Browse Articles

A deep representation learning model to predict response to vagus nerve stimulation

Dermcidin has antiviral activity and protects against influenza

Despite the high incidence of influenza virus infections, one-fifth of people infected with influenza remain asymptomatic. The mechanisms associated with this immune resilience are, however, unknown. Here, we show that the human antimicrobial peptide dermcidin has antiviral activity against influenza viruses through binding to hemagglutinin and extends its effect to taxonomically unrelated respiratory viruses such as measles virus and human coronavirus OC43. We show that dermcidin is present in all anatomical regions associated with the entry routes of respiratory viruses, that its levels increase during viral respiratory infections, and that it protects mice against influenza disease. Notably, dermcidin levels were higher in asymptomatic individuals than in susceptible peers, suggesting a role in the onset of disease symptoms. Thus, we show that dermcidin inhibits influenza virus infection in vitro and in vivo, with potential as a human-derived product for the prevention and treatment of respiratory viral infections.

Sulfur-enriched sub-arc fluids drive deep sulfur cycling in subduction zones

Abstract Arc magmas are enriched in sulfur relative to mid-ocean ridge basalts, commonly attributed to slab-derived sulfur inputs during subduction. However, the contribution of slab fluids remains debated because sulfur concentrations in sub-arc fluids have not been directly measured. Here we quantify sulfur in slab-derived fluids preserved as multiphase fluid inclusions composed of H 2 O, calcite, and chalcopyrite in omphacite from ultrahigh-pressure eclogites in the Sumdo orogenic belt. Three-dimensional Raman spectroscopy reveals high sulfur concentrations averaging ~6 wt.%. Mass-balance calculations indicate that such fluids can efficiently enrich the mantle wedge and supply up to ~70% of the sulfur emitted by arc volcanism. We further suggest that chalcopyrite formed through post-entrapment reduction of oxidized sulfur species by host omphacite, followed by precipitation with co-entrapped copper and iron. Our findings identify sub-arc depths as a critical window for slab sulfur release and provide key constraints on deep sulfur cycling and copper mobilization in arc systems.

How spatial patterns can lead to less resilient ecosystems

Several theoretical models predict that spatial patterning increases ecosystem resilience. However, these predictions rely on simplifying assumptions, such as assuming isotropic and infinitely large ecosystems, and empirical evidence directly linking spatial patterning to enhanced resilience remains scarce. We introduce a unifying framework, encompassing existing models for vegetation pattern formation in water-stressed ecosystems, that relaxes these assumptions. This framework incorporates finite vegetated areas surrounded by desert and allows varying levels of anisotropic environmental conditions that lead to nonreciprocal plant interactions. Under these more realistic conditions, we identify a desertification mechanism, known as nonlinear convective instability in physics but largely overlooked in ecology. These instabilities form when nonreciprocal interactions destabilize the vegetation-desert interface and can trigger desertification fronts even under stress levels where isotropic models predict stability. Importantly, ecosystems exhibiting periodic vegetation patterns are more susceptible to nonlinear convective instabilities than those with homogeneous vegetation, suggesting that spatial patterning may reduce, rather than enhance, resilience. These findings challenge the prevailing view that self-organized patterning enhances ecosystem resilience and provide a framework for investigating how spatial dynamics shape the stability and resilience of ecological systems under changing environmental conditions.

Daily steps offset risks of sedentary behavior in the All of Us research program

Abstract 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.

Cytotoxic T cell recognition of α-synuclein drives pathogenic immune responses in multiple system atrophy

