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Droplet-on-demand mass spectrometry reveals curvature-dependent interfacial reactivity in aqueous microdroplets

Water microdroplets offer a chemical environment that can dramatically accelerate reaction rates compared to bulk-phase solutions and even drive chemical transformations not found in bulk solutions. While mass spectrometry has proven indispensable for studying microdroplet chemistry, current methods rely on ensemble-averaged data from polydisperse droplet populations, obscuring the molecular details and droplet-size dependencies of reactions in individual droplets. Here, we present a piezoelectric-driven droplet-on-demand platform that enables direct mass spectrometric analysis of single, size-controlled microdroplets. We demonstrate a broad range of reactions occurring within isolated droplets. These reactions yield products comparable to those generated in conventional spray-based microdroplet systems, confirming that enhanced reactivity is intrinsic to the microdroplet environment. Crucially, we reveal a pronounced droplet-size-dependent reactivity, with smaller droplets exhibiting markedly higher activity per unit surface area. This consistent trend across different reaction types underscores the pivotal role of curvature-modulated interfacial electric fields in governing microdroplet reaction dynamics. Higher electric field strengths cause more radicals to be formed, but these radicals recombine with one another, removing them for reactions with other substrates. Consequently, as our experimental data show, there is an optimum droplet size to yield the highest product reaction rate.

Climate sensitivity is widely but unevenly spread across zoonotic diseases

Climate change is expected to exacerbate infectious diseases, yet the climate sensitivity of zoonotic diseases (driven by spillover from animal reservoirs) is understudied compared to vector-borne and water-borne infections. To address this gap, we conducted a scoping review and quantitative synthesis to identify relationships between climatic indicators (temperature, precipitation, humidity) and zoonotic disease risk metrics worldwide. We identified 218 studies from 65 countries describing 852 measures across 53 diseases, with most studies testing linear (n = 193) rather than nonlinear (n = 28) relationships. We found evidence of climate sensitivity across diverse zoonotic diseases (significant nonzero relationships in 69.1% of temperature effects, 63.5% of precipitation effects, and 53.6% of humidity effects), but with variation in direction and strength. Positive effects of temperature and rainfall on disease risk were more common than negative effects (46.5% vs. 22.6% and 37.8% vs. 25.7% of all records, respectively). These studies were predominantly located in areas expected to have substantial increases in annual mean temperature (>1.5 °C in 97% of studies) and rainfall (>25 mm in 53% of studies) by 2041 to 2070. Notably, the most consistent relationship was between temperature and vector-borne zoonoses (56% of positive effects, mean Hedges’ g = 0.36). Our analyses provide evidence that climate sensitivity is common across zoonoses, likely leading to substantial yet complex effects of climate change on zoonotic burden. We emphasize the need for future studies to utilize biologically relevant models, apply rigorous space-time controls, consider causal perspectives, and address taxonomic and geographic biases to allow robust consensus of climate–risk relationships to emerge.

Three distinct components of pragmatic language use: Social conventions, intonation, and world knowledge–based causal reasoning

Successful communication requires frequent inferences. Such inferences span a multitude of phenomena: from understanding metaphors, to detecting irony and getting jokes, to interpreting intonation patterns. Do all these inferences draw on a single underlying cognitive ability, or does our capacity for nonliteral language comprehension fractionate into dissociable components? Using an approach that has successfully uncovered structure in other domains of cognition, we examined covariation in behavioral performance on diverse nonliteral comprehension tasks across two large samples to search for shared and distinct components of pragmatic language use. In Experiment 1, n = 376 participants each completed an 8 h battery of 20 critical tasks. Controlling for general cognitive ability, an exploratory factor analysis revealed three clusters, which can be post hoc interpreted as corresponding to i) understanding social conventions (critical for phenomena such as indirect requests, conversational implicatures, and irony), ii) interpreting contrastive and emotional intonation patterns, and iii) making causal inferences based on world knowledge. This structure largely replicated in a new sample of n = 400 participants (Experiment 2, preregistered) and was robust to analytic choices. This research uncovers structure in the human communication toolkit and can inform our understanding of pragmatic difficulties in individuals with brain disorders. The hypotheses put forward here about the underlying cognitive abilities can now be evaluated in new behavioral studies, as well as using brain imaging and computational modeling, to continue deciphering the ontology of the component pieces of linguistic and nonverbal communication.

