Browse Articles

Speech-based digital endpoints track ALS progression and align with standard clinical outcomes: evidence from the VRG50635 trial

An acetyltransferase family required for biosynthesis of diverse marine carotenoids

Chromalveolate algae such as diatoms, haptophytes, and dinoflagellates are main contributors to oceanic primary production, sustaining marine ecosystems and global carbon cycles while synthesizing a striking array of acetylated carotenoids like fucoxanthin and peridinin. These pigments optimize photosynthetic light harvesting in the algae and offer nutritional benefits for humans, yet knowledge of their biosynthetic pathways is still incomplete, particularly the shared acetylation step. By screening 39 candidate genes in the diatom Phaeodactylum tricornutum , we identified an enzyme with x anthophyll ac etyl t ransferase (XACT) activity that is indispensable for this modification. Disrupting XACT in Phaeodactylum and the eustigmatophyte Nannochloropsis oceanica abolished xanthophyll acetylation. Phylogenetic analyses revealed that XACT is exclusively present in chromalveolates synthesizing acetylated xanthophylls. In vitro assays with recombinant XACT enzymes from Phaeodactylum , Nannochloropsis , the brown alga Ectocarpus siliculosus , the dinoflagellate Symbiodinium tridacnidorum , and a haptophyte confirmed their general activity toward allenic precursor carotenoids but exhibited lineage-specific substrate preferences, explaining the diversified carotenoid structures across lineages. The broad substrate specificity of XACT from Phaeodactylum led us to reinvestigate the substrate specificities of other enzymes involved in fucoxanthin formation, indicating that fucoxanthin biosynthesis in diatoms proceeds via a multibranched rather than a linear pathway. XACT from Ectocarpus showed a distinctly narrow substrate spectrum, providing key evidence for the order of the two previously proposed steps in brown algal fucoxanthin biosynthesis. Our work resolves a long-standing gap in marine carotenoid biosynthesis and identifies the relaxed substrate specificities of the enzymes involved as an important driver for the multitude of algal carotenoid structures.

5-hydroxymethylcytosine signatures of tissue as potential predictive markers for platinum resistance in epithelial ovarian cancer patients

B cells enable autoreactive T cells to avoid suppression

Clinical trials and experimental observations have shown that B cells are essential for development of T cell–mediated organ-specific autoimmunity, although their exact contribution is not clear. As antigen presentation by B cells is focused on antigens cognate to their antigen receptors, we reasoned that B cells would facilitate activation of T effector cells (Teff) with the same antigen specificity but would poorly activate regulatory T cells (Treg) due to insufficient presence of antigen-specific Tregs among polyclonal/multispecific Tregs at the early stages of pathogenesis. At the same time, activation of Teff by autoantigens presented by dendritic cells (DC) would be sensitive to by-stander suppression by Tregs as DCs express a variety of antigenic peptides. We used Teff cells (KRN) and B cells (121) reactive to the same antigen – glucose-6-phosphate-isomerase (GPI) to show that KRN T cells activation was sensitive to polyclonal Tregs only when activated by DCs but not by B cells. However, as expected, GPI-specific Tregs were fully capable of suppressing Teff activation by B cells. Our findings shed light on the role of B cells in organ-specific autoimmunity and provide knowledge-based support for application of anti-B cell immunotherapies.

Face perception and impact of face masks at 6 months post-term age in preterm and term infants (The BabyFace Study)

Light-activated cAMP signaling controls sodium-driven motility in <i>Vibrio cholerae</i>

