To evaluate health outcomes and identify risk factors for reinfection and persistent symptoms among COVID-19 survivors 4 years after hospital discharge.

ALECT2 amyloidosis is a rare systemic disease characterized by the pathological deposition of leukocyte cell-derived chemotaxin-2 (LECT2) as amyloid fibrils, primarily affecting the kidneys and liver. The molecular mechanisms underlying LECT2 aggregation remain poorly defined, hindering diagnostic and therapeutic development. Here, we present cryo-electron microscopy structures of ex-vivo ALECT2 fibrils extracted from a patient's kidney. We identified three fibril polymorphs: a predominant single-protofilament morphology and two minor double-protofilament morphologies. The dominant single-protofilament morphology comprises the full-length 133-residue LECT2 protein and retains all three native disulfide bonds. Low-resolution reconstructions of double-protofilament morphologies suggest they adopt a similar fold to the single protofilament morphology, but form paired assemblies with different inter-filament interfaces. Mass spectrometry also reveals acetylation within the fibrils. These findings offer critical insights into the structural basis of ALECT2 amyloid formation and identify molecular features that could inform future diagnostic and therapeutic approaches.

Tumor initiation and progression frequently involve oncogenic programs that favor proliferation at the expense of lineage commitment and differentiation. Here, we identify a MYC-driven mechanism that suppresses neuronal identity in glioblastoma (GBM) through repression of the transcription factor aryl hydrocarbon receptor nuclear translocator 2 (ARNT2). ARNT2 is highly expressed in the brain, cerebellum, and iPSC-derived neurons but is markedly reduced in GBM tumors and cell lines, where its loss correlates with higher tumor grade and poor survival. Mechanistically, MYC represses ARNT2 expression, and ARNT2 loss results in reduced expression of neuronal and glial identity genes. Although ARNT2 depletion does not alter GBM cell proliferation in vitro, it significantly enhances tumor growth and lipid metabolic remodeling in vivo. Conversely, ectopic ARNT2 expression suppresses tumor burden in both subcutaneous and orthotopic GBM xenograft models and promotes features of neuronal differentiation. Together, these findings identify ARNT2 as a tumor suppressor in GBM and establish MYC-mediated repression of ARNT2 as a critical mechanism by which GBM maintains a proliferative, undifferentiated, stem-like state.

Bladder cancer (BCa) remains a major global health challenge with high recurrence and progression rates. Although metabolic reprogramming is recognized as a hallmark of cancer, the molecular mechanisms driving glycolysis in BCa are incompletely understood. ATAD3A, a mitochondrial membrane protein implicated in various malignancies, has not been characterized in BCa. This study aimed to investigate the role of ATAD3A in BCa progression and elucidate the molecular mechanisms linking ATAD3A to tumor metabolism.

Effective rehabilitation for persistent post-stroke motor impairment is a major clinical need. The efficacy of combining acupuncture with robot-assisted therapy for hemiplegia is unclear. This study aimed to evaluate the efficacy of combining acupuncture with rehabilitation robot (RR) for improving limb function in patients with hemiplegia after ischemic stroke.

Alveolar epithelial injury serves as a primary driver of idiopathic pulmonary fibrosis (IPF), where the functional integrity of alveolar type 2 (AT2) cells is essential for lung repair. Mitochondrial pyruvate carrier 2 (Mpc2) is a key component of the pyruvate transport system that sustains mitochondrial oxidative phosphorylation and energy metabolism in AT2 cells. However, the specific role of Mpc2 in AT2 cell function and lung injury remains unclear. Mpc2 expression in AT2 cells was examined in lung tissues from patients with IPF and in mice subjected to bleomycin-induced lung injury. AT2 cell–specific conditional knockout (CKO) mouse models, single-cell transcriptomic analyses, and AT2 organoid cultures were employed to investigate the functional consequences of Mpc2 deficiency during lung injury. Mpc2 expression in AT2 cells was significantly reduced in patients with IPF and in mice following bleomycin-induced lung injury. Conditional deletion of Mpc2 in AT2 cells resulted in decreased expression of the Na⁺/K⁺-ATPase α1 subunit (ATP1A1) and surfactant protein C (SPC), impaired AT2 differentiation during lung injury, and a shift in pulmonary inflammatory profiles toward neutrophil predominance. These changes were associated with increased early mortality in male mice after bleomycin challenge. In contrast, female mice with AT2-specific Mpc2 deletion did not exhibit a significant survival disadvantage but developed more severe pulmonary fibrosis and sustained impairment of AT2 cell differentiation at later stages following bleomycin administration. Mpc2 is essential for maintaining AT2 cell function during lung injury and contributes to the regulation of alveolar epithelial differentiation and inflammatory balance. Targeting Mpc2 may offer novel therapeutic opportunities for lung injury-related diseases.

