The integration of data-driven continuous monitoring into chronic disease management is often presented as a solution for clinical efficiency. However, this technological shift may substantially reshape care relations, power, and intimacy. Prevailing research, focused on technical validation, fails to capture how such systems operate as social forces. A critical, theory-informed examination of these lived transformations is needed. This study goes beyond documenting ethical dilemmas by critically investigating how data-driven surveillance restructures nurse-patient dynamics. We aim to uncover the mechanisms through which data-driven surveillance disciplines both caregivers and recipients, and to identify where and how the irreducible elements of humanistic care persist and resist. A critical qualitative design was employed, guided by Foucault's concept of governmentality as a sensitising lens. Semi-structured interviews were conducted with 12 registered nurses and 15 patients with hypertension or type 2 diabetes in one Chinese tertiary hospital that had, for six months, implemented real-time automated physiological monitoring. Data were analysed using reflexive thematic analysis with a hybrid (deductive-inductive) approach. Our analysis reveals three core mechanisms: (1) systematic arbitration (nurses as constant negotiators between automated alerts and situated clinical judgment); (2) datafied self-surveillance, patients internalise the data-driven gaze, policing their own behaviour; (3) a shared convergence around the human boundary, both nurses and patients actively defend empathy, contextual interpretation, and emotional recognition as domains irreducible to data. This boundary is not a passive remnant but an active, shared accomplishment. Digital surveillance in chronic care does not act as a neutral adjunct. Instead, it operates as a disciplinary technology that asymmetrically disciplines nurses and patients. However, the identified human boundary represents a critical site of resistance and re-humanisation. The future of humane digital health depends on deliberately designing socio-technical systems that strengthen, rather than erode, the relational and interpretive core of clinical practice.
Although human pluripotent stem cells (hPSCs) can generate all tissues of the body, hPSCs in vitro frequently exhibit differentiation biases or failure that pose substantial challenges for disease modeling and regenerative medicine. The origins of these biases remain incompletely understood and extend beyond reprogramming artifacts. Here we show that loss of default neural differentiation capacity and failure to form brain organoids are linked to erosion of bivalent chromatin marks at developmental gene loci, independent of DNA methylation, driving acquisition of a posterior epiblast-like state and premature developmental gene expression. We develop a chemical chromatin restoration (CHR) approach that rescues this differentiation bias by reinstating transcriptional programs and chromatin landscapes characteristic of the competent anterior epiblast-like state, restoring broad differentiation potential. These findings establish locus-specific patterns of repressive and activating histone post-translational modifications as a tractable and experimentally targetable determinant of hPSC fate competency, and offer an effective route to rescue differentiation-compromised hPSC lines for applications in disease modeling and regenerative medicine.
CCR2+ monocytes are recruited to sites of acute myocardial injury, where they play a critical role in clearing necrotic debris and replenishing the depleted resident macrophage population. Although this response is necessary for early tissue repair, prolonged activation of inflammatory pathways and persistent recruitment of CCR2+ monocytes have been associated with accelerated ventricular remodeling and adverse outcomes. Inhibition of CCR2 has shown promise in preclinical models of myocardial injury and represents a potential therapeutic target. Cardiosphere-derived cell extracellular vesicles (CDC-EVs) have demonstrated cardioprotective effects partly through modulation of the immune response. We investigated whether CDC-EVs regulate inflammatory monocyte trafficking through effects on CCR2 signaling. We found that CDC-EVs reduce the surface availability of CCR2 on human monocytes through an miR-146a-dependent mechanism, resulting in decreased monocyte migration toward CCL2. These findings identify a previously unrecognized mechanism by which CDC-EVs modulate CCR2-dependent monocyte trafficking and provide new insight into how EVs regulate innate immune responses after myocardial injury.
