Physics

Intestinal epithelium relies on intestinal stem cells (ISCs) for rapid and precise tissue replenishment to maintain gut normal function. The self-renewal maintenance of ISCs is finely regulated by multiple stemness factors and signaling pathways. However, the transcription mechanisms of some key stemness factors remain poorly understood. Here, we identify that small nucleolar RNA Snora61 is highly expressed in ISCs. Snora61 is mainly distributed in the nucleoplasm. Snora61 knockout impairs ISC self-renewal and intestinal regeneration. Mechanistically, Snora61 binds to the promoter region of Lgr5 gene and engages with RNA-binding protein RBMX to recruit HMGB2 onto Lgr5 promoter, leading to Lgr5 transcription and expression. Snora61 promotes the self-renewal of small intestinal stem cells, which in turn enhances the proliferation of differentiated epithelial cells, thereby contributing to the maintenance of intestinal homeostasis. Conversely, Snora61 knockout causes reduced LGR5 expression. Deletion of Lgr5 with Snora61 displays more severely impaired ISC self-renewal and intestinal regeneration. Our findings reveal a regulatory mechanism of Lgr5 transcription underlying ISC self-renewal maintenance.

Sedentary behavior is associated with increased mortality and chronic diseases, yet it remains unclear whether higher daily step counts can mitigate these risks. In this study, we analyzed longitudinal sedentary and step data from Fitbit devices in the All of Us Research Program to examine incident diagnoses of chronic conditions. We show that greater sedentary time was associated with higher risk of obesity, diabetes mellitus, hypertension, coronary artery disease, heart failure, chronic kidney disease, metabolic dysfunction-associated steatotic liver disease, chronic obstructive pulmonary disease, major depressive disorder, sleep apnea, and atrial fibrillation. Increasing daily steps offset the excess risk of high sedentary time (14 vs. 8 hours/day) for several conditions, with the additional steps required ranging from 1700 to 5500 per day. However, no step count fully offset sedentary risks for coronary artery disease or heart failure. These findings support personalized, behavior-based recommendations that consider both sedentary behavior and daily steps.

Ethionamide (Eto) and prothionamide (Pto) are second-line antibiotics used for tuberculosis (TB) treatment. Both are prodrugs whose antibacterial activity depends on bioactivation by oxidases in Mycobacterium tuberculosis, including the Baeyer-Villiger monooxygenase MymA. Through biophysical, genetic, and cellular assays, we show that the clinical candidate alpibectir (Alp, BVL-GSK098) binds the transcriptional regulator VirS, increasing MymA expression and potentiating Eto and Pto activity. Alpibectir also boosts the activity of the corresponding host-derived sulfoxide metabolites. We additionally show that alpibectir exhibits intrinsic antibacterial activity via overexpression of the mymA operon. The alpibectir/Eto (AlpE) combination is rapidly bactericidal in vitro and in mice, lowers the frequency of spontaneous resistance of Eto, and remains active on Eto- and isoniazid-resistant strains, including isolates with inhA promoter mutations. Alpibectir was safe in a Phase 1 human clinical trial. Together with the potentiation data presented here, these findings highlight its potential to optimize TB chemotherapy by reducing Eto/Pto doses, which can minimize dose-related side effects, enhancing adherence.

Information on the maintenance of tissue homeostasis is important for developing effective therapeutic methods. However, reports on the cellular composition and tissue stem cells of the larynx are scarce. Therefore, we analyzed mouse laryngeal mucosa using single-cell RNA- sequencing and spatial transcriptomics by photo-isolation chemistry, and we also generated laryngeal organoids as an in vitro model. Consequently, we found a SOX9-positive basal cell subpopulation and a Lgr5-positive cell subpopulation in the mouse vocal fold, and obtained three types of epithelial organoids from laryngeal epithelium. We also confirmed the differences in pseudostratified ciliated columnar epithelium characters between the supraglottis and subglottis of the mouse larynx. These findings provide valuable insights and tools for future research in laryngology and stem cell biology.