Photodynamic therapy (PDT) utilizing organic photosensitizers like indocyanine green (ICG) faces several intrinsic limitations. These challenges include a propensity to aggregate, insufficient stability, and low intersystem crossing (ISC) efficiency that yields inadequate reactive oxygen species (ROS). Furthermore, the tumor microenvironment imposes additional restrictions on its efficacy. To address these challenges, we implemented a cetyltrimethylammonium bromide (CTAB)-templated metal coordination approach and rationally designed cerium(IV)-coordinated, self-assembled ICG nanoparticles (CINPs). Cooperative coordination between Ce4+ and ICG, combined with hydrophobic interactions, significantly enhances ICG stability. It also optimizes the energy gap between the lowest singlet excited state (S1) and the lowest triplet state (T1), thereby promoting ISC and equipping the system with robust ROS-generating capacity. Moreover, Ce4+ exhibits dual catalytic activity, on the one hand catalyzing the decomposition of endogenous hydrogen peroxide (H2O2) to generate oxygen and alleviate tumor hypoxia, and on the other hand oxidizing and depleting intracellular glutathione (GSH) to weaken antioxidant defenses. In a hepatocellular carcinoma model, CINPs harnessed efficient ROS production to induce mitochondrial dysfunction, lipid peroxidation (LPO), and DNA strand breaks, which collectively activated multiple cell death pathways and significantly suppressed tumor growth. Unlike nanoplatforms that require elaborate designs, complex compositions, and fine chemical synthesis, the nanoparticles developed here are assembled from a small set of reliable, clinically established materials and can be rapidly formed through a simple process in less than 30 min. Despite the streamlined preparation, CINPs effectively remodel the tumor microenvironment, induce vigorous ROS generation during treatment, and achieve potent antitumor activity via oxidative stress-related mechanisms across multiple pathways, highlighting strong translational potential and broad prospects for clinical application.

Pseudomonas aeruginosa, a ubiquitous opportunistic pathogen, coordinates virulence gene expression primarily through three quorum-sensing (QS) systems: Las, Rhl, and Pqs. Despite the functions of QS systems in P. aeruginosa being relatively well-documented, the regulatory mechanisms modulating their activities remain largely unexplored. Here, we isolated and characterized a Las-null strain, PA_HN008, which overproduces pyocyanin (PYO) at the late growth stage due to its active RhlI-RhlR-PqsE pathway. Leveraging PYO production as a phenotypic marker, we conducted a genome-wide screening for upstream QS modulators and successfully identified PA5348 (designated as HupA), the α subunit of the nucleoid-associated protein HU, as a specific activator of the Pqs system and PYO production. RNA-seq and protein-DNA interaction assays further revealed that HupA directly binds to the promoters of pqs and phz genes, thereby inducing PqsE expression and PYO production. This study demonstrates that HupA acts as a novel transcriptional factor to control QS activity and virulence gene expression in P. aeruginosa, which not only reveals the regulatory function of the HU subunit HupA on virulence factor production but also uncovers the sequence-specific DNA-binding capability of HupA for stimulating gene transcription.IMPORTANCEThe nucleoid-associated protein HU is abundant and evolutionarily conserved in bacteria, which typically binds DNA in a sequence-nonspecific manner with high affinity to abnormal DNA structures during DNA damage and then contributes to DNA compaction, replication, recombination, and other physiological functions. However, the potential involvement of HU in regulating quorum sensing (QS), a critical cell-to-cell communication system governing bacterial virulence factor production, is poorly understood. In this study, we demonstrated that the α subunit of the HU protein, namely HupA, is a key regulator that activates the Pqs system and pyocyanin production through genome-wide screening in a clinical isolate PA_HN008. This study reveals the capability of the HU subunit to selectively bind target DNA sequences and stimulate QS activity as well as virulence factor production. Our findings provide novel insights into the biochemical properties of the HU subunit and its regulatory role in bacterial virulence.

