Proceedings of the National Academy of Sciences of the United States of America最新文献

Nonanalytic Bloch eigenstates at isolated band degeneracy points exhibit singular behavior in the quantum metric. Here, a description of superfluid weight for zero-energy flat bands in proximity to other high-energy bands is presented, where they together form a singular band gap system. When the singular band gap closes, the geometric and conventional contributions to the superfluid weight as a function of the superconducting gap exhibit different cross-over behaviors. The scaling behavior of superfluid weight with the band gap is studied in detail, and the effect on the Berezinskii-Kosterlitz-Thouless transition temperature is explored. It is found that tuning the singular band gap provides a unique mechanism for enhancing the supercurrent and critical temperature of two-dimensional superconductors.

Poststroke inflammation critically influences functional outcomes following ischemic stroke. Arginase-1 (Arg1) is considered a marker for anti-inflammatory macrophages, associated with the resolution of inflammation and promotion of tissue repair in various pathological conditions. However, its specific role in poststroke recovery remains to be elucidated. This study investigates the functional impact of Arg1 expressed in macrophages on poststroke recovery and inflammatory milieu. We observed a time-dependent increase in Arg1 expression, peaking at 7 d after photothrombotic stroke in mice. Cellular mapping analysis revealed that Arg1 was predominantly expressed in LysM-positive infiltrating macrophages. Using a conditional knockout (cKO) mouse model, we examined the role of Arg1 expressed in infiltrating macrophages. Contrary to its presumed beneficial effects, Arg1 cKO in LysM-positive macrophages significantly improved skilled forelimb motor function recovery after stroke. Mechanistically, Arg1 cKO attenuated fibrotic scar formation, enhanced peri-infarct remyelination, and increased synaptic density while reducing microglial synaptic elimination in the peri-infarct cortex. Gene expression analysis of fluorescence-activated single cell sorting (FACS)-sorted CD45^low microglia revealed decreased transforming growth factor-β (TGF-β) signaling and proinflammatory cytokine activity in peri-infarct microglia from Arg1 cKO animals. In vitro coculture experiments demonstrated that Arg1 activity in macrophages modulates microglial synaptic phagocytosis, providing evidence for macrophage-microglia interaction. These findings present unique insights into the function of Arg1 in central nervous system injury and highlight an interaction between infiltrating macrophages and resident microglia in shaping the poststroke inflammatory milieu. Our study identifies Arg1 in macrophages as a potential therapeutic target for modulating poststroke inflammation and improving functional recovery.

We implement a variant of the quantum pigeonhole paradox thought experiment to study whether classical counting principles survive in the quantum domain. We observe strong measurements significantly violate the pigeonhole principle (that among three pigeons in two holes, at least one pair must be in the same hole) and the sum rule (that the number of pigeon pairs in the same hole is the sum of the number of pairs across each of the holes) in an ensemble that is pre- and postselected into particular separable states. To investigate whether measurement disturbance is a viable explanation for these counterintuitive phenomena, we employ a we employ variable-strength nonlocal measurements. As we decrease the measurement strength, we find the violation of the sum rule decreases, yet the pigeonhole principle remains violated. In the weak limit, the sum rule is restored due to the cancellation between two weak values with equal and opposite imaginary parts. We observe the same kind of cancellation at higher measurement strengths, thus raising the question: do strong measurements have imaginary parts?

Microbes use quorum-sensing systems to respond to ecological and environmental changes. In the oral microbiome, the pathogenic bacterium Streptococcus mutans uses quorum-sensing to control the production of bacteriocins. These antimicrobial peptides kill off ecological competitors and allow S. mutans to dominate the microenvironment of dental plaques and form dental caries. One class of bacteriocins produced by S. mutans, the lantibiotic mutacins, are particularly effective at killing due to their broad spectrum of activity. Despite years of study, the regulatory mechanisms governing production of lantibiotic mutacins I, II, and III in S. mutans have never been elucidated. We identified a distinct class of quorum-sensing system, MutRS, that regulates mutacins and is widespread among the streptococci. We demonstrate that MutRS systems are activated by a short peptide pheromone (Mutacin Stimulating Peptide) and show that MutRS controls production of three separate lantibiotic mutacins in three different strains of S. mutans. Finally, we show that paralogous MutRS systems participate in inter- and intrastrain crosstalk, providing further evidence of the interplay between quorum-sensing systems in the oral streptococci.

