TMPRSS11E is a serine protease whose expression is upregulated in macrophages during inflammation. Here, we identify TFR1 as an interacting protein of TMPRSS11E via LC-MS/MS. In vitro experiments reveal that TMPRSS11E cleaves TFR1 and releases soluble TFR1 (sTFR1). In alveolar macrophages isolated from pneumonia patients and inflammatory animal models or cultured LPS-challenged cell lines, upregulated TMPRSS11E expression and significantly increased sTFR1 release are observed. Moreover, THP-1 cells stably expressing TMPRSS11E present decreased iron uptake, increased cell surface IFN-γR2 accumulation, and a stronger response to IFN-γ stimulation. During M0 macrophage differentiation to the pro-inflammatory M1 phenotype, the specific induction of TMPRSS11E, decreased cell surface TFR1, and increased IFN-γR2 cell membrane localization are also observed. Taken together, our results suggest that TMPRSS11E contributes to M1 macrophage differentiation by regulating iron uptake and affecting IFN-γR2 internalization through TFR1 cleavage, indicating that TMPRSS11E plays an important role in iron homeostasis and the innate immune response.

Alteration of chromosomal dosage severely affects the expressions of cis and trans genes in human and fruit fly. However, its effect on gene expression in plants needs to be further explored. Here, we generated 84 aneuploid lines with extra 1 to 16 chromosomes by crossing a female diploid poplar and a male triploid poplar. The chromosome compositions of the aneuploid population were dissected by DNA sequencing and cytogenetics. An RNA-seq analysis showed that cis genes were affected by both dosage and inverse effects, while trans genes were mainly affected by inverse effect. When the chromosomal dosage in an aneuploid line exceeds a threshold, the inverse effect may exceed the dosage effect on cis genes, causing dosage overcompensation. Interestingly, we found that even the genes located on the same chromosome may be subjected to different types of effect. These findings provided an important theoretical basis for analyzing the gene expression from the perspective of chromosomal dosage level.

Microorganisms thrive in complex communities shaped by intricate interactions, yet the extent and ecological implications of biosynthetic dependencies in natural communities remain underexplored. Here, we used a dilution approach to cultivate 204 microbial model communities from the Baltic Sea and recovered 527 metagenome-assembled genomes (MAGs) that dereplicated into 72 species-clusters (>95% average nucleotide identity, ANI). Of these species, at least 70% represent previously uncultivated lineages. Combined with 1073 MAGs from Baltic Sea metagenomes, we generated a genomic catalog of 701 species-clusters. Our results show that cultures with more than three species included microorganisms with smaller genome sizes, lower biosynthetic potential for amino acids and B vitamins, and higher prevalence and abundance in the environment. Moreover, the taxa found together in the same model communities had complementary biosynthetic gene repertoires. Our results demonstrate that cultivating bacteria in dilution model communities facilitates access to previously uncultivated but abundant species that likely depend on metabolic partners for survival. Together, our findings highlight the value of community-based cultivation for unraveling ecological strategies. Finally, we confirm that metabolic interdependencies and genome streamlining are widespread features of successful environmental microorganisms.

The trimeric ATP-gated receptor P2X offers a minimalist scaffold for dissecting subunit-coupled allosteric activation. Despite closed and open structures, the physical origin of the transient 'flip' intermediate and P2X's negative cooperativity remain unresolved. Rapid patch-clamp kinetics parsed by Bayesian inference (MacroIR) and supported by atomistic simulations reveal that P2X activates through a sequential, asymmetric coupling mechanism. ATP binding to any inter subunit pocket selectively reduces the rotational barrier on one of the two framing subunits, triggering partial activation of the receptor while the other subunit is minimally affected. This rotation then raises the barrier for the next ATP-binding event, accounting for the receptor's negative cooperativity. Under ligand-free conditions, heightened rotation barriers trap the channel in its closed conformation and quantitatively reproduce the spontaneous current fluctuations we record. These results overturn the canonical view of symmetric, concerted gating in P2X and explains the classical flip state as an obligatory structural intermediate.

