搜索结果：Proceedings of the National Academy of Sciences of the United States of America

The Bantu language family of sub-Saharan Africa is among the largest in the world by the number of languages, by geographical extent, and by the number of speakers. The expansion of the Bantu languages is an important example of large-scale language-family expansions in the history of humankind. To learn the early prehistory of the Bantu language family, one needs to disentangle the signal of the original splits and diversification from that of the subsequent language contact, known to be strong in the Bantu languages. We introduce a coalescent-theoretic model to computationally study the prehistory of the Bantu family. Our model treats language contact as a norm rather than a rare exception, in contrast to earlier computational work. Applying Approximate Bayesian Computation, we show the rates of both language change and language contact to have been so high within the Bantu family that the signal of the original diversification has been largely erased in the currently available Bantu lexical data.

Membrane pearling, the transformation of a smooth tubule into a chain of bead-like swellings connected by narrow membrane tethers, is a widely observed shape change. While it has been well studied for synthetic lipid and unilamellar intracellular membranes, the mechanism underlying the pearling of the peculiar double-membrane architecture of tubular mitochondria remained elusive. Here, we addressed the role of the strongly convoluted inner mitochondrial membrane (IMM) in pearling driven by stretching. Using a light-gated, mitochondria-specific mechanostimulator to apply stretching forces to mitochondria in live cells, we demonstrated that stretching triggers pearling of whole tubular mitochondria. Moreover, we found that pearling requires the presence of the IMM, as unilamellar tubules derived solely from the mitochondrial outer membrane elongate uniformly under stretching and never undergo pearling. To understand the physical mechanism by which IMM controls pearling, we developed a theoretical model that considers the lumen, effectively spanned and volumetrically stiffened by cristae, as an elastic continuum. Our computations show that pearling requires the luminal volume to be sufficiently resistant to change, with its effective bulk rigidity modulus exceeding a critical value. Our experimental observations further revealed the functionally important consequences of stretching-induced pearling. mtDNA nucleoids partitioned into the bulges of pearled configurations, suggesting a role for pearling in the reorganization of luminal components. In addition, the membrane fission GTPase DRP1 accumulated at the constrictions of pearled shapes, leading to membrane scission and mitochondrial fragmentation. Our work uncovers the unique biophysical mechanism of mitochondrial pearling and its functional significance for organelle dynamics.

Snakebite maims or kills several hundred thousand people each year. For more than a century, treatment has relied on antivenoms derived from animals immunized with whole venoms, but their efficacy, safety, and availability are highly variable, and it is often not well understood which specific venom components must be inhibited to prevent mortality and major morbidities. New therapeutic approaches are needed. Here, we take an evolutionary approach to antivenom design inspired by the longstanding observation that vipers have evolved serum-borne toxin inhibitors that confer resistance to their own venoms. We have investigated the abilities of a family of four rattlesnake metalloproteinase (MP) inhibitors derived from the ancestral serum glycoprotein Fetuin-A (FETUAs) to neutralize the enzymatic, hemorrhagic, and lethal activities of viper venoms. We find that while certain individual FETUA proteins are able to inhibit enzymatic or hemorrhagic activity, they are unable or only partially able to inhibit venom lethality. However, we show that specific combinations of FETUA proteins complement one another's activities and are sufficient to fully neutralize rattlesnake venom lethality with approximately 10 times greater potency than commercial antivenom. Moreover, we demonstrate that FETUA proteins are well conserved among viper subfamilies and that rattlesnake FETUAs are able to inhibit the MPs and neutralize the lethality of several evolutionarily distant pit viper or true viper venoms. Our results highlight the critical importance of inhibiting MPs in hemorrhagic venoms and the potential general utility of combinations of naturally evolved, recombinant MP inhibitors in the treatment of viper snakebite.