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Accurate assessment of systemic drug exposure in humans remains challenging, as conventional approaches rely on intermittent blood sampling and laboratory-based assays that are invasive and provide limited temporal resolution. Exhaled breath contains volatile and semi-volatile compounds arising from drug metabolism and downstream biological processes, suggesting that it may serve as a non-invasive matrix for integrated pharmacokinetic sensing. We conducted a prospective observational study using exhaled breath metabolomics based on secondary electrospray ionization high-resolution mass spectrometry (SESI-HRMS) to estimate systemic drug exposure from a breath-sampling session. A total of 117 adults provided 127 paired breath-serum measurements under routine outpatient conditions. Model performance was evaluated using repeated k-fold cross-validation and quantified using concordance correlation coefficients. Breath-derived estimates of valproic acid, levetiracetam, lamotrigine, and lacosamide showed moderate concordance with measured serum concentrations, with concordance correlation coefficients ranging from 0.733 to 0.895 across medications. The lacosamide findings should be considered preliminary because of the limited subgroup size (n = 16). The observed concordance supports proof-of-concept exposure estimation but does not establish clinical interchangeability with serum-based therapeutic drug monitoring. The previously defined 11-feature VPA breath signature retained predictive utility in a separate adult cohort, supporting its cross-cohort transferability within the present analytical framework. These findings support the feasibility of exhaled breath analysis for non-invasive estimation of systemic drug exposure across pharmacologically distinct medications. Breath analysis should currently be considered complementary to serum-based monitoring, and external multicenter and longitudinal validation is required before clinical implementation.
Fast, highly constrained sensorimotor acts require rapid coordination of distributed cortical systems on subsecond timescales. Here, we used source-resolved magnetoencephalography to characterise time-locked cortical connectivity during voluntary swallowing in 74 healthy adults. Cluster-based network statistics revealed focal swallowing-related connectivity changes confined to anatomically selective subnetworks. Undirected phase-lagged connectivity identified theta- and low-gamma weighted phase lag index (wPLI) effects involving somatosensory, motor, supramarginal, and insular regions. Directed connectivity revealed sparse high-gamma phase slope index (PSI) subnetworks centred on the primary somatosensory cortex and anterior insula. Time-window analyses demonstrated temporally evolving low-gamma interactions between posterior parietal and insular regions, while laterality analyses showed rightward theta-band directed asymmetries during later swallowing phases. In contrast, global graph-theoretical metrics and node-level hub measures remained largely stable after correction for multiple comparisons. These findings indicate that voluntary swallowing is supported by focal, frequency-specific, and temporally structured cortical interactions rather than broad global network reconfiguration.
Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disorder caused by an abnormally long polyglutamine-encoding CAG repeat in the ATXN3 gene. We aimed to determine whether somatic expansion of the mutant ATXN3 (mATXN3) CAG repeat is present in the output cell of the cerebellar cortex, the Purkinje cell (PC), in individuals affected with SCA3. We combined sorting of cell nuclei from post-mortem brain tissue, transcriptome analysis-based confirmation of sample purity, and high-depth sequencing of ATXN3 exon 10 amplicons to analyze the stability of mATXN3 CAG repeat in PCs in individuals with SCA3. We demonstrated that the expansion of mATXN3 CAG repeat in PCs is minimal, comparable with cerebellar granule neurons, and the repeat is more stable in PCs compared with striatal medium spiny neurons. The modest somatic expansion of the mATXN3 CAG repeat observed in PCs is likely not responsible for their loss in individuals with SCA3. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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The neuronal pentraxin receptor (NPTXR) is mainly expressed in the cytoplasm of a subset of neuronal cells in the cerebral cortex. While NPTXR may be involved in mediating uptake of synaptic material during synapse remodeling or synaptic clustering of AMPA glutamate receptors at a subset of excitatory synapses during embryonic development, NPTXR expression has recently been shown to be elevated in tissues from patients with gastric cancer. NPTXR protein expression was evaluated in human cancer and healthy tissue samples. We then generated antibody-drug conjugates based on YB-800 (YB-800ADCs), a fully humanized monoclonal antibody selectively targeting NPTXR. The cross-reactivity of YB-800 and YB-800ADCs were assessed, as well as their tumor inhibitory effects in experimental tumor models. NPTXR protein was highly and consistently expressed in human tissue samples from multiple cancer types but only minimally expressed, if at all, in healthy tissues. Treatment with YB-800ADCs inhibited tumor cell proliferation/survival in engineered HEK293 cells overexpressing the human NPTXR. YB-800ADCs were also found to have pronounced anti-tumor effects in mice bearing NPTXR-expressing HEK293 tumors at well-tolerated doses. Initial anti-tumor findings were further confirmed using a naturally occurring NPTXR-expressing human bladder PDX model. NPTXR is an oncofetal protein that is highly expressed in multiple human cancers but minimally expressed in healthy tissues. We have established NPTXR as a new tumor marker and have developed antibody-drug conjugates using YB-800, a novel, first-in-class, humanized monoclonal antibody targeting the human NPTXR. Initial results demonstrate that YB-800ADCs have pronounced anti-tumor effects in vivo in NPTXR-expressing cancer cells. Continued evaluation of YB-800ADCs is warranted.