Organization principles of dynamic three-dimensional genome architecture associated with centromere clustering states

Fungal centromeres are clustered near microtubule organizing centers to help adopt the Rabl chromosomal organization. The role of centromere clustering in driving large-scale changes in structural and functional chromatin assembly remains unclear. Here, using Hi-C and superresolution microscopy, we show that cell cycle-dependent centromere declustering and clustering states in Cryptococcus neoformans drive global changes in the 3D genome architecture. Centromeres and telomeres are scattered around the nuclear periphery at interphase G1 , and this arrangement constrains the interarm interactions within a chromosome, providing a unique interphase G1 chromosome organization. Moreover, centromeres and telomeres are organized as separate compartments, segregating them from active euchromatic regions. Polymer modeling reveals that the transition from the unclustered to clustered centromere state during the cell cycle involves changes from a globular to an elongated chromosome architecture. Strikingly, while clustered centromeric regions replicate early in most yeasts, C. neoformans centromeres replicate late in S-phase, hinting at a possible link between centromere clustering dynamics and CEN DNA replication timing. Overall, our study uncovers several unique organizational principles governing the dynamic genome architecture in an evolutionarily diverged basidiomycete yeast.

Molecular mechanisms underlying p62-dependent secretion of the Alzheimer-associated ubiquitin variant UBB ⁺¹

UBB +1 , a ubiquitin variant protein resulting from a frameshift in the ubiquitin-B gene, is a pathological hallmark of Alzheimer disease (AD). At the cellular level, UBB +1 disrupts the ubiquitin–proteasome system while inducing autophagy. Notably, UBB +1 itself is secreted via autophagosome-like vesicles. Here, we demonstrate that UBB +1 can be removed from the cell by degradative and secretory autophagy. Sequestosome 1 (SQSTM1)/p62 functions as a pivotal ubiquitin receptor for UBB +1 , recognizing its ubiquitin domain and facilitating loading into autophagosomes. Oligomerization of SQSTM1/p62 was critical to isolate UBB +1 in bodies preventing its aggregation. Intriguingly, both gain- and loss-of-function SQSTM1/p62 suppressed UBB +1 secretion, causing intracellular retention: SQSTM1/p62 knockout led to UBB +1 accumulation in insoluble aggregates, while its overexpression promoted the formation of p62-UBB +1 bodies. We further identified distinct roles for SNARE-mediated membrane fusion in secretory autophagy of UBB +1 . Specifically, the R-SNARE SEC22B and the Q-SNAREs Syntaxin-4 and SNAP23 participated in UBB +1 exocytosis. Disruption of SEC22B impaired the fusion of UBB +1 -containing autophagosomes with the plasma membrane, reducing UBB +1 secretion without affecting its intracellular turnover. Inhibition of lysosomes partially stabilized UBB +1 indicating that degradation and secretion are complementary processes that determine the fate of UBB +1 . This study elucidates the dual roles of autophagy in managing neurotoxic proteins, highlighting SQSTM1/p62 as a key mediator of UBB +1 trafficking and secretion. Although ubiquitin typically acts as a degradation signal, our findings reveal a rare instance of a ubiquitin-related protein driving secretory autophagy. These findings advance our understanding of cellular mechanisms underlying the clearance of misfolded proteins in neurodegenerative diseases.

Resolved tropical cyclones trigger CO ₂ uptake and phytoplankton bloom in an Earth system model simulation

The ocean carbon cycle is directly impacted by storms in the atmosphere. Tropical cyclones (TCs), particularly, are known to drive intense air–sea CO 2 fluxes and to trigger phytoplankton blooms. However, the current generation of Earth system models (ESM) cannot realistically represent TCs due to their coarse spatial resolution (typically 100 to 200 km grid spacing). Here, we present a km-scale coupled, global, storm- and eddy-resolving (5 km ocean, 5 km atmosphere) ESM simulation including ocean biogeochemistry that is able to resolve TCs, and the cascade of physical-biogeochemical mechanisms that unfold in their response. Our simulated TCs enhance CO 2 fluxes by 20 to 40 times and cool the surface ocean by 2 to 3 ° C, thus contributing to inverting the CO 2 flux direction from ocean outgassing to uptake. Our TCs furthermore trigger a phytoplankton bloom in autumn in the western North Atlantic, which is missed by coarser ESMs. While TCs cool the ocean surface, they also warm the subsurface, thus causing counteracting impacts on temperature-dependent organic matter remineralization. In summary, our model configuration reproduces mechanisms underlying the ocean carbon cycle variability that remained so far unresolved in ESMs. By representing fine-scale atmosphere-ocean biogeochemistry interactions in our ESM, we pave the way for future work to constrain uncertainties in the role of km-scale events in the ocean carbon cycle at global and climatic scales.