Light is one of the most pervasive physical cues in aquatic environments, yet its impact on nonphototrophic pathogens remains largely unexplored. Here, we show that a strain of cholera bacterium Vibrio cholerae directly couples illumination to motility through cyclic AMP (cAMP) signaling. Exposure to visible light rapidly elevates intracellular cAMP and increases swimming speed, whereas deletion of the single adenylyl cyclase gene ( cyaA ) abolishes both responses; complementation or addition of exogenous cAMP restores the phenotype. Heterologous expression of V. cholerae CyaA in an Escherichia coli Δ cyaA Δ cpdA background reconstitutes light-activated cAMP synthesis, indicating that CyaA confers photoreactivity. Purified CyaA exhibits a reversible light-dependent spectral shift consistent with flavin-dependent photochemistry, identifying it as a light-responsive cyclase. Illumination triggers rapid membrane hyperpolarization and sodium efflux, strengthening the sodium-motive force that powers the flagellar motor. This response persists under nutrient-limited conditions. Together, these findings define a light → cAMP → sodium-motive force coupling axis in V. cholerae , suggesting that ambient light may influence motility and dispersal in sunlit environments.

Cognitive integration of internet of things and feedforward learning models for smart irrigation in sustainable agriculture

Maternal IntS11 primes embryonic totipotency by organizing early zygotic transcription initiation

Zygotic genome activation (ZGA) marks the first transcriptional milestone and establishes embryonic totipotency. Although pioneer factors have been reported to initiate this process, how chromatin is primed for the totipotent state, allowing the binding of pioneer factors for successful ZGA, remains unclear. Here, we identify IntS11, the catalytic subunit of the Integrator complex, as a totipotent determinant of embryonic chromatin governing ZGA in Drosophila . We show that IntS11 functions upstream of pioneer factors in early embryos: Maternal IntS11 depletion substantially impairs RNA polymerase II (Pol II) recruitment, thereby preventing pioneer factors Zelda and GAGA factor (GAF) from accessing regulatory elements and initiating genome-wide zygotic transcription. Mechanistically, IntS11 exerts dual roles: its canonical endonuclease activity is required to sustain major-wave zygotic transcription, while a distinct enzyme-independent function drives de novo Pol II loading and pioneer factor engagement. These findings uncover a fundamental maternal-specific mechanism whereby IntS11 establishes transcriptional competence, ensuring totipotent chromatin states and successful ZGA.

Digital documentation and virtual representation of built heritage using terrestrial LiDAR

Structure-guided design of 7-azaindole DNMT1 inhibitors active against hypomethylating agent–resistant acute myeloid leukemia

Pharmacological reversal of abnormal promoter DNA hypermethylation at tumor suppressor genes (TSGs) is a key therapeutic paradigm for cancer management. However, the clinical efficacy of currently approved nucleoside analog hypomethylating agents (HMAs) is limited by dose-dependent toxicity and high resistance rates. Nonnucleoside, DNA methyltransferase 1 (DNMT1)-selective inhibitors offer a promising alternative. To date, only limited chemotypes, exemplified by the dicyanopyridine derivative GSK3685032 (GSK5032), have demonstrated translatable DNMT1 inhibition, with resistance emerging upon prolonged exposure. To address these limitations, we employ structure-guided scaffold hopping and chemical optimization to develop a series of DNMT1 inhibitors (DNMT1i) featuring a bicyclic 7-azaindole scaffold. We identify DMI46, a potent enzymatic DNMT1i capable of reversing cancer-specific DNA methylation abnormalities and TSG silencing, leading to robust antileukemic effects and favorable tolerability. Cryoelectron microscopy (cryo-EM) studies reveal that the 7-azaindole inhibitor exhibits enhanced intercalation into hemi-methylated CpG dyads and increased minor-groove contacts within the DNMT1/hemimethylated DNA complex compared to GSK5032. These structural features enable sustained DNMT1 targeting and significant antiproliferative activity of DMI46 in GSK5032-resistant acute myeloid leukemia (AML) cells. We also demonstrate DMI46’s capacity to overcome AML resistance to nucleoside-based HMAs both in vitro and in vivo. These findings introduce a distinct DNMT1i chemotype with enhanced on-target engagement and broad applicability against HMA-resistant AML.

