bioRxiv : the preprint server for biology最新文献

Springtails execute millisecond-scale escape jumps with a single appendage, the furca, on soil, snow, leaf litter, and water. Across 15 taxonomic families (n=552 individuals), relative furca length is bimodal. High-speed video and confocal imaging show that in some long-furca springtails, the resilin-rich manubrium-dens joint behaves as a compliant hinge. It bends during push-off to prolong contact, suppress pitch, and bias takeoff forward, whereas rigid joints drive backward launches with rapid body rotation. We translate this mechanism to a 20-mm, 84-mg jumping robot with an elastic robo-furca hinge. This flexible hinge reduces body rotation by ~90% on flat ground compared to rigid-hinge designs, while maintaining takeoff speed on gravel, springboards, leaves, and pine needles, enabling passive, terrain-adaptable launches for power-limited insect-scale robots without onboard sensing or active control.

Neurexins are synaptic adhesion molecules associated with vast neurologic changes in humans, including neurodevelopmental delay, autism, schizophrenia, Tourette syndrome, and seizures. The NRXN1 gene produces >100 protein isoforms through alternative promoters and extensive splicing, which are differentially impacted by NRXN1 deletions found in patients. Yet pharmacologic targeting of NRXN1 isoforms or deletions has not been comprehensively studied. Here, we developed a behavioral screening approach in C. elegans to identify small molecule compounds that modify decreased activity levels caused by isoform-specific deletions of neurexin (nrx-1). Screening 190 compounds, we discovered that monoamine-targeting drugs differentially improve behavioral phenotypes depending on which nrx-1 isoforms are disrupted. Broad modulation of monoamine signaling or antagonism of specific serotonin receptors are required to increased activity of both alleles tested. Modulation of adrenergic signaling uniquely improved loss of α-isoform, and additional antagonism of dopamine signaling was required to increase activity with loss of γ isoform. The FDA-approved atypical antipsychotic olanzapine was the sole validated compound achieving Z-scores >2 in both screens. In Drosophila Nrx-1 mutants, olanzapine, but not the related compound asenapine maleate, significantly improved activity deficits, demonstrating evolutionary conservation of the neurexin-monoamine relationship. Multi-behavior testing revealed pharmacological specificity: olanzapine improved both activity and social feeding phenotypes of nrx-1 alleles, while asenapine maleate improved activity, but worsened social feeding, indicating distinct modifier impacts across behavioral domains. Our findings establish monoamine modulation as a conserved compensatory mechanism for neurexin loss, identify olanzapine as a lead compound for targeting neurexin loss, and demonstrate that allele stratification and pharmacogenomic approaches are needed for precision intervention in behavioral conditions.

Mechanistic simulations of blood flow and oxygen exchange showed regions of cortical tissue tolerating substantial increase in local oxygen consumption (CMRO2) before reaching hypoxia (pO2<10 mmHg). The observed robustness in O ₂ supply was attributed to overcapacity in convective oxygen transport in the pial arterial network combined with a surplus in the number of capillary flow paths. Microcirculatory flux analysis suggests that network induced hemodynamic flow patterns impart intrinsic reserve to protect the brain against perfusion variances or metabolic demand surges during activation. Furthermore, oxygen transport in cortical tissue is characterized by two regimes: in the transport zone - centered on penetrating arteriole trees composed of a single penetrating vessel connected to the post-arteriole capillary transition zone - strong diffusion supports high oxygen tension with only modest contribution from capillaries. This regime transitions into the terminal/reactive zone where oxygenation is sensitive to capillary density and perfusion. Quasi-dynamic simulations also enabled reconstruction of the BOLD signal underlying functional imaging. Simulations at single micron resolution further show that age-related reductions in arterial saturation and systemic hematocrit were sufficient to induce hypoxic tissue pockets in the terminal zone at nominal perfusion (CBF) and metabolic activity (CMRO ₂ ), and neutrophil adhesion induced capillary flow stalling further exacerbates hypoxia.