Multiple system atrophy (MSA) is a progressive neurologic disease, known as an α-synucleinopathy. There are currently no effective disease-modifying therapies for MSA. While neuroinflammation is a hallmark of MSA, the contribution of adaptive immune mechanisms remains poorly understood. Here, we profiled peripheral and central T cell responses in patients with MSA, in comparison with Parkinson’s disease (PD) and healthy control cohorts, using single-cell transcriptomics, flow cytometry, and antigen-specific functional assays. We demonstrated that peripheral T cells from MSA patients are activated and skewed toward cytotoxic and inflammatory phenotypes. Single-cell transcriptomics further revealed clonal expansion of cytotoxic CD8 + T cells expressing GZMB , GNLY , and chemokine and integrin programs associated with brain homing. We also demonstrated that both CD4 + and CD8 + T cells from MSA patients recognize α-synuclein monomers and preformed fibrils in an HLA class I/II-dependent manner, driving proliferation, clonal expansion, and acquisition of cytotoxic features. Consistent with these peripheral responses, CD8 + T cell density was increased in the parietal cortex of postmortem MSA brain tissues, along with cytotoxic (GZMB + , GZMK + ) and proinflammatory (IFNγ + ) CD8 + T cells. Together, these findings demonstrate that cytotoxic T cells targeting α-synuclein are engaged in MSA, suggesting that their activity may contribute to neuroinflammation and disease progression, and highlighting this immune axis as a candidate therapeutic target for further investigation.

Direct observations of atmospheric oxidized mercury speciation in polar areas

Fatty acid regulation of feeding in <i>Caenorhabditis</i> elegans reveals the potential ancestral origin of a GLP-1-like multiagonist signaling system

Regulation of food intake in mammals is complex and controlled by an interplay between hedonic and homeostatic signals, including hormones like leptin, which senses fat storage and suppresses food intake. Caenorhabditis elegans lack leptin and leptin receptors but still exhibit controlled eating. Here, we show that in C. elegans eating can be regulated by a balance between saturated and monounsaturated fatty acids interacting with transcriptional pathways regulating lipid synthesis, c-AMP response element binding protein and AMP kinase. This effect is mediated at the endoplasmic reticulum through formation of phospholipids and activation of the IRE-1 sensor in the nervous system, which controls behavior through neuronal serotonin and the G-protein-coupled ligand/receptor pair PDF-1/PDFR-1. We show that this peptide/receptor pair may be an ancestral precursor of the whole family of GLP-1/GIP-related peptides and their receptors. Indeed, administration of a 37 amino acid peptide derived from PDF-1 resulted in a reduction in body weight and improved insulin sensitivity in mice. In worms, signaling through this pathway induced food-leaving behavior on concentrated food and roaming behavior on dispersed food, a state we have termed “food-apathy,” paralleling pharmacologic effects of GLP-1/GIP-related peptides in humans. These findings highlight the potential evolutionary origin of this family of hormones and their receptors, and its link to metabolic and neuronal responses in control of feeding behavior.

Strain-programmable liquid metal fibers for anti-interference electronic textiles

Temporal neuronal differentiation programs safeguard neuronal diversity

Differentiation programs actively lock neurons into a terminally differentiated state. How differentiation programs operate in distinct neuronal lineages remains obscure. Here, we found that previously well-characterized Drosophila neuronal differentiation factors are specifically expressed in the central brain late-born neurons but not early-born neurons, indicating the existence of a distinct, early differentiation program. We next identified T cell factor (TCF) and Odd-paired (Opa)/Zic as part of the early differentiation program that is specifically expressed in the early-born neurons to prevent neuronal dedifferentiation, partly through restricting Chinmo expression. At the molecular level, TCF promotes neuronal differentiation through a Wnt-independent noncanonical mode, via forming a transcriptional complex with Opa. Together, our study unveils that distinct differentiation programs operate in fly central brain early-born versus late-born neurons. Such customized differentiation mechanism whereby temporal differentiation programs safeguard their corresponding temporal identity specification programs is likely to also operate in mammalian brain development.

