AI News Today — Part 29
Jul 7, 2026 · Sourced from 500+ daily AI sources, scored by relevance.
- Proliferative and Motile Cell Interplay in Glioma Invasion: Go-or-Grow Switching Caps the Invasion Speed
Diffuse gliomas are deadly because the individual tumor cells invade - they travel far from the imageable mass, so it is impossible to remove the tumor completely. On the cellular level, glioma cells seem to be in either a "go" state (in which they do not divide) or a "grow" state (in which they do not migrate). We investigate what this tiny choice has to say about the large-scale speed of the invasion front and whether the implication is sufficiently strong to rule out the classical description of the Fisher-Kolmogorov-Petrovsky-Piskunov (Fisher-KPP) type, in which a single phenotype migrates and proliferates. We derive a two-phenotype reaction-diffusion model with density-dependent switching, and we prove the cooperative (quasi-monotone) structure and the associated comparison principle and study travelling-wave solutions of the model. A leading-edge linearization gives minimal front speed as minimizer of an explicit dispersion relation, and direct simulation verifies the predicted speed. In the experimentally relevant fast switching limit, we find a closed-form expression for the speed, that is, we obtain an effective Fisher-KPP equation with rescaled diffusivity and growth rate, with the fractions of the phenotypes. The "go-or-grow" (GoG) front can move at a maximum speed of half the Fisher speed for the same single-cell motility $D$ and proliferation rate $r$, which occurs only when the cells divide their time equally between the two phenotypes. This bound is directly testable: measurement of the front speed, plus independent determination of $D$ and $r$, discriminates the two hypotheses, and in the GoG case, yields recovery of the phenotype balance. We then extend the result to anisotropic (DTI-informed) invasion along white-matter tracts and discuss implications for understanding clinical measurements of growth rate.
- SupeRJump: Determining normal and leukemic differentiation fate through semi-supervised jump diffusion modeling
Single cell RNA-seq (scRNA) has provided unprecedented resolution into cellular and clonal heterogeneity. Computational approaches have enabled recovery of differentiation dynamics, yet current approaches do not evaluate discontinuous differentiation processes present in malignant leukemia. To address these gaps, we developed SupeRJump: a jump-drift-diffusion based supervised cell-fate model (https://github.com/namwob44/SupeRJump/). We deploy this approach in human bone marrow, murine aging hematopoiesis, and lentivirally barcoded mouse models of acute myeloid leukemia. Our framework introduces a semi-supervised pseudotime strategy to fit a jump-drift-diffusion model and batch correction for lineage fate predictions from absorbing Markov chains. We introduce metrics to quantify cell skewness toward particular lineages, transitions through intermediate progenitor states toward terminally differentiated states, and discontinuous transition dynamics. We use these metrics to identify cells preferentially biased for differentiation, their underlying transcriptional networks, and gene programs responsible for differentiation discontinuity.
- Judging the reasons for fixations: A direct experimental method to assess the contribution of saliency and semantic factors to gaze control
Current debates regarding the relative contribution of saliency versus semantics to gaze control often rely on comparing the predictive power of saliency and meaning maps. We argue that such indirect, global approaches are fundamentally limited because fixations arise from heterogeneous, local causes that are conflated in whole-scene comparisons. To substantiate this claim, we used a direct method where participants explicitly identified the reasons for fixation at specific clusters of high fixation density, distinguishing between low-level saliency and various semantic categories, as well as the most important one. The obtained judgments revealed that multiple factors contribute simultaneously to gaze control. Although their influence varied across fixation clusters, semantics generally dominated saliency. Notably, abstract semantic categories, particularly "unknown/unusual," proved important, highlighting the role of prior knowledge and novelty besides personal relevance in guiding attention. To interpret these findings in the context of existing models, we propose a framework distinguishing between processes highlighting interesting locations in the image from a sampling strategy translating this information into scanpaths. Within this framework, classic saliency and meaning maps are viewed as restricted inputs to the strategy, whereas deep learning-based models (e.g., DeepGaze IIE) are more general and may also implicitly encode aspects of the strategy itself. Consistent with this, we found that the predictive performance of DeepGaze IIE varied less significantly with the specific reasons for fixation than that of classic saliency and meaning map approaches.
- Opioid- and NMDA-receptor-dependent neural plasticity mediates long-term analgesia from motor cortical stimulation
Exogenous opioids that activate mu-opioid receptors (MORs) in nociceptive circuits mediate transient pain relief lasting minutes to hours but have more limited utility for treating chronic pain. By comparison, electrical or magnetic stimulation of the motor cortex can induce pain relief lasting weeks, for which the underlying mechanisms have remained unclear. Here we report an unconventional role for endogenous opioidergic signaling in the rapid induction of long-lasting analgesia from motor cortical stimulation, which triggers opioid-peptide-dependent neural plasticity in the rostral ventromedial medulla (RVM), a key node in the brain's descending pain control pathways. To dissect the circuit and cellular bases for these effects, we created a miniaturized, millimeter-sized device allowing focal, non-invasive transcranial magnetic stimulation (TMS) of the mouse motor cortex. In mice with chronic neuropathic pain, reflexive and affective pain behaviors diminished for 1-2 weeks after one session of TMS treatment. Chemogenetic and optogenetic manipulations showed that motor cortical layer 5 pyramidal neurons with axonal projections to the RVM mediated TMS-induced pain relief. High-density electrophysiological recordings revealed that TMS treatment shifted the balance of RVM activity between pain-ON and pain-OFF neurons to a state promoting greater suppression of pain. Genetic and neuropharmacological manipulations revealed that NMDA-receptor-dependent signaling and MOR activation by endogenous opioid peptides in the RVM jointly mediate the long-lasting analgesia induced by a transient bout of TMS. Strikingly, enkephalinase inhibition in the RVM during TMS treatment enhanced the amplitude and duration of analgesia, showing that transiently boosting endogenous opioidergic signaling during TMS increases analgesia-conferring plasticity. In accord, re-analyses of data from human subjects with chronic pain support the idea that opioid administration amplifies analgesia from motor cortical TMS. Overall, our results showcase miniaturized TMS devices as versatile tools for basic and translational neuroscience and detail a hybrid, long-range neural network and NMDA- and opioid-receptor-dependent plasticity mechanism for durable pain relief. These findings point the way to mechanistically grounded, synergistic neurostimulation and drug therapies for brain diseases and disorders that jointly target neural circuit and molecular signaling pathways.
- Opposing GIPR brainstem circuits differentially control feeding behaviour
Central glucose-dependent insulinotropic polypeptide receptor (GIPR) signalling is required for the efficacy of GIP-based obesity therapeutics, yet how distinct subpopulations of GIPR neurons shape appetite remains undefined. Here we show that GIPR neurons in adjacent brainstem nuclei, the area postrema (AP) and nucleus tractus solitarius (NTS), exert opposing control over ingestion. We find GIPRAP neurons dampen post-ingestive satiation, permitting hyperphagia, whereas GIPRNTS neurons are anorectic. In line with this model, we show Gipr expression in AP, but not NTS, neurons is necessary for appetite suppression following GIPR antagonism. Additionally, we reveal that GIPR neurons in the AP and NTS occupy distinct gut-brain circuits, and are differentially sensitive to obesity-driven circuit remodelling. These data offer a framework for understanding how current GIPR agonist and antagonist strategies elicit weight loss.
- ScaleSurfer: multi-scale anatomical segmentation and parcellation of the human brain
Human brain magnetic resonance imaging (MRI) revolutionized our ability to non-invasively probe individual differences in neuroanatomy. These anatomical scans, in turn, also allow us to accurately localize functional MRI (fMRI) activity. However, extracting anatomical labels and structural characteristics, such as cortical surface area or thickness, is a computationally demanding task, taking on the order of hours per brain volume. This is an intrinsically multi-scale problem given that local image structure defines fine boundaries, whereas accurate assignments depend on broader anatomical context. Here, we introduce ScaleSurfer, a three-dimensional convolutional vision transformer model based on multi-scale learning. Convolution blocks capture local anatomical detail and a transformer bottleneck integrates the distributed spatial context. This approach provides rapid, whole-brain morphometric feature estimation, including volume, cortical thickness, surface area, and curvature. Importantly, ScaleSurfer accomplishes this nearly five orders of magnitude faster than current pipelines, taking 150-500 ms instead of ~5 hours. We validated ScaleSurfer on multiple datasets, showing stable learning across heterogeneous MRI collections, and demonstrate feasibility by training an interpretable Alzheimer's disease classifier that identifies reductions in primarily medial temporal lobe subregions compared to healthy controls. ScaleSurfer positions multi-scale representation learning as a practical route toward faster, anatomically faithful structural MRI processing, whose speed paves the way for nearly real-time anatomical quality control during scanning.