Antibiotic resistance is a global challenge driven by the persistence and spread of resistance genes across ecological contexts. While mobile genetic elements (MGEs) facilitate horizontal gene transfer, gene duplication represents an additional mechanism through which resistance genes can be amplified, diversified, and maintained under selection. How these processes interact across environments remains poorly understood. Here, we examined genome-level patterns of resistance gene abundance, duplication, and mobilization across clinical, agricultural, and wastewater settings, focusing on both antibiotic resistance genes (ARGs) and metal resistance genes (MRGs). Resistance gene profiles were strongly structured by environment, with distinct duplication patterns emerging across sources. Duplicate genes were frequently associated with MGEs, although the strength of this relationship varied by resistance type and ecological context. Despite frequent co-occurrence of ARGs and MRGs, their duplication and mobilization dynamics were not uniformly coupled at the genome level. Together, these findings highlight gene duplication as a context-dependent contributor to resistance evolution and underscore the importance of ecological setting in shaping how resistance genes persist and spread across microbial communities.

The fitness landscape metaphor remains resonant in evolutionary theory and has facilitated the birth of newer concepts-like the fitness seascape-that consider the role of environmental context in shaping the dynamics of evolution. Since the emergence of the fitness seascape, it has appeared in several studies that examine how different and fluctuating environments shape evolutionary outcomes. Despite a growing interest in these topics, we lack comprehensive examinations of the role of environmental context in shaping features of fitness seascapes. In this study, we address this gap by deconstructing empirical fitness seascapes across scales of granularity: mutational steps, loci, locus interactions, alleles, trajectories, and entire seascapes. For each, we examine how environmental context influences qualitative and quantitative aspects of seascapes, and find that they change appreciably, with patterns that are specific to individual systems of study. In summary, we reflect on the implications of the seascape metaphor with respect to the incorporation of environmental effects into theoretical population genetics, for understanding how the environment shapes evolution in disease systems, and for contemporary bioengineering excursions.

Sirtuin 6 (SIRT6) is an important regulator of DNA repair, metabolism, chromatin maintenance and longevity. SIRT6 Serine 10 phosphorylation controls SIRT6 recruitment to the sites of DNA damage. To explore the effect of SIRT6 Serine 10 phosphorylation on lifespan, we generated two SIRT6 mutant mouse strains: phospho-null S10A and phosphomimetic S10E. The S10E mutant mice demonstrated enhanced DNA repair capacity, elevated LINE1 expression and reduced lifespan in male mice compared to the wild-type and S10A mice. This result suggests that SIRT6 S10E mutation enhances DNA repair capacity at the expense of reduced LINE1 silencing leading to shorter lifespan. While both SIRT6 functions in DNA repair and chromatin maintenance are important for longevity, our results suggest that when the balance between these functions is shifted, diminished of LINE1 control has a stronger impact on lifespan than enhanced DNA repair.

Background: Temperature choice is a vector trait that influences microhabitat selection and can have important implications for vector species, as it may affect how often vectors encounter hosts. Aedes aegypti and Ae. albopictus are disease vectors whose geographic ranges continue to expand each year. One aspect that remains largely understudied is the altitudinal range of these species and the extent of differences in thermal behavior between lowland and highland populations.

Methods: I collected Ae. aegypti and Ae. albopictus on the islands of Bioko and São Tomé. I compared the distribution of the two species along an altitudinal cline spanning 2,000 m of elevation. I then used live specimens to test temperature preference for both species in a laboratory thermocline.

Results: I report the distribution of these two species on the island of Bioko and show that the abundance of immature stages of both species follows a negative exponential decay with altitude. I compare this distribution with that observed on the neighboring island of São Tomé, also in the Gulf of Guinea. Overall, the distribution patterns of the two species are similar, but models indicate a higher abundance at sea level in São Tomé than in Bioko. I used specimens from this survey to study temperature preference under controlled conditions. I found no significant differences between species or between sexes; however, I detected an altitudinal cline in temperature preference, with high-elevation populations preferring cooler temperatures on both islands.

Conclusions: These results indicate the presence of phenotypic variation in a key trait-temperature choice-that may alter the likelihood of contact between these vectors and humans.

