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Cell Mol Gastroenterol Hepatol. 2025 Nov 4:101671. doi: 10.1016/j.jcmgh.2025.101671. Online ahead of print.

ABSTRACT

BACKGROUND & AIMS: Localised acidification from immune cell infiltration and heightened glycolysis contributes to colitis pathology by activating acid-sensing receptors such as GPR68, a proton-sensing GPCR expressed on immune and stromal cells. Single-cell RNAseq analysis revealed GPR68 is also expressed in colonic sensory neurons, prompting us to investigate its role in acid-induced colonic nociception.

METHODS: Expression of GPR68 in colonic nociceptors and tissue from people with colitis was confirmed by in silico analysis of our RNAseq databases. Its contribution to disease activity was assessed using the acute dextran sulphate sodium (DSS) model of colitis. Acid-evoked sensory signalling was evaluated via colonic afferent recordings and Ca2+ imaging in DRG neurons from wild-type and GPR68-/- mice, supported by pharmacological studies using Ogerin (a GPR68 positive allosteric modulator) and Ogremorphin (a GPR68 antagonist).

RESULTS: RNAseq analysis showed GPR68 is robustly expressed in Trpv1+ colonic nociceptors and upregulated in tissue from people with inflammatory bowel disease, consistent with reduced disease activity in DSS-treated GPR68-/- mice. Genetic deletion of GPR68 abolished colonic afferent responses to acid, which were also attenuated by Ogremorphin and enhanced by Ogerin. In Ca2+-free buffer, DRG neurons from GPR68-/- mice or those pre-treated with Ogremorphin showed significantly reduced acid-evoked intracellular Ca2+ responses. By contrast the colonic afferent and DRG Ca2+ response (in Ca2+-containing buffer) to capsaicin was comparable between tissue from wild-type and GPR68-/- mice highlighting the involvement of divergent proton-dependent cellular signalling cascades.

CONCLUSIONS: These findings identify GPR68 as a key mediator of acid-induced colonic nociception and highlight its potential as a therapeutic target for the treatment of pain in colitis.

PMID:41197770 | DOI:10.1016/j.jcmgh.2025.101671

Cell Mol Gastroenterol Hepatol. 2025 Nov 4:101671. doi: 10.1016/j.jcmgh.2025.101671. Online ahead of print.

ABSTRACT

BACKGROUND & AIMS: Localised acidification from immune cell infiltration and heightened glycolysis contributes to colitis pathology by activating acid-sensing receptors such as GPR68, a proton-sensing GPCR expressed on immune and stromal cells. Single-cell RNAseq analysis revealed GPR68 is also expressed in colonic sensory neurons, prompting us to investigate its role in acid-induced colonic nociception.

METHODS: Expression of GPR68 in colonic nociceptors and tissue from people with colitis was confirmed by in silico analysis of our RNAseq databases. Its contribution to disease activity was assessed using the acute dextran sulphate sodium (DSS) model of colitis. Acid-evoked sensory signalling was evaluated via colonic afferent recordings and Ca2+ imaging in DRG neurons from wild-type and GPR68-/- mice, supported by pharmacological studies using Ogerin (a GPR68 positive allosteric modulator) and Ogremorphin (a GPR68 antagonist).

RESULTS: RNAseq analysis showed GPR68 is robustly expressed in Trpv1+ colonic nociceptors and upregulated in tissue from people with inflammatory bowel disease, consistent with reduced disease activity in DSS-treated GPR68-/- mice. Genetic deletion of GPR68 abolished colonic afferent responses to acid, which were also attenuated by Ogremorphin and enhanced by Ogerin. In Ca2+-free buffer, DRG neurons from GPR68-/- mice or those pre-treated with Ogremorphin showed significantly reduced acid-evoked intracellular Ca2+ responses. By contrast the colonic afferent and DRG Ca2+ response (in Ca2+-containing buffer) to capsaicin was comparable between tissue from wild-type and GPR68-/- mice highlighting the involvement of divergent proton-dependent cellular signalling cascades.

CONCLUSIONS: These findings identify GPR68 as a key mediator of acid-induced colonic nociception and highlight its potential as a therapeutic target for the treatment of pain in colitis.

PMID:41197770 | DOI:10.1016/j.jcmgh.2025.101671

Psychiatr Serv. 2025 Nov 6:appips20240554. doi: 10.1176/appi.ps.20240554. Online ahead of print.