- Determinants of Blood Group Antigen Expression and Prediction of Phenotypes by Machine Learning
Blood group antigens, defined by epitopes on the erythrocyte surface, are central to transfusion safety and maternal-fetal compatibility. While the genetic basis of many clinically relevant blood group antigens is well established, which structural and biophysical parameters determine whether a single-nucleotide variant gives rise to an antigenic phenotype remains unclear. Here, we integrate structural, biophysical, and evolutionary analyses to systematically evaluate features associated with single amino acid substitutions across 24 human protein-based blood group systems. We analyse 319 variants with curated phenotypic annotations alongside 481 control variants, identifying key determinants of null and antigenic phenotypes. Null variants are characterized by high evolutionary conservation, burial within the protein core, loss of hydrophobicity, increased polarity, and a propensity for arginine substitutions. Antigenic variants are also enriched in arginine; however, in contrast to null variants, they tend to occur at less conserved, more solvent-accessible, and structurally flexible sites. Supervised machine learning models trained on structural and biophysical descriptors were applied to distinguish (i) null and (ii) antigenic variants from controls, achieving balanced accuracies of 0.82 and 0.63, respectively. Feature importance analysis identified predicted pathogenicity, solvent accessibility, and evolutionary conservation as the most predictive determinants of null variants, whereas hydrophobicity, conservation, and flexibility dominated antigen prediction. This work establishes a framework linking molecular variation to blood group phenotypes and provides a foundation for predicting the impact of novel missense mutations in transfusion medicine and beyond.
- Clinically derived micro- and nanoplastics uptake drives spatiotemporally confined metabolic stress revealed by bond-selective imaging
Although microplastics and nanoplastics (MP/NP) are pervasive environmental contaminants, our understanding of cellular toxicity remains incomplete, as adverse effects are often attributed to long-term intracellular accumulation, while the spatiotemporal onset of cellular damage remains poorly defined. Here, we employ chemical-bond-selective stimulated Raman scattering (SRS) microscopy and cell models that decouple continuous exposure from intracellular retention to directly visualize clinically derived MP/NP-cell interactions. Cellular stress occurs primarily during MP/NP exposure, accompanied by alterations in lipid droplet (LD) composition. In contrast, following extracellular removal, intracellularly retained MP/NP become largely inert, with recovery of lipid metabolism and cellular functions. Lipidomics identifies arachidonic acid (AA) as a key dysregulated metabolite, and SRS imaging further reveals transient, spatially confined AA enrichment in MP/NP-proximal LDs during uptake. Importantly, phospholipid coating of MP/NP attenuates LD alterations and cytotoxicity while preserving particle internalization, establishing uptake-driven metabolic stress, rather than long-term intracellular retention, as primary source of MP/NP-induced damage.
- A Procoagulant Peptide Analog of the SARS-CoV-2 Nucleocapsid C-terminal Domain
Background: Uncontrolled bleeding complicates trauma, surgery and many medical conditions. While currently available procoagulant therapies (e.g., plasma-derived factors, recombinant proteins, antifibrinolytics) have crucial limitations. Methods: N389 (CQQTVTLLPAADLDDFSC) was synthesized by Fmoc solid-phase chemistry, characterized by HPLC and LC-MS, then tested in normal human pooled plasma in microplate mechanical clot-formation assays using incubated and immediate addition formats. Kinetic parameters (plasma recalcification, PRT; maximum absorbance, Amax) were obtained from absorbance curves fit to four-parameter logistic models. Mixing studies with modified (i.e., aged, adsorbed) plasma probed factor dependence. Results: In plasma coagulation assays activated with 25 mM CaCl2, baseline clotting showed a PRT of 23.74 +/- 0.27 min and Amax of 0.1813 +/- 0.0043 (n = 3), whereas N389 significantly reduced PRT to 8.442 +/- 6.0395 min without incubation (p = 0.0012), further decreased PRT after incubation (p < 0.0001), increased Amax to 0.2523, and retained comparable activity across normal, adsorbed, and aged plasma, in contrast to S1255 which showed a faster but incubation-labile effect with PRT 2.353 +/- 1.3685 min (p = 0.0007) and marked attenuation in factor-depleted and aged plasma. Mixing studies showed N389 activity persisted across normal, aged and adsorbed plasma, consistent with a mechanism that does not require intact plasma coagulation factor profiles (specifically factors II, V, VIII, VII, IX, X). Discussion: Collectively with prior evidence on anionic surfaces, Ca2+-binding Gla domains, and peptide-modulated fibrin polymerization, these results support a model in which N389 functions as a stable, charge-based scaffold that coordinates divalent cations and/or directly nucleates fibrin(ogen), while highlighting limitations of bulk clotting assays and the need for targeted thrombin generation, binding, aggregation, and contact-activation studies. Conclusions: The aspartate-rich peptide N389 is a sustained, factor-independent procoagulant at least in vitro. N389 thus merits further mechanistic and translational evaluation as a synthetic hemostatic agent.
- Age-associated erosion of organ-specific endothelial programs compromises tissue function and resilience
Endothelial cells (ECs) express organ-specific gene programs supporting tissue homeostasis and resilience. However, the mechanisms by which aging reshapes these organ-specific endothelial programs and how the resulting changes affect tissue homeostasis, resilience, and disease susceptibility remain largely unknown. Herein, we performed single-cell RNA sequencing of ECs harvested from five organs across the lifespan and found that aging progressively erodes organ-specific endothelial programs while inducing shared interferon-responsive and antigen-presentation programs across organs. Although vascular subtype identity and conserved capillary subset identity were mostly preserved, these organ-specific transcriptional programs were broadly attenuated with aging, indicating erosion of organ-specific endothelial identity to be a fundamental feature of endothelial aging. Importantly, these alterations were associated with declines in specialized EC functions, including alveolar barrier maintenance in the lung, scavenging activity in the liver, angiogenic capacity in the heart, and homeostatic programs in the kidneys and the brain, suggesting that age-related EC alterations compromise tissue homeostasis and resilience in multiple organs. Furthermore, we established a single-cell aging index for alveolar capillary ECs in mice and humans, revealing stress-associated endothelial activation to potentially be an intermediate state linking functional deterioration to cellular senescence, and also demonstrating marked heterogeneity in aging states among ECs of the same chronological age. Notably, alveolar capillary ECs exhibited progressive functional decline before reaching a senescent-like state, suggesting endothelial dysfunction to precede overt cellular senescence as the organism ages. Collectively, our findings establish progressive erosion of organ-specific endothelial programs as a central feature of vascular aging and provide a conceptual framework for elucidating how endothelial aging contributes to tissue dysfunction and reduced resilience across organs.
- Investigating nanostructure and -mechanics of contracting actin stress fibers by scanning ion conductance microscopy
Scanning ion conductance microscopy (SICM) provides gentle, non-contact cell surface imaging, but it has not been used to investigate intracellular structures because the plasma membrane restricts nanopipette access. Here, we combined SICM with microsonication-based cell de-roofing to expose intracellular actin stress fibers (SFs) in U2OS cells for nanotopographical and -mechanical characterization. Importantly, the de-roofing conditions preserved actomyosin contractility, allowing analysis of SF structural and biomechanical changes during ATP-induced contraction. Resting SFs displayed an average height of 203{+/-}38 nm and width of 357{+/-}73 nm, and a complex surface architecture characterized by regularly spaced long-range height modulations (~500 nm periodicity; Wq ~25 nm) and smaller irregular corrugations (Ra ~19.2 nm). ATP stimulation reduced SF height and width by ~39% and ~15%, respectively, while largely preserving surface corrugation patterns. During contraction, some SFs separated into two longitudinal strands. High-resolution SICM imaging also revealed filamentous crosslinks mechanically coupling neighboring SFs, and nanomechanical measurements demonstrated local stiffening during contraction. These findings provide new insight into the structural and mechanical regulation of SF contraction and highlight the potential of SICM combined with cell de-roofing as a powerful platform for studying dynamic intracellular processes at nanometer resolution.
- UVfinder: a tool to extract bryophyte sex-linked gene copies from the GoFlag408 probe set
Target enrichment sequencing using probe sets like GoFlag 408 has revolutionized phylogenetics, yet recent genomic data indicate that some probes may be sex-linked, potentially introducing topological conflict while also allowing studies of sex-specific evolutionary processes. To test for sex-linkage across the bryophytes, we developed UVfinder, a pipeline designed to identify sex-linked GoFlag loci across published moss genomes and enable sex-aware downstream analyses. Applying UVfinder to 50 dioicous moss genomes, we identified 93 probes that exhibit sex-linkage in one or more lineages, providing genomic evidence for neo-sex chromosome formation via autosome-sex chromosome fusion and gene translocation. Furthermore, by comparing species trees derived from sex-linked versus autosomal loci in Hypnales and Dicranidae, we demonstrate that sex-linked loci harbor phylogenetic information that is distinct from that in autosomes. We also discovered a pervasive female sampling bias in the genomic data, perhaps reflecting a preference among collectors for plants with sporophytes. Ultimately, our findings highlight the dynamism in sex linkage across bryophytes and suggest that sex-aware phylogenomics can be used to reconstruct ancestral karyotypes and potentially resolve topological conflict. We expect that UVfinder will facilitate the further study of sex-specific evolutionary processes, particularly with improved genome assemblies and increased sampling in males.
