Browse Articles

Mapping tissue-specific protease dynamics in the pig respiratory tract during influenza a virus infection

Abstract Influenza A virus (IAV) is a zoonotic pathogen capable of infecting diverse avian and mammalian hosts, causing seasonal epidemics and occasional global pandemics in humans. Viral entry requires proteolytic activation of hemagglutinin (HA). While serine proteases such as TMPRSS2 and HAT are known HA activators, the respiratory tract harbours additional proteases whose contributions to infection remain unclear. Dysregulation of these proteases can enhance viral replication, tissue damage, and inflammation, highlighting the need for a systems-level view of the proteolytic landscape. Here, we use high-throughput, proteome-wide proteomics and N-terminomics to identify 112 host proteases across the nasal mucosa, trachea, and lung. We monitor and validate 28 proteases with targeted proteomics and microfluidic qPCR, representing a comprehensive degradome analysis in the respiratory tract of the highly translational pig model of influenza infection. We show that protease abundance and activity were highly tissue-specific: while the nasal mucosa showed selective activation of broad- and narrow-specificity proteases alongside robust antiviral responses, the trachea exhibited modest modulation with subtle shifts in protease–inhibitor balance, and the lung maintained predominantly active proteases despite lower viral loads but severe tissue damage, indicative of immune-mediated pathology. Sequence motif analysis revealed distinct cleavage preferences across tissues, indicating differential protease processing across the studied respiratory tissues in antiviral pathways, antigen processing, and tissue remodelling. Several identified proteases, including ST14, KLKB1, PRSS8, and LGMN, were increased and functionally active upon infection, suggesting roles in viral processing and host immune regulation. Collectively, our results define a spatially organised proteolytic network that shapes tissue-specific antiviral host responses and contributes to H1N1 influenza pathogenesis.

Metabolic breadth links insect pathogenicity and plant association in <i>Metarhizium robertsii</i>

Fungi frequently transition between pathogenic, endophytic, and saprophytic lifestyles, yet the functional traits enabling these ecological shifts remain unclear. Comparative analyses of early and recently diverged lineages of Metarhizium robertsii reveal contrasting life-history strategies. Early diverged strains exhibit limited plant root association, slower insect lethality, extensive within-host proliferation, and high sporulation, whereas recently diverged strains display rapid germination on insect cuticle and plant roots, accelerated host killing, and hyphal growth from cadavers to plant roots; most also exhibit destruxin activity. Carbon utilization profiling across 95 substrates demonstrates that expanded metabolic breadth strongly predicts cuticle and plant-responsive germination, virulence across multiple insect hosts, and root colonization efficiency, linking cross-kingdom performance to nutritional breadth. Host immune activation further modulates strain-specific virulence but does not obscure the central role of metabolic flexibility. Collectively, these findings identify metabolic capacity as a functional axis coupling nutrient acquisition to ecological diversification, providing a mechanistic framework for understanding ecological plasticity in host-associated fungi.

Low PEEP ventilation in TGF-β1 induced lung injury triggers a reversible lung mechanical deterioration without promoting persistent structural damage

