Browse Articles

Molecular mechanism of phosphate import by the bacterial PstSCAB transporter

Soluble adenylyl cyclase in nonmammalian sperm is directly controlled by pH, not by HCO ₃ ⁻ or Ca ²⁺

In mammalian sperm, high HCO 3 − concentrations in semen and the oviduct activate soluble adenylyl cyclase (sAC), which synthesizes cyclic AMP to regulate sperm motility. Here, we demonstrate that sAC orthologs in echinoderms and fish, species whose sperm fertilize eggs in aquatic environments with low HCO 3 − , are activated by alkaline pH rather than HCO 3 − . In human sAC, two charged residues coordinate HCO 3 − and are essential for HCO 3 − -mediated activation. In contrast, pH-regulated sACs and orthologs from 13 phyla have these residues replaced by neutral ones. These substitutions abolish the enzyme’s responsiveness to HCO 3 − and suggest that pH regulation of sAC is widespread in nonmammalian metazoans. Furthermore, we show that in sea urchin sperm, a rise of pH during spawning stimulates cAMP synthesis, a key step in the activation of motility. An evolutionarily significant pattern is emerging: Across phyla, sAC regulation by pH or HCO 3 − represents an adaptation to environments with low or high HCO 3 − , respectively.

Escherichia coli promotes colorectal cancer metastasis by maintaining enhancer-promoter loops through releasing neutrophil extracellular traps

Friction-controlled reentrant aging and fluidization in granular materials

Granular materials densify under repeated mechanical perturbations, nonequilibrium dynamics that underlies many natural and industrial processes. Because granular relaxation is governed by frictional contacts and energy dissipation, this aging behavior fundamentally differs from that of thermal glasses despite their apparent similarities. Here, we uncover how friction controls the compaction dynamics of granular packings subjected to quasistatic cyclic shear. Using discrete element simulations, we construct a dynamic state diagram as a function of strain amplitude and friction, revealing a rich interplay among jamming marginality, stabilization, and fluidization. We identify a friction-dependent crossover strain that separates aging and fluidized regimes, showing reentrant, nonmonotonic behavior: Increasing friction first suppresses fluidization but then promotes it through smooth, creep-like rearrangements. This transition is marked by a shift from intermittent, avalanche-like rearrangements to continuous, diffusive motion. Our findings demonstrate that friction exerts a dual role in granular aging—both stabilizing and fluidizing—thereby uncovering the fundamental nonequilibrium mechanisms that govern compaction, rheology, and aging in athermal disordered systems. More broadly, our results reveal a general principle for how friction governs metastability and flow in athermal matter—from granular and frictional colloids to soils and seismic faults—linking microscopic contact mechanics to macroscopic dynamics.

Metabolic characterization of tumor-immune interactions by multiplexed immunofluorescence reveals spatial mechanisms of immunotherapy response in non-small cell lung carcinoma (NSCLC)

Abstract Immune checkpoint inhibitors (ICI) have improved clinical outcomes for some patients with advanced NSCLC, however a substantial proportion of patients remain treatment resistant. Here we analyze the NSCLC tumor microenvironment (TME) using multiplexed immunofluorescence (mIF) of biopsies taken from patients prior to ICI treatment. We apply a deep-learning model to classify the cellular phenotypes and probe functional and metabolic states of both tumor and immune cells, aiming to reveal predictive features of response to ICI. Tissue neighborhoods are generated to allow geometric profiling of spatial densities and interactions at a range of scales. Multivariate modelling of ICI response yields a model that predicts progression-free survival (PFS) over 24 months (AUC = 0.8). The selected features in the model imply a role for cell-cell proximities within discrete metabolic contexts. These tissue insights may supplement our understanding of the current paradigms around classical immunology in the NSCLC TME and its influence on immunotherapy outcomes.

Lack of synergy between AR-targeted therapies and PARP inhibitors in homologous recombination–proficient prostate cancer

Recent clinical trials have explored the combination of androgen receptor (AR) pathway inhibitors and poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors as a potential treatment for castration-resistant prostate cancer. This combination treatment is based on the premise that AR directly regulates expression of DNA repair genes, leading to synergy between PARP and AR inhibition. Despite some promising preclinical evidence, this combination therapy has shown limited efficacy in patients with homologous recombination (HR)–proficient tumors. To investigate this discrepancy between preclinical and clinical results, we profiled the effects of PARP inhibition in prostate cancer models in the presence or absence of AR inhibition. Surprisingly, AR inhibition impaired response to PARP inhibitors in castration-sensitive cells and had no effect on response in castration-resistant cells. AR inhibition also did not regulate DNA repair in either the castration-resistant or castration-sensitive setting. Instead, we find that cell cycle progression is required for response to PARP inhibition in homologous recombination–proficient prostate cancer.