Most widely studied option evaluation strategies rely on knowledge accumulated across repeated experiences. But how should options be evaluated in unfamiliar environments, in which knowledge is sparse? In these situations, how do decision makers make efficient use of limited past experience to guide their choices? One possible strategy is episodic sampling, in which a decision maker retrieves a small number of past decisions from memory to estimate the value of present options. By virtue of their age, children and adolescents have less experience than adults, making episodic sampling a particularly useful strategy for them. At the same time, the effectiveness of episodic sampling derives from memory's precision and context sensitivity-properties that continue to develop into adolescence and young adulthood. This tension raises a key question: are developmental differences in episodic memory associated with differences in episodic sampling? To address this question, 106 participants, ages 8 to 25, completed a 2-d choice task that dissociated the influence of a single episodic memory from the influence of multiple episodes sharing a common context. At all ages, single episodes biased choices. But, only adults were sensitive to the broader evoked context. Further clarifying the relationship between episodic memory and decision making, differences in memory precision predicted differences in episodic sampling, even after taking into account age, while episodic sampling, in turn, accounted for individual differences in forward planning. Together, these findings suggest that episodic memory guides decision making throughout development, but the character of its influence evolves as memory becomes more precise and richly structured.

Retrons are prokaryotic defense modules that protect bacteria from phage infection through abortive infection. The retron Ec78 system employs a two-component effector complex PtuAB to execute this defense. Despite recent advances in structural research, the molecular mechanism by which PtuAB effector is regulated remains unknown. Here, we reveal that PtuAB is subject to a dual-inhibitory mechanism mediated by ATP/ADP and the RT-msDNA antitoxin. ATP/ADP binds nucleotide-binding domain (NBD) of PtuAB and induces the assembly of an inactive tetrameric complex, whereas the RT-msDNA stabilizes an inhibited conformation of Ec78 complex and stimulates ATP turnover to prime PtuAB for rapid activation. Structural analyses show that RT-msDNA dissociation and nucleotide release from PtuA induce conformational rearrangements in the NBD of PtuA and a downward displacement of a key β-loop-β motif, driving disassembly of the PtuAB tetramer through an allosteric mechanism and thereby activating its tRNATyr cleavage activity. Our findings uncover how nucleotides-specifically ATP and ADP-regulate the activity of this abortive infection system, and establish a dual-inhibition model of retron Ec78 system, expanding the understanding of the regulation mechanism of PtuAB activation in prokaryotic immune systems.

Animals are not known to biosynthesize floral chemical signals to manipulate pollinators, although such mimicry could profoundly shape plant-pollinator interactions. Larvae of the poisonous European blister beetle Meloe proscarabaeus parasitize multiple solitary bee species, yet the mechanism enabling host attraction has remained unresolved. Here we show that these larvae lure bees by emitting a bouquet of volatile compounds that closely resembles floral scent. Chemical analyses reveal a complex blend of monoterpenoids derived from (S)-linalool, a ubiquitous floral volatile. Behavioral assays demonstrate that these compounds function as floral-scent mimics, eliciting attraction in bees and acting as allomones (i.e., interspecific chemical signals that benefit the emitter while disadvantaging the receiver). Transcriptomic and functional analyses identify cytochrome P450 enzymes that oxidize (S)-linalool, suggesting that larvae biosynthesize these plant-like volatiles de novo. Together, these findings broaden the scope of interkingdom chemical mimicry and uncover a striking form of sensory deception in which an insect chemically assumes the signal identity of a flower, revealing that animals can evolve biosynthetic pathways to exploit plant-pollinator communication.

In avocado and certain wild relatives in Lauraceae, a highly synchronized daily rhythm of floral sex timing promotes cross-pollination between two hermaphroditic flowering types. A-type plants present female-phase flowers in the morning and male-phase flowers in the afternoon, while B-types show the complementary pattern-a form of heterodichogamy. We mapped this dimorphism to a pair of dominant and recessive haplotypes at SDMYB, which belongs to a subgroup of R2R3 MYB transcription factors established as key regulators of floral maturation with links to circadian hormone signaling. Rhythmic diel SDMYB expression is associated with biphasic floral anthesis, and the dominant allele, which contains nonsynonymous changes in conserved functional domains, exhibits a cis-regulated phase delay, corresponding to the delayed second anthesis of A-type flowers. The SDMYB haplotypes form an ancient trans-species polymorphism, maintained by negative frequency-dependent balancing selection over 42 My, and they segregate in at least 26 nonavocado species, including in a genus where this mating system has not been reported. Although exceptionally old, the polymorphism is absent in other magnoliids with highly similar mating systems, suggesting daily forms of heterodichogamy can convergently evolve when rhythmic floral movements are coupled with the temporal separation of sexes.

