University Medical Center

Empirical research on sensory processing often focuses on group averages to uncover how sensory input translates into behavior. While this population-level approach has revealed important general principles of genetic and environmental control of behavior, it masks the rich and potentially meaningful variation observed at the level of individuals. Key features of sensory processing are reactivity, the degree to which a stimulus elicits a response, and habituation, a fundamental learning process that serves as a cognitive filter by reducing the response to repeated, irrelevant stimuli. We developed a model-based approach to quantify individual sensory processing dynamics, using a visual escape paradigm in Drosophila. We collected light-off jump responses in more than two hundred flies and quantified them individually via Bayesian inference of a dynamical model's parameters. Considering both reactivity and habituation, we found that quantitative properties of individual responses vary greatly even in an isogenic population raised under identical environmental conditions. By moving from population averages to individual-based analyses, we uncover and quantify pronounced stochasticity in individual responses. Furthermore, we found that individual reactivity and habituation parameters display substantial temporal stability over a two-week interval, indicating that these behaviors are stable, intrinsic properties of an individual. The presented framework enables robust stratification of individual behavioral phenotypes and provides a quantitative platform for modeling interindividual differences in sensory processing, including frequently observed atypical responses in neurogenetic diseases.

The DNA demethylase ten-eleven translocation enzyme 2 (TET2) is frequently inactivated in hematologic malignancies, yet how its loss shapes oncogene-driven transformation remains unclear. Using a mouse model in which MYC is overexpressed in the B cell lineage, driving aggressive B cell lymphoma, we show that Tet2 loss increases lymphoma penetrance and biases disease toward an IgM+ immunophenotype. Established lymphomas are broadly similar across genotypes, suggesting that Tet2 loss exerts much of its effects before lymphoma onset. Accordingly, Tet2 loss expands a premalignant IgM+ B cell subset with reduced apoptotic sensitivity and an increased frequency of BCL2+BIMhi cells. Consistently, Tet2 deficient IgM+ B cells persist better in in vitro cultures, show increased clonogenic survival, and exhibit clonal skewing. These findings support a model in which Tet2 loss heightens MYC-driven lymphoma penetrance by promoting the survival and selection of premalignant B cells under apoptotic stress.

Summary The role of the peripheral immune system in Alzheimer’s Disease (AD) remains insufficiently resolved, limiting the understanding of systemic disease effects and mechanisms. Here, we employed three high-resolution single-cell techniques, including flow cytometry, single-cell RNA- and ATAC-sequencing, to investigate peripheral immunity in AD dementia and earlier stages of the AD trajectory in over 100 patients. We identified reduced humoral immune responses in AD, characterized by a diminished B cell compartment displaying an impaired activation phenotype. Classical monocytes expanded in mild cognitive impairment and early AD dementia, acquiring a NF- k B/AP-1-mediated low-grade inflammation phenotype. Our findings link peripheral dysregulation in innate and adaptive immunity at cell frequency, transcriptional and epigenetic levels to the AD trajectory and provide insights into distinct phenotypes that define AD progression in contrast to healthy aging across cohorts.