Abstract TGF-β1-induced lung injury initially results in surfactant dysfunction and alveolar instability (microatelectases). Morphology showed that at end-expiratory pressure of 2cmH 2 O the burden of microatelectasis was high but could be mitigated with a pressure of 8cmH 2 O by 35% without undue strain. Hence, we hypothesized that ventilation of lungs with a higher burden of microatelectasis at positive end-expiratory pressure (PEEP) of 2cmH 2 O triggers more pronounced injury progression compared to PEEP=8cmH 2 O. Mice were randomized to receive either TGF-β1 (AdTGF-β1) for injury induction or empty control vector (AdCl). After a second randomization one week later, mice were ventilated for 4 h with PEEP = 2 or 8cmH 2 O resulting in 4 experimental groups: AdTGF-β1-PEEP2 ( n  = 11), AdTGF-β1-PEEP8 ( n  = 10), AdCl-PEEP2 ( n  = 11) and AdCl-PEEP8 ( n  = 10). During ventilation, every 30 min, Quick-Prime (tissue elastance) and Snap-Shot (dynamic compliance) measurements were performed immediately before and after deep inflations. Finally, lungs were either fixed for stereology (both PEEP2 groups n  = 6/ both PEEP 8 groups n  = 5) or broncho-alveolar lavage ( n  = 5) and tissue harvest for transcriptome analyses. During ventilation the increase in tissue elastance was largest in AdTGF-β1-PEEP2 group but reversible by deep inflations. Finally, both AdTGF-β1-groups showed comparable worsening in lung mechanics, and BAL-albumin and neutrophils were elevated. Quantitative morphology showed no differences and transcriptome minimal differences attributable to PEEP-level. Low-PEEP ventilation of AdTGF-β1 lungs with a high burden of microatelectases induced lung mechanical worsening most likely due to progressive alveolar derecruitment. This injury pattern was reversible upon deep inflations and not linked with signs of persistent lung injury such as vascular leakage, edema or inflammation.

Debt as a blessing: A capital screening mechanism

We challenge a recently popular view that a negative interest-growth rate gap ( r &lt; g ) offers a “free lunch” for debt-financed government spending by formulating a model in which r and g are endogenous variables shaped by fiscal policy through its effects on equilibrium multiplicity and capital allocation. Observing r &lt; g can signal that sustained government deficits have generated multiple steady states, and the economy has converged to a stable low-efficiency equilibrium. With its heterogeneous entrepreneurs, the model’s real interest rate serves as a screening device for investment efficiency. Causation runs from the fiscal regime to equilibrium selection and outcomes: Fiscal surpluses eliminate equilibrium multiplicity and anchor expectations that sustain a unique, high-productivity equilibrium, thereby rationalizing Alexander Hamilton’s characterization of “debt as a blessing.” Persistent deficits can push the economy into a “misallocation trap” characterized by scarce safe assets, low interest rates, survival of inefficient firms, depressed aggregate productivity, and self-validating low growth. Thus, costs of debt-financed fiscal deficits consist not only of deferred taxes, but also of permanently lower national productive capacity.

Serum vitamin D level and its association with vertigo frequency and severity in Meniere disease

Morphogenesis and topological evolution of a frustrated nematic liquid crystal under confinement

Liquid crystals (LC) represent topological soft matter that spontaneously form assemblies of constituents and mesoscale textures to minimize free energy. Depending on boundary conditions, they exhibit transformable topological defects, whose study provides fundamental insights applicable to a wide array of disciplines. However, their three-dimensional (3D) structures and dynamics remain largely unexplored due to the subdiffraction limit length scales and submillisecond time scales characteristic of conventional molecular LCs. Here, we report a morphogenesis from conventional nematic tactoids to a unique flower-shaped morphology using a colloidal LC composed of Eu 3+ -doped LaPO 4 nanorods. We demonstrate 3D orientational tomography based on polarized photoluminescence spectroscopy of the Eu 3+ dopants, revealing dramatic topological and topographical modulations. We find that this morphogenesis is driven by a theoretically unexpected vertical anchoring of the nanorods on the substrate, which exerts conflicting boundary conditions and leads to a competition between elastic energy and relatively weak surface tension. Our results provide valuable insights into how energy balance in topological matter can be modulated by tuning physicochemical properties of its building blocks.

Comparative clinical significance of HPV DNA, HPV E6/E7 mRNA, and p16INK4a in cervical cancer among Indian and USA populations: a meta-analysis and systematic review

Corkscrew motion of <i>Trypanosoma brucei</i> is driven by helical beating of the flagellum and facilitated by its bent shape

In the pathogenic parasite Trypanosoma brucei , a laterally attached flagellum drives rapid deformation of the complex cell body, producing puzzling dynamics. High-speed defocusing imaging reveals that surface points trace flower-like patterns in transverse planes. The petals arise from clockwise flagellar beating, which generates a right-handed helical wave propagating from the anterior tip along the body, advancing the cell like a twisted corkscrew. The central lobes result from slower counterclockwise body rotation required to balance the active torque. The bent cell shape underneath the flagellum superimposes these two chiral motions at different radial distances, producing the observed patterns. Three-dimensional hydrodynamic simulations using the method of regularized Stokeslets reproduce these dynamics and show that bent cell shape enhances swimming, suggesting an adaptive advantage of T. brucei ’s morphology.

