iScience最新文献

Host bone microenvironment is a critical factor for successful bone regeneration during implantation. In this work, we identified a spatiotemporal mismatch at drilling-induced injury sites where initial apoptosis outpaces macrophage recruitment, leading to apoptotic cell accumulation and oxidative stress that impairs osteogenic differentiation. To mitigate this phenomenon, we developed a synergistic strategy co-delivering interleukin 4 (IL-4) and arginine (Arg) to reprogram the microenvironment. Mechanistically, IL-4 recruits and polarizes macrophages toward a pro-reparative M2 phenotype, while Arg fuels the arginase-1 metabolic pathway to sustain continual efferocytosis and secretion of pro-regenerative cytokines. In a mouse bone injury model, transcriptomic and histological analyses confirmed that this strategy accelerates apoptotic clearance and establishes an M2-dominant environment, significantly enhancing early bone regeneration. Altogether, this work proposes a novel therapeutic paradigm targeting macrophage efferocytosis to resolve early microenvironmental imbalances, providing a promising therapeutic approach to promote bone defect healing and offering novel insights into optimizing host microenvironments for osseointegration following implantation.

The energy transition and transportation electrification have increased the reliance of lithium ion battery supply chains on critical minerals, including lithium, cobalt, and nickel. Here, we construct a multi-tier interfirm supply network of nine major battery manufacturers and develop a propagation recovery model to assess mineral shortage impacts and recovery pathways. Lithium shortages generate the largest cascading losses, followed by cobalt and nickel shortages. Recovery is primarily achieved through cross-tier resource reallocation, which contributes approximately 70% of total recovery, whereas newly established supply links provide a smaller contribution. Manufacturer resilience varies across minerals, reflecting heterogeneous supply chain exposure and recovery capacity. These findings identify mineral-specific risk pathways and recovery mechanisms, providing insights for resilient supply chain management and critical mineral governance during energy transitions.

Boid inclusion body disease (BIBD) is an infectious disease of captive boid snakes of major relevance since the 1970s. It is caused by reptarenaviruses and characterized by intracytoplasmic inclusion bodies in most cell types. Affected snakes frequently develop secondary bacterial infections, suggesting virus-associated immunosuppression. To investigate this, we analyzed peripheral blood from 48 Boa constrictor with confirmed BIBD, three infected snakes without disease, and 84 reptarenavirus-negative snakes, assessing hematology, biochemistry, stress parameters, and immune function. A functional phagocytosis assay on peripheral blood revealed a significantly reduced proportion of phagocytic cells (Iba1⁺ monocytes/azurophils) in BIBD-positive and reptarenavirus-infected snakes compared to uninfected animals, indicating impaired phagocytic capacity. In addition, BIBD-positive snakes showed reduced cholesterol and total immunoglobulin concentrations, while virus-specific IgY and IgM levels were elevated. These findings indicate selective impairment of innate and humoral immune components, providing mechanistic evidence for increased susceptibility to secondary bacterial infections in BIBD.

Highly pathogenic avian influenza viruses (HPAIVs) have become widespread among wildlife including within the Arctic. We summarize histopathological findings for three cases of HPAIV infection among polar bears (Ursus maritimus) inhabiting Alaska, genomically characterize viruses causing disease, and assess probable non-lethal exposures. Polar bears found dead and infected with HPAIVs exhibited meningoencephalomyelitis and neuronal necrosis, consistent with neurologic disease. Genomic sequence information obtained for H5N1 and H5N5 subtype HPAIVs associated with two cases supported epidemiologically independent spillovers. Serologic testing provided evidence for antibodies reactive to H5 and N1 antigens among most polar bears inhabiting Alaska during 2023-2024, consistent with contemporary non-lethal exposures, whereas antibodies were not found among bears sampled during 2013. These data indicate that HPAIV infection may represent an emerging threat to polar bear health within the Alaska Arctic; though, population immunity seems to be building and may protect this species from widespread demographic impacts of disease.

The BMP signaling pathway plays a pivotal role in regulating the formation and maintenance of our vascular system, employing a diverse set of ligands, receptors, and cytoplasmic mediators. However, little is known about how the interplay of these elements is regulated dynamically in individual living endothelial cells. Here, we developed fluorescent reporter to quantify BMP signaling and used a combination of time-resolved microscopy and computer-aided analysis to demonstrate ligand-specific dynamics of SMAD1, SMAD5, and SMAD9. Using this approach, we identified FKBP12 as a critical regulator of receptor complex activity that determines the balance of SMAD1/5/9 and SMAD2/3 signaling upon treatment with angiogenic ligands such as BMP7 and Activin A. This provides insights into the regulation of the BMP pathway in endothelial cells and offers a potential node for modulating vascular pathologies where the SMAD1/5/9-SMAD2/3 balance is disrupted.