Generative epigenetic landscapes map the topology and topography of cell fates

Epigenetic landscapes were proposed by Waddington as the central concept to describe cell fate dynamics in a locally low-dimensional space. In modern landscape models, attractors represent cell types, and stochastic jumps and bifurcations drive cellular decisions, allowing for quantitative and predictive descriptions. However, given a biological problem of interest, we still lack tools to infer and build possible Waddington landscapes systematically. In this study, we propose a generative model for deriving epigenetic landscapes compatible with data. To build the landscapes, we combine gradient and rotational vector fields composed of locally weighted elements that encode “valleys” of the Waddington landscape, resulting in interpretable models. We optimize landscapes through computational evolution and illustrate our approach with two developmental examples: metazoan segmentation and neuromesoderm differentiation. In both cases, we obtain ensembles of solutions that reveal both known and original landscapes in terms of topology and bifurcations. Conversely, topographic features appear strongly constrained by dynamical data, which suggests that our approach can generically derive interpretable and predictive epigenetic landscapes.

Intracellular <i>Acinetobacter baumannii</i> acts as a transient reservoir in lung infection via a “persist and resist” strategy

Although considered primarily extracellular, Acinetobacter baumannii can survive and replicate within macrophages in vitro. Intracellular bacteria are often protected from the host immune system and antibiotic treatment, potentially leading to chronic or recurrent infections. To investigate the role of intracellular A. baumannii during infection, we transferred b roncho a lveolar l avage f luid (BALF) from infected mice, containing an intracellular bacterial population, into naïve immunocompromised mice, enabling us to assess the fate of bacteria following internalization. The BALF transfer resulted in A. baumannii lung infection, indicating that intracellular bacteria can egress from host immune cells and establish infection in the lungs, thereby acting as a transient reservoir during pulmonary infection. Using dual proteomics, we characterized the A. baumannii –macrophage interactions. Infected macrophages exhibit an inflammatory and type I interferon response, marked by increased Acod1/IRG1 protein levels. Intracellular A. baumannii upregulates proteins involved in evading nutritional immunity, stress response, surface modification, and metabolic adaptation. Collectively, these findings indicate that A. baumannii employs a multifactorial strategy to persist and replicate within macrophages, potentially shaping infection dynamics in vivo and undermining therapeutic efficacy.

Correction: Relaxation of selective constraint on the sweet-taste receptor gene TAS1R2 in lorisiform primates

IL-27 promotes Treg cell expression of CD122 and fitness at homeostasis

Regulatory T (Treg) cells express high levels of the IL-27R, and in the setting of infection and autoimmunity, the cytokine IL-27 promotes Treg cell activities that mitigate tissue pathology. However, IL-27 appears dispensable for Treg cell development and maintenance as lineage-specific depletion of the IL-27R on Treg cells does not impact these populations at steady state. In contrast, when mice were generated in which the Treg compartment comprised a mix of IL-27R-sufficient and -deficient Treg cells, those that lacked IL-27R were at a competitive disadvantage. Aging experiments illustrate that IL-27R-deficient Treg cells are preferentially eroded, and this defect was associated with reduced expression of CD122, the β chain of the IL-2/15R. Moreover, blockade of CD122 led to a similar loss of Treg cells, and in vitro and in vivo studies highlight that IL-27 promotes Treg cell expression of CD122 and improves responsiveness to IL-2/15. These datasets reveal that homeostatic IL-27 signals provide a competitive advantage that shapes the composition of the Treg cell pool by modulating responsiveness to growth factors.