Influence of design parameters on peripheral defocus after keratorefractive lenticule extraction

Elastocapillary adhesion of soft gel microspheres

Softer means stickier for solid adhesives, because material compliance facilitates close contact between nonconformal surfaces. Recent discoveries have revealed that soft materials can exhibit a rich array of new physics arising from competing effects of continuum elasticity, fluid-like surface mechanics, and internal poroelastic flows, all of which can directly impact interfacial interactions. In this work, we investigate this complex interplay across several orders of magnitude of elastic stiffness by measuring the complete adhesive contact geometry between compliant silicone gel microspheres and flat, rigid substrates. We observe a continuous elastocapillary transition in adhesion mechanics, revealed by both the breadth of data and the detailed contact geometries. Importantly, soft gel spheres exhibit a remarkably broad range of near-equilibrium contact morphologies and their contact line deformation is always mediated by a fluid contact zone that phase separates from the gel. To explain this, we develop a model incorporating elastocapillary and poroelastic mechanics that predicts the complete range of adhesive behavior and elucidates energetic tradeoffs. The data and model together reveal a shallow energy landscape that may contribute to the robustness of everyday adhesives.

Enhanced hydrovoltaic energy conversion via optimized tubular MnO2-activated carbon composites

Tau protein as a regulator of mitochondrial function and dynamics

Mitochondrial damage is a shared hallmark of brain aging and neurodegeneration. While pathological Tau mutations disrupt mitochondrial dynamics and function, the physiological role of wild-type (WT) Tau in the maintenance of mitochondrial homeostasis remains poorly understood. Here, using Caenorhabditis elegans and mice lacking PTL-1, the nematode Tau-like homolog, and Tau respectively, we demonstrate that Tau deficiency promotes a shift toward a pro-fusion mitochondrial state associated with enhanced mitochondrial function and stress resistance. In both models, loss of Tau leads to increased mitochondrial activity and altered redox homeostasis, while it enhances resistance to heat and mitochondrial stress in C. elegans . Strikingly, loss of FZO-1, the mitofusin homolog, abolishes the beneficial phenotypes, whereas its overexpression phenocopies key aspects of Tau/PTL-1 deficiency. Together, our findings uncover a conserved role for WT Tau in restraining mitochondrial fusion and functional adaptation, highlighting its contribution to mitochondrial homeostasis and cellular stress responses.

School screening for adolescent idiopathic scoliosis in China: a five-year evaluating the evaluation in Zhongshan city

Large language models accurately identify decision reasons in verbal reports

Understanding the reasons behind human choices under risk is a central goal of decision scientists, but traditional methods relying on behavioral data are limited by strict invariance assumptions. We introduce a scalable analytical framework using large language models (LLMs) to analyze verbal reports and identify articulated reasons for choice between monetary lotteries. A validated LLM accurately identified predefined decision reasons in participants’ free-text reports, aligning with their actual choices in 95% of trials. Our analysis reveals that the reasons behind people’s decisions vary systematically and are driven more by the structure of the choice problem than by individual differences. Crucially, reasons identified from verbal reports yield more parsimonious and informative representations of decision processes compared to those inferred from choices alone; furthermore, problem-specific reason profiles achieve out-of-sample prediction accuracy that is competitive with established computational models. This work demonstrates that verbal reports are a rich data source and our analytical framework can unlock their potential, delivering results that challenge the field’s foundational invariance assumptions and pave the way for more context-sensitive and interpretable models of human decision making.