ABSTRACT

Metabolic illness is a major source of morbidity and mortality both for people with mental illness and those with intellectual or developmental disability. In this column, the authors describe the pilot testing of the metabolic risk management index system, a quality improvement initiative for managing metabolic health risk in clinical and residential settings that includes data-based tools that can be easily used by direct-care staff. They also report some preliminary outcomes (N=199 individuals). The pilot test was conducted in an organization that serves individuals with mental illnesses and developmental disorders, but the index could easily be adapted for use in other clinical settings.

PMID:41194655 | DOI:10.1176/appi.ps.20240554

Nature. 2025 Nov 5. doi: 10.1038/s41586-025-09684-7. Online ahead of print.

ABSTRACT

Breast cancer is the leading cause of cancer-related death in women worldwide1. Here, in the Breast Cancer-Anti-Progestin Prevention Study 1 (BC-APPS1; NCT02408770 ), we assessed whether progesterone receptor antagonism with ulipristal acetate for 12 weeks reduces surrogate markers of breast cancer risk in 24 premenopausal women. We used multilayered OMICs and live-cell approaches as readouts for molecular features alongside clinical imaging and tissue micromechanics correlates. Ulipristal acetate reduced epithelial proliferation (Ki67) and the proportion, proliferation and colony formation capacity of luminal progenitor cells, the putative cell of origin of aggressive breast cancers2. MRI scans showed reduction in fibroglandular volume with treatment, whereas single-cell RNA sequencing, proteomics, histology and atomic force microscopy identified extracellular matrix remodelling with reduced collagen organization and tissue stiffness. Collagen VI was the most significantly downregulated protein after ulipristal acetate treatment, and we uncovered an unanticipated spatial association between collagen VI and SOX9high luminal progenitor cell localization, establishing a link between collagen organization and luminal progenitor activity. Culture of primary human breast epithelial cells in a stiff environment increased luminal progenitor activity, which was antagonized by anti-progestin therapy, strengthening this mechanistic link. This study offers a template for biologically informed early-phase therapeutic cancer prevention trials and demonstrates the potential for premenopausal breast cancer prevention with progesterone receptor antagonists through stromal remodelling and luminal progenitor suppression.

PMID:41193807 | DOI:10.1038/s41586-025-09684-7

Nature. 2025 Nov 5. doi: 10.1038/s41586-025-09684-7. Online ahead of print.

ABSTRACT

Breast cancer is the leading cause of cancer-related death in women worldwide1. Here, in the Breast Cancer-Anti-Progestin Prevention Study 1 (BC-APPS1; NCT02408770 ), we assessed whether progesterone receptor antagonism with ulipristal acetate for 12 weeks reduces surrogate markers of breast cancer risk in 24 premenopausal women. We used multilayered OMICs and live-cell approaches as readouts for molecular features alongside clinical imaging and tissue micromechanics correlates. Ulipristal acetate reduced epithelial proliferation (Ki67) and the proportion, proliferation and colony formation capacity of luminal progenitor cells, the putative cell of origin of aggressive breast cancers2. MRI scans showed reduction in fibroglandular volume with treatment, whereas single-cell RNA sequencing, proteomics, histology and atomic force microscopy identified extracellular matrix remodelling with reduced collagen organization and tissue stiffness. Collagen VI was the most significantly downregulated protein after ulipristal acetate treatment, and we uncovered an unanticipated spatial association between collagen VI and SOX9high luminal progenitor cell localization, establishing a link between collagen organization and luminal progenitor activity. Culture of primary human breast epithelial cells in a stiff environment increased luminal progenitor activity, which was antagonized by anti-progestin therapy, strengthening this mechanistic link. This study offers a template for biologically informed early-phase therapeutic cancer prevention trials and demonstrates the potential for premenopausal breast cancer prevention with progesterone receptor antagonists through stromal remodelling and luminal progenitor suppression.

PMID:41193807 | DOI:10.1038/s41586-025-09684-7

BMC Public Health. 2025 Oct 30;25(1):3669. doi: 10.1186/s12889-025-24368-7.

ABSTRACT

BACKGROUND: Adherence to tuberculosis(TB) preventive treatment (TPT) remains a significant challenge in high-TB burden countries like Bangladesh, where approximately 44 million people are infected with latent tuberculosis.