Whole-exome sequencing increases variant detection compared to karyotyping and CMA in an unselected FGR cohort

Probing rock rupture with naturally occurring nuclide signals

Rocks release subtle geochemical warning signals before breaking. These signals, coming from naturally occurring nuclides (e.g., radon, helium, argon, and thoron), have often been reported before earthquakes, volcanic eruptions, landslides, and rock and ice avalanches. However, despite their high sensitivity to deformation, their detectability, as well as myriad promising observations over half a century, nuclide signals are still far from being applied to geohazard prediction or widely used for monitoring. Here, we first develop a decomposition and interpretation method for nuclide signals. By analyzing nuclide signal time series observed from a month-long laboratory rock failure experiment and year-long slope deformation in a field setting, we identify a universal paradigm unit of nuclide signal evolution. We find that this paradigm unit is characterized by two core characteristics: a transient pulse and equilibrium fluctuation which are intrinsically correlated to rupture area and crack aperture, respectively. Through analytical derivation and pore-scale simulations, we establish the constitutive equations that link these characteristic nuclide signals to key rupture structural parameters. Rooted in these constitutive relations, we further develop a diagnostic theory of rock rupture via nuclide signals. We apply the model to track rock failures at the laboratory and field scale. The proposed nuclide signal decomposition and rupturing model enable the unification of discrete signal units emitted by individual microrupturing events, with the integrated signal evolution observed during macroscopic failure. This integration may serve as a foundation for both the mesoscopic assessment of rock damage and the early warning of geohazards induced by rock ruptures.

Large herbivores and abiotic drivers jointly shape spatiotemporal grassland dynamics in a subalpine ecosystem

Abstract Managed grazing has a larger geographic extent than any other global form of land use. In subalpine grasslands, the spatiotemporal dynamics of vegetation during its growing season may depend on grazing intensity, the type of vegetation and abiotic drivers, as well as their complex interactions. Here, we examine how free-range grazing cows and abiotic factors (climate and topography) drive grassland dynamics over three growing seasons in a Pyrenean valley. We combine high spatial resolution satellite imagery to estimate our response variable (the Soil-Adjusted Vegetation Index (SAVI), a proxy of vegetation greenness and biomass that correlates with forage quantity and quality), with GPS-tracking of cows (80–85 cows per year), the primary herbivores in the valley. We generated a detailed vegetation map and used GPS accelerometer data to separate grazing from resting cow activities, the latter resulting in higher trampling and nutrient deposition on vegetation. Results indicate that cows showed a clumped spatial distribution, consistent with collective behaviour and a heterogeneous use of the available space. SAVI showed clear seasonal cycles, peaking in early summer and declining to winter dormancy. Grassland dynamics were influenced by climate variability, both seasonal (solar radiation and temperature) and non-seasonal (soil water content, precipitation, and wind). The other drivers were also selected in the best multiple regression model, which explained 46% of SAVI temporal variance. Both cow activities had negative impacts on vegetation, with lower SAVI values associated with resting; grazing showed non-linear negative effects on SAVI, varying synergistically with elevation, slope, and orientation. The nonlinearity resulted from a steep initial decline in SAVI with grazing, followed by a diminishing negative effect as grazing intensity increased. These findings reveal the complex interplay between biotic and abiotic drivers in SAVI dynamics, emphasising the role of large herbivores in the ecological processes in subalpine ecosystems under varying environmental conditions.

MDFIC2 is a sensory neuron–specific PIEZO channel auxiliary subunit

PIEZO channels are critical for sensory mechanotransduction. While MyoD-family inhibitor proteins were identified as PIEZO1 auxiliary subunits, their broader regulatory roles, particularly in sensory cells, remained unclear. Here, we demonstrate native MDFIC and MDFI regulate endogenous PIEZO channel currents in various nonsensory cell types. However, neither MDFIC nor MDFI are expressed in primary sensory neurons. In these cell types, we identified an uncharacterized third member of this family, Mdfic2 / Gm765 , that shares the ability to physically bind to PIEZO1 and PIEZO2. MDFIC2 is selectively expressed in subsets of mechanosensitive neurons, including dorsal root ganglia, trigeminal ganglia, and vagal sensory neurons. Like its paralogues, MDFIC2 alters PIEZO1/2 mechanosensitivity and inactivation kinetics, converting them into high-threshold slowly inactivating mechanoreceptors. Extensive cryo-EM reveals a conserved binding pocket for these auxiliary subunits in the pore modules of both PIEZO1 and PIEZO2 mediated by the posttranslationally modified distal C termini of MyoD-family inhibitor proteins. This structural and functional characterization of MyoD-family inhibitor proteins as PIEZO1/2 channel auxiliary subunits offers insights into the mechanobiology of nonsensory and sensory cells.