Apatinib-Induced STAT1/NK axis activation augments PD-1 inhibitor efficacy in advanced Hepatocellular Carcinoma

Enhanced dispersion of active microswimmers in confined flows

In the presence of a laminar shear flow, the diffusion of passive colloidal particles is enhanced in the direction parallel to the flow. This classical phenomenon is known as Taylor–Aris dispersion. Besides, microorganisms, such as active microswimmers, exhibit an effective diffusive behavior at long times. Combining the two ingredients above, a natural question then emerges on how the effective diffusion of active microswimmers is altered in shear flows—a widespread situation in natural environments with practical implications, e.g., regarding biofilm formation. In this Letter, we investigate the motility and dispersion of Chlamydomonas reinhardtii microalgae, within a rectangular microfluidic channel subjected to a sinusoidal Poiseuille flow. Using high-resolution optical microscopy and a particle-tracking algorithm, we reconstruct individual trajectories in various flow conditions and statistically analyze them through moment theory and sliding windowed demodulation. We find that the velocity fluctuations and the dispersion coefficient increase as the flow amplitude is increased, with only weak dependencies on the flow periodicity. Importantly, our results demonstrate that the generalization of Taylor–Aris law to active particles is valid.

Bhadran’s point of generation segregation theory for behavioral precision in biomedical waste management

Abstract Biomedical waste (BMW) mis-segregation remains a persistent global challenge, threatening infection control, occupational safety, and environmental sustainability. Recognizing that waste segregation is ultimately a behavioral act, this study conceptually introduces Bhadran’s Point-of-Generation Segregation Theory (PGST)—a proposed hybrid behavioral-systems model designed to measure, benchmark, and improve BMW management. To conceptualize and operationalize a framework that links micro-level staff behaviors to institutional waste outcomes and global performance classification. Methodology: PGST integrates six constructs — Segregation Accuracy, Occupational Hazard Risk, Environmental Contamination Potential, Irreversible Contamination Index, Segregation Compliance Behavior, and Training Effectiveness—and is anchored by Moment-Based Precision Behavioral Fidelity (MBPBF), which quantifies four behavioral elements (Cognitive Anchoring, Visual Discrimination, Repetition Reinforcement, and Error-Responsive Feedback). Behavioral metrics generate the Precision Behavior Score (PBS), Precision Change Score (PCS), Point-of-Generation Segregation Accuracy (PGSA), and Point-of-Generation Segregation Index (PGS Index). While PGSA feeds into the Waste Quality Metrics (WQM) composite and the Global Segregation Safety Scale (GSSS), a five-tier benchmarking tool from EcoPlatinum to EcoBlack, the PGS Index serves as an internal behavioural diagnostic index Results: Illustrative application of PGST suggests that higher behavioral precision was strongly correlated with segregation accuracy and overall institutional waste quality. The model demonstrates that the Precision Behavior Score (PBS), Precision Change Score (PCS), and Point of Generation Segregation Accuracy (PGSA) reliably predict Waste Quality Metrics (WQM) and placement on the Global Segregation Safety Scale (GSSS). These findings highlight that measuring behavioral fidelity at the point of generation provides actionable insights for training design, compliance audits, and evidence-based policy development, as part of a proposed theoretical framework pending empirical validation.

WDFY4-dependent cross-presentation proceeds via a vacuolar antigen-processing route

The intracellular processing route used by type I conventional dendritic cells (cDC1) for cross-presentation of viral- or tumor-associated antigens remains controversial. One model proposes that captured antigens exit from damaged phagolysosomes and enter the cytosol, where they are processed for presentation by MHC class I molecules (MHC-I). This model relies on proteasomal degradation and TAP-dependent peptide transport into the endoplasmic reticulum (ER) for loading by the peptide loading complex (PLC). An alternative model proposes a vesicular route in which captured antigens are retained and processed within an endocytic compartment. A compelling argument favoring the cytosolic model is the dramatic loss of cross-presentation by TAP-deficient cDC1, which presumes that peptides derived from phagocytosed cells require TAP for their transport into the ER to reach the PLC. However, here we show that cross-presentation by cDC1 is TAP-dependent because TAP is required for the normal trafficking of MHC-I molecules. Our work demonstrates that MHC-I must reach a post-Golgi compartment for loading in cross-presentation and that this process may occur independently of TAP.

