parietal areas whose timing, amplitude, and build-up predict the participants' decision accuracy.

There is a widely held perception that science is becoming more international-through multi-national collaborations-and interdisciplinary, drawing on knowledge from multiple domains. However, these hypothesized trends have not yet been quantitatively characterized. With the publication metadata from OpenAlex, we examine trends in two groups of journals: disciplinary journals in natural sciences, life sciences, social sciences, and multidisciplinary journals that publish articles in multiple fields. Supporting existing perceptions, we find an almost universal trend towards increasing internationalization of both sets of journals. Nevertheless, we find disparities: medicine journals are less international than journals in other disciplines and do not increase their levels of internationalization, whereas physics journals appear to be segregating between those that are international and those that are not. We also find that multidisciplinary journals have undergone significant shifts in their disciplinary focuses over the past century, whereas disciplinary journals appear to have largely maintained their degree of interdisciplinarity.

CD8⁺ tissue-resident memory T cells (T_RM) develop from effectors that seed peripheral tissues where they persist providing defense against subsequent challenges. T_RM persistence requires autocrine TGFβ transactivated by integrins expressed on keratinocytes. T_RM precursors that encounter antigen in the epidermis during development outcompete bystander T_RM for TGFβ resulting in enhanced persistence. ScRNA-seq analysis of epidermal T_RM revealed that local antigen experience in the skin resulted in an enhanced differentiation signature in comparison with bystanders. Upon recall, T_RM displayed greater proliferation dictated by affinity of antigen experienced during epidermal development. Finally, local antigen experienced T_RM differentially expressed TGFβRIII, which increases avidity of the TGFβRI/II receptor complex for TGFβ. Selective ablation of Tgfbr3 reduced local antigen experienced T_RM capacity to persist, rendering them phenotypically like bystander T_RM. Thus, antigen-driven TCR signaling in the epidermis during T_RM differentiation results in a lower TGFβ requirement for persistence and increased proliferative capacity that together enhance epidermal T_RM fitness.

Previously, we showed that the genetic diversity of SARS-CoV-2 nucleocapsid (N) protein explores a wide range of biophysical properties facilitated by non-local impact of point mutations to its intrinsically disordered regions (Nguyen et al., 2024). This includes modulation of self-association, such as the creation of a de novo binding interface through the P13L mutation characteristic of Omicron variants. In the present work, we focus on the key function of N condensing viral RNA into ribonucleoprotein particles (RNPs) for viral assembly. Lacking high-resolution structural information, biochemical and biophysical approaches have revealed architectural principles of RNPs, which involve cooperative interactions of several protein-protein and protein-RNA interfaces, initiated through oligomerization of conserved transient helices in the central disordered linker of N. Here, we study the impact of defining N-protein mutations in variants of concern on RNP formation, using biophysical tools, a virus-like particle assay, and reverse genetics experiments. We find convergent evolution in repeated, independent introduction of amino acid substitutions strengthening existing binding interfaces, compensating for other substitutions that promote viral replication but decrease RNP stability. Furthermore, we show that the P13L mutation of Omicron variants enhances RNP assembly and increases viral fitness. Overall, our data reveal RNP complexes to be highly variable not only in sequence and conformations but also in thermodynamic and kinetic stability, with its pleomorphism affecting basic architectural principles. We hypothesize that the formation of polydisperse, fuzzy N-RNA clusters with multiple distributed weak binding interfaces optimizes reversible RNA condensation, while supporting host adaptation and allowing for a large sequence space to be explored.

CDK4/6 inhibitors (CDK4/6i) with endocrine therapy are standard for hormone receptor-positive (HR⁺) metastatic breast cancer. However, most patients eventually develop resistance and discontinue treatment, and there is currently no consensus on effective second-line strategies. Using preclinical HR⁺ human breast cancer models with acquired resistance to CDK4/6i, we demonstrate that maintaining CDK4/6i therapy, either alone or combined with CDK2 inhibitors (CDK2i), slows the growth of resistant tumors by prolonging G1 progression. Mechanistically, sustained CDK4/6 blockade in drug-resistant cells reduces E2F transcription and delays G1/S via a noncanonical, posttranslational regulation of retinoblastoma protein (Rb). Durable suppression of both CDK2 activity and growth of drug-resistant cells requires co-administration of CDK2i with CDK4/6i. Moreover, cyclin E overexpression drives resistance to the combination of CDK4/6i and CDK2i. These findings elucidate how continued CDK4/6 blockade constrains resistant tumors and support clinical strategies that maintain CDK4/6i while selectively incorporating CDK2i to overcome resistance.