A three-week mindfulness intervention on mental skills, internal-load regulation, and performance in youth swimmers: a randomized controlled trial

Abstract This study examined whether a three-week mindfulness program integrated into swim training could enhance mental skills, stabilize internal-load responses, and affect short-term endurance performance in youth swimmers. Thirty trained swimmers (20 males, 10 females; aged 19.7 ± 1.7 years) were randomly assigned to an experimental group (EG, n  = 15) or a control group (CG, n  = 15). The EG completed 12 pre-swim mindfulness sessions, each lasting 30–45 min and incorporating breathing regulation, body awareness, and attentional-focus exercises, while the CG followed standard training only. Pre- and post-intervention assessments included 400 m freestyle time, mean velocity, and mental skills (basic, psychosomatic and cognitive). Peak heart rate (HRpeak), expressed as a percentage of theoretical maximum HR, was recorded throughout each training session, and the rate of perceived exertion (RPE) was assessed at the end of each session. The EG exhibited greater improvements in mental skills across basic, psychosomatic, and cognitive domains (all p  &lt; 0.01; cohen’s d = 2.02–2.83) compared with the CG. Despite higher HRpeak and RPE values ( p  &lt; 0.001), the EG showed significantly lower intra-subject and inter-session variability, indicating a more stable internal-load profile. No significant interactions were observed for 400-m performance variables ( p  &gt; 0.05). Mindfulness appears to improve athletes’ self-regulation and training consistency rather than producing immediate performance gains. Longer interventions are warranted to evaluate the long-term transfer of these benefits to competition settings.

Variability in alluvial river width driven by intermittent bank collapse

Alluvial rivers have long been described by hydraulic geometry theory, which links equilibrium channel dimensions to flow discharge. Yet natural rivers are inherently dynamic, with planforms evolving over time and widths fluctuating around an equilibrium state. Despite increasingly refined datasets, the mechanisms underlying river width variability remain poorly understood. Here, we analyze a globally distributed set of alluvial rivers using high-resolution satellite imagery to examine spatial patterns of width variability. When normalized by mean channel width, we identify three characteristic wavelengths of width variability, each associated with a distinct geomorphic feature: meander bends, mid-channel bars, and localized bank-line incisions linked to intermittent bank collapse. Fourier analysis reveals a strong inverse relation between intermittent collapse-driven width variability and bend-average curvature, suggesting that intermittent bank collapse plays a prominent geomorphic role in mildly curved rivers. Numerical modeling further demonstrates that intermittent bank collapse affects the overall river morphodynamics, accelerating lateral migration and enhancing floodplain reworking. By illustrating intermittent bank collapse as a significant mechanism of river width adjustment, our findings refine classical fluvial geomorphology theory and hold implications for river restoration and organic carbon flux estimation in a warming era.