Biological invasions can strongly disrupt ecosystems, reshaping their structure and functioning. We investigate how two widespread invasive parrots -the rose-ringed parakeet Psittacula krameri and the monk parakeet Myiopsitta monachus- affect plant-bird interaction networks using a multilayer framework. Field data were collected over a full annual cycle in an area with both species, accumulating 288 h of observations and tracking 24,561 fruits from 576 plants. Parakeets modified networks by introducing novel interactions, increasing species turnover and altering modularity and nestedness. Acting as both seed predators and dispersers, they became central connectors, enabling native birds to access previously unavailable resources and increasing rare dispersal mechanisms. Their activities increased antagonisms and generated new interspecific interactions with numerous plant species. By exploiting plants not previously used by local birds, parakeets heightened the risk of secondary invasions and the spread of exotic plants. These findings underscore their dual roles in disrupting and restructuring ecological networks and stress the need to reassess their contributions in native and invaded ecosystems. Understanding their potential to facilitate exotic plant expansion is critical, as their ecological impacts will likely intensify with population growth and geographic spread. Comprehensive assessments are essential to predict and mitigate these far-reaching consequences.

Paliurus hemsleyanus Rehd., a deciduous shrub or small tree endemic to China, is valued for its hardiness, economic and ornamental importance, and widespread used as a rootstock for Chinese jujube (Ziziphus jujuba Mill.). Despite its ecological and economic significance, genomic resources for this genus remain limited. Here, we assemble a haplotype-resolved, telomere-to-telomere (T2T), gap-free genome of P. hemsleyanus (2n = 24), representing the genus Paliurus. The genome comprises two haplotypes of 306.65 Mb and 306.21 Mb, with contig N50 values of 24.91 Mb and 24.94 Mb, respectively. Each haplotype encodes over 29,000 protein-coding genes, with all centromeres and telomeres fully predicted. Allele-specific expression analysis reveals a positive correlation between gene expression divergence and sequence variation, indicating functional differentiation between haplotypes. Comparative genomic analysis shows relatively stable genome evolution within Rhamnaceae, with all examined extant species containing 12 chromosomes. Disease resistance (NLR) genes exhibit a root-preferred expression pattern, and allelic copies expressed more strongly than non-allelic ones between haplotypes. Ascorbic acid (AsA) metabolic genes show leaf-preferred expression; and moreover MDHAR genes exhibit Rhamnaceae-specific tandem duplications, suggesting lineage-specific adaptive evolution. This high-quality genome provides an essential resources for evolutionary studies, functional genomics, breeding, and the conservation of Rhamnaceae species.

The interplay between brain metabolism and function supports the brain's adaptive capacity in cognitively demanding processes. Prior work has linked glucose metabolism to resting-state fMRI activity, but often overlooks both hemodynamic confounders in the BOLD signal and the brain's dynamic nature. To address this, we employed a novel effective connectivity decomposition, separating symmetric partial covariance, capturing "true" statistical dependencies between regions, from antisymmetric differential covariance, reflecting directional brain flow. In 42 healthy subjects, we show that partial covariance corresponds to metabolic connectivity across regions, while node directionality relates to standardized uptake value ratio, a proxy for local glucose consumption. We subsequently tested the sensitivity of detected couplings in 43 glioma patients, identifying disruptions in both local and network-level effective-metabolic interactions that varied with tumor anatomical location. Our findings provide novel insights into the coupling between brain metabolism and functional dynamics at rest, advancing understanding of healthy and pathological brain states.

The highly specialised dentitions of modern sharks enable them to exploit a wide range of food sources. Exceptional fossil preservation of three Late Devonian basal chondrichthyan taxa from the Anti-Atlas, Morocco, provides the unique opportunity to study these dentitions in detail, including their tooth histology, replacement patterns, and mineralisation sequences. Thin sections and CT-data of tooth files reveal a high histological diversity and evidence a noticeable disparity in mineralisation patterns early in chondrichthyan evolution. The presence of similar tooth histology and mineralisation patterns in phylogenetically and chronostratigraphically distant chondrichthyan taxa opposes a phylogenetic signal. Although the pseudoosteodont histotype is considered plesiomorphic, we found a high disparity regarding the arrangement of dental tissues in early chondrichthyans. Tooth size differences indicate slow tooth replacement rates for Ctenacanthus and Maghriboselache. Smaller differences in Phoebodus suggest an elevated rate. Tooth retention in Maghriboselache might constitute a precursor for the holocephalan evolution of tooth plates.