We develop a demographic theory of similarity-biased social learning that formalizes our understanding of when and why individuals should preferentially copy others that look or act like them. We build an evolutionary model in which individuals can either learn on their own or copy others from a demonstrator pool that contains varying proportions of in-group and out-group members, and where group tags can be more or less informative about local knowledge. We find that where social learning becomes common, selection favors copying biases that track the direction of informational advantage-toward the group that tends to be better adapted to local conditions, including an antisimilarity bias when tags are negatively associated with local correctness (as may be the case for some immigrant communities). We also find conditions in which a similarity bias can stabilize social learning when such learners are already common, but not when they are rare, with implications for the role of group identities in cultural evolution. We discuss implications for understanding parochialism as risk aversion, majority-minority dynamics, the sociology of immigration, and the lasting impacts of colonialism.

Patients with myasthenia gravis (MG) may produce autoantibodies neutralizing type I interferons (AAN-I-IFN), which underlie severe viral diseases, including critical COVID-19 pneumonia, in patients without MG. We studied an international cohort of 85 unvaccinated SARS-CoV-2-infected MG patients not given antiviral treatment. Hypoxemic pneumonia occurred in 48 of these patients, including 22 (45.8%) with AAN-I-IFN, which neutralized both IFN-α2 and IFN-ω in 14 (29.2%) patients. Six (16.2%) of the remaining 37 patients had AAN-I-IFN, neutralizing both IFN-α2 and IFN-ω in three patients. The risk of hypoxemic pneumonia was greater in MG patients with AAN-I-IFN neutralizing 10 ng/mL of both IFN-α2 and IFN-ω (odds ratio and 95% confidence interval (OR [95% CI]): 12.7 [2.1 to 78.9], P = 0.0010) or IFN-α2 at any dose (OR [95% CI]: 4.7 [1.5 to 15.0], P = 0.0054) than in those without such autoantibodies. The risk of producing AAN-I-IFN was much higher in MG patients than in the general population (OR [95% CI]: 28.9 [10.8 to 77.7], P = 4.9 × 10-27). Thymoma was found in 14 patients and increased the risk of AAN-I-IFN (64% versus 27%, (OR [95% CI]: 5.6 [1.6 to 19.4], P = 0.0050) and hypoxemic pneumonia (9.2 [1.9 to 44.2]; P = 0.0019). Thymoma is, thus, associated with a higher risk of producing AAN-I-IFN, which are, in turn, associated with a higher risk of developing life-threatening COVID-19 pneumonia in patients with MG.

Antimicrobial resistance is a severe public health burden. Especially concerning are multidrug resistant (MDR) infections, which restrict treatment options and significantly increase mortality risk. A major cause of MDR infections worldwide is carbapenem-resistant Klebsiella pneumoniae (CRKp). The predominant CRKp sequence type worldwide is ST258. However, the factors underlying ST258's epidemic success are not well defined. Genomic analyses of clinical isolates of CRKp have found that the two-component regulatory system CrrAB is a genomic feature of ST258, suggesting that it may contribute to its global dominance. Despite this, the molecular details underpinning CrrAB's contribution to ST258 Kp biology and pathogenicity are poorly understood. We used RNA-sequencing to identify the regulon of CrrA and found that CrrAB induces the expression of a gene, encoding Crr-regulated fimbriae modifying protein (CfmP), that is essential for pathogenesis driven by this two-component system. We performed mass spectrometry analyses of fimbriae purified from Kp expressing or lacking cfmP and found that CfmP induces a novel oxidation to a histidine residue in the major pilin subunit of fimbriae, FimA. We demonstrate that this oxidation significantly increases host cell adhesion and high bacterial loads within the host. CrrAB also drives high antibiotic resistance in CRKp. Thus, our results place CrrAB at the intersection of pathogenicity and antibiotic resistance supporting its function as an important regulatory system driving the global dominance of ST258.