Peroxidase-mimicking chitosan/dextran-coated cobalt ferrite-graphene oxide nanozyme enhances hydrogen peroxide–mediated killing of cariogenic pathogens in dental biofilm models

Metabolite mimicry identifies butyrate analogs with select protective functions in the intestinal mucosa

Microbial-derived short-chain fatty acids regulate a variety of pathways in the healthy colonic mucosa. In particular, butyrate serves as the primary energy source for colonocytes and regulates gene transcription by stabilizing the transcription factor hypoxia-inducible-factors (HIF) and functioning as a histone deacetylase (HDAC) inhibitor. A limitation of butyrate as a therapeutic is its rapid metabolism in differentiated colonocytes. Furthermore, intestinal stem cells (ISCs) respond differently to butyrate, preferentially using glucose for energy procurement. To address these limitations, we explored metabolite mimicry to identify compounds with potent or selective biological responses within the butyrate pathway(s). We found an analog, 3-chlorobutyrate (3-Cl BA), that significantly enhances epithelial barrier formation and wound healing in vitro. Mechanistically, we revealed that 3-Cl BA is a potent HDAC inhibitor. Furthermore, unlike butyrate, 3-Cl BA does not stabilize HIF and it is not used as metabolic fuel. In vivo studies in a dextran sulfate sodium-colitis model revealed that contrary to butyrate, 3-Cl BA is protective. Studies in stem-like colonoids demonstrated that only butyrate inhibits ISC proliferation and differentiation. Furthermore, it was recently reported that HIF stabilization inhibits ISCs activity. Given the fact that butyrate but not 3-Cl BA stabilizes HIF, we surmised that 3-Cl BA would circumvent these detrimental functional consequences. We demonstrate here that pharmacologic HIF stabilization inhibits colonoid differentiation and that genetic loss of HIF significantly promotes ISC differentiation. This study reveals a promising butyrate analog protective in colitis and demonstrates the advantages of metabolite mimicry to dissect selective biological functions from major metabolites in the gut.

Hantavirus L protein exhibits shutoff activity mediated by its N-terminal endonuclease domain

Abstract The hantavirus L protein is a viral polymerase essential for viral transcription and replication; however, its expression in mammalian cells has been notoriously difficult. In this study, we achieved robust plasmid-based expression of the L protein by combining a T7-driven system with mutations that reduce endonuclease activity. This strategy was pivotal, as conventional RNA polymerase II (Pol II)-dependent systems failed to yield detectable expression. Although wild-type L protein was barely detectable, its presence suppressed co-expressed genes, suggesting a potent host shutoff activity that inhibits both trans-gene and its own (cis-) expression. Leveraging functional homology to the influenza PA-X protein, we identify amino acid residues essential for the shutoff activity of L protein by using its N-terminal fragment, which can be expressed via standard Pol II-dependent systems. Our mutagenesis analysis established a toolset for the predictable fine-tuning of shutoff activity and L protein expression levels, facilitating a detailed analysis of the interplay between polymerase activity and viral replication. These findings elucidate the mechanisms underlying the difficulty in expressing the hantavirus L protein and emphasize the necessity of accounting for these cis- , and trans- regulatory effects in functional analyses, such as in minigenome assays, to prevent data misinterpretation.

Diffusive spreading across dynamic mitochondrial network architectures

In eukaryotic cells, mitochondria form networks that range from highly fused interconnected structures to fragmented populations of individual organelles that undergo transient interactions. These structures can be described as temporal networks of physical units, whose dynamic topology is determined by fusion, fission, and motion of the mitochondria through intracellular space. The heterogeneity of the mitochondrial population is governed by diffusive transport and interunit exchange of proteins, lipids, ions, and RNA within these networks. We present a unifying framework for the dispersion of material within temporal networks of spatially embedded units that span across a broad connectivity range. Specifically, we consider filling of the networks with a locally produced but globally consumed material, demonstrating that the steady-state content is determined by the balance of timescales for spatial encounter between clusters, local fusion, fission, and diffusive transport within a cluster. As the connectivity increases, filling behavior transitions from three-dimensional spread through a “social network” limited by cluster interactions to low-dimensional transport through a largely stationary “physical network” limited by material diffusivity. We extract parameters for mitochondrial networks in three human cell lines, demonstrating that different cells can access both the social and the physical network regimes. These results provide a quantitative basis for predicting the homogenization of biomolecules through a mitochondrial population. Our framework unifies a variety of temporal network structures into an overarching theory for transport through populations of interacting and interconnected units.