Quantifying animal behavior is pivotal for identifying the neuronal and genetic mechanisms involved. Computational approaches have enabled automated analysis of complex behaviors such as aggression and courtship in Drosophila. However, existing approaches rely on rule-based algorithms and expensive hardware, limiting sensitivity to behavioral variations and accessibility. Here, we present the Drosophila Aggression and Courtship Evaluator (DANCE), a low-cost, open-source platform that combines machine learning-based classifiers and inexpensive hardware to quantify aggression and courtship. DANCE consists of six novel behavioral classifiers trained using a supervised machine learning algorithm. DANCE classifiers address key limitations of rule-based algorithms, capturing dynamic behavioral variations more effectively. DANCE hardware is constructed using medicine blister packs and acrylic sheets, with recordings acquired using smartphones, making it affordable and accessible. Benchmarking demonstrated that DANCE hardware performs comparably to high-cost setups. We validated DANCE in diverse contexts, including social isolation vs. enrichment, which modulates aggression and courtship; RNAi-mediated downregulation of the neuropeptide Dsk; and optogenetic silencing of dopaminergic neurons, which promotes aggression. DANCE provides a cost-effective and portable solution for studying behaviors in resource-limited settings or near natural habitats. Its accessibility and robust performance democratize behavioral neuroscience, enabling rapid screening of genes and neuronal circuits underlying complex social behaviors.

Hepatocellular carcinoma (HCC), the common liver cancer, exhibits higher incidence in males. Here, we report that mice lacking bile acid (BA) regulators, Farnesoid X Receptor (FXR also termed NR1H4) and Small Heterodimer Partner (SHP also termed NR0B2), recapitulate the sex difference in liver cancer risk. Since few therapeutic options are available, we focused on understanding the intrinsic protection afforded to female livers. Transcriptomic analysis in control and NR1H4 and NR0B2 double knockout livers identified female-specific changes in metabolism, including amino acids, lipids, and steroids. To assess translational relevance, we examined if transcriptomic signatures obtained from this murine HCC model correlate with survival outcomes for HCC patients. Gene signatures unique to the knockout females correspond with low-grade tumors and better survival. Ovariectomy blunts the metabolic changes and promotes liver tumorigenesis in females that, intriguingly, coincides with increased serum bile acid (BA) levels. Despite similar genetics, knockout male mice displayed higher serum BA concentrations, while female knockouts excreted more BAs. Decreasing enterohepatic BA recirculation using cholestyramine, an FDA-approved resin, dramatically reduced the liver cancer burden in male mice. Overall, we reveal that sex-specific BA metabolism leading to lower circulating BA concentration protects female livers from developing cancer. Thus, targeting BA excretion may be a promising therapeutic strategy against HCC.

Evolutionary adaptations associated with the formation of a folded cortex in many mammalian brains are thought to be a critical specialization associated with higher cognitive function. The dramatic surface expansion and highly convoluted folding of the cortex during early development is a theme with variations that suggest the need for a comparative study of cortical gyrification. Here, we use a combination of physical experiments using gels, computational morphogenesis, and geometric morphometrics to study the folding of brains across different species. Starting with magnetic resonance images of brains of a newborn ferret, a fetal macaque, and a fetal human, we construct two-layer physical gel brain models that swell superficially in a solvent, leading to folding patterns similar to those seen in vivo. We then adopt a three-dimensional continuum model based on differential growth to simulate cortical folding in silico. Finally, we deploy a comparative morphometric analysis of the in vivo, in vitro, and in silico surface buckling patterns across species. Our study shows that a simple mechanical instability driven by differential growth suffices to explain cortical folding and suggests that variations in the tangential growth and different initial geometries are sufficient to explain the differences in cortical folding across species.

Hypoxia-ischemia (HI), which disrupts the oxygen supply-demand balance in the brain by impairing blood oxygen supply and the cerebral metabolic rate of oxygen (CMRO₂), is a leading cause of neonatal brain injury. However, it is unclear how post-HI hypothermia helps to restore the balance, as cooling reduces CMRO₂. Also, how transient HI leads to secondary energy failure (SEF) in neonatal brains remains elusive. Using photoacoustic microscopy, we examined the effects of HI on CMRO₂ in awake 10-day-old mice, supplemented by bioenergetic analysis of purified cortical mitochondria. Our results show that while HI suppresses ipsilateral CMRO₂, it sparks a prolonged CMRO₂-surge post-HI, associated with increased mitochondrial oxygen consumption, superoxide emission, and reduced mitochondrial membrane potential necessary for ATP synthesis-indicating oxidative phosphorylation (OXPHOS) uncoupling. Post-HI hypothermia prevents the CMRO₂-surge by constraining oxygen extraction fraction, reduces mitochondrial oxidative stress, and maintains ATP and N-acetylaspartate levels, resulting in attenuated infarction at 24 hr post-HI. Our findings suggest that OXPHOS-uncoupling induced by the post-HI CMRO₂-surge underlies SEF and blocking the surge is a key mechanism of hypothermia protection. Also, our study highlights the potential of optical CMRO₂ measurements for detecting neonatal HI brain injury and guiding the titration of therapeutic hypothermia at the bedside.