- IFN and IFN mimetics prevent IFN-I-mediated TB susceptibility by regulating iron metabolism and lipid peroxidation
Type I interferons (IFN-I) and IFN{gamma} exert divergent effects during tuberculosis, but the mechanisms that determine whether macrophage activation promotes host defense or inflammatory pathology remain incompletely understood. Here, we dissect the interplay between IFN-I and IFN{gamma} in macrophage activation using genetically susceptible B6.Sst1S macrophages. We show that, during tumor necrosis factor (TNF) stimulation, susceptible macrophages enter a persistent pathological activation state (pPAS) characterized by sustained lipid peroxidation and super-induction of IFN-I responses. This pathological state is maintained by autocrine IFN-I signaling. In contrast, IFN{gamma} priming prevents pPAS development by enhancing macrophage resilience to oxidative stress, in part through regulation of iron metabolism and induction of ferritin expression. Computational cell state transition assessment and regulation (cSTAR) analysis identified pathways and small molecules predicted to promote the transition of susceptible macrophages toward an IFN{gamma}-induced, Mtb-resistant state. Consistent with these predictions, the CDK4/6 inhibitor trilaciclib reduced lipid peroxidation by regulating iron metabolism, whereas retinoic acid signaling enhanced GPX4 expression and lipid biosynthesis programs. Combined CDK4/6 inhibition and retinoic acid receptor activation efficiently prevented the pathological activation state. Together, these findings delineate a mechanism of IFN-I/IFN{gamma} crosstalk during macrophage activation and identify pharmacologic strategies to prevent IFN-I-dominant, lipid peroxidation-driven macrophage pathology.
- High-Intensity Interval Training Remodels Adipose Tissue Inflammatory Signaling and Enhances Immunometabolic Health via microRNA Regulation
Sedentary behavior promotes chronic low-grade inflammation in adipose tissue, contributing to metabolic dysfunction and insulin resistance. High-intensity interval training (HIIT) is a time-efficient exercise strategy with potent anti-inflammatory and metabolic benefits; however, its effects on adipose tissue inflammatory signaling and microRNA (miRNA) regulation remain incompletely understood. This study investigated the effects of eight weeks of HIIT on inflammatory and epigenetic markers in interscapular white adipose tissue (iWAT) of male Wistar rats. Fourteen rats were randomly assigned to either a sedentary (SED; n = 7) or HIIT (n = 7) group. The HIIT protocol consisted of treadmill running five days per week for eight weeks. Body weight and iWAT mass were assessed, and molecular adaptations were evaluated at multiple regulatory levels using RT-qPCR for mRNA targets (NLRP3, TNF-, PPAR-{gamma}, and IL-10) and miRNAs (miR-21 and miR-30d-5p), while protein levels of NLRP3 and PPAR-{gamma} were assessed using Western blotting. Compared with the SED group, HIIT significantly reduced body weight (p < 0.001) and iWAT mass (p = 0.002). Furthermore, HIIT downregulated the expression of pro-inflammatory mediators, including NLRP3 (gene: p = 0.001; protein: p < 0.001) and TNF- (p = 0.025), while upregulating anti-inflammatory regulators PPAR-{gamma} (gene: p = 0.026; protein: p = 0.020) and IL-10 (p = 0.010). In parallel, inflammation-associated miRNAs, including miR-21 (p = 0.004) and miR-30d-5p (p = 0.002), were markedly downregulated. These coordinated transcriptional, post-transcriptional, and translational adaptations suggest that HIIT attenuates adipose tissue inflammation and promotes a favorable immunometabolic phenotype through integrated molecular and epigenetic mechanisms.
- Immobilization-free chemotaxis analysis reveals the novel behavioral mode of leaving in Caenorhabditis elegans
Animals balance staying in a favorable environment with exploring new ones. In C. elegans chemotaxis, the process by which worms migrate toward an attractant has been extensively studied. However, what happens after they reach it remains largely unexplored, partly because conventional assays immobilize worms at the point of arrival. Here, we quantitatively analyzed chemotactic behavior upon reaching an attractive odor source using an immobilization-free chemotaxis assay. We observed that 62% animals left the isoamyl alcohol region after initially approaching it, a behavior we termed "leaving behavior." Quantitative analysis revealed that leaving behavior represents a distinct locomotor state compared with free-moving, high-concentration odor avoidance, and approach behavior. To test whether leaving behavior is related to olfactory adaptation, we analyzed mutants in adaptation-related genes. The proportion of leaving behavior was significantly increased in egl-4 loss-of-function mutants compared with wild-type animals, whereas arr-1 mutants showed no significant difference. These results suggest that egl-4 negatively regulates leaving behavior, suggesting a role for this kinase in stabilizing post-arrival behavioral states beyond its known function in olfactory adaptation. Our findings indicate that chemotaxis involves dynamic behavioral transitions even after reaching an attractant, consistent with an exploration-exploitation trade-off framework.
- Genomic compartmentalization of pervasive sex-biased gene expression in the vine mealybug Planococcus ficus
The vine mealybug, Planococcus ficus, is a globally invasive pest of grapevine and a vector of leafroll viruses. Like other mealybugs, it reproduces through paternal genome elimination, a sex-determination system that operates without sex chromosomes and is associated with extreme sexual dimorphism. To characterize genome organization and sex-biased expression in this species, we generated a long-read reference genome spanning 369 Mb with 23,489 annotated genes and macrosynteny conserved with the citrus mealybug, Planococcus citri. Resequencing of four California field individuals yielded a first whole-genome estimate of nucleotide diversity and 132 microsatellite markers for population monitoring. Among 2,129 candidate secreted proteins, a conserved core is shared with P. citri, but each species carries a distinct set of lineage-specific effectors. Comparing adult male and female transcriptomes, we found sex-biased expression to be pervasive and skewed toward females: 41% of tested genes differed between the sexes, with female-biased genes both more numerous and showing larger fold changes. These female-biased genes were not randomly distributed but concentrated in discrete blocks of coordinately expressed, tandemly duplicated gene families, a pattern not previously described in a mealybug. Male- and female-biased secreted proteins also differed in origin, with male-biased proteins drawn from a conserved repertoire shared with P. citri and female-biased proteins spanning a more lineage-specific pool. Together, these results reveal a female-skewed, spatially clustered architecture of sex-biased expression in a mealybug that lacks sex chromosomes, and provide genomic resources for managing an invasive vineyard pest.
- YAP/TAZ Signaling in Endothelial Cells Mediates the Pathogenesis of Abdominal Aortic Aneurysm Formation
Background: Abdominal aortic aneurysms (AAA) are characterized by dilation of the aorta that can lead to aortic rupture and death. The transcriptional co-activators Yes-Associated Protein (YAP) and WW-domain-containing transcriptional co-activator with PDZ-binding motif (TAZ) are mechanosensitive effectors of the highly conserved Hippo signaling pathway. It is hypothesized that cell-specific YAP/TAZ signaling in endothelial cells (EC) plays a pivotal role in mediating AAA formation and rupture. Methods: Single-cell RNA-sequencing in human AAAs was performed and differentially expressed genes (DEGs) were identified in the endothelial cell cluster. YAP/TAZ mRNA and protein expression were also assessed in human AAA and control aortic tissue. Two established murine AAA models were used with male C57BL/6 and EC-CreERT2-YAPfl/fl/TAZfl/fl mice with/without Verteporfin (VPF, YAP/TAZ inhibitor) and XMU-MP-1 (YAP/TAZ activator) treatments. On postoperative days 14 and 28, aortic diameter, histology, cytokine, and MMP2 expressions were evaluated. Results: A significant alteration in EC-specific differentially expressed YAP/TAZ-related genes was observed in which 242 genes were upregulated and 71 genes were downregulated in AAA compared to controls. Human AAA tissue showed a significant increase in YAP and TAZ protein expressions compared to controls. Elastase-treated EC-YAP/TAZ-/- mice showed a significant decrease in AAA diameter compared to littermate controls. Histological quantification revealed preservation of -smooth muscle actin, reduced elastin fiber breaks, and decreased macrophage infiltration in EC-YAP/TAZ-/- mice compared to littermate controls. Importantly, pharmacological inhibition of YAP/TAZ using VPF significantly attenuated AAAs in two experimental murine models. In vitro data demonstrates that VPF inhibits endothelial cell YAP expression, downregulating pathways associated with pathogenic angiogenesis and vascular inflammation. Conclusions: These data suggest that EC-specific YAP/TAZ signaling mediates AAA formation. Pharmacological inhibition of the Hippo pathway can significantly mitigate aortic inflammation and vascular remodeling to decrease the progression of AAAs and prevent aortic rupture.
- Modeling human echolocation using a Kalman filter
Some blind individuals use echolocation, a skill that allows them to better navigate their environment using echoes from self-generated mouth clicks reflected off surrounding surfaces. Echolocation involves a complex interplay of sensory accumulation, information processing, dynamic prediction, motor planning and execution in real-time. Computational modeling offers a valuable approach to understanding the cognitive and neural mechanisms underlying echolocation performance, in particular the temporal dynamics of the process. We present a computational model of human echolocation behavior based on a Kalman filter, where we treat the echolocator as an active sensor that maintains an internal belief about the target's location and continuously refines it via echo feedback. The model, based on observations of echolocation in blind human experts, simulates the use of mouth clicks and returning echoes to localize and orient toward a target under varying conditions. In the experiment, the target is placed at a random azimuth in the frontal plane. An echolocator aims a series of mouth clicks in various directions and infers the target azimuth using acoustic information received from the click echoes. The system integrates three major components: (1) a simulation of echoacoustic interaural time differences (ITD) to estimate the relative head-target angle; (2) a Kalman filter that processes these ITDs to iteratively update probabilistic beliefs about target location and associated uncertainty; and (3) a motor control system that modulates head movements with the current belief state. The Kalman filter serves as a representation of the internal state of the observer, where its beliefs drive the direction of head rotation, and its uncertainty estimates drive head velocity adjustments. Model performance demonstrates that simple predictive computational approaches can reproduce key aspects of echo-guided sensorimotor learning, providing a framework that may be leveraged to develop biologically plausible models, advance understanding of best practices, and potentially improve intervention strategies.