Mangroves are ecosystems located at land-sea transition zones, where they are continuously exposed to plant biomass and plastic pollution. Their soils harbor extensive microbial diversity with potential for discovering polymer-degrading enzymes. Here, we perform a microcosm experiment to examine how mangrove soil microbial communities respond to inputs of lignocellulose or polyethylene terephthalate (PET) in the presence and absence of seawater, and to explore the selection of putative PET-active enzymes (PETases) using gene- and genome-resolved metagenomics. Incubation conditions lead to a gradual increase in salinity, resulting in the enrichment of halophilic taxa, including spore-forming bacteria and archaeal species, particularly in seawater-depleted treatments. Lignocellulose input is the primary driver of soil microbial community restructuring, followed by seawater presence. In dry, lignocellulose-amended microcosms (L treatment), microbial diversity is significantly reduced, while lignocellulolytic taxa within the phyla Bacillota and Actinomycetota are enriched. Twelve potential PETases are identified in the L treatment, sharing >70% sequence similarity with known PETases, and three are predicted to be thermostable. Two putative PETases from Microbulbifer species display distinct sequence and structural features, thereby expanding the currently limited PETase sequence landscape. This study demonstrates that perturbing environmental microbiomes with plant-derived polymers represents a promising strategy for capturing novel PETases.

Genetic and immunologic studies implicate the interleukin (IL)-23/T helper (Th)17 pathway in inflammatory bowel disease (IBD). IL-23 and IL-1β drive human Th17 differentiation, while prostaglandin E2 (PGE₂) and transforming growth factor-β (TGF-β) further modulate Th17 development and plasticity. However, how these inflammatory mediators influence human T cell regulatory programs remains incompletely understood. We used single-cell multi-omics to profile 171,829 peripheral blood T cells from 25 healthy donors in 64 samples exposed to activation stimuli, IL-1β and IL-23 alone or in combination with PGE₂, TGF-β, or both. PGE₂ broadly suppressed T cell activation, except in Th17 and T follicular helper cells, and markedly altered chromatin accessibility and gene expression, particularly in Th17, Th1, and regulatory T cells, where IBD-associated SNPs were enriched in open chromatin and connected to cell type-specific cis-regulatory elements. Our study demonstrates the utility of single-cell multi-omics for defining stimulus-specific effects on T cells and prioritizing disease-associated genes.

We studied 132,525 Danish general population individuals to examine whether risk of osteoarthritis and/or use of pain-relieving medication was increased in haemochromatosis C282Y homozygotes with normal or low plasma iron, transferrin saturation, or ferritin. We genotyped all 132,525 individuals for the HFE C282Y and H63D variants. During a median follow-up of 40 years, 31,636 individuals had osteoarthritis. Risk of osteoarthritis was increased even in C282Y homozygotes with normal or low plasma iron (hazard ratio:1.37;95% confidence interval:1.12-1.68 compared to non-carriers with normal/low iron), transferrin saturation (1.55;1.10-2.16), or ferritin (1.96;1.11-3.45). Here we show that risk of osteoarthritis is increased in those C282Y homozygotes not usually recommended for genotyping according to clinical guidelines, challenging the presumption that the increased risk of osteoarthritis is mainly caused by systemic iron accumulation. Indeed, C282Y homozygotes with normal or low ferritin levels had a particularly high cumulative incidence of any osteoarthritis (24% at age 60 years, 60% at age 80 years).

Neuronal intranuclear inclusion disease is caused by abnormal GGC repeat expansion in the NOTCH2NLC gene, though its pathogenic mechanism remains incompletely understood. This study shows that the abnormally expanded polyG-uN2C protein, encoded by the repeat sequence, contains intrinsically disordered regions and forms aggregates, leading to mislocalization of nucleophosmin and downregulation of fibrillarin. PolyG aggregates interact with nucleophosmin and rRNA, disrupting ribosomal homeostasis. Furthermore, polyG facilitates the downregulation of chromatin structural proteins CTCF and RAD21, thereby impairing chromatin organization. This pathological manifestation can be mitigated by restoring CTCF/RAD21 expression. Furthermore, in brain organoids derived from neuronal intranuclear inclusion disease patients, we observe nucleolar stress accompanied by genome-wide chromatin structural alterations. These changes correlate with increased DNA damage and cellular senescence phenotypes. Notably, antisense oligonucleotides targeting GGC effectively reduce polyG aggregation and ameliorate related molecular defects, ultimately alleviating senescence-associated phenotypes. These findings establish key mechanisms underlying neuronal intranuclear inclusion disease pathogenesis and provide proof-of-concept for targeted therapy.