All glioblastoma (GBM) molecular subsets share the common trait of accelerated progression following necrosis, which cannot be adequately explained by cellular proliferation arising from accumulated genetic alterations. Counter to dogma that "cancer outgrows its blood supply," we suggest that development of necrosis is not merely a consequence of aggressive neoplastic growth but could be a contributing force causing tumor microenvironment (TME) restructuring and biologic progression. Mechanisms related to necrotic contributions are poorly understood due to a lack of methods to study necrosis as a primary variable. To reveal spatiotemporal changes related to necrosis directly, we developed a mouse model and methodology designed to induce clinically relevant thrombotic vaso-occlusion within GBMs in an immunocompetent RCAS/tv-a mouse model to study TME restructuring by intravital microscopy and demonstrate its impact on glioma progression. Diffuse high-grade gliomas are generated by introducing RCAS-PDGFB-RFP and RCAS-Cre in a Nestin/tv-a; TP53^fl/fl PTEN^fl/fl background mouse. We then photoactivate Rose Bengal in specific, targeted blood vessels within the glioma to induce thrombosis, hypoxia, and necrosis. Following induced necrosis, GBMs undergo rapid TME restructuring and radial expansion, with immunosuppressive bone marrow-derived, tumor-associated macrophages (TAMs) and glioma stem cells (GSCs) increasing dramatically in the perinecrotic niche. Collectively, this model introduces necrosis as the primary variable and captures glioma TME and growth dynamics in a manner that will facilitate therapeutic development to antagonize these mechanisms of progression.

Multiple cell death and inflammatory signaling pathways converge on two critical factors: receptor-interacting serine/threonine kinase 1 (RIPK1) and caspase-8. Careful regulation of these molecules is critical to control apoptosis, pyroptosis, and inflammation. Here, we found a pivotal role of Raver1 as an essential regulator of Ripk1 pre-mRNA splicing, expression, and functionality and the subsequent caspase-8-dependent inflammatory cell death. We show that Raver1 influences mRNA diversity primarily by repressing alternative exon inclusion. Macrophages from Raver1-deficient mice exhibit altered splicing of Ripk1. As a result, Raver1-deficient primary macrophages display diminished cell death and decreased interleukin-18 and interleukin-1ß production, when infected with Yersinia bacteria, or by restraining TGF-ß-activated kinase 1 or IKKβ in the presence of lipopolysaccharide, tumor necrosis factor family members, or interferon-γ. These responses are accompanied by reduced activation of caspase-8, Gasdermin D and E, and caspase-1 in the absence of Raver1. Consequently, Raver1-deficient mice showed heightened susceptibility to Yersinia infection. Raver1 and RIPK1 also controlled the expression and function of the C-type lectin receptor Mincle. Our study underscores the critical regulatory role of Raver1 in modulating innate immune responses and highlights its significance in directing in vivo and in vitro inflammatory processes.

Systemic infections caused by Cryptococcus claim over 161,000 lives annually, with global mortality rate close to 70% despite antifungal therapies. Currently, no vaccine is available. To develop an effective multivalent vaccine against this free-living opportunistic eukaryotic pathogen, it is critical to identify protective antigens. We previously discovered ZNF2^oe strains elicit protective host immune responses and increase the abundance of antigens present in the capsule, which is required for its immunoprotection. Capsule is a defining feature of Cryptococcus species and composed of polysaccharides and mannoproteins. Here, we found increased levels of exposed mannoproteins in ZNF2^oe cells. As mannoproteins are the primary components recognized by anticryptococcal cell-mediated immune responses and few have been characterized, we systemically screened all 49 predicted GPI-mannoproteins in Cryptococcus neoformans for enhanced host recognition. We identified those highly present in ZNF2^oe cells and found Cig1 to be a protective antigen against cryptococcosis either as a recombinant protein vaccine or an mRNA vaccine. Cig1 is induced by iron limitation and is highly expressed by this fungus in infected mice and in patients with cryptococcal meningitis. Remarkably, iron restriction by the host induces cryptococcal cells to express iron-uptake proteins including Cig1, which act as cryptococcal antigens and in turn enhance host detection. Our results highlight an arms race between the pathogen and the host centered on iron competition, and the trade-off between cryptococcal iron acquisition and antigen exposure. These findings demonstrate the potential of leveraging this host-pathogen interaction for vaccine development.

Habitat fragmentation is causing the collapse of seed dispersal interactions and ecosystem functioning. When management and conservation strategies aim to sustain ecosystem functioning of fragmented forests, species' traits and functional performance are critical in guiding decisions. However, to date, we lack a quantitative understanding of the role of frugivores' body size and dispersal ability in ecosystem sustainability among fragmented forests. Focusing on avian frugivory and seed dispersal in a multi-island setting, we address the data gap by recording more than 20,000 frugivory events in an artificial insular fragmented landscape constructed in 1959 and nearby unfragmented forests on the mainland. We show that large-bodied and dispersal-limited frugivorous birds are largely confined to large islands and the unfragmented mainland, whereas on small islands, small-bodied and highly mobile birds predominantly engage in frugivory interactions. The plant-frugivore meta-network exhibits a distinct compartmentalization, driven by island area and bird mobility. Birds with smaller size and greater mobility have higher topological importance, and the presence of small-bodied birds significantly enhances meta-network robustness. These results suggest that among insular fragmented forests where frugivory interactions are degraded, small-bodied and highly mobile birds disproportionately contribute to meta-community cohesion and ecosystem functioning because of the lack of large-bodied and dispersal-limited birds. We thus advocate for the restoration of landscapes to facilitate seed dispersal and functional connectivity, ensuring the presence of large patches along with small patches as stepping-stones. Meanwhile, we recommend prioritizing conservation on small-bodied and highly mobile birds in fragmented landscapes, a subset of underappreciated species that yet play crucial roles in ecosystem functioning.