METHODS/DESIGN: This study protocol describes a mixed-methods observational study to evaluate "iDOTS," a locally developed digital adherence technology adapted from 99DOTS, for monitoring and improving TPT adherence among adult household contacts of bacteriologically confirmed pulmonary TB patients. The study will be conducted in two districts in Bangladesh with similar geographical and societal characteristics, with Narsingdi as the intervention site and Manikganj as the control site. Applying the Unified Theory of Acceptance and Use of Technology (UTAUT), we will assess technology acceptance, implementation challenges, and effectiveness through quantitative and qualitative approaches. The mixed method approach will compare TPT adherence between iDOTS users and non-users, and will explore user experiences and attitudes among healthcare providers and patients. Adherence will be verified through a combination of digital records, self-reports, and random isoniazid urine testing.

DISCUSSION: With an estimated sample size of 422 patients and 77 healthcare providers, this study aims to generate evidence that if digital adherence technologies can strengthen TPT implementation in resource-limited settings. The findings will address critical gaps in the TPT cascade and inform strategies for scaling up TPT nationally, ultimately supporting global efforts to reduce the TB disease burden through effective preventive measures.

TRIAL REGISTRATION: 'Not applicable'.

PMID:41168758 | DOI:10.1186/s12889-025-24368-7

Front Psychiatry. 2025 Oct 13;16:1669530. doi: 10.3389/fpsyt.2025.1669530. eCollection 2025.

ABSTRACT

Behavior arises from the convergence of multiple constraints rather than single causes. The ARCH × Φ model formalizes this process as a computational grammar of behavior, in which Archetype (A), Drive (D), and Culture (C) interact multiplicatively, and expression occurs only when a context-sensitive threshold (Φ) is crossed. This scalar-vector framework specifies behavior as probabilistic and testable, supporting hypotheses that can be evaluated across neurobiological, behavioral, and symbolic domains. We define a provisional taxonomy of ten archetypal systems (Systema Behavorum), such as Agonix (competition), Theromata (caregiving), and Sacrifex (self-sacrifice), which serve as structured inputs to the grammar. ARCH × Φ integrates ethology, affective neuroscience, psychiatry, and cultural psychology, reframing archetypes not as metaphors but as conserved neural scripts subject to scalar amplification and symbolic modulation. The framework supports falsifiable predictions, operational definitions, and clinical applications in decoding motivation, threshold dysregulation, and symbolic distortion. ARCH × Φ thus reframes behavior as an emergent property of convergent constraints across biology, affect, culture, and context.

PMID:41158971 | PMC:PMC12554726 | DOI:10.3389/fpsyt.2025.1669530

Eur Spine J. 2025 Oct 29. doi: 10.1007/s00586-025-09460-1. Online ahead of print.

ABSTRACT

BACKGROUND: Mechanical complications requiring revision represent one of the main issues after surgical management for adult spine deformity (ASD). The heterogeneity of the population and the multifactorial nature of mechanical complications have not yet allowed to identify patient-specific risk factors for this complication. The aim of this study was to utilize machine learning (ML) to create homogeneous patient clusters, which could then be analyzed with classical statistical methods to evaluate with granularity the type and rate of mechanical complications and the relative risk factors.

METHODS: All patients who underwent surgical management for ASD and had a minimal follow-up of two years were clustered into three homogeneous groups. For each, the type and rate of mechanical complication requiring revision were analyzed and logistic regression and marginal effect study were used to evaluate possible risk factors.

RESULTS: For Cluster 1 (N = 192, younger subjects with coronal deformity), the revision rate for mechanical complication was 6% (33% pseudarthrosis, 13% screw loosening); the main risk factors were implant density, coronal balance and pelvic incidence at 6 weeks and presence of pelvic fixation. In Cluster 2 (N = 455, older patients with mild coronal and sagittal imbalance and mild disability) the revision rate was 19% (41% pseudarthrosis, 24% proximal junctional kyphosis - PJK); the main risk factors were thoracic kyphosis (TK) at 6 weeks, n. of instrumented levels, ODI, preoperative sacral obliquity, TK and pelvic tilt, and presence of pelvic fixation. In Cluster 3 (N = 172, older patients with severe imbalance and mild disability), the revision rate was 30% (58% pseudarthrosis, 14% screw loosening); the main risk factors were n. of instrumented levels and global tilt at 6 weeks.

CONCLUSION: ML allows to cluster patients into homogeneous groups, which showed differences for mechanical complication rates requiring revision, with specific risk factors in each group. This ML approach might improve preoperative risk assessment.

PMID:41152502 | DOI:10.1007/s00586-025-09460-1