Influence of B cell-lineage targeted CAR-T cell therapy on humoral immunity and vaccine-induced antibody response

Species range shifts often speed ahead of their modeled climatic niches

Anticipating how species distributions will shift with climate change is key for biodiversity conservation and management. Commonly, species’ range shifts are observed by analyzing changes in occurrence or abundance data through time, or predicted across different climate change scenarios by modeling species’ climatic niches. However, it remains unclear how well these climate-based forecasts align with empirically documented range shifts from monitoring efforts. Here, we tested the congruence between modeled range shifts, predicted using climatic niche models, and documented range shifts, derived from empirical observations collected over recent decades, for more than 9,500 range shifts across over 3,500 marine and terrestrial species. We found that documented and modeled range shifts tend to align in latitudinal direction, with greater alignment for marine (76%) than terrestrial (56%) cases. However, even when the directions aligned, documented shifts exceeded modeled shifts in 62% of cases, nearly twice as often as they lagged behind (38%), and their median rates were four times faster than those of the modeled shifts. Our findings suggest that climate-based models can approximate observed range dynamics under specific conditions, particularly over long time periods and restricted spatial areas, when habitats remain well connected and under low climate fluctuations over time. These insights provide valuable guidance for both improving predictions and informing responses to climate-driven biodiversity redistribution.

Small nucleolar RNA Snora61 drives self-renewal of intestinal stem cells via initiation of Lgr5 transcription

National identity reconfigures brain responses from “them” to “us”

How the human brain flexibly adapts social perception by recategorizing out-group (them) to in-group (us) remains unclear. Using functional MRI in Singapore’s multicultural population, we investigated how priming subordinate (ethnic) versus superordinate (national) identities reshapes neural processing of ethnic in-group and out-group faces. We demonstrate that the ventromedial prefrontal cortex, a hub for self-referential processing, preferentially activates for ethnic in-group faces under ethnic identity priming, while showing increased engagement for ethnic out-group faces under national identity priming. Representational similarity analyses reveal that national priming reduces the neural representational distance between in-group and out-group faces, though ethnic distinctions persisted. These findings provide neural evidence for the Common Ingroup Identity Model, revealing a partial recategorization process in which superordinate identity priming increases self-referential processing of former out-group members while maintaining underlying ethnic category distinctions. These results elucidate the neural mechanisms supporting identity flexibility with implications for improving intergroup relations in diverse societies.

All-optical control of second-harmonic generation in β-BaB2O4 via coherent, terahertz-driven acentric lattice displacement

Abstract Dynamical control of the nonlinear optical properties of solids – with light itself – will be essential for future ultrafast photonic technologies. Previously, methods to modulate nonlinear processes including second-harmonic generation (SHG) have relied primarily on non-resonant light-matter interaction or photo-generation of hot electrons in nanoscale materials. However, these approaches are typically constrained by limited interaction lengths and the initial frequency conversion is relatively weak under equilibrium conditions. Here, a ~ 30% modulation of efficient phase-matched SHG in bulk beta-barium borate (β-BaB 2 O 4 ) is achieved through transient lattice deformation by intense terahertz (THz) pulses that are tuned to resonance with an infrared-active phonon mode. The effect originates from modification of the index of refraction ellipsoid and the corresponding nonlinear phase-matching conditions, rather than from direct modulation of the nonlinear susceptibility through THz-mediated $${\chi }^{(3)}$$ χ ( 3 ) processes. This mechanism, of resonant selective lattice excitation, points toward novel THz-control schemes to tune the nonlinear optical response in materials.

Molecular kinetics dictate population dynamics in CRISPR-based plasmid defense

Understanding and manipulating the spread of mobile genetic elements represents a great challenge with potential benefits across synthetic biology, agriculture, and medicine. A key part of this challenge is the multiple scales in play, from the molecular kinetics of defense systems such as CRISPR-Cas, to single-cell variability in immunity levels, to spatial structure in bacterial populations. In this work, we use a time-lapse, imaging-based approach to characterize conjugative plasmid dynamics at the molecular, single-cell, and population levels. By fluorescently tagging the conjugative plasmid RP4 and CRISPR-Cascade complexes, we quantify population dynamics as a function of spacer target number, Cascade expression level, and the presence of plasmid addiction modules. Using single-cell tracking, we report conjugation rate per neighboring donor cell, estimate the latent period between plasmid uptake and subsequent onward transmission, and quantify the effect of Cascade expression variability on plasmid clearance kinetics. Finally, using a spatially resolved, agent-based model, we show that plasmid population dynamics can be successfully predicted using these single-cell biophysical parameters as inputs. This synthesis of population and single-cell measurements suggests that plasmids are the subject of a dynamic tug-of-war between defense expression, spacer distribution, neighboring cell identity, and plasmid cost–benefit tradeoffs. The imaging and analysis techniques used here will facilitate the disentanglement of how these factors coordinate to realize community-wide plasmid dynamics in diverse contexts.