Golden hamster (Mesocricetus auratus) and ferret (Mustela putorius furo) are important animal models in studies of human infectious disease. They are used widely to investigate pathogen-spreading mechanisms and host immunology to evaluate the safety and efficacy of small molecules, biologic drugs and vaccines. To this end, immunoglobulin A (IgA) and its Fcα receptor (FcαR) play critical roles in humans but are not well characterized in these 2 species. Golden hamster and ferret IgA and FcαR were recombinantly expressed, purified, and characterized for N-linked glycosylation site occupancy and binding affinity. Based on sequence and structural alignments, hamster IgA showed greater similarity to human IgA than did ferret, and hinge domains in both small animal models suggested greater structural homology to human IgA2 than IgA1. Despite considerable sequence divergence in both immunoglobulins and receptors, and the lack of binding between ferret FcαR and ferret IgA, human IgA bound to both hamster and ferret FcαR with high affinity. Further, differences in dissociation rates were dependent on test format, suggesting that the 2:1 stoichiometry of human FcαR: IgA is recapitulated in these animals. Overall, this work suggests the suitability of these animals to model protection or pathology driven by interactions between human IgA and host FcαR and will aid in critical and confident interpretation of infection and immunization studies in each species.
Productivity in pharmaceutical R&D continues to fall despite deeper biological insight and steady gains in clinical development operations - a phenomenon termed Eroom's Law. Agentic AI workflows powered by reasoning-trained large language models (LLMs), increasingly described as large reasoning models (LRMs), could potentially dent this trend. Unlike earlier task-specific models, these systems couple multi-step reasoning with the ability to plan, invoke external tools and retrieve authoritative information, enabling them to decompose and execute complex scientific and operational tasks. This review discusses agentic AI applications across the drug development continuum, from target discovery to post-market surveillance, and highlights three near-term use cases: algorithmic drug repurposing, informed consent support and automated drafting of regulatory documents. For each, we outline plausible architectures, the current level of supporting evidence and the principal failure modes that constrain deployment. Realizing these gains, however, requires prospective validation, rigorous human oversight and governance frameworks that align algorithmic outputs with clinical, ethical, legal and regulatory standards. When implemented responsibly, agentic AI could transform human-AI collaboration in biopharma, improving R&D efficiency and accelerating delivery of safer, more-effective therapies.
Inositol is an essential nutrient for most living organisms, as combinatorial phosphorylation on this cyclic sugar generates key cellular messengers, such as lipid-bound phosphoinositides (PtdInsPs), water-soluble inositol phosphates (InsPs), and high-energy inositol pyrophosphates (PP-InsPs). Although the kinases and phosphatases modifying inositol-derived molecules are well-characterised, the molecular pathways controlling the cellular homeostasis of the inositol backbone and transport carriers remain unclear. Using a combination of LC-MS analysis and a screen based on the inositol-exporting opi1Δ mutant yeast, we here discovered that inositol export is tightly regulated by PP-InsPs and that the high-affinity phosphate transporter Pho84 also acts as an inositol exporter. We further expanded these observations to the mammalian system and revealed that inositol export in human cells is similarly controlled by PP-InsPs, and that the human homolog of the yeast Pho84, GLUT2, contributes to inositol export. In summary, we discovered an evolutionarily conserved crosstalk pathway linking PP-InsPs to both phosphate and inositol homeostasis.
Male infertility is a growing global health issue, with declining sperm quality being a major contributing factor. Zearalenone (ZEA), a widespread mycotoxin, is frequently detected in human populations through contaminated food and water. Here, we investigated the mechanism by which environmentally relevant concentrations of ZEA disrupt the blood-testis barrier (BTB) and impair sperm quality. We found that exposure to ZEA disrupted BTB integrity and reduced sperm quality in mice. Mechanistically, ZEA activated the inositol-requiring enzyme 1α (IRE1α), leading to regulated IRE1α-dependent decay (RIDD) of GA binding protein transcription factor α (Gabpa) mRNA. GABPA binds directly to and transcriptionally activates the promoters of genes encoding the tight junction proteins ZO1 and Occludin. This binding was attenuated by ZEA treatment. GABPA overexpression rescued the ZEA-induced downregulation of ZO1 and Occludin and restored barrier function, whereas GABPA knockdown exacerbated these defects. Both Ern1 (encoding IRE1α) knockdown and pharmacological inhibition of IRE1α RNase activity with 4μ8C rescued GABPA expression, restored BTB function, and ameliorated ZEA-induced sperm defects. Our findings unveil a novel IRE1α-GABPA signaling axis as a central mechanism in ZEA-mediated male reproductive toxicity, highlighting IRE1α and GABPA as potential therapeutic targets for intervention against environmental pollutant-induced infertility.