- ORBIT: Annotation-Aware Empirical Enrichment and Semantic Reranking for Interpretable Functional-Class Recovery
Gene-set interpretation workflows are widely used to summarize transcriptomic and proteomic experiments, yet standard enrichment tools often return long, redundant result tables that require substantial manual consolidation. We developed ORBIT (Ontology-Ranked Biological Interpretation Tool), an annotation-aware interpretation workflow that combines empirical enrichment, semantic reranking, and redundancy-aware representative-term selection to prioritize interpretable functional summaries from gene sets. We evaluated ORBIT on a curated tiered benchmark of human functional-class gene sets spanning clean reference sets, size-ladder variants, and mixed-difficulty cases. On the 45-set core benchmark, ORBIT semantic achieved higher expected-class recovery than Enrichr and PANTHER Gene Ontology molecular-function baselines, with a mean reciprocal rank of 0.916 and top-1 recovery of 0.889. Bootstrap confidence intervals and paired permutation testing supported the robustness of this advantage, and supplemental analyses extended the comparison to g:Profiler. In a GPCR mixed-function case study, ORBIT compressed redundant enriched terms into semantic representative neighborhoods, illustrating how long enrichment outputs can be converted into reviewable biological summaries. We then used ORBIT to interpret immune-cell identity, interferon-response biology, and breast-cancer subtype programs. ORBIT linked PBMC3K markers to cytotoxic, antigen-presentation, and innate-immune cell states; prioritized antiviral, cytokine-response, RNA-binding, and secreted-factor biology after IFNB stimulation; and separated TCGA-BRCA basal-like proliferative chromosome/cell-cycle programs from luminal transporter and receptor-associated biology while retaining gene-level support.
- Spatial lung niches shape Pseudomonas aeruginosa persistence
Chronic Pseudomonas aeruginosa lung infection is a major cause of morbidity and mortality in people with pre-existing lung disease. Once established, infection is rarely eradicated and often persists despite prolonged antimicrobial therapy, but the underlying mechanisms remain poorly understood. To define how P. aeruginosa occupies and adapts to diseased lung tissue, we applied host-pathogen spatial transcriptomics to profile over 23 million lung cells from explanted and resected lungs from people with Cystic Fibrosis (CF) and chronic obstructive pulmonary disease (COPD), mapping bacterial niches and transcriptional states in situ. We found that P. aeruginosa adopted distinct niche-linked states across chronically infected human lung tissue. Bacterial burden was highest in airway lumens, but bacteria also occupied submucosal glands, parenchyma and, unexpectedly, blood vessel lumens in CF tissue. Within airway lumens, two coupled host pathogen states emerged: an alginate-rich biofilm-like state linked to PI3+ neutrophil inflammation and host chemical-sensing programmes; and a motile, quorum-sensing state with activated type 6 secretion linked to human ciliary stress, epithelial remodelling and proteolytic injury. Intravascular bacteria co-localised with neutrophils, fibrin and vascular-remodelling signatures, suggesting local breach of barrier integrity and subsequent immune containment. P. aeruginosa also displayed disease-specific cellular associations, with neutrophil-dominated interactions in CF and greater association with macrophages and dendritic cells in COPD. Together, these data reveal chronic P. aeruginosa infection as a spatially partitioned ecosystem in which anatomical microenvironments impose distinct bacterial lifestyles and host inflammatory states. This niche-resolved framework helps explain how persistent infection can diversify within a single lung and suggests that eradication therapies may need to target multiple anatomical and cellular niches to be effective.
- Walking in circles: Linking high- and low-level parameter scaling of visually guided and spontaneous turning behaviour
The ability of animals to adjust their heading, i.e. to turn, is essential for all walking animals. While several studies have addressed how leg movement or inter-leg coordination may change during turning, relatively little is known about how turning-related changes scale with turn magnitude. Here, we used spontaneous and visually induced turns of unrestrained walking stick insects to test (i) how high-level parameters of unrestrained turning scale with low-level parameters of leg movement, and (ii) the effect of visual guidance on turning parameters. To this end, we used a step change in stationary landmark position in an open-field arena to constrain timing and magnitude of target-directed turns. These visually guided turns were compared with spontaneous turns in an all-white condition. We show that visually induced turns were walked at a larger forward velocity and had fewer short steps than spontaneous turns. The scaling of turning responses was dominated by an increase in turning duration (factor 1.87) rather than turning speed (factor 1.32). Increased rotational velocity correlated with reduced forward velocity, though with flexible timing of both effects. These changes were accompanied by larger shifts in step direction, as well as an increased asymmetry of step types between inner and outer legs, suggesting a mix of distinct turning strategies, that depend on overall turn angle. Future models on six-legged locomotion should thus consider the incorporation of more than one mechanism to govern turning.
- Rapid odorant metabolism organizes identity- and timing-based odor representations by olfactory bulb inputs and outputs
Sensory neurons encode information about external stimuli in the form of stimulus-specific patterns of activity across their population. In the mammalian olfactory system, olfactory sensory neurons (OSNs) encode odor identity with odorant-specific combinatorial patterns that are temporally structured by inhalation. We investigated the stimulus features that determine these inhalation-linked patterns, leveraging receptor- and functionally-defined OSN populations in awake mice. We found that both the chemical tuning and temporal dynamics of many odorant-evoked responses deviate from prevailing models of receptor-ligand binding and sensitivity-based timing relationships. These deviations were well-explained by rapid metabolism of odorants within the olfactory mucosa, which generates secondary odorants that activate additional OSNs within a single breath. This process fundamentally reshapes odor representations at naturally-occurring concentrations and timescales relevant to perception. Importantly, we found that timing features robustly discriminate inhaled from metabolism-generated odorants, and that these timing differences persist at the level of olfactory bulb output. Our results suggest a novel role for inhalation-linked timing in odor coding - to disambiguate inhaled odorants from those generated internally - and raise the possibility that the nervous system may differentially process external and internally-sourced olfactory stimuli on the basis of their temporal dynamics.
- Brain, genetic and demographic factors predict current body fat estimate and weight gain in (pre)adolescents: evidence from the ABCD study
ABSTRACT IMPORTANCE Childhood obesity is a growing global health concern associated with adverse physical, psychiatric, and neurodevelopmental outcomes. Although previous neuroimaging studies have linked obesity to widespread alterations in brain structure and function, it remains unclear how well multimodal neuroimaging measures and genetic markers can predict future weight gain and inform early intervention strategies. OBJECTIVE To evaluate the predictive utility of multimodal MRI measures and polygenic risk scores for obesity in estimating proportional body weight at baseline and predicting weight gain over one year in preadolescent children. DESIGN, SETTING, AND PARTICIPANTS This study used data from the Adolescent Brain Cognitive Development (ABCD) Study, a large-scale, multisite longitudinal cohort of children aged 9 to 10 years (N = 11,880). Analyses included baseline data collected between 2016 and 2018, and one-year follow-up data collected between 2018 and 2020 across multiple imaging sites. MAIN OUTCOMES AND MEASURES Elastic net regression models were applied to structural MRI (including diffusion tensor imaging) and resting-state functional MRI data to predict baseline triponderal mass index (TMI), a weight-for-height measure that more accurately reflects adiposity in children than body-mass index (BMI). Longitudinal classification models were developed to predict excess weight gain relative to normative developmental trajectories at one-year follow-up. Models were evaluated with and without the inclusion of polygenic risk scores and other non-imaging covariates. Generalizability was assessed using leave-one-site-out cross-validation. RESULTS Structural MRI measures predicted baseline TMI with an R^2 of 0.21, whereas resting-state functional MRI measures predicted TMI with an R^2 of 0.08. Classification models predicted one-year weight gain with area under the receiver operating characteristic curve (AUC) values of 0.73 for structural MRI and 0.60 for resting-state functional MRI. Including polygenic risk scores and other covariates improved model performance (structural MRI: R^2 = 0.25, AUC = 0.75; resting-state functional MRI: R^2 = 0.15, AUC = 0.69). Leave-one-site-out cross-validation revealed reduced generalizability across imaging sites (structural MRI R^2 = 0.13-0.17; resting-state functional MRI R^2 = 0.02-0.09; structural MRI AUC = 0.73-0.74; resting-state functional MRI AUC = 0.60-0.67). CONCLUSIONS AND RELEVANCE Multimodal MRI measures were associated with proportional body weight and demonstrated modest predictive utility for future weight gain in preadolescent children, explaining up to one fifth of the variance in weight-related outcomes. The addition of genetic and non-imaging variables improved prediction accuracy, underscoring the multifactorial nature of childhood obesity. However, the observed decline in performance under site-wise cross-validation highlights the need to address site-related variability to enhance reproducibility and generalizability in neuroimaging-based predictive models of pediatric obesity.