Dysregulation of inorganic phosphate (Pi) homeostasis contributes to metabolic disease, cancer, pathological calcification, and kidney disease. Systemic phosphate balance is regulated by SLC34 transporters that mediate renal Pi retention (SLC34A1/A3) and intestinal dietary Pi absorption (SLC34A2). SLC34s couple Pi uptake to the symport of sodium (Na+) down its electrochemical gradient. Mutations or altered expression of SLC34 proteins are linked to disorders such as chronic kidney disease, where hyperphosphatemia is a major complication, and the lung disease pulmonary alveolar microlithiasis, caused by inactivating SLC34A2 mutations. SLC34A2 is also overexpressed in most ovarian and uterine tumors, making it an attractive target for antibody-drug conjugates. We present cryoelectron microscopy structures of SLC34A2 when the transporter is empty, bound to Na+ ions only, fully loaded with Na+ ions and Pi, and bound to an inhibitor phosphonoformic acid, revealing its distinct architecture, substrate and ion binding sites, the role of Na+, and multiple transporter states. Pi binds at a highly symmetric, membrane-embedded pocket positioned approximately mid-membrane and is coordinated by its signature four residue QSSS repeat motifs. Na+ shapes the Pi-binding pocket and drives the transition from the outward-open to occluded state. Integrated with functional analyses, these structures reveal that SLC34 transporters operate through an atypical alternating access cycle defined by coordinated elevator movements of an auxiliary gate domain. This work lays a foundational framework for understanding Pi regulation and opens avenues for therapeutic strategies targeting disorders linked to phosphate imbalance.

Inosine triphosphate (ITP) is a noncanonical nucleotide. Human cells possess inosine triphosphate pyrophosphatase (ITPA), and ITPA deficiency causes ITP accumulation within cells, leading to the onset of "Developmental and Epileptic Encephalopathy 35." Two potential pathways for ITP biosynthesis have been proposed: i) oxidative deamination of the adenine base in adenosine triphosphate or ii) a two-step phosphorylation reaction of inosine monophosphate (IMP), an intermediate in the de novo synthesis of purine nucleotides. However, the mechanisms responsible for ITP biosynthesis in mammals remain unclear. In this study, using an Itpa knockout (KO) mouse cell line, we identified guanylate kinase 1 (Guk1) as a responsible gene for inosine accumulation in RNA. In Itpa-KO/Guk1 knockdown (KD) cell lines, Guk1 mRNA expression levels were positively correlated with the amount of inosine in RNA, most of which is incorporated during RNA synthesis in ITPA-deficient cells. The transient expression of human GUK1 in Itpa-KO/Guk1-KD mouse cells significantly increased inosine levels in RNA. Recombinant human GUK1 phosphorylates IMP into inosine diphosphate. Furthermore, in brain-specific Itpa-KO mice, Guk1 haploinsufficiency resulted in a significant reduction in inosine in cortical RNA and an extended lifespan. Thus, our results suggest that GUK1 is probably an enzyme responsible for ITP biosynthesis although the Km of GUK1 for IMP is very high in vitro.

Autophagy degrades various intracellular components by sequestering them within membrane vesicles called autophagosomes and delivering them to lysosomes or vacuoles. Previous studies have revealed that the conserved, bridge-like lipid transfer protein Atg2 tethers autophagosome precursors to the endoplasmic reticulum (ER) and mediates lipid supply from the ER to drive their expansion into autophagosomes. However, how Atg2 docks onto the ER has remained unclear. Here, we show in Saccharomyces cerevisiae that Atg2 interacts with the ER-resident VAP family protein Scs2. This interaction is mediated by a phospho-FFAT motif in Atg2 and the major sperm protein domain of Scs2 and enhanced by phosphorylation of the motif by the autophagy-initiating kinase Atg1, which is activated at the autophagosome formation site upon autophagy induction. This interaction cooperates with the N-terminal region of Atg2, which contains a weakly amphipathic helix, to mediate Atg2 association with the ER. Thus, the Atg2-Scs2 interaction functions as a spatiotemporal switch that controls Atg2-ER association. We also show that mammalian ATG2 interacts with the VAP-like proteins MOSPD1 and MOSPD3 to promote autophagosome formation. Collectively, this study reveals a conserved mechanism that initiates lipid transfer during autophagosome formation.