Mid-infrared spectroscopy offers unparalleled opportunities in sensing through chemically specific detection of molecular absorption fingerprints. Yet its practical applications are limited by weak light-matter interaction and complex and relatively slow instrumentation relying on scanning components. Here, we develop a rapid imaging-based mid-IR spectroscopy platform that combines broadband resonance gradient metasurfaces and radiofrequency-modulated quantum cascade laser generating broad (250 cm^-1) instantaneous spectrum. We match the resonance spectrum of the gradient metasurface with the laser emission for targeted amplification of local electromagnetic field of all its spectral components. This enables capturing of enhanced absorption signatures of analytes deposited on the metasurface as barcode images in a single shot of room-temperature low-cost mid-infrared camera, reducing the acquisition time by up to 3 orders of magnitude compared to measurements with Fourier-transform infrared spectrometers and external cavity quantum cascade lasers. Eliminating the need for tunable light sources, bulky spectrometers, and expensive low-temperature detectors, our approach enables high-throughput, miniaturized, and highly specific molecular diagnostics for diverse chemical and biological applications.

Atomic scale processes such as plasma-enhanced atomic layer deposition (ALD) and atomic layer etching (ALE) are vital to fabricate critical features in semiconductor devices that require excellent thickness control. Inert atomic plasmas are typically used for material removal by plasma ALE, whereas reactive molecular plasmas are used for synthesizing thin films by plasma ALD. To achieve accurate thickness control, high etch selectivity, and desirable material properties, accurate control of the ion energy is often important for these plasmas. However, controlling the ion energy by conventional radio-frequency sinusoidal waveform biasing results in a broad ion energy distribution. In this work, we investigate more precise ion energy control with tailored waveform biasing in atomic and molecular plasmas. A commercial remote plasma reactor was equipped with a prototype tailored voltage waveform generator for applying tailored bias waveforms, consisting of a positive voltage pulse and a negative linear voltage ramp. Various aspects of tailored bias waveforms including the voltage ramp rate, voltage pulse amplitude, voltage pulse duty cycle, and waveform repetition frequency were thoroughly investigated in terms of their influence on the ion flux-energy distribution functions of an inert atomic plasma (Ar). Moreover, it is demonstrated that this accurate ion energy control can be applied to reactive molecular plasmas (O2, Ar–H2, and N2) as well. This work serves as a guideline for the implementation of tailored waveform biasing in plasma-enhanced atomic scale processing.

Hybrid superconductor–semiconductor platforms can host subgap electronic excitations such as Andreev bound states; in topological regimes, a special zero-energy class, Majorana bound states, can emerge. Here we report the growth of epitaxial Al films by molecular-beam epitaxy on In0.75Ga0.25As under near-room-temperature substrate conditions. Using a combination of AFM/SEM, cross-sectional TEM, and in situ RHEED, we map how substrate temperature and Al deposition rate govern film morphology, continuity, and interface quality. We identify a growth window that yields continuous, superconducting Al films with an abrupt Al/In0.75Ga0.25As interface and no detectable indium interdiffusion. We further investigate the thermal stability of these films under in situ postgrowth heating and ex situ annealing following surface oxidation. For unoxidized Al, rapid surface diffusion triggers solid-state dewetting at approximately 165°C, resulting in the formation of {111}-faceted Al islands. In contrast, the presence of a native oxide largely suppresses dewetting, with failure occurring only locally at surface defects. Annealing above the indium melting point (156.6°C) induces significant In surface migration in both cases, leading either to localized interfacial In inclusions beneath Al agglomerates or to uniform surface contamination at sites of localized layer breakdown. Together, these results define growth and annealing conditions for thermally robust epitaxial Al on III–V semiconductors and provide practical guidance for fabricating high-quality superconductor–semiconductor hybrid platforms for quantum devices.

Carbon exhibits both a layered ground-state structure that produces two-dimensional (2D) nanosheets and a nonlayered diamond structure created under high pressure conditions. Motivated by this metastability relationship, we revisit the ground state structure of metal dichalcogenides that are known to have a nonlayered pyrite-type structure. Ultrathin films of pyrite-type ${\mathrm{ZnSe}}_{2}$ spontaneously transform into a layered phase. This phase is identified as a ground state, and the monolayer exhibits strong elastic anisotropy and a semiconducting bandgap larger than that of the pyrite phase by a factor of two. We demonstrate that a two-valued but directional potential energy surface exists along a Bain-like distortion path, hiding the layered ground state. This work implies that many 2D materials are hidden in nonlayered materials and connects 2D materials science with surface and high-pressure science.