Patch-sampled contrastive learning for dense prediction pretraining in metallographic images

<i> <i>Vibrio cholerae</i> </i> biofilm matrix assembly and growth are shaped by a glutamate-specific TAXI/TRAP protein

Biofilms are critical for the environmental persistence, survival, and infectivity of Vibrio cholerae , the causative agent of cholera. Here, we find that GluP, a glutamate-specific TRAP-TAXI protein, is an uncharacterized matrix component that plays a critical role in biofilm architecture. Loss of GluP reduces biofilm corrugation, expands colony size, and disperses cells from microcolonies, arguing that this factor maintains biofilm structure and organization. While GluP does not affect the abundance or localization of known matrix proteins, its absence reduces Vibrio exopolysaccharide (VPS) production. We determined the crystal structure of GluP, which revealed that GluP binds glutamate, and its biofilm-related phenotypes depend on this binding capability. We further examined the role of GluP in V. cholerae growth under defined conditions where L-glutamate serves as a carbon source, nitrogen source, or both. GluP-deficient strains specifically showed reduced growth when glucose was the carbon source and glutamate the nitrogen source. This defect is dependent on glutamate binding by GluP and highlights its role in coordinating nutrient acquisition and biofilm formation. Importantly, both biofilm assembly and growth defects occurred independently of the predicted membrane component of the Glu TRAP-TAXI system, GluQM. These findings indicate that GluP plays a dual role in biofilm assembly and growth, providing insight into its functional importance in V. cholerae physiology.

Correction: Fabrication of novel vildagliptin loaded ZnO nanoparticles for anti diabetic activity

HLA-DQB1*03:01 strongly affects age of onset of type 1 narcolepsy independently of DQA1 and ethnicity

Type 1 narcolepsy (T1N), an autoimmune disease associated with a disruption of hypocretin/orexin neurons, has conserved genetic effects transcending cultures and ethnicities. We pooled data from 5,339 cases from China, Europe, Korea, Japan, and the United States to conduct the first transethnic genome-wide association study (GWAS) on age of onset. Only one strong GWAS significant effect was observed across all ethnicities, summarized by the presence of human leukocyte antigen (HLA)-DQB1*03:01, and centered around the coding region of this gene. In contrast, HLA-DQB1*06:02-positive heterodimer (DQ0602) dosage did not strongly affect onset, and other known narcolepsy-associated genetic loci had minor effects. The HLA-DQB1*03:01 effect (mean −3.47 y, P = 1.7 × 10 −18 ) showed no heterogeneity across ethnic groups and was independent of common allelic variation at HLA-DQA1 in cis of HLA-DQB1*03:01 (DQA1*03:03; DQA1*05:05; DQA1*06:01). This effect may be due to a peptide being presented by all DQ0301 heterodimers (which are tolerant at the P1 binding position), or it may stem from genetic effects of HLA on T cell receptor genes TCRA and TCRB usage that influence the TCR repertoire. Using bulk and single-cell RNA sequencing data across Chinese and Caucasians, who have distinct patterns of linkage disequilibrium around DQB1*03:01, we found that HLA-DQB1*03:01 alters TCR repertoire at specific positions, most significantly within the CDR2α, CDR2β, and CDR3β loops. These results illustrate the remarkable conservation of genetic effects in narcolepsy across ethnicity. The identification of the disease-causing T cells will be crucial for elucidating how this finding relates to the underlying pathophysiology.

Association of social support with sleep and subjective health outcomes in Ghanaian artisanal miners

Heterogeneous template-dependent transcription dynamics of T7 RNAP revealed by single-molecule imaging

Bacteriophage T7 RNA polymerase (T7 RNAP) is commonly used for large-scale RNA synthesis in science and industry. Although T7 RNAP exhibits high processivity, its usage faces two major challenges: During initiation, the enzyme frequently aborts transcription, producing potentially immunogenic short RNA by-products; transient pausing during elongation facilitates premature termination, which leads to shorter transcripts and reduces the overall product yield. Here, we present a single-molecule high-throughput transcription assay using DNA curtains to study initiation, elongation, pausing, and termination of individual polymerases and examine what drives transcription aborts. We introduced two different promoter sites on the template DNA and found that transcription initiation is directly influenced by the DNA shape parameters of the initiation region downstream of the conserved promoter sequence. Furthermore, we showed that dimethyl sulfoxide can alleviate the effects of suboptimal initiation sequences. During elongation, we identified two sequence-dependent pause types that differ in length, of which the short pauses relate to ubiquitous pauses in bacterial polymerases. Longer pauses emerged by direct contact of the enzyme with a recognition motif on the template and were stabilized through interactions of the nascent RNA with the enzyme. These insights into transcriptional initiation and pausing highlight common impediments to the performance of the T7 RNAP transcription system.