Antiviral drugs are among the few countermeasures available during the critical interval between the emergence of a novel influenza pandemic and vaccine availability. Antiviral stockpiling is a key pandemic preparedness measure, yet existing stockpiling estimates vary widely and rest on outdated assumptions about healthcare-seeking behavior and drug-specific effectiveness-limitations that the COVID-19 pandemic and recent clinical trial evidence have made untenable. We developed a multiscale transmission model incorporating heterogeneous healthcare-seeking behavior and direct clinical estimates of antiviral transmission risk reduction to estimate country-specific demand and mortality impact across four pandemic scenarios in 186 countries. We find that baloxavir marboxil (BXM), due to its transmission-reducing potential, could avert 37 to 68% of mean pandemic deaths in the first epidemic wave, approximately double the impact of oseltamivir, while requiring a mean stockpile approximately 5 to 10% smaller (7 to 34% of the population, compared to 28 to 36% for oseltamivir). Uncertainty in viral load dynamics and transmission reduction benefits from clinical trials means that BXM's impact could vary, but sensitivity analyses consistently suggest that BXM is likely to be more effective than oseltamivir. Under limited drug availability, priority should be given to treatment over postexposure prophylaxis. Although drug rationing for high-mortality populations (e.g., elderly) can substantially reduce BXM demand, doing so leads to greater total pandemic deaths. Critically, each week of delay in initiating antiviral distribution erodes impact by up to 3% of averted deaths, meaning that antiviral stockpiles must be accompanied by rapid deployment infrastructure to deliver their potential impact.

The amount of variation observed among early complex societies has challenged efforts to understand their social dynamics. We advocate for a comparative approach that directly investigates the forces producing this variation. By holistically ranking 63 trajectories of societal change along five axes of differentiation, we characterize their development from a multidimensional perspective. Our analysis reveals that the majority of these trajectories align with one of six recurrent pathways through "complexification," identified from broadly similar courses of development shared across multiple trajectories. These patterns provide a framework for understanding the conditions under which different forms of complexity emerged-or failed to do so. Particular attention is paid to the ways in which social and demographic forces interact along these pathways. Crucially, these forces interact probabilistically rather than deterministically, producing widespread tendencies rather than inevitable outcomes. Focusing future research on mediating and confounding variables, expanding the sample of trajectories available for analysis, identifying additional complexification pathways and the social forces at work in them, and leveraging the explanatory potential of trajectories that do not align well with any developmental pattern, will further enrich our understanding of the complexification process.

Sighted people rely on vision to recognize and navigate the local environment. By adulthood, human cortex contains at least three regions that respond selectively to visual scene information, but it remains unknown when or how these regions develop. One hypothesis is that development of scene selectivity depends on passive exposure to the low-level visual statistics of scenes. Another hypothesis is that development depends on active experience using scene information to plan and guide navigation. Using ecological momentary assessment, we measured the quantity of forward-facing ego-motion and active navigation that infants experienced in the first months of life. By age 5 mo, infants cumulatively experienced around 340 h of forward facing ego-motion, almost exclusively passive. Next we used functional MRI in infants aged 2 to 9 mo to measure neural responses to scenes. Awake infants watched videos of ego-motion through real-world scenes, as well as videos of faces, objects, and scrambled videos. We found stronger responses to scenes than control conditions in the location of all three cortical scene regions. Responses in infant scene regions a) were dissociable from those in nearby face and object regions; b) could not be fully explained by low-level visual features; and c) were found even in subsamples of infants with no locomotor experience. Thus, the basic signature of scene selectivity emerges prior to independent navigation and with limited passive visual exposure to the diagnostic visual statistics of scenes.