HCMV infection disrupts barrier functions and promotes epithelial–mesenchymal transition in a cholangiocyte organoid model

Correction for Richter and Schneidman, Building the connectome of a small brain with a simple stochastic developmental generative model

Gut microbiota-dependent 24-hydroxycholesterol metabolism contributes to capsaicin-induced amelioration of Alzheimer’s disease-like pathology in mice

The BK channel-NS1619 agonist complex reveals molecular insights into allosteric activation gating

BK channels play essential roles in a wealth of physiological functions, including regulating smooth muscle tone and neurotransmitter release. Its dysfunction, often caused by loss-of-function mutations, can lead to severe phenotypes, including ataxia and sensory impairment. Despite the therapeutic potential of BK channel agonists, the molecular mechanisms by which they stabilize the pore’s open conformation remain unclear. Using cryoelectron microscopy and molecular dynamic simulations, we identified that NS1619, a synthetic benzimidazolone agonist, first described as a BK opener, binds within a pocket formed by the S6/RCK1 linker and the S4 transmembrane segment. Our simulations suggest that agonist binding promotes a twisting motion in the S6 segment, enabling critical interactions with residues K330, K331, and F223. These findings provide a molecular model for the mechanism of NS1619 and suggest that its binding site can accommodate other agonists, highlighting a promising target for therapeutic development.

Cracking the code of multi-layer films to promote circularity in single-use plastic packaging

Olfactory inputs to appetite neurons in the hypothalamus

The sense of smell has potent effects on appetite, but the underlying neural pathways remain undefined. Here, we investigated how olfactory signals reach two subsets of appetite-linked (“appetite”) neurons in the hypothalamic arcuate nucleus: Agouti-related peptide (AgRP) neurons, which stimulate appetite, and POMC (pro-opiomelanocortin) neurons, which suppress it. Using polysynaptic viral tracing, we show that AgRP and POMC neurons receive indirect input from partially overlapping but distinct areas of the olfactory cortex, indicating that they process different sets of olfactory information. We also identify different complements of neurons more directly upstream of AgRP and POMC neurons that could relay olfactory cortical signals to the appetite neurons. Single-cell transcriptomics shows heterogeneous expression of neuromodulator receptors among AgRP neurons, suggesting variations in the signals they receive. Integrated viral tracing and RNA localization further reveals selected brain areas where upstream neurons express cognate receptor ligands. Together, these findings outline multiple pathways by which distinct olfactory and modulatory signals are differentially routed to neurons that promote versus inhibit appetite.

Altered B cell activation contributes to the immunopathogenesis of childhood arthritis-associated uveitis

Abstract In Juvenile Idiopathic Arthritis (JIA), the most common childhood rheumatic disease, many patients also develop uveitis (JIA-uveitis), risking life-long vision loss. The mechanisms driving uveitis development in JIA remain understudied. Here, we demonstrate that peripheral blood CD19 + IgD - CD27 - double negative type 1 (DN1) B cells are elevated in JIA-uveitis compared to JIA patients without eye disease (JIA). The B cell receptor (BCR) repertoire was also more clonal and somatically hypermutated in JIA-uveitis and antigen-activated B cells infiltrated chronically inflamed JIA-uveitis eyes. Features of heightened B cell activation were recapitulated in experimental autoimmune uveoretinitis (EAU) and disrupting B and T cell interactions using monoclonal antibodies and transgenic mice suppresses uveitis. Together, these findings support a conceptual shift that uveitis is a primarily T cell driven disease and provide evidence for potential new therapeutic strategies that also consider B cells as drivers in disease pathology.

Correction for Choi et al., Antibody-mediated blockade for galectin-3 binding protein in tumor secretome abrogates PDAC metastasis

Multifunctional lithium niobate platform for photodetection and photoacoustic and thermoelastic gas sensing

Abstract Leveraging the intrinsic multi physics nature of ferroelectric lithium niobate, we present a multi-functional platform (LN-MFP) that seamlessly integrates photoacoustic spectroscopy, light-induced thermoelastic spectroscopy and photodetection into a single on-chip device. The proposed LN-MFP operates over a broad spectral range spanning from the visible to the mid infrared. We experimentally demonstrate trace gas detection of nitrogen dioxide, water vapor, acetylene, carbon dioxide, methane and ammonia, achieving parts-per-billion detection limits. We implement a custom packaging solution where the LN-MFP chip and a 4.6 µm quantum cascade laser chip are mounted on a printed circuit board together with transimpedance amplification, demonstrating system-level integration. Using this co-packaged module, we demonstrate carbon monoxide detection via second-harmonic measurements, outlining a clear route towards fully integrated on-chip implementations. This compact, hybrid, multi-functional architecture markedly reduces system complexity and footprint compared with conventional benchtop systems and is intrinsically compatible with the rapidly developing lithium niobate integrated photonics ecosystem. The LN-MFP provides a core sensing building block for future all-lithium-niobate spectroscopic chips for environmental monitoring, point-of-care diagnostics and on-site chemical analysis.