Traumatic brain injury (TBI) remains a leading cause of chronic neurological impairment, yet the cellular mechanisms underlying long-term neurodegeneration in TBI remain incompletely understood. Astrocytes, the most abundant glial cell type, are central to maintaining neuroglial and neurovascular homeostasis. Following TBI, however, astrocytic activation contributes to sustained inflammation and neurotoxicity. In this study, we employed immunohistochemistry and RNA sequencing to longitudinally profile astrocyte morphology and transcriptional states at acute (2 days), subacute (2 weeks), and chronic (1 year) stages after controlled cortical impact in mice. We identified a temporally evolving astrocyte response-beginning with a pro-inflammatory profile acutely, transitioning through a profile suggestive of mixed inflammatory and neurodegenerative signatures subacutely, and culminating in a chronic state marked generally by expression of Alzheimer's and Parkinson's disease-associated genes. Notably, a subset of astrocyte-derived progenitor cells also was found up to one-year post-injury, expressing markers associated with neurogenesis. These findings reveal that astrocyte activation is not transient but persists chronically, undergoing a dynamic shift from inflammation to degeneration. The observed parallels between astrocyte states in chronic TBI and neurodegenerative disorders underscore their potential role in post-traumatic cognitive decline and highlight astrocyte-targeted interventions as a promising avenue for therapeutic development.

Understanding the anaerobic deconstruction of recalcitrant lignocellulose remains challenging. Combining substrate composition and transcriptomic analyses, we shortlisted Ruminiclostridium cellulolyticum enzymes that modify lignocelullose and distinguished two members of the large SGNH hydrolase superfamily potentially enhancing lignocellulosic biomass degradation by acting on decorations of lignin and hemicelluloses but also on cross-links implicating lignin. Using genetic modifications, bioinformatics and biochemistry, we show they promote the plant cell wall ester-linked hydroxycinnamic acid derivatives release, a role never described for these proteins mainly synthesized by the restricted group of cellulolytic and cellulosome-producing bacteria. In addition to the recent observation of fungal limited lignin alterations in oxygen absence, this discovery is to the best of our knowledge, the first evidence of such anaerobic bacterial process that provides a better comprehension of the biogeochemical Earth's carbon cycle. Furthermore, a better knowledge of the anaerobic plant biomass degradation could help to design non-fossil resources based biotechnological applications, a cornerstone of bioeconomy development.

Marine fungi play key roles in organic matter cycling, yet their distribution across particle size fractions remains understudied. We analyze 18S rDNA data from four size fractions (0.8-5, 5-20, 20-180, and 180-2000 μm) collected across the global sunlit ocean. Here, we show fungal diversity and relative abundance decline with increasing particle size. Fungal community structure is influenced by eukaryotic diversity and chlorophyll levels. Fungi co-occur with other eukaryotes, especially zooplankton, hinting at potential predator-prey interactions. Generalist fungi dominate smaller fractions, while specialists dominate larger fractions, likely due to stronger microenvironmental selection. Co-occurrence networks are dominated by positive interactions and driven by fungal specialists. Dispersal limitation emerges as the main ecological process shaping community assembly. Our findings reveal strong niche differentiation among marine fungi along the particle continuum and emphasize the role of particle size and biological interactions in structuring fungal diversity and biogeography.

Parental cooperation is not self-evident, as conflicts often arise over individual contributions. Evolutionary game theory suggests this conflict may be resolved through negotiation, where parents adjust their care level based on their partner's contribution. However, mathematical negotiation models typically predict low parental cooperation. As these models are not dynamically explicit and mostly neglect stochasticity, we employ individual-based simulations to investigate how parental negotiation strategies evolve and shape care patterns. Our results differ markedly from earlier analytical predictions. Parental negotiation strategies readily evolve, resulting in four alternative care patterns: uniparental care, sex-biased care and two types of egalitarian biparental care. Effective cooperation evolves regularly but, contrary to common expectations, always relies on a Tit-for-Tat strategy rather than parental compensation. Our study underscores that diverse cooperative patterns in animals can emerge from sex-specific negotiation strategies, even in the absence of initial sex roles and environmental variation.

Glucocorticoid-induced skeletal muscle atrophy severely limits the clinical use of glucocorticoids and occurs in various endocrine and metabolic diseases. However, a detailed understanding of how glucocorticoid receptor (GR) transcriptional responses contribute to muscle atrophy is lacking. Irisin is a myokine induced by exercise and has been shown to exert multiple beneficial effects on muscle mass and metabolism regulation. Here, we show that glucocorticoid genomic effects are the main pathway through which glucocorticoids induce muscle atrophy in mice. Increased GR Ser212 and Ser234 site phosphorylation reduces glucocorticoid-induced muscle atrophy in mice. Irisin ameliorates high-fat diet (HFD) and dexamethasone (Dex)-induced muscle atrophy. Mechanistically, this effect depends on irisin promoting the phosphorylation of ERK and JNK through integrin αVβ5 receptors, which in turn impairs the dephosphorylation of GR Ser212 and Ser234 sites, affecting the GCs genomic effect on the transcription of muscle atrophy-related genes. These findings highlight the genomic effects of GCs as an intervention target to ameliorate GC-induced muscle atrophy and suggest that irisin could be a potential therapeutic target.