Multi-attention enhanced encoder–decoder network with hybrid transformer bottleneck for echocardiography image segmentation

Sustained A2AR expression and loss paradoxically promote CD8 ⁺ T cell exhaustion

Although A2AR is a key immunoregulatory receptor that suppresses CD8 + T cell activation in response to elevated extracellular adenosine in inflamed or hypoxic microenvironments, its role in CD8 + T cell differentiation and cell-fate decisions during chronic viral infection and cancer remains poorly understood. Using A2AR-eGFP reporter mice, we show that A2AR expression is rapidly induced by TCR stimulation and persists under chronic antigen exposure and hypoxia, with sustained expression strongly associated with terminal exhaustion via the canonical Gα s –cAMP–PKA pathway. Paradoxically, A2AR loss does not alleviate exhaustion but instead accelerates differentiation toward the terminally exhausted state. Single-cell multiomics profiling revealed that A2AR deficiency activates CD122 (IL-2Rβ)–dependent signaling, driving T cell exhaustion. Genetic deletion of CD122 in A2AR-deficient CD8 + T cells reduced terminal exhaustion, identifying CD122 signaling as a key mediator of A2AR loss–driven exhaustion. Intriguingly, both sustained A2AR expression and A2AR loss converge to promote T cell exhaustion differentiation through distinct mechanisms. These findings uncover a paradoxical role of A2AR in shaping CD8 + T cell fate choices during chronic infection and cancer.

High-intensity interval training enhanced cardioprotective effects of neuregulin-1 against doxorubicin-induced cardiotoxicity

RNA polymerase inhibitors reveal active-site motions essential for the nucleotide addition cycle

The nucleotide addition cycle (NAC) of multisubunit DNA-dependent RNA polymerases (RNAPs) involves coordinated conformational changes in conserved active-site structural elements, including the trigger loop (TL). The TL is open (unfolded) in most RNAP structures but can close (fold) in substrate-bound (post- or pretranslocated) states of the RNAP, promoting catalysis. TL closure has been associated with closure of another conserved structural element, the Rim-Helices/F-loop (RH-FL), but the role of the RH-FL in the NAC is unclear. Antibiotic leads CBR9379 and AAP-SO 2 inhibit the Escherichia coli and Mycobacterium tuberculosis RNAPs, respectively, by binding in a pocket formed by the bridge helix and RH-FL. The precise mechanism of action for these inhibitors is yet to be defined. We present cryoelectron microscopy structures showing that both compounds inhibit the RNAP NAC by preventing RH-FL closure, thereby allosterically destabilizing the closed TL. This work reveals a conserved mechanistic principle of RNAP catalysis across all domains of life and provides insight for antibiotic design.

Laparoscopic ovum pick-up (LOPU) in neotropical primates of Amazonia: a post mortem model study

A scalable, dividing cell model for the robust propagation and quantification of human sporadic Creutzfeldt–Jakob disease prions

Prion diseases represent a unique biological paradigm with mechanistic parallels to other neurodegenerative conditions like Alzheimer’s and Parkinson’s diseases. However, the study of human prion pathobiology and the development of effective therapeutics has been severely constrained by the inability to propagate human prions in dividing cells—forcing reliance on costly and slow animal bioassays. Here, we report the generation of EKV cells—a humanized cell model which supports the robust, indefinite propagation of sporadic Creutzfeldt–Jakob disease (sCJD) prions. We demonstrate that these cells replicate bona fide human prion infectivity in culture—cell lysates induce lethal neurodegeneration in humanized mice that is clinically and neuropathologically indistinguishable from inoculation with sCJD-infected brain tissue. We use EKV cells to develop the Human Prion Assay (HPA), which quantifies sCJD infectivity with sensitivity comparable to gold-standard mouse bioassay, while reducing the experimental timeline from years to weeks. Furthermore, we demonstrate that established sCJD infection can be cured by an anti-prion protein antibody, validating the system as a high-throughput platform for drug discovery. This model bridges a critical translational gap, offering a renewable alternative to animal bioassays, a paradigm to dissect the biology of human sCJD prion disease and screen for therapeutic agents.