Correction for Coste, The Kinship Formula: Inferring the numbers of all kin from any structured population projection model

Hierarchical assembly of a Ti24 metal-organic polyhedron via kinetic trapping of intermediates

<i>Arabidopsis thaliana</i> phytochrome A sensory properties in canopy shade

Canopy shade environments can negatively impact plant growth and survival. Phytochrome A (phyA) is essential for seedling adaptation to deep shade, yet its role under moderate natural canopy conditions remains unclear. By expressing a phyA-nanoLUC reporter in Arabidopsis thaliana , we quantify diurnal fluctuations in phyA and its induction by low red to far-red (R:FR) ratio, simulating canopy shade. We uncover a key regulatory function for phyB, which increases phyA stability postdawn in unshaded conditions and modulates expression of PHYA in low R:FR. Further, we demonstrate that beyond its role as a deep shade sensor, phyA is an adept sensor of canopy shade, capable of detecting a range of R:FR ratios across light intensities. Mathematical modeling demonstrates that this property arises from the dynamic features of the phyA High Irradiance Response (HIR) mode of action. Interestingly, phyA synthesis is strongly induced by subtle reductions in R:FR ratio, and is robust to light perturbation, suggesting the phyA-sensory module is configured to detect modest shade. Spectral data from natural shade habitats provide ecological context for our laboratory findings. Physiological analysis indicates that under canopy shade phyA promotes seedling de-etiolation, organizes resource management, and accelerates reproductive development. We propose that this suite of responses, termed the “canopy adaptation strategy,” enhances survival chances under conditions where shade avoidance strategies are maladaptive.

A microphysiological human mini-bladder reveals urine-urothelium interplay in tissue resilience and UPEC recurrence in urinary tract infections

Abstract Urine is a dynamic and highly variable biofluid. Urine-urothelium interactions are a critical yet underexplored factor in bladder homoeostasis and urinary tract infections (UTIs). Here, we report on a human ‘mini-bladder’ model that exposes a stratified urothelium to urine of defined composition, and incorporates micturition. Prolonged exposure to high-solute concentration urine weakens tight junctions, dysregulates immune responses, and reduces bladder tissue resilience. This increases susceptibility to colonisation of the bladder by uropathogenic Escherichia coli (UPEC) which reduces efficacy of antibiotic therapy. In high-solute concentration urine, Fosfomycin monotherapy – prescribed for uncomplicated UTIs, induces the formation of cell wall-deficient (CWD) UPEC in the urine (as observed in patients with recurrent UTIs) but also within deeper urothelial layers. Tissue-associated CWD UPEC directly contributes to recurrence. Our findings expand the conceptual role for CWD UPEC in UTIs, and demonstrate the power of the mini-bladder platform to capture urine-urothelial microenvironment dynamics that actively shape UTI pathogenesis and antibiotic tolerance.

Integrated mutational landscape analysis of endometrial stromal sarcoma

Endometrial stromal sarcoma (ESS) is a rare uterine malignancy with limited treatment options. We performed integrated whole-genome, whole-exome, and transcriptome sequencing on 80 ESS tumors, comprising 32 low-grade (LG) and 48 high-grade (HG) tumors, to characterize their genetic landscape. The overall mutation burden was modest, with no significant difference between grades; however, we identified six hypermutated cases (7.5%) harboring POLE or mismatch repair mutations, genomic features predictive of immunotherapy response. We identified focal RAD54B amplifications in 15 tumors (18.8%), leading to elevated RAD54B expression and significantly shorter survival. This establishes RAD54B as an oncogenic driver in ESS. Known tumor suppressors (PTEN, TP53) were frequently mutated in HG-ESS but rare in LG-ESS, highlighting distinct grade-specific drivers of malignancy. HG-ESS exhibited widespread chromosomal gains, frequent loss of cell-cycle regulators (RB1, CDKN2A), and numerous private gene fusions arising from complex DNA rearrangements. In contrast, LG-ESS were defined by canonical fusions (e.g., JAZF1–SUZ12 ) and co-occurring deletions in metabolic regulator genes (TSC2, STK11). Finally, in an activating NRAS-mutant (p.Q61R) HG-ESS xenograft, the combination of MEK and FAK inhibition dramatically suppressed tumor growth and prolonged survival, highlighting a promising targeted treatment strategy. Overall, our comprehensive analysis defines the molecular basis of ESS and provides a strong preclinical rationale for precision therapies in this aggressive cancer.