The central AAA+ ClpC/ClpP protease in Gram-positive bacteria is crucial for virulence and stress resistance and has been recognized as drug target. Natural cyclic peptides deregulate the essential Mycobacterium tuberculosis ClpC1 and cause cell death. Similarly, overactivated mutants of the non-essential Staphylococcus aureus ClpC homolog cause uncontrolled proteolysis and severe toxicity in vivo. However, no chemical modulators of S. aureus ClpC have been described. Here, using a biochemical high-throughput screen, we identify eight distinct bona fide small molecules that stimulate ClpC ATPase and proteolytic activity in vitro. Structural, computational, and mutational analyses define two ligandable regulatory sites within the ClpC N-terminal domain (NTD) as compound targets: a conserved hydrophobic groove and an allosteric pArg1 pocket, both engaged in substrate recognition. These findings establish S. aureus ClpC as chemically targetable and provide mechanistic insight into its regulatory architecture, enabling future development and optimization of chemical probes to deregulate AAA+ protease control.

Respiratory viruses frequently initiate infection in the nasal mucosa, where virus-host interactions shape disease progression and transmission. Yet this site remains undercharacterized due to anatomical and technical challenges. Spatially resolved technologies are limited by cost and complexity, leaving most studies reliant on bulk or descriptive approaches lacking spatial context. We present a framework for spatially resolved investigation of infections in the nasal cavity. Using wild-type SARS-CoV-2 and two live-attenuated vaccines (OTS-206, OTS-228) as model viruses in Syrian hamsters, we integrate standardized sampling, histopathology, immunohistochemistry, multiplex RNA in situ hybridization, and quantitative image analysis across spatial scales, including tissue, single-cell, and subcellular resolution. We identified distinct infection patterns and graduated tissue damage from wild-type to OTS-228. Despite limited infection, OTS-228 induces a robust tissue-preserving immune response. Subcellular analysis shows that both vaccines exhibit a primarily cytoplasmic distribution of host antiviral transcripts, whereas WT infection is characterized by predominantly nuclear RNA localization.

Pulmonary tuberculosis (PTB) remains a major infectious disease globally. This study aimed to identify determinants of Mycobacterium tuberculosis (MTB) transmission clustering, treatment outcome, and pulmonary cavitation by simultaneously analyzing host and pathogen genomic data. Whole-genome sequencing of 1,960 MTB isolates identified four major lineages (L1-L4). Host population stratification by principal component analysis of genome-wide single nucleotide polymorphisms (SNPs) classified 899 patients (70%) into a genetically homogeneous main group for genome-wide association study (GWAS). Multivariate regression demonstrated that MTB lineage was the primary determinant of transmission clustering, rifampicin resistance was the dominant predictor of unfavorable treatment outcome, and host genetic group was independently associated with pulmonary cavitation. GWAS identified novel loci in collectin subfamily member 10 (COLEC10), CTNNA3, and long intergenic non-coding RNA 2775 (LINC02775) associated with clustering, treatment outcome, and cavitation, respectively, with the association of COLEC10 also found in the remaining group of patients. These findings highlight the importance of integrating bacterial and human genomic analyses to understand tuberculosis host-pathogen interaction.

Compact energy absorbers are needed to protect testing electronics in high-impact systems with limited installation space. Unlike previous studies that mainly examined tubular or fully filled configurations, this work investigates selective filling within a 12-mm-high multi-cell thin-walled structure. Partial and full configurations using aluminum foam (AF) and polyurethane-infiltrated aluminum foam (AF/PU) were evaluated through quasi-static compression, dynamic impact testing, finite element simulations, and theoretical analysis. Comparisons among five configurations and three wall thicknesses showed that filler distribution affected the balance between crushing resistance and effective crushing stroke. The partially filled AF/PU structure with a 1.2 mm wall thickness exhibited the best overall performance, absorbing 895.41 J quasi-statically and 984.40 J dynamically, with a volumetric specific energy absorption of 21.32 J/cm³ and crushing force efficiency of 0.84. Compared with full filling, selective AF/PU filling uses less filler while retaining greater deformation space, providing a practical strategy for compact impact protection.

Finding the ideal biomaterial with all required properties to replace specific tissues is an unmet challenge. In this study, twin-layered fibers with two well-established medical biomaterials, PHAs and PLA, have been produced via pressurized gyration and characterized thoroughly for surface properties, mechanical properties, and in vitro cell responses using a range of cell types for both hard and soft tissue engineering. The diameters of fibers produced ranged from 0.9 to 1.2 μm. The PHA sheath fibers increased cell attachment of live viable cells compared to PLA sheath fibers, due to their relatively higher biocompatibility, increased surface roughness, and protein adsorption. PLA, as a core, increased the stiffness and tensile strength of the fibers. This approach produced fibers in a cost-effective, scalable, and sustainable manner, providing a highly effective solution to the challenging clinical need of the regeneration of tissues.