Folic acid (FA) supplementation during pregnancy is the commonly accepted treatment to prevent neural tube defects. The mechanism by which FA prevents neural tube defects (NTDs) remains unclear. FA also prevents other developmental malformations, including alcohol-induced malformations in Fetal Alcohol Syndrome models. We show that FA acts through a metabolic link to retinoic acid (RA) signaling. Using a pax3-knockdown Xenopus model of FA-rescuable NTDs, we show that RA or its precursors equally rescue these defects. Similarly, FA rescues alcohol-induced NTDs in a model previously shown to be rescued by retinoids. We identify the FA-metabolizing enzyme, formyl tetrahydrofolate dehydrogenase (ALDH1L1, FTHFD), encoded by the aldh1l1 gene, as essential for this rescue. Mechanistically, FA upregulates aldh1l1 expression, thereby increasing RA biosynthesis. Knockdown of ALDH1L1 activity using CRISPR/Cas9 abolishes the FA protective effect. To support these observations, we show that the human ALDH1L1 enzyme converts retinaldehyde to RA, and its overexpression restores neural tube closure in aldh1l1-knockdown embryos when retinaldehyde is provided. At the cellular level, reduced RA signaling results in overproliferation of neural plate precursors and a pathological expansion of the neural tube. ALDH1L1 enables FA to restore normal neural plate proliferation, thereby preventing NTDs. These findings establish ALDH1L1 as an unexpected enzymatic link between FA (vitamin B9) and RA signaling, revealing how FA supplementation safeguards neural development and suggesting opportunities to refine strategies for NTD prevention.

Sensory inputs are rich with temporal patterns that unfold across multiple timescales. Uncovering these regularities is essential for anticipating future events and navigating the environment efficiently. Numerous models have been proposed to account for learning at specific temporal scales; however, they are often designed in isolation and rely on narrowly tuned statistical measures, limiting their generalizability to other paradigms. In contrast, humans typically learn without prior knowledge of the underlying structure or the relevant timescale at which regularities occur. Here, we present a unifying account of statistical learning that spans a wide range of temporal dependencies, from adjacent and nonadjacent transitions to complex network structures. This model, long-horizon associative learning, offers a biologically grounded implementation of the successor representation, or equivalently, the free energy minimization model. Reanalyzing data from 11 previously published studies, we show that a single neural mechanism captures both local statistical regularities and higher-order structural properties. This mechanism rests on graded temporal overlap of associative traces and is governed by a single free parameter (β). This initial domain-general associative learning process, emerging from the graded structure of associations, may later scaffold to higher-level operations such as grouping, categorization, rule abstraction, and memory formation. Overall, this framework offers a conceptual synthesis that bridges disparate strands of the statistical learning literature and reframes apparent paradigm-specific effects as different expressions of a common underlying computation.

Oocytes rely on a cohort of proteins whose sustained expression ensures normal meiotic progression and reproductive competence throughout an animal's reproductive life. Age-related declines in these proteins are a major cause of reduced oocyte quality and female fertility during reproductive aging. Here, we report that the cohesin regulatory protein PDS5B, a dynamically maintained factor in oocytes, declines with age and plays a noncanonical role in the spindle pole formation independent of its cohesion function during oocyte meiotic maturation. Specifically, we found that PDS5B was expressed throughout the oocyte meiosis and localized at the spindle poles at metaphase stages, while its protein abundance was reduced in aged oocytes, concomitant with decreased messenger ribonucleic acid (mRNA) levels and translational efficiency. Knockdown or heterozygous knockout of PDS5B caused spindle assembly defects, meiotic arrest, and aneuploidy in oocytes, ultimately leading to female subfertility. Mechanistically, immunoprecipitation/mass spectrometry analyses revealed that PDS5B recruited deubiquitinating enzyme USP9X to spindle poles to stabilize nuclear mitotic apparatus and promote proper spindle assembly. Moreover, expression of exogenous PDS5B in aged oocytes partially alleviated meiotic defects associated with advanced maternal age. Altogether, our findings uncover a unique spindle pole-specific function of PDS5B in oocytes and suggest that maintaining PDS5B levels may be a potential strategy to improve the quality of aged oocytes.