A live biohybrid bacterial therapy based on engineered Serratia marcescens

Abstract Bacterial therapeutics hold great promise for cancer treatment by targeting oxygen-poor tumor regions and complementing existing therapies. However, current approaches often struggle with safety concerns and complex engineering. Developing a safe, effective delivery platform relying entirely on natural bacterial biosynthesis remains a challenge. Here we show that attenuated Serratia marcescens serves as a powerful biohybrid platform for cancer therapy by leveraging its natural biosynthesis of prodigiosin, a photosensitive pigment. We engineer S. marcescens to yield high prodigiosin levels, which exhibit strong intrinsic anti-cancer activity and near-infrared photosensitivity. In female mouse models of melanoma and colorectal cancer, this platform triggers robust systemic immune responses, including enhanced T cell recruitment and long-term memory against tumor recurrence. Furthermore, the bacteria induces tumor cell death via mitophagy, while photothermal properties of prodigiosin enables rapid, light-controlled bacterial clearance post-treatment. These findings establish S. marcescens as a versatile, self-regulating biosynthetic platform for precise and safe cancer immunotherapy.

“Target species complex” concept: Strengthening environmental risk assessment of engineered gene drives

PHIP suppresses NuRD to enable the growth of SWI/SNF-mutant cancers

Abstract SWI/SNF chromatin remodeling complexes are perturbed in 20% of all cancers and in several developmental disorders, yet the mechanisms by which these mutations dysregulate transcription and drive disease are poorly understood. To both elucidate these mechanisms and identify vulnerabilities caused by these mutations, we leverage genome-wide CRISPR-Cas9 screening in hundreds of cancer cell lines and identify the chromatin reader protein PHIP as a specific dependency in cancers with broadly disrupted SWI/SNF function. Mechanistically, we reveal that PHIP cooperates with SWI/SNF to facilitate transcriptional activation by ubiquitinating and suppressing subunits of the repressive Nucleosome Remodeling and Deacetylase (NuRD) complex. We demonstrate that loss of SWI/SNF results in NuRD complexes accumulating at promoters where they would otherwise cause widespread transcriptional silencing if not antagonized by PHIP. Collectively, we identify PHIP as a regulator of the interplay between distinct chromatin regulators that function in development and disease and as a targetable vulnerability in cancers with broad SWI/SNF inactivation.

Co-opting the bacterial lipoprotein pathway for the biosynthesis of lipidated macrocyclic peptides

Ribosomally synthesized and posttranslationally modified peptides (RiPPs) are structurally diverse natural products that possess a range of bioactivities, often acting as antibiotics, antifungals, or metallophores. In RiPP biosynthesis, different modifying enzymes install an array of chemical motifs onto a precursor peptide. A recently described RiPP-modifying enzyme, ChrH, catalyzes a remarkably complex reaction on its precursor peptide that results in a macrocycle, heterocycle, and S- methyl group. By leveraging comparative genomics, we demonstrate that the products from a subfamily of enzymes related to ChrH display unexpected structural diversity, including the production of unmethylated macrocyclic congeners and C-terminally modified proteins over 30 kDa in size. Several of these precursors contain a signal peptide, sending them for downstream maturation by the bacterial lipoprotein biosynthetic pathway. Like bacterial lipoproteins, such peptides are modified by addition of a diacylglycerol (DAG) group to the N-terminal cysteine residue along with acylation of the N-terminal amine. Genome mining reveals that these RiPP–lipoprotein hybrids, which we term DAG-RiPPs, are widespread across bacterial phyla and are likely involved in different biological roles. Together, these results highlight a maturation paradigm for membrane-bound RiPPs and lay the foundation for the future discovery and bioengineering of other RiPP–lipoprotein hybrids.