Intermittent exotropia (IXT), the most common childhood divergent strabismus, disrupts binocular vision and psychosocial function.

Impaired glucose metabolism, a known precursor to type 2 diabetes, is associated with dysregulation of the autonomic nervous system. To assess such autonomic states, consumer wearable devices provide continuous, non-invasive physiological monitoring and may capture autonomic signatures related to metabolic status. This exploratory study examined whether dynamic features of heart rate (HR) and heart rate variability (HRV) during sleep-derived from a consumer wrist-worn device (Fitbit)-are associated with glucose metabolism status in free-living adults. We analyzed 189 nights from 18 participants (7 participants in the higher-glycemic-risk group, estimated glycated hemoglobin (HbA1c) ≥ 5.5%; 11 participants in the lower-glycemic-risk group, estimated HbA1c < 5.5%). From 28 candidate HR/HRV variables, Elastic Net regression (α=0.5) was applied to identify features associated with nocturnal mean glucose. Fourteen features retained non-zero coefficients; notably, dynamic features capturing overnight trends and variability patterns showed stronger associations than conventional static mean values. The nocturnal trends of within-window standard deviation and variance of ln(RMSSD) (root mean square of successive differences between consecutive RR intervals, estimated here from PPG-derived inter-beat intervals; RMSSD) emerged as prominent candidates, alongside HR variability indices. Independent between-group comparisons further confirmed that two dynamic HRV features differed significantly between the lower- and higher-glycemic-risk groups (both p<0.05; Cohen's |d|>1.1). Specifically, the lower-glycemic-risk group exhibited decreasing overnight trends in HRV variability, consistent with progressive autonomic stabilization during sleep. In contrast, the higher-glycemic-risk group showed increasing variability trends, suggestive of persistent autonomic instability. These directional patterns are consistent with prior evidence linking autonomic dysfunction to impaired glucose metabolism. We characterize these findings as hypothesis-generating. The identified dynamic HR/HRV features represent physiologically plausible candidate correlates of glycemic status and warrant confirmatory investigation in larger, independent cohorts with laboratory-measured HbA1c. More broadly, this work highlights the potential of widely available, consumer-grade wearable devices to move beyond activity tracking and support continuous, real-world assessment of cardiometabolic health, thereby expanding their utility in everyday health monitoring and preventive medicine.

Stress urinary incontinence (SUI), a common condition impacting quality of life, stems frominvoluntary urine leakage due to increased abdominal pressure. Its pathology involves excessive extracellular matrix (ECM)degradation, particularly collagen, in pelvic floor tissues, driven by an imbalance between matrix metalloproteinases (MMPs)and their inhibitors (TIMPs). While electroacupuncture (EA) and repetitive Trans-spinal Magnetic Stimulation (rTSMS) areeach beneficial for SUI, their combined synergistic effects and mechanisms are unexplored. We hypothesized that combinedEA and rTSMS would synergistically repair pelvic floor support structures in SUI rats by modulating the TGF-β1/CTGFsignaling pathway and ECM metabolism.

Extremely preterm birth (at <28 postconceptional weeks) leads to brain injury and represents the leading cause of childhood-onset neuropsychiatric diseases. No effective therapeutics exist to reduce the incidence and severity of brain injury of prematurity. Hypoxic events are the most important environmental factor, along with inflammation. Among other developmental processes, the second half of in utero fetal development coincides with the migration of cortical interneurons from the ganglionic eminences into the cortex; this process is thus prone to disruptions following extremely preterm birth. To date, no studies have directly investigated the migration of human cortical inhibitory neurons under hypoxic conditions. Using multi-day confocal live imaging in human forebrain assembloids (hFA) derived from human-induced pluripotent stem cells (hiPSCs) and ex vivo developing human brain tissue, we found a substantial reduction in the migration of hypoxic interneurons. Using transcriptomics, we identified adrenomedullin (ADM) as the gene with the highest fold change increase in expression. Based on previous literature about the protective role of supplemental ADM for other injuries, here, we demonstrated that addition of exogenous ADM to the hypoxic media restores the migration defects of interneurons. Lastly, we showed that one of the mechanisms of protection by ADM is through the activation of the cAMP/PKA pathway and subsequent pCREB-dependent rescued expression of a subset of GABA receptors, which are known to promote migration. Overall, in this manuscript, we provide the first direct evidence for hypoxia-induced deficits in the migration of human cortical interneurons and identify ADM as a possible target for therapeutic development.

Sorbic acid (SA) and its salts are among the world's most widely used and safest food preservatives, yet their industrial production still relies on fossil fuel-derived feedstocks via chemical synthesis. Here, we report bioproduction of SA through microbial fermentation by decoding its biosynthetic pathway and metabolic engineering of Saccharomyces cerevisiae as a chassis. Here, we identify SA and its amide derivative sorbamide (SN) from Myrothecium sp. FJNU6, representing identification of SA from a microbial source. Genome sequencing and heterologous expression reveal the SA/SN biosynthetic gene cluster, comprising a highly reducing polyketide synthase (SoaA), a hydrolase (SoaB), and an amidotransferase (SoaC). To enable sustainable overproduction, we reconstitute and optimize the SoaA-SoaB pathway in S. cerevisiae through multilevel engineering, including dynamic promoter control, acetyl-CoA/malonyl-CoA pathway enhancement, peroxisomal compartmentalization, and two-stage fed-batch fermentation. These strategies collectively enable a production titer of 1.84 g/L SA in a 50 L bioreactor. This study uncovers a microbial biosynthetic pathway for SA/SN and establishes a microbial platform for SA production, providing a foundation for developing sustainable alternatives to fossil-based manufacturing.

Schisandra chinensis (Turcz.) Baill. (Schisandraceae) is a medicinal plant widely distributed in East Asia and has long been used in traditional herbal medicine. Phytochemical studies have identified lignans as the major bioactive constituents of S. chinensis, among which Schisandrin B (Sch B) is one of the most abundant and pharmacologically active compounds. Previous studies have demonstrated that Sch B exhibits a variety of biological activities, including antioxidant, anti-inflammatory, hepatoprotective, and cytoprotective effects. As a natural lignan compound derived from S. chinensis, Sch B has attracted increasing attention for its potential protective effects against environmental and inflammatory insults. This study aimed to investigate the protective effects of Sch B against PM2.5-induced inflammatory injury in THP-1 cells and to elucidate the underlying molecular mechanisms. An in vitro PM2.5-induced THP-1 cell injury model was established by stimulating THP-1 cells with PM2.5. Subsequently, Sch B was applied to the model, and inflammation-related indicators and pathways were detected using methods such as ELISA, PCR, and Western Blot (WB). The results showed that Sch B significantly inhibited interleukin-1β (IL-1β) secretion and attenuated PM2.5-induced pyroptosis in THP-1 cells. Mechanistically, Sch B alleviated cell membrane damage and inflammatory factor release by suppressing Caspase-1 activation and inhibiting the cleavage of gasdermin D (GSDMD) into its active N-terminal fragment (N-GSDMD). Furthermore, Sch B treatment was associated with the up-regulation of ALG-2, ALIX, and TSG101, suggesting the potential involvement of ESCRT-III-associated membrane repair mechanisms. In conclusion, Sch B, a natural lignan compound derived from S. chinensis, exhibits protective effects against PM2.5-induced THP-1 cell pyroptosis by reducing cell membrane damage and inflammatory cytokine release. These effects are associated with the inhibition of Caspase-1 activity and GSDMD cleavage, as well as the activation of ESCRT-III-associated membrane repair responses. Collectively, these findings highlight the potential of Sch B as a natural cytoprotective compound against particulate matter-induced inflammatory injury.

Acute pancreatitis (AP) is a common gastrointestinal condition characterized by inflammation of the pancreas. AP treatment is highly challenging due to the long hospital stays, higher medical expenses, and multiple complications. Traditional Chinese medicine has been used in China for thousands of years and is clinically proven to be a safe and effective treatment strategy for pancreatitis.

Obvious size-dependent bending responses are observed in porous polymer beams, particularly as their thickness approaches the scale of the lattice constant. However, the relationship between the size dependency and the microstructure remains unclear. Direct numerical simulations are computationally expensive due to the complexity of the microstructures, while classical multiscale methods, which neglect the surface effect, yield results that deviate significantly from actual behavior. In this study, an equivalent model for porous polymer beams incorporating surface-driven moment of inertia is developed to capture the size-dependent Young's modulus by introducing a surface strength factor and surface thickness. Then, an online prediction framework based on the offline dataset generated by the moment-of-inertia-dependent surface homogenization method was established for size-dependent bending response. The proposed framework is evaluated in terms of accuracy and computational efficiency. Results show that the classical multiscale homogenization method can produce relative errors as high as 1108%, whereas the surface homogenization method maintains relative errors below 4%. Moreover, the computational cost is substantially reduced compared to direct numerical simulations. This work not only uncovers the underlying moment-of-inertia-dependent surface mechanism of the size-dependent behavior in metamaterial beams but also delivers an accurate and efficient tool for their structural design and performance prediction.

Despite being hailed as a significant advancement in cancer treatment, immune checkpoint blockade (ICB) has not yielded favorable outcomes in colorectal cancer, both in approximately 85% of cases characterized by microsatellite stability (MSS) and approximately 50% of microsatellite instability (MSI) cases. How ICB efficiency in colorectal cancer treatment can be improved remains unclear. Here, we identify a new immunoregulatory long non-coding RNA (lncRNA) gene named lncRNA of IFN-γ-signaling suppressor (LISS). LISS expression is increased in colorectal cancers and is linked to poor prognosis, as well as a high CD8+ score. Functional studies reveal that LISS impairs T cell-mediated cytotoxicity, regardless of MSS/MSI status. Mechanistically, LISS interacts directly with the kinase regulatory domain in calmodulin-dependent kinase (CamK)IIγ through a microdomain containing two independent RNA stem-loops. This interaction prevents the binding and phosphorylation of its substrate signal transducer and activator of transcription1 (STAT1) at serine(S)727, a modification necessary for optimal activation of STAT1 and the subsequent major histocompatibility complex I (MHC-I) gene expression. Analysis of human colorectal cancer samples reveals significant inverse correlations between LISS and pS-STAT1 or MHC-I. The knock-in of LISS in intestinal epithelium promotes adenoma development in Apcmin/+ mice. LISS antisense oligonucleotide (ASO)-based therapies enhance the responses of both MSS and MSI colorectal cancers to ICB in vivo, mainly by restoring MHC-I expression. Therefore, we have identified the previously uncharacterized lncRNA LISS to be a regulator of T cell immunity. Targeting it may be an effective therapeutic strategy to improve ICB in colorectal cancers with varying MSI characteristics.

This study aimed to investigate the role of lncRNA GAS5 and GADD45a in H₂O₂-induced oxidative stress and mitochondrial dysfunction in human lens epithelial cells (LECs), and to explore the underlying ceRNA mechanism involving miR-3666.

Early antibiotic exposure frequently induces gut dysbiosis in preterm infants. Although probiotics, such as the live combined preparation of Bacillus subtilis and Enterococcus faecium (LCBE), may mitigate this disruption, high-quality clinical evidence in this high-risk population remains limited. This prospective observational study investigated the association of early LCBE supplementation with the incidence of feeding intolerance (FI) and gut microbiota composition in antibiotic-exposed preterm infants.

Allergic asthma (AA) may result in repeated episodes of chest constriction and coughing. In its most serious manifestations, it can cause death by asphyxiation. Currently, no efficacious therapeutic interventions exist to avert or counteract these serious outcomes. Baicalein (BAI) is a core quality marker of the traditional Chinese medicine Scutellaria baicalensis, but the mechanism of its oral action remains unclear.