KRAS G12 mutations are frequent oncogenic drivers, yet their differential immunogenicity complicates T cell-based therapies. Here, we integrate structural, biophysical, and functional analyses to examine how KRAS G12 variants remodel peptide-MHC-I (pMHC) architecture and T cell receptor (TCR) recognition. Using HLA-A*11:01, we show that single residue substitutions at position 12 induce distinct conformational changes in the MHC groove, with G12D uniquely destabilizing the complex through a buried aspartate side chain. Notably, G12D peptides adopt two registers, a 9-mer and a 10-mer, that diverge sharply in structure and immunogenicity. The 10-mer forms a compact, stable pMHC with a TCR-accessible surface, while the 9-mer adopts a bent conformation incompatible with recognition. Molecular dynamics and NMR titration confirm the superior stability and binding affinity of the 10-mer. These results highlight how peptide length and conformation critically shape immune visibility, offering mechanistic insight for optimizing TCR-T therapies against elusive neoantigens like KRAS G12D.

Anopheles darlingi is the primary malaria vector in Central and South America and is responsible for most malaria transmission in the Amazon region. In this study, we perform whole-genome analysis of individual An. darlingi mosquitoes to explore genomic diversity, signatures of selection, and insecticide resistance markers. We analysed wild-caught (n = 20) and colony-maintained (n = 8) mosquitoes from the State of Rondônia, Brazil. In total, 1.54 million high-quality single-nucleotide polymorphisms (SNPs) were identified. Population genomic analysis revealed genetic differentiation between the colony and wild populations. No SNPs previously associated with insecticide resistance were detected. However, several SNPs were observed in four genes commonly associated with insecticide resistance: ace1, rdl, gste2, and vgsc. Genes under directional selection were identified, but no clear selective sweeps were found using genome-wide selection scans. Gene duplications were identified in cytochrome P450 genes, which are known to metabolise pyrethroids. This study provides a detailed genetic profile of An. darlingi, highlighting genes potentially involved in insecticide resistance, and presents an analysis of signatures of selection based on WGS data for this species. Our findings identify markers in insecticide resistance-associated genes that warrant further investigation through phenotypic-genotypic assays.

Synaptic activity-regulated gene expression supports neuroprotection, plasticity, and memory. The transcription factor CREB is central to these processes. It is activated by synaptic NMDA receptors but inactivated by excitotoxic extrasynaptic NMDAR (esNMDAR) signaling. Using primary hippocampal neurons, we modeled neurodegeneration and found that esNMDAR activation, which causes CREB shut-off and inactivation of the ERK/MAPK-ELK1/SRF pathway, extensively distorted control of synaptic activity over transcription. This resulted in the suppression of key neuroprotective genes, in particular Inhba and Bdnf, but also of genes involved in synaptic function (Homer1, Btg2, Mir132, Mir212) and transcription factor genes (Atf3, Egr1, Fos, Npas4). In a Huntington's disease (HD) mouse model, treatment with memantine or targeting the NMDAR/TRPM4 complex with FP802 restored gene expression, notably Inhba, Homer1 and Bdnf, and attenuated the decrease of the HD disease marker Ppp1r1b (DARPP-32). These findings identify esNMDAR-driven transcriptional dysregulation as a key pathomechanism in neurodegenerative disease, supporting inhibition of esNMDAR-signaling as a promising therapeutic approach.

Corneocytes, the fundamental units of the epidermis outer layer, are essential for skin's barrier function. This study employs Atomic Force Microscopy (AFM) to explore the topographical and biomechanical properties of volar forearm cells. A detailed protocol is presented to eliminate experimental artefacts that have led to variability in reported Young's moduli. The goal is to create a consistent material model reflecting the elastic and inelastic behaviour of corneocytes. Using standard sharp AFM probes allows for accurate cell topography capture and targeted indentation for mechanical property measurements without changing probes. The methodology for interpreting mechanical data from sharp indenters is also addressed. Results indicate that corneocytes in a dry state exhibit Young's moduli similar to glassy organic polymers and demonstrate viscoplastic behaviour, described by the Herschel-Bulkley model. These detailed protocols enhance our understanding of skin biomechanics, potentially guiding advancements in biomimetic materials and dermatological studies.