- Same Inputs, Different EDSS: Measuring Specification Drift in Clinical Scoring Pipelines
Clinical informatics pipelines increasingly compute validated clinical endpoints from upstream NLP outputs. Even when the endpoint is defined by an established rubric, translating that rubric across representations - natural language instructions, program logic, and reference implementations - can introduce specification drift, where ostensibly equivalent calculators yield meaningfully different scores. We study this phenomenon for the Expanded Disability Status Scale (EDSS), a standard measure of disability in multiple sclerosis. Holding constant a shared set of functional system (FS) subscores extracted by a large language model (LLM), we compare EDSS values computed across three representations of the same scoring rubric: prompt-executed natural language, LLM-generated code, and a canonical reference implementation. We characterize disagreement structure, distributional shifts, and clinically salient boundary flips, and we propose an audit workflow that treats endpoint computation as a first-class verification target in clinical NLP systems.
- Multi-Timepoint Risk Stratification in Rare Cancers: A Computational Framework Validated against Published Ewing Sarcoma Trial Data
Three audiences -- the family of a newly diagnosed Ewing sarcoma patient, the long-term survivor, and the cooperative-group trial statistician -- receive cohort-mean answers to patient-level questions because the patient-level data machine learning requires do not exist for rare cancers. We present a framework producing patient-level predictions from published aggregate trial data. A six-stage discrete-event Monte Carlo simulation integrates genetic risk factors, serial biomarker dynamics with genotype-conditional weighting, post-surgical ctDNA-based minimal residual disease (ctDNA-MRD) assessment, and treatment-related mortality as a separable competing risk. Adverse-effects modules project 30-year incidence across five organ systems from chemotherapy and radiation exposures. Its four structural ingredients are instantiated in Ewing sarcoma and validated against trial data from more than 3,400 patients. The framework achieves 3.2% mean absolute error across 23 efficacy endpoints (none exceeding 6%) and falls within published confidence intervals for all 20 toxicity endpoints. ctDNA-MRD stratification separates candidate populations -- 5.5% recurrence (de-escalation) versus 87.8% (intensification) -- and multi-timepoint integration produces 16-fold five-year EFS resolution spanning 5-96%, exceeding the 3- to 5-fold ranges of single-timepoint approaches. The 16.1-fold recurrence risk ratio emerges from simulation, not as a supplied parameter. Genotype-conditional weighting improves discrimination over equal-weight scoring in every subgroup (Pearson r +0.060 to +0.129), with largest gains where biological rationale is strongest. A Monte Carlo framework calibrated to published aggregate data turns cohort-mean answers into patient-level predictions as exemplified in the rare cancer Ewing sarcoma, where the conventional patient-level machine-learning pathway is structurally unavailable; transfer to other rare cancers remains a hypothesis for future validation. Survivorship-surveillance refinement is the most concrete current use; trial-design and prognostic counseling are next-decade pathways.
- Mapping generalizable brain-based depression subtypes across clinical, cognitive, and neurotransmitter dimensions
Identifying generalizable brain-based biotypes across independent cohorts is critical for parsing heterogeneity in Major Depressive Disorder (MDD), yet robust subtypes spanning micro- and macroscales remain poorly defined. We applied stability-based clustering to cortical thickness data from 1,531 MDD individuals in UK Biobank (UKB), with external validation in 144 inpatients from IRCCS Ospedale San Raffaele (HSR). Two distinguishable clusters emerged (accuracy=87.5%), with one showing widespread cortical thinning, anergy-related symptoms, childhood trauma, and diabetes comorbidity. This profile generalized with 96.5% accuracy in a hold-out UKB sample and 80.6% in HSR. Mapping clusters cortical profiles onto Neurosynth meta-analytic activation patterns revealed a ventral-dorsal gradient linked with emotion regulation, interoceptive, and motivational processes. Spatial correlations with 19 neurotransmitter receptors and transporters obtained from positron emission tomography identified dopamine transporter as the dominant contributor in UKB, and histamine receptor H3 in HSR. These findings provide a reproducible framework linking MDD subtypes to multiscale biological complexity.
- Understanding end-of-life multimorbidity: An analysis of multiple causes of death in Denmark
Background: Mortality analysis traditionally focuses on the single underlying cause of death (UCD), which obscures the wider morbidity process at the end of life. Multiple causes of death (MCoD) data, recording all conditions on the death certificate, are increasingly used as a proxy for end-of-life multimorbidity, yet how accurately they represent it remains underinvestigated. We assessed whether recorded causes reflect end-of-life health conditions or rather the chain of events leading to death. Methods: Using linked Danish registers (Population, Cause of Death, Chronic Diseases, and Cancer), we studied residents aged 50+ diagnosed with COPD, dementia, diabetes, or cancer who died in 2010-2022 (ranging from 38779 to 224330 per disease cohort). We examined how often each diagnosed disease appeared on the certificate, its location and selection as the UCD, factors associated with its appearance (logistic regression), disease-specific mortality (multiple decrement life tables), and disease associations (Cause of Death Association Indicator, CDAI). Results: Cancers appeared on the death certificate far more often than chronic diseases (around 75% versus 19-58%) and were usually recorded in Part 1 and selected as the UCD, whereas chronic diseases were rarely the UCD. The odds of a disease appearing depended on factors such as age at and time since diagnosis. When a diagnosed disease was recorded, the certificate traced a coherent path to death; when it was absent, ill-defined causes became more common. The CDAI highlighted specific association pathways between diseases. Conclusions: MCoD data capture only part of the chronic disease burden present at death and should be interpreted cautiously as a proxy for end-of-life multimorbidity. They are, however, well suited to describing the pathways leading to death.
- Dietary Traits, Systemic Inflammatory Proxies, and Insomnia-Related Outcomes: Exploratory Mendelian Randomization and Population-Based Evidence
High-dimensional Mendelian randomization (MR) screens can prioritize candidate dietary and immune pathways for insomnia, but their interpretation is constrained by multiple testing, cross-dataset instability, and limited correspondence between genetic constructs and measured population variables. We conducted an exploratory cross-design analysis that combined MR screening of 231 dietary traits and 731 immune phenotypes, targeted cross-release genetic follow-up in FinnGen R12 and R13, and population-based analyses in NHANES and CHARLS. The targeted R13 follow-up prioritised an omelette-related dietary signal (OR 0.773, 95% CI 0.651-0.917; within-layer FDR q=0.00783), a mixed-fruit signal (OR 1.285, 95% CI 1.102-1.498; within-layer FDR q=0.00683), and CD33- and HLA-DR-related immune-cell traits. In NHANES, mapped omelet/scrambled-egg intake was associated with lower odds of sleep problems in 2017-March 2020 (OR 0.746, 95% CI 0.600-0.927; FDR=0.033) and doctor-reported sleep disorder in 2005-2006 (any intake: OR 0.313, 95% CI 0.157-0.624; FDR=0.008; per 50 g: OR 0.721, 95% CI 0.569-0.914; FDR=0.019). Mixed-fruit proxies were not directionally concordant. Higher C-reactive protein (CRP) was associated with sleep problems in NHANES (OR 1.192, 95% CI 1.085-1.309; FDR=0.001) and frequent restless sleep in CHARLS (OR 1.097, 95% CI 1.049-1.147; FDR<0.001). These findings provide exploratory genetic prioritization and population-based association evidence for selected dietary constructs and systemic inflammatory proxies. They do not establish a causal diet-immune-insomnia mechanism, confirm flow-cytometry immune-cell phenotypes, or support dietary intervention recommendations.