The sarco-endoplasmic reticulum Ca²⁺-ATPase (SERCA) is a ubiquitous P-type ATPase that restores cytosolic Ca ²⁺ to the sarco-endoplasmic reticulum. SERCA is essential for cardiac Ca ²⁺ cycling and cellular energy metabolism. Several small molecules enhance SERCA function and show promise in models of metabolic and cardiovascular diseases. However, the structural basis for SERCA activation has remained unknown, hindering mechanism-driven lead optimization. Here we present cryo-EM structures of SERCA bound to two chemically distinct activators: the quinoline derivative CDN1163 (2.6 Å resolution) and a benzofuran derivative UM-52 (3.1 Å resolution). Biochemical assays show that both compounds stimulate Ca ²⁺ -dependent ATPase activity of SERCA without altering the apparent Ca²⁺ affinity. The structures reveal a previously unrecognized "activation hotspot" in the transmembrane domain, a shallow groove formed by helices M3 and M4 and capped by M1. Despite low chemical similarity, both activators occupy the same pocket and share conserved interactions with Ser ²⁶⁵ , Trp ²⁷² , and Phe ²⁹⁶ . These residues are unique to SERCA and help explain selectivity relative to other P-type ATPases. Activator binding stabilizes a catalytically competent conformation, shifting SERCA toward an E1-like state poised for ATP binding and coordinated movements of the M1-M4 bundle and the cytosolic domains. Notably, density consistent with a detergent acyl chain bridges an otherwise open cavity adjacent to the compound, suggesting that altered protein-lipid interactions may contribute to activation. Together, these findings define a structural framework for SERCA activation and provide a blueprint for rational design of next-generation SERCA activators.

Significance statement: SERCA pumps Ca²⁺ into the sarco-endoplasmic reticulum, enabling muscle relaxation and shaping calcium signals across tissues. Small-molecule SERCA activators improve cardiac and metabolic phenotypes in animal models, but drug development has been limited by the absence of a defined binding site and activation mechanism. We determined cryo-EM structures of SERCA bound to two distinct activators, CDN1163 and UM-52. Both compounds occupy a groove formed by transmembrane segments M3-M4, anchored by a hydrogen bond to the SERCA-specific Ser ²⁶⁵ and aromatic contacts near Trp ²⁷² and Phe ²⁹⁶ . An acyl chain bridges a gap in the binding pocket toward M1, suggesting that protein-lipid coupling may play a role in SERCA activation. These results directly enable structure-mechanism guided design of next-generation selective SERCA activators.

Motivation: Alternative splicing (AS) is a fundamental regulatory mechanism that expands transcriptomic and proteomic diversity by generating multiple mRNA isoforms from a single gene. Aberrant AS has been implicated in numerous diseases through the production of dysfunctional or pathogenic protein variants. However, much of the existing AS research has focused predominantly on exon skipping and constitutive splicing, with comparatively limited attention to other biologically relevant AS event types. Moreover, many current computational approaches rely on short genomic sequence windows and conventional deep learning architectures, which may limit their ability to capture broader regulatory context associated with complex splicing decisions. Bridging these methodological and conceptual gaps is essential for advancing comprehensive AS characterization and improving our understanding of its role in human health and disease.

Results: We present ASPECT, an alternative splicing event classification framework built upon DNABERT-2 with Byte Pair Encoding (BPE) tokenization. Across multiple binary alternative splicing event pair classification tasks, ASPECT achieves consistently strong performance as measured by AUC, F1-score,and accuracy, demonstrating reliable discrimination between closely related splicing event types. Importantly, ASPECT demonstrates consistent performance when applied to TCGA BRCA cancer-associated splicing events reconstructed from SpliceSeq annotations, supporting its applicability beyond the canonical splicing events used for training.

Availability: The open-source code, data, and detailed documentation used in this study are available at https://github.com/OluwadareLab/ASPECT .

Contact: Oluwatosin.Oluwadare@unt.edu.

Supplementary information: N/A.

Tau pathology in the entorhinal cortex (EC) is associated with spatial memory decline in aging and early-stage Alzheimer's disease, but its impact on EC computations during learning is not well understood. We performed longitudinal two-photon calcium imaging of layer 2 excitatory neurons in the medial EC (MEC) of PS19 tauopathy mice over 10 days of an operant spatial learning task. Male PS19 mice showed marked learning impairments accompanied by dysregulated MEC activity and unstable spatial coding. Their activity also showed weakened representations in cue-poor relative to cue-rich regions, correlated with attenuated speed modulation. These changes suggest that impaired path integration destabilizes MEC spatial maps, leading to impaired spatial memory. In contrast, female PS19 mice exhibited only mild behavioral and neural deficits despite a comparable tau burden, suggesting sex-specific resilience. Among MEC cell types, pyramidal cells accumulated more phosphorylated tau than stellate cells and displayed the most severe functional disruption, linking cellular tau load to circuit dysfunction. Finally, general linear models of MEC activity reliably predicted learning performance, highlighted particularly strong contributions from non-grid and pyramidal cells, and accurately classified PS19 versus wild-type mice. These findings identify aberrant MEC dynamics as a key circuit mechanism underlying tau-related spatial memory deficits and point to early diagnostic and circuit-targeted therapeutic strategies.