Diabetic kidney disease (DKD) is a frequent complication of type 2 diabetes and is closely linked to systemic inflammation. Peripheral blood mononuclear cells (PBMCs) are markers of systemic inflammatory and metabolic stress. It is unknown if metabolism-related transcriptomic alterations in these cells is associated with DKD. Using the nCounter® Human Metabolic Pathways Panel we profiled PBMC metabolic transcripts in individuals with type 2 diabetes or DKD and in controls (n = 12/group), and integrated transcriptomic data with clinical, inflammatory, and mitochondrial parameters. Patients with DKD showed increased inflammatory biomarkers and reduced PBMC mitochondrial membrane potential and mass, consistent with mitochondrial dysfunction. Metabolism-related transcriptomic profiling identified 13 differentially expressed genes across groups. DKD subjects displayed downregulation of SLC7A11 versus controls and HLA-DQA1 versus type 2 diabetes, and upregulation of CPT1A and GBA1 versus controls. CPT1A upregulation was confirmed by RT-qPCR and supported by external GEO datasets, though ROC analyses indicated a limited discriminatory performance. Pathway analyses revealed enrichment of immune-related, fatty acid oxidation, and fructose-6-phosphate pathways and reduced cell proliferation pathways in DKD patients. Inflammatory markers correlated positively with energy-regulating pathways and negatively with anabolic processes. In conclusion, these findings suggest that PBMCs reflect immunometabolic remodeling in response to DKD, thus highlighting an association between systemic inflammation, mitochondrial dysfunction, and altered energy metabolism in circulating immune cells.
Humans are chronically exposed to ionizing radiation. Natural background radiation is generally harmless, yet potential risks arise from nuclear accidents, accidental medical irradiation, and high-background-radiation regions. The effects of high-dose radiation are well established, whereas research on low-dose ionizing radiation (LDIR, ICRP-defined as doses below 100 mSv) remains limited and highly controversial. As the most prevalent exposure type, LDIR originates from medical imaging, occupational exposure, and environmental background radiation. Previous studies have largely focused on its neurotoxicity, implicating neuroinflammation, oxidative stress, and synaptic damage. Nevertheless, emerging evidence indicates that LDIR administered at specific doses and regimens may exert neuroprotective effects via hormesis: it reduces Aβ deposition, promotes anti-inflammatory microglial polarization, and enhances hippocampal neurogenesis, thereby ameliorating cognitive impairment. Constrained by ethical considerations, sample size limitations, and inter-model variability, no consensus has been reached regarding its dual mechanisms, safety thresholds, and long-term outcomes. This review systematically synthesizes studies published over the past five years, integrating both detrimental and protective effects and identifying key modulating factors (radiation parameters, biological characteristics, and socioeconomic variables). Importantly, we also discuss the translational potential of LDIR in clinical settings, summarize current evidence, and highlight barriers to implementation. By examining preclinical data and prospective clinical applications, this review provides a theoretical framework for refining radiation protection standards and developing non-pharmacological interventions for cognitive disorders, filling critical knowledge gaps in this field.
BICSTaR (BICtegravir Single Tablet Regimen) is a multinational observational study assessing the virologic effectiveness and safety of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in people with human immunodeficiency virus (HIV). Previously, the 12-month analysis of the Japan cohort of BICSTaR showed high levels of virologic effectiveness and tolerability with B/F/TAF. Data for 84 treatment-experienced (TE) or 116 treatment-naïve (TN) participants aged ≥20 years receiving B/F/TAF as part of routine clinical care in Japan were collected retrospectively and prospectively. Outcomes analyzed at 24 months included HIV-1 RNA <50 copies/mL, treatment persistence, drug-related adverse events (DRAEs), and patient-reported outcomes (prospective cohort only). At 24 months, 97% of TN and TE participants had HIV-1 RNA <50 copies/mL (missing-equals-excluded analysis), and 96% of participants remained in the study and were receiving B/F/TAF. DRAEs were reported by 14% of participants (TN: 16%; TE: 10%), with diarrhea (TN: 3%; TE: 2%) and weight gain (TN: 4%; TE: 0%) being the most common; the majority of DRAEs occurred in the first 12 months. Participants enrolled prospectively reported stable or improved quality of life through 24 months. Treatment with B/F/TAF in routine HIV clinical care in Japan was associated with high persistence, virologic effectiveness, and was well tolerated through 24 months.