Monkeypox virus (MPXV) caused the 2022-2023 global mpox and the concurrent outbreaks in Africa, disproportionately affecting immunocompromised individuals such as people living with HIV. With no approved treatment available, we developed a robust artificial intelligence (AI) pipeline for discovering broad-spectrum poxvirus inhibitors that target the viral DNA polymerases. Among the identified leading candidates, we found that the clinically used antiretroviral drugs bictegravir and etravirine potently inhibit MPXV clade Ia, Ib and IIb infections in human intestinal and skin organoids. The broad anti-poxvirus activities of bictegravir and etravirine were further demonstrated against infections of other Orthopoxviruses such as vaccinia virus and cowpox virus. These findings support the repurposing of bictegravir and etravirine for treating mpox, especially for patients co-infected with HIV, warranting follow-up clinical investigation. The established AI pipeline and our antiviral drug discovery strategies bear major implications for responding to the ongoing mpox emergency and preparing for future poxvirus epidemics.

Viruses replicate intracellularly, and extracellular proteins may play a crucial role in preventing viral infections. Peroxinectin (PXN), a myeloperoxidase homolog, is activated extracellularly and possesses peroxidase and cell adhesion activity, defending against bacterial infection through the prophenoloxidase (proPO) system. However, the mechanism of PXN in antiviral immunity requires further study. In this study, PXN was found to be secreted into the hemolymph of crayfish (Procambarus clarkii) to recognize VP28 of white spot syndrome virus (WSSV), which then interacts with LPS and β-1,3-glucan binding protein (LGBP) to activate activator protein-1 (AP-1). AP-1 in the nucleus induced the transcription of crustin1 (Cru1). Cru1 exerts its antiviral function by binding to VP28 and subsequently inhibiting the assembly and reinfection of WSSV. These results indicate that the PXN-LGBP-AP-1-Cru1 pathway restricts virus proliferation by inducing the expression of Cru1, representing a mechanism distinct from the previously reported antibacterial immunity mediated by PXN and LGBP.

Glucocorticoid-induced osteonecrosis of the femoral head (ONFH) is a debilitating bone disorder characterized by impaired osteogenesis and apoptosis-driven bone collapse. This study identifies significantly reduced pentraxin 3 (PTX3) levels in patient samples and models. Recombinant PTX3 (rPTX3) alleviated dexamethasone-induced osteogenic suppression and apoptosis in vitro by activating TLR4/NF-κB pathway to downregulate fibroblast growth factor 21 (FGF21). In Ptx3-knockout mice, glucocorticoid-induced bone deterioration was exacerbated, while PTX3 administration preserved bone architecture. Pharmacological blockade of TLR4/NF-κB signaling abolished PTX3's protective effects. Notably, FGF21 suppression by activating transcription factor 3 (ATF3) retained bone-protective effects even in PTX3-deficient models, underscoring its role as a downstream effector. These findings establish the PTX3-TLR4/NF-κB-FGF21 axis as a key mechanism and suggest PTX3 supplementation as a potential therapeutic strategy against glucocorticoid-induced ONFH.

Chronic cold exposure in mice increases metabolic demand and food intake; the gut correspondingly expands its absorptive surface area. Gut enteroendocrine cells produce peptide hormones including glucagon-like peptide-1 (GLP-1), GLP-2, and glucose-dependent insulinotropic polypeptide (GIP) in response to a meal to facilitate nutrient absorption and post-prandial metabolism. The requirement of GLP-1, GLP-2, and GIP receptor signaling for small intestinal adaptations to chronic cold stress has not been investigated. Here, we show that male and female wild-type, double incretin receptor knockout (Glp1rGipr; DIRKO), and glucagon-like peptide double receptor knockout (Glp1rGlp2r; GLPDRKO) mice consume significantly more food over five weeks in cold (6⁰C) compared to thermoneutral (27 ⁰C; TN) conditions. Jejunal circumference, villi length, and crypt depth are significantly greater with cold-stress in WT and DIRKO mice, but not GLPDRKO mice, compared to TN controls. We show that the GLP-2R is required for jejunal villi length expansion upon cold stress despite significantly elevated plasma active GLP-1 levels. In line with this, GLPDRKO mice fail to gain body weight over the five-week experiment compared to WT controls. Therefore, while GLP-2R action is required for cold stress-induced jejunal villi lengthening, this adaptation is dispensable for body weight gain in the presence of GLP-1R signaling.