- Tobacco Associated Disease Claims and ICD 10 F17 Tobacco Dependence Coding Among Psychiatric Patients in Indonesia National Health Insurance Dataset: A Retrospective Claims-Based Observational Study, 2015 2023
Objectives To compare hospital claims and costs for major tobacco associated diseases with ICD 10 F17 tobacco dependence coding in Indonesian national health insurance claims and to assess whether the insurer records tobacco addiction or mainly pays for its complications. Design Retrospective claims based observational study using routinely collected administrative claims reported according to STROBE and the RECORD extension. Setting Indonesian national health insurance scheme Jaminan Kesehatan Nasional including referral hospital and primary care claims from 2015 to 2023. Participants A national mental health claims sample of 54820 members with at least one ICD 10 mental or behavioral F code diagnosis weighted to 1032022 members and 2074277 referral hospital visits. Primary and secondary outcome measures The primary outcome was verified claim costs in USD for hospital visits with a primary diagnosis of chronic obstructive pulmonary disease J44 or tracheal bronchial or lung cancer C33 to C34 or ischemic heart disease I20 to I25 or stroke I60 to I69. Secondary outcomes were counts of ICD 10 F17 tobacco dependence coding and the disease to F17 coding ratio. Results The four tobacco associated disease groups accounted for 13946 visits among 5223 patients and USD 4.20 million in verified costs representing 6.0 percent of hospital spending in the sample. Weighted costs were USD 74.7 million of which cardiovascular and cerebrovascular disease accounted for 95 percent. F17 appeared in only 51 referral hospital encounters and 26 primary care encounters. Only 2 of 5223 patients with these tobacco associated diseases or 0.04 percent were ever coded with F17. Conclusions The Indonesian national insurer paid substantially for tobacco associated morbidity while tobacco dependence was almost never coded. Smoking related diseases were reimbursed but tobacco dependence treatment was not captured as a financed care target. Embedding brief cessation care reimbursable pharmacotherapy and routine F17 coding into primary care could help shift tobacco related expenditure from downstream complications toward addiction care. Keywords tobacco dependence smoking cessation F17 coding health expenditure administrative claims Indonesia
- Development and Accuracy Determination of a Peptide Diagnostic Based on the N-terminal Ectodomain of the Membrane Glycoprotein
Background: The N-terminal ectodomain (NTE) of the SARS-CoV-2 membrane (M) glycoprotein is a short, flexible region that remains exposed on the virion surface and exhibits immunogenic potential across multiple coronaviruses. Despite its small size and conformational plasticity, this region contains conserved linear epitopes that may serve as practical surrogates for full-length proteins in serological diagnostics. Objective: To develop and evaluate a synthetic peptide-based diagnostic assay targeting the NTE of the SARS-CoV-2 M protein. Methods: Epitope prediction, peptide synthesis, and antibody affinity assays were performed to design homomultivalent peptide analogs that exploit avidity effects through disulfide polymerization. The resulting peptide antigens were tested in an enzyme-linked immunosorbent assay (ELISA) using clinical samples from RT-PCR-confirmed COVID-19 patients and biobanked controls. Results: The selected peptide analogs (M1, M1i, M1s) corresponded to a conserved surface-exposed motif of the SARS-CoV-2 M protein. Polymeric M1 exhibited a twofold gain in apparent affinity (Kdapp = 4.33 nM) compared with the monomeric form (Kdapp = 8.00 nM). Clinical validation using 1,222 patient samples yielded a sensitivity of 95.26% and specificity of 52.27%, with an overall diagnostic accuracy of 88.70%. Conclusion: The M peptide analogs demonstrate that synthetic peptide antigens can serve as stable, high-sensitivity surrogates for whole-protein assays. This design principle may be applied to other emerging pathogens where rapid assay development and scalability are critical. Keywords: Peptides, Antibodies, COVID-19, Enzyme-Linked Immunosorbent Assay, Protein Binding
- Development and Internal Validation of a County-Level Screening Index for Postpartum Medicaid Access Barriers
Background: Postpartum Medicaid coverage and support are central maternal health policy issues, but county-level tools for identifying where postpartum Medicaid populations may face overlapping administrative, clinical, and contextual access barriers remain limited. Methods: We developed and internally validated a county-level Postpartum Medicaid Access Barrier Index for all 3,144 counties and county equivalents in the 50 states and District of Columbia. Public data sources included geocoded Medicaid office locations from Shafer et al. (2024), U.S. Census county boundaries, American Community Survey 2024 5-year county indicators, the National Center for Health Statistics 2023 Urban-Rural Classification Scheme for Counties, and county-level hospital-based obstetric care status from the University of Minnesota Rural Health Research Center. Medicaid office locations were spatially assigned to counties, then merged with ACS indicators, rurality, and obstetric care status by county FIPS. The theoretical score range was 0-11; the index assigned higher weights to two core infrastructure measures and lower weights to contextual indicators. Internal validation assessed component structure, known-groups validity, geographic clustering, weighting sensitivity, added value over simpler infrastructure screens, and separation across concern levels. Results: Across 3,144 counties, observed scores ranged from 0 to 10 on the theoretical 0-11 score, with a mean of 3.65 and median of 3. High or highest concern counties accounted for 665 counties (21.2%), including 56 counties (1.8%) in the highest concern group. Component correlations were low-to-moderate, with an average absolute phi of 0.176 and no pairwise component correlation at or above 0.50. Known-groups validity was strong: dual administrative and clinical gap counties scored 4.43 points higher than counties with neither gap (Cohen's d = 3.28, p < 0.001). Scores were geographically clustered (Moran's I = 0.375, permutation p = 0.005). A dual-gap-only screen captured 386 of 665 high/highest concern counties (58.0%) but missed 279 high/highest counties; a parsimonious rule requiring one infrastructure gap plus at least four contextual flags recovered 265 of these 279 missed counties (95.0%) with 100.0% precision. Discussion: The Postpartum Medicaid Access Barrier Index provides a transparent county-level screening tool for identifying places where administrative, clinical, and contextual barriers may overlap for postpartum Medicaid populations and should be externally validated against Medicaid enrollment, renewal, churn, coverage continuity, and postpartum care outcomes.
- Oral levosulpiride adjuvant to intravitreal ranibizumab for diabetic macular oedema: A 24-week randomized placebo-controlled trial
Background/Objective: Diabetic macular oedema (DMO) is a leading cause for visual impairment primarily managed with intravitreal anti-VEGF agents such as ranibizumab (RBZ). Levosulpiride (LSP), a prokinetic medication, was recently repositioned as a safe oral treatment for naive DMO. Here, we investigated the adjuvant effect of oral LSP in combination with intravitreal RBZ injections for treating persistent DMO. Subjects/Methods: Double-blinded, dual-centre, phase 2 trial in patients with centre-involving DMO randomly assigned to be orally treated with placebo (15 patients, 18 eyes) or LSP (18 patients, 19 eyes) along with 3 successive (4 weeks apart) RBZ intravitreal injections and a 24-week follow-up. Results: Baseline best-corrected visual acuity (BCVA) improved (p[≤]0.04) at week 12 in both RBZ+placebo and RBZ+LSP, but improvement was maintained (p=0.009) at week 24 only in RBZ+LSP. In agreement, longitudinal changes from baseline in BCVA from weeks 12 to 24 defined superior (p=0.02) visual gains measured by the Area Under the Curve (AUC) in RBZ+LSP vs. RBZ+placebo. The baseline value of mean central foveal thickness (CFT) decreased (p[≤]0.002) in both groups at week 12 and CFT reduction was significant (p=0.006) at week 24 only in RBZ+LSP. Also, longitudinal changes from baseline in CFT resulted in a higher AUC reduction (p[≤]0.04) at weeks 4 to12 in RBZ+LSP vs. RBZ+placebo. No significant adverse side effects were detected. Conclusions: Adjunctive LSP showed functional and anatomical benefits over the first-line therapy with RBZ. Adjuvant properties may involve the LSP-induced intraocular upregulation and downregulation of vasoinhibin and VEGF, respectively. Larger clinical trials are warranted.
- Prognostic Features of Anti-Cancer Drugs Response in Resected/Unresected Primary Non-Small Cell Lung Cancer: A Retrospective Cohort Study
Abstract Aim: Low chemotherapy response is a major risk factor for early mortality in cancer patients; it is one of the biggest challenges in cancer treatment. Main aim of this study is to identify chemotherapy non-responder, prognostic significance of pre-chemotherapy baseline variables in survival, distinguish most effective anti-cancer drug classes and formulation. Methods: In this multi-center retrospective cohort (n=2459) patients deceased with NSCLC and received anti-cancer drugs were included for analyses. To identify chemotherapy non-responder, patient population was divided into three sub-groups based on chemotherapy prescription frequency [1-15] as group-A, [16-30] as group-B, and [[≥]31] as group-C. Multivariate analysis was performed to identify risk of 1-year mortality in these groups. To prognose chemotherapy response in resected and unresected NSCLC patients, 0-7 days pre-chemotherapy white blood cell (WBC) count total five-ranges were compared as per overall survival in abnormal Vs normal WBC counts. Results: Post-stratification in group-A there were (n=1289) patients, in group-B (n=648) patients, and in group-C (n=522) patients. In group-A (n=301) patients 23% were found to have no new metastasis post-diagnosis significantly less p-value (0.004) compared to Group-B (n=125) 19.3%, and group-C (n=110) 19.2% patients p-value (0.008). Metastasis during chemotherapy was found significantly less in 20% patients of group-A, compared to (33%) in group-B, and (43%) in group-C p-value (<0.001). Post-chemotherapy initiation OS in group-A patients were significantly less 9 months (95% CI 9.3 - 9.6) compared to group-B 19 months (95% CI 17.7 - 20.2) and group-C 36.6 months (95% CI 34.6 - 38.5) patients p-value (<0.0001). Despite of low new metastasis and post chemo metastasis, group-A patients survived significantly less based on these outcomes group-A patients were considered as chemotherapy non-responder. Males and NSCLC stage III/IV patients were at higher risk; clinical benefits are corelated to surgery and radiotherapy for chemotherapy non-responder. Leukocytosis in both resected/unresected NSCLC group-A (13%) patients were found to be bad prognostic factor of survival in unresected group-B (5%) patients. Oral formulation of receptor tyrosine kinase inhibitors (RTKI) was effective in non-responders. Conclusion: Stratification of patient population based on chemotherapy prescriptions could be a useful method to find chemotherapy response in retrospective analysis. Patients with pre-chemotherapy leukocytosis should be closely monitored prior to selection of chemotherapy dose and formulation.
- In-clinic validation of a smartphone-based finger tapping test for use in neurodegenerative and neurological populations.
Background: Motor disturbances are common in neurologic and neurodegenerative syndromes. A standard motor speed and dexterity measure is the finger tapping test (FTT). The FTT has traditionally been administered in clinic using a mechanical FTT, limiting accessibility and early motor change quantification. This study assessed the validity of a smartphone app-based FTT, which may expand access and enable more frequent testing. Methods: The cohort was diagnostically diverse, including participants with frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), corticobasal syndrome, primary progressive aphasia, multiple sclerosis, and clinically unimpaired controls. Participants completed a 20-second ALLFTD Mobile App (mApp)-FTT with each hand. Tapping speed metrics were extracted. Participants completed the gold-standard mechanical FTT, a neurologist-administered finger tapping exam, the PSP Rating Scale (PSPRS) and the Unified Parkinson`s Disease Rating Scale (UPDRS). Correlations assessed mApp-FTT and mechanical FTT relationships; regressions evaluated associations with neurologist-rated finger tapping impairment, PSPRS and UPDRS, adjusting for age and sex. Results: The mApp-FTT showed moderate-to-strong correlations with the mechanical FTT (dominant: r=0.63, p<0.001; non-dominant: r=0.55, p<0.001). Taps per second were associated with PSPRS motor severity (dominant hand: std. {beta}=-0.59, 95% CI [-0.91, -0.27], p<0.001) and the UPDRS (dominant hand: std. {beta}=-0.41, 95% CI [-0.82, 0.00], p=0.049). Flight time was modestly associated with neurologist-rated finger tapping impairment (dominant hand: std. {beta}=0.15, 95% CI [0.00, 0.29], p=0.044). Conclusion: These findings support mApp-FTT validity as a measure of motor function across neurodegenerative conditions. Validation in longitudinal and unsupervised remote settings is warranted to understand scalability and evaluate change over time.
- Plasma proteomics reveals continuous molecular heterogeneity rather than discrete subtypes in Alzheimer's disease
Alzheimer's disease is clinically and biologically heterogeneous. We asked whether plasma proteomics separates patients into discrete molecular subtypes or instead reflects continuous biological variation. We studied 5,895 Global Neurodegeneration Proteomics Consortium (GNPC) participants with Alzheimer's disease or mild cognitive impairment using protein coexpression networks, clustering, and continuous molecular-axis analysis. External analyses used Stanford Alzheimer's Disease Research Center (ADRC) biomarker/imaging data and UK Biobank proteomics.Four continuous axes captured 81.5% of module-level proteomic variation. Although a two-cluster solution was reproducible, separation was weak and added little clinical information beyond the continuous axes. Stanford ADRC analyses showed selected fluid biomarker associations, but imaging and PET results did not provide consistent support. In UK Biobank, projected axes were more strongly related to APOE genotype and systemic hematologic, renal, lipid, inflammatory, and hepatic traits than to clear dementia-risk replication. Plasma proteomics did not support robust Alzheimer's disease subtypes. Continuous molecular coordinates better describe plasma proteomic heterogeneity and may guide future biological stratification.
- Ketotifen for Moderate-to-Severe Uremic Pruritus in Chronic Dialysis Patients: A Prospective Observational Study
Background: Uremic pruritus affects up to 90% of individuals and substantially impairs quality of life, in the group of patients undergoing chronic dialysis. Despite multiple therapeutic options, an optimal and well tolerated treatment remains elusive. Ketotifen, a mast cell stabilizer with antihistaminic properties prevent itch by inhibition of mast cell derived tryptase, which modulates protease-activated receptor-2 (PAR-2) in the cowhage itch pathway. Materials and Methods: In this prospective observational study, 230 chronic dialysis patients were screened, of whom 48 (20.9%) had clinically significant pruritus identified using a structured questionnaire. Twenty-four patients with moderate-to-severe symptoms who were prescribed ketotifen as part of routine clinical care consented to prospective follow-up. Ketotifen was initiated at 1 mg twice daily, with dose escalation to 2 mg twice daily in patients with persistent symptoms according to routine clinical practice. Pruritus severity was assessed using visual (VAS), verbal (VRS), and numerical (NRS) rating scales before and after treatment. Results: After two weeks of initial 1mg therapy, 19 showed significant clinical improvement. Mean scores reduced 77.5 [->] 27.1 (VAS), 87.5 [->] 20.8 (VRS), and 74.2 [->] 25 (NRS) (around 65% reduction with p < 0.001 across all scales). Clinical relief was achieved in 83.3% overall and mild tolerable drowsiness occurred only at the 2mg dose. Conclusion: Ketotifen is a safe, effective and well tolerated option for moderate to severe uremic pruritus in dialysis patients. Larger multicenter studies are warranted to confirm efficacy and optimize dosing.
- Pediatric nicotine exposures from devices and liquids: a comparative analysis of U.S. poison center data
Introduction: Pediatric nicotine exposures remain an important and preventable public health issue, particularly with the rapid expansion of electronic nicotine delivery systems. This study compared demographic characteristics, exposure circumstances, and clinical outcomes between pediatric cases involving nicotine devices and bottled liquids reported to U.S. poison centers. Method: This retrospective cohort study analyzed National Poison Data System cases from 2011-2022 involving children aged less than 6 years exposed to nicotine devices or bottled liquids. Analyses were limited to cases with definitive medical outcomes. The primary outcome was defined as a moderate or major clinical effect or death. Odds ratios with 95% confidence intervals were calculated, with a secondary analysis restricted to route-concordant exposures. Results: The final cohort included 15,497 cases: 10,168 device exposures and 5,329 liquid exposures. Demographic characteristics were similar between groups. Device exposures more frequently involved inhalation, while ingestion predominated overall. Clinical effects were typically mild and transient, with vomiting and coughing most commonly reported. The primary outcome occurred in 1.9% of device cases and 2.0% of liquid cases (OR = 1.05; 95% CI 0.82-1.34). A secondary analysis restricted to inhalation-only device exposures and ingestion-only liquid exposures similarly found no significant difference in clinically important outcomes (OR = 1.38; 95% CI 0.92-2.12). Two deaths occurred, one in each group. Conclusion: These findings suggest that, despite differences in formulation and route of exposure, nicotine devices and bottled liquids produce broadly similar clinical toxicity profiles in young children. Prevention strategies should address all household nicotine products rather than focusing on specific delivery systems.
- Estimating future vaccine manufacturing capacity requirements using discrete event simulation: a case study on Africa's 2040 vision
The Africa CDC's New Public Health Order aims to improve health, regional self-reliance, and health security by boosting local vaccine manufacturing capacity from <1% in 2022 to 60% by 2040. Although multiple studies have examined vaccine manufacturing capacity in Africa, none quantified future vaccine manufacturing capacity requirements and complexities in capacity planning. We fill this gap by integrating a deterministic approach and discrete event simulation (DES) to estimate vaccine manufacturing capacity requirements and assess the impact of process variability and uncertainty on manufacturing capacity needs. A total of 51 experts were interviewed to design vaccine-specific supply chain networks, collect, and validate data on process-specific parameters. Our findings reveal that deterministic approach provides optimistic capacity estimates but realistic estimates of capacity requirements is possible using DES as it captures variability and uncertainty inherent in vaccine manufacturing. Further evidence shows that reduction in batch yield at any manufacturing stage significantly reduces throughput, while the impact of high batch deviations is vaccine specific and dependent on the manufacturing stage. For multi-antigen vaccines, capacity estimation is complicated by the amplification of process variability, and synchronization of batch arrival and volume. Finally, we estimated that 11 vaccine manufacturing facilities staffed by approximately 8,599 fulltime employees, of whom 43% are technical personnel, would be required to achieve Africa's 2040 ambition. Overall, adopting a system-level perspective, maintaining a high, reliable, and sustainable manufacturing process yield and quality, are important when establishing new vaccine manufacturing facilities.
- Large-scale assessment of socioeconomic, demographic and health system structures with US county excess mortality, 2020-2024
Socioeconomic, demographic, and health system structures may have shaped COVID-19 pandemic impact across populations, but past analyses typically examined few factors. We systematically examined correlates of COVID-era excess mortality, considering 2,745 county-level variables of demography, race/ethnicity, income, insurance, education, employment, housing, and health system. Pearson correlation coefficients (CCs) were obtained for the most recent available pre-pandemic value against age-standardized county excess-death for each year during 2020-2024. Counties were population-weighted. Variables were grouped by meaning into 11 semantic super-clusters. Overall, 17.3% of variables reached at least a moderate correlation level (|CC| > 0.30) and 2.8% reached strong correlations (|CC| > 0.45). Strongest correlations were seen for college attainment (CC -0.54), uninsurance among adults 40-64 (+0.53), and high income (-0.53). At least moderate correlations were seen for 9.1% of variables in 2020 and 8.5% in 2021, but only 1.8%, 0%, and 1.3% in 2022, 2023, and 2024, respectively. Similar patterns of concentration of moderate correlations in the first two pandemic years appeared in both elderly and non-elderly populations. Of 472 variables with |CC| > 0.30, 362/395 moderate-band and 77/77 strong-band variables belonged to demography and socioeconomic super-clusters. Only 7% of health system variables reached |CC| > 0.30, versus 31% of socioeconomic and demographic variables. Using the most recent available value until 2023 or 2015, different population weighting, and Spearman correlations yielded similar results. Overall, these ecological analyses suggest strong relationships of socioeconomic structure and demographics rather than health-care resources/supply with excess mortality across US counties especially during 2020-2021.
- Association Between Area Deprivation and Dental Provider Density in California: A Cross-Sectional Ecological Study
Abstract Background Neighborhood socioeconomic disadvantage may contribute to inequities in access to dental care by influencing the geographic distribution of providers. The Area Deprivation Index (ADI) is a validated measure of neighborhood deprivation, but its association with dental workforce availability has not been examined statewide in California. This study evaluated the relationship between neighborhood deprivation and dental provider density across California ZIP Code Tabulation Areas (ZCTAs). Methods We conducted a cross-sectional ecological study of California ZCTAs using publicly available data from the National Plan and Provider Enumeration System (April 2026), the Neighborhood Atlas 2023 ADI, and 2024 U.S. Census population estimates. Active dental providers were linked to ZCTAs and provider density was calculated per 10,000 residents. ADI was aggregated to the ZCTA level using the median ADI national percentile. Negative binomial regression was used to assess the association between ADI and dental provider density, with population included as an offset. Secondary analyses examined California-specific ADI quartiles, dental deserts, and specialist versus general dentist availability. Results The final analytic sample included 1,426 California ZCTAs representing 39,016,384 residents and 37,945 active dental providers. Greater neighborhood deprivation was significantly associated with lower dental provider density. Each one-percentile increase in ADI corresponded to a 1.8% reduction in provider density (incidence rate ratio [RR] 0.9823, 95% confidence interval [CI] 0.9799-0.9847; p < 0.001). Compared with the least deprived quartile, the most deprived quartile had 61% fewer dental providers (RR 0.39, 95% CI 0.34-0.45; p < 0.001). Overall, 15.9% of ZCTAs contained no active dental providers, increasing from 6.8% in the least deprived quartile to 31.1% in the most deprived quartile. Specialist availability demonstrated an even steeper deprivation gradient, with specialist density declining by 86% between the least and most deprived quartiles.
- Evolutionarily conserved pathways of caregiving breakdown underlie contemporary child maltreatment
Child maltreatment is a leading cause of preventable harm, yet how diverse risk factors accumulate to precipitate caregiving failure remains unclear. In non-human mammals, fatal abandonment or aggression toward offspring occurs under specific ecological conditions, suggesting evolutionarily conserved pathways for caregiving breakdown. To test whether similar structures apply to humans, we conducted a case-control study enrolling 39 caregivers imprisoned for (near-) lethal child maltreatment and 351 control caregivers in Japan. Across 70 examined factors spanning caregivers' childhood, socioeconomic, neurobiological, and proximate environmental profiles, severe maltreatment was associated with 4.6- and 5.9-fold higher exposure to cross-species factors in men and women, respectively. Developmental pathway modeling identified significant standardized total effects of low educational attainment, non-kin caregiving, isolated parenting, behavioral addiction, and maternal absence before age 15. This proof-of-concept study presents an integrated framework bridging evolutionary biology with contemporary human caregiving and suggests targets for actionable intervention.
- Leptospirosis occurs as frequently as malaria among adolescent and adult acute febrile patients in Hoima, Uganda: A prospective health facility-based study
Background Leptospirosis is substantially underdiagnosed across sub-Saharan Africa, with its contribution to acute undifferentiated fever (AUF) poorly characterized. We determined the prevalence, risk factors, and clinical profile of leptospirosis among adolescents and adults presenting with AUF at a referral hospital and health centre in Hoima, western Uganda. Methods: In a prospective health facility-based study with convalescent follow-up, blood and urine from AUF patients were tested by LipL32 real-time PCR (qPCR) and microscopic agglutination (MAT). Leptospirosis was confirmed by qPCR positivity, a single test MAT titre of 1:800, or at least a fourfold titre rise or seroconversion in paired sera. Seroconversion was defined as a change from negative or 1:50 to 1:100 (conservative) or 1:200 (lenient). Seroprevalence was defined as a MAT titre of 1:100 or above in any sample. Risk factors were identified by multivariable logistic regression. Results: Among 330 AUF patients, acute leptospirosis prevalence was 27.0% (95% CI 22.3 to 32.1; conservative) and 32.7% (95% CI 27.7 to 38.1; lenient), comparable to malaria at 30.3% (95% CI 25.3 to 35.3), with co-infection in 8.8% (95% CI 5.7 to 11.8). qPCR detected Leptospira DNA in 9.1%, with 63.3% of qPCR-positive cases serologically confirmed and 24.4% of serological cases, qPCR-positive. Seroprevalence was 35.8% (95% CI 30.6 to 41.2); L. interrogans serovar Bataviae was predominant (18.2% of serological cases), reported here for the first time in Uganda. Skinning animals (aOR 5.19, 95% CI 1.40 to 21.16) and mosquito exposure (aOR 2.31, 95% CI 1.17 to 4.70) were the only independent risk factors in multivariable analysis. Discussion: Leptospirosis occurs as frequently as malaria among AUF patients in Hoima and warrants inclusion in Uganda's national febrile illness guidelines. The association of leptospirosis with skinning of animals suggests a potential role of animal exposure in leptospirosis transmission. Poor qPCR-MAT concordance confirms that accurate case ascertainment requires combined molecular and serological diagnostics.
- Prevalence of cancer in patients with cardiovascular diseases and risk factors: a systematic review and meta-analysis
Background No systematic review has been conducted to pool the existing evidence and quantify cancer prevalence rates in cardiovascular diseases (CVDs). We aimed to estimate pooled cancer prevalence in coronary artery disease (CAD), heart failure (HF), atrial fibrillation (AF), hypertension, type 2 diabetes mellitus (DM), stroke, peripheral arterial disease (PAD), and valvular heart diseases (VHD). Methods PubMed, Web of Science, and Scopus were searched from 2010 to July 2024. The outcomes were proportions of patients with active, any, previous, blood, solid, and metastatic cancer. The prevalence rates were estimated via one-step generalized linear mixed models. Results Totally, we retrieved 676 studies with enrollment of roughly 180 million participants. The analysis for active cancer included 59 studies with a population of 4,759,695 patients. The pooled prevalence of active cancer was 4.22% (95% confidence interval (CI) 2.18-5.32), 4.43% (95% CI 2.78-6.38), 4.60% (95% CI 1.72-8.13), 4.61% (95% CI, 2.83-6.97), 4.90% (95% CI 3.84-6.37), and 5.55% (95% CI 3.97-7.01) in patients with type 2 DM, chronic HF, any stroke, CAD, VHD, and AF. For any cancer, prevalence rates ranged from 14.10% (95% CI 12.20-15.99) in AF to 7.04% (95% CI 6.05-8.03) in CAD. Conclusion Pooled prevalence rates demonstrate a measurable burden of cancer among patients with a wide range of CVDs, highlighting the need for multidisciplinary management in this population.
- AI Project Manager
AI Project Manager Built In
- Seeing Nothing, Saying Something: The Lack of Visual Grounding and Confabulation in Gemini Models for Histopathology
Large vision-language models (VLMs) have demonstrated remarkable perfor- mance on computational pathology benchmarks, yet their reliability under adversarial or vacuous inputs remains poorly understood. This paper examines the visual grounding behaviour of two Gemini models Gemini 3.0 Flash Pre- view (gemini-flash) and Gemini 3.1 Pro Preview (gemini-pro) on a well known histopathology classification task, and probes for confabulation using a adver- sarial blank-image set. On the real histopathology dataset both models achieve near-perfect accuracy (98.75% - 100%) across three temperatures (0.0, 0.5, 1.0) and three independent runs. On a controlled adversarial set of blank white images labelled as either benign or malignant, however, a stark divergence emerges. Gemini-flash consistently acknowledges the absence of visual content and assigns zero confidence, while Gemini-pro fabricates detailed, clinically plausible histo- logical descriptions and reports high confidence (mean {approx} 0.95) across the same blank inputs, a behaviour we term confident confabulation. The confabulation rate of gemini-pro reaches 77.8% image-responses at temperature 0.0, dropping to 44.4% at temperature 0.5 and rising to 66.7% at temperature 1.0, while gemini- flash records 0% at all temperatures. These findings raise important questions about the safety and trustworthiness of VLMs in clinical decision-support con- texts, and underscore the need for comprehensive evaluation beyond standard accuracy metrics.
- Photo Upscaler AI
Photo Upscaler AI
- Nasdaq sinks as AI worries hit chipmakers
Nasdaq sinks as AI worries hit chipmakers Reuters
- Nasdaq sinks as AI worries hit chipmakers
Nasdaq sinks as AI worries hit chipmakers The Straits Times
- Anthropic J-space research 🧠, Apple + Broadcom ⚡, continual agent learning 🤖
Anthropic J-space research 🧠, Apple + Broadcom ⚡, continual agent learning 🤖
- Your Personal AI Assistant | Ask, Chat, Create and More
Your Personal AI Assistant | Ask, Chat, Create and More AI at Meta