Age-related genome mosaicism is an inherent feature of multicellularity and genomic instability. It occurs because of DNA mutations, the accumulation of which leads to diverse genomic landscapes across different tissues. DNA mutations in the genome are consequences of DNA damage, changes in the chemical structure of DNA, such as strand breaks or loss of bases. DNA damage is very frequent and normally repaired quickly. However, errors intrinsic to DNA repair or replication can give rise to permanent changes in genome sequence information. Such DNA mutations are diverse and include single-nucleotide variants, small insertions and deletions, and larger genome structural variants. Since the 1950s, somatic mutations have been proposed to be a major cause of aging. Indeed, somatic mutations are the cause of cancer, the risk of which increases exponentially with age, and possibly other age-related diseases, such as neurodegenerative diseases and cardiomyopathies. Somatic mutations vary from cell to cell owing to the innate stochasticity of their occurrence, from error-prone processing of randomly inflicted DNA damage. With the emergence of single-cell and single-molecule sequencing, it has become possible to quantitatively analyze somatic mutations in human cells and tissues. Here, we discuss a possible causal relationship between mutation-driven mosaicism of the somatic genome and aging-related functional decline and disease by exploring several predictions of the somatic mutation theory of aging.
Effort is integral to the regulation of behavior. It can be central for achieving goals in a range of activities, including sports, exercise, learning, and work. For centuries, researchers have tried to understand what effort is and how it shapes human behavior. Yet, despite its importance, there is no overarching consensus on what effort represents and how it should be measured. Attesting to this, academic disciplines conceptualize and measure effort in strikingly different ways. While this highlights the multitude of factors relevant to understanding effort, it has also led to siloed approaches, making interdisciplinary integration challenging. To facilitate interdisciplinary exchange, this guide aims to provide a descriptive and impartial overview of frequently used effort conceptualization and proxies. We first review three prominent conceptualizations of effort: force-based, resource-based, and mediation-based accounts. Second, we present a broad overview of commonly used effort proxies, reflecting changes in one system: neurophysiological, metabolic, psychological, and behavioral output. For each, we provide a brief review of properties, applications, and limitations relevant to effort-related research. With this approach, our aim is not to resolve disciplinary differences by pitting the utility of different conceptualizations and proxies against each other. Rather, we aim to provide a shared conceptual framework on which more integrative theorizing and cumulative progress in effort research can be achieved across disciplines.
Endometriosis is characterized by inflammation and fibrosis, in which cytokines and cytokine-macrophage interactions serve as critical mediators. However, the specific mechanisms that initiate the fibrotic cascade in endometriosis remain poorly defined. Spatial transcriptomics (ST) and cellular interaction analyses were performed on human specimens of endometriotic lesions and normal endometrium. An endometriosis mouse model was used to evaluate the effect of IL-17 C neutralization with the MOR106 antibody on ectopic lesion growth and fibrosis. In vitro experiments were conducted to explore the role of IL-17 C in macrophage polarization and extracellular matrix (ECM) production by endometrial stromal cells (ESCs). IL-17RE expression was significantly upregulated in endometriotic tissues compared with normal endometrium and correlated with endometriosis fibrosis. IL-17 C levels were markedly higher in patient-derived tissues and peritoneal fluid. In a mouse model of endometriosis, neutralization of IL-17 C with the MOR106 antibody inhibited ectopic lesion growth and alleviated fibrosis in both eutopic and ectopic endometrium. Importantly, MOR106 selectively reduced CD206 + M2 macrophage infiltration in lesions without significantly altering the M1 macrophage population, suggesting that IL-17 C primarily drives M2-like macrophage accumulation in vivo. In vitro, IL-17 C promoted macrophage polarization toward a pro-fibrotic M2-like phenotype, and these IL-17 C-induced M2 macrophages enhanced ECM production by ESCs via activation of the MAPK/ERK pathway. Targeting the IL-17 C/IL-17RE axis provides a promising novel therapeutic strategy for mitigating fibrosis in endometriosis.