ObjectiveLiver diseases represent a major global health burden. Growth Differentiation Factor 15 (GDF-15), a stress-induced cytokine, has been suggested to protect against fibrosis progression through neuro-metabolic-immunologic pathways and to regulate energy and lipid homeostasis, potentially influencing hepatic steatosis. This study evaluated the role of GDF-15 in steatosis and fibrosis, considering prior liver injury, alcohol intake, insulin resistance, and obesity.Design and methodsIn this retrospective cohort study, 626 participants from a large population-based cohort were analyzed. Associations of baseline GDF-15, alcohol intake, FIB-4 score, and metabolic risk factors with hepatic steatosis and fibrosis over 6 years were examined using linear regression models.ResultsIn participants with elevated baseline FIB-4, the interaction of GDF-15 and FIB-4 was positively associated with follow-up liver stiffness (β = 0.47, p = 0.045). Interactions between GDF-15 and higher alcohol intake (3rd/4th quantiles) were negatively associated with stiffness (β = −1.68, p = 0.002; β = −1.43, p = 0.038). GDF-15 was positively associated with follow-up steatosis (β = 37.14, p = 0.006). Higher HOMA-IR (3rd/4th quantile) was linked to increased steatosis (β = 31.15, p = 0.032; β = 38.15, p = 0.023), whereas interactions of HOMA-IR × GDF-15 were inversely associated (β = −38.98, p = 0.008; β = −38.54, p = 0.019), suggesting a protective modulation.ConclusionsGDF-15 appears to modulate hepatic steatosis and fibrosis in individuals with metabolic or lifestyle risk factors, supporting its potential as a therapeutic target and warranting further investigation of the neuro-metabolic-immunologic axis.

Fecal incontinence is a common, yet underdiagnosed condition, disproportionately affecting women and significantly impacting health and quality of life. Pelvic floor muscle training and biofeedback are recommended first-line treatments, yet access, adherence, and stigma remain substantial barriers to care. Digital therapies may offer an effective alternative to address barriers. To evaluate real-world outcomes with use of a prescription digital therapeutic device for treatment of fecal incontinence in women. This observational cohort study analyzed de-identified data from women who used the device between July 1, 2023-August 1, 2024. Commercial users of the device in the United States. Adult women with fecal incontinence, identified by self-report or clinical diagnosis, who completed baseline and 8-week Colorectal Anal Distress Inventory-CRADI-8 symptom surveys. Eight weeks of use of an intravaginal motion-based biofeedback device paired with smartphone application to guide pelvic floor muscle training. Baseline-to-8-week Colorectal Anal Distress Inventory-CRADI-8 score change; achievement of Colorectal Anal Distress Inventory-CRADI-8 minimum clinically important difference, global improvement scores, adherence, pelvic floor performance metrics. Among 214 eligible users, 200 self-reported FI symptoms and 14 had a clinical diagnosis with mean age 58.8 years and mean body mass index 27.5 kg/m 2. Mean CRADI-8 score change was -8.2 points (±15.5; p < 0.0001); 58.4% met the minimum clinically important difference. Of 142 respondents, 73% reported global improvement. Device-captured pelvic floor performance improved significantly. Weekly adherence remained high. No serious device-related adverse events were reported. Selection bias, lack of comparator, reliance on patient reported outcomes, limited clinical diagnostic confirmation, generalizability. Use of a digital therapeutic device was associated with significant improvements in fecal incontinence and pelvic floor function in a real-world cohort of women. High user engagement and clinically important symptom reduction support the potential of home-based digital interventions to expand access to conservative management and address persistent gaps in women's pelvic health care. See Video Abstract.

Previous studies reported low [ 18 F] fluorodeoxyglucose ([ 18 F]FDG) PET uptake in estrogen receptor-positive breast tumours, potentially missing detection of distant metastases. This study assessed the proportion of estrogen receptor-positive hypometabolic tumours, clinical factors influencing [ 18 F]FDG uptake, and the prognostic impact. Baseline [ 18 F]FDG PET/computed tomography (CT) and [ 18 F]FDG PET/MRI exams of female patients diagnosed with estrogen receptor-positive locally advanced (cT3-4N0 or cT1-4N+), metastatic, or recurrent breast cancer between 2013-2022 were retrospectively collected. Different thresholds of maximum standardised uptake value (SUV max ) and tumour-to-background ratio (TBR; SUV max tumour/SUV max background) were applied to determine the proportion of hypometabolic [ 18 F]FDG PET exams. Logistic regression and survival analysis were performed. 119 patients underwent [ 18 F]FDG PET/CT and 31 [ 18 F]FDG PET/MRI. The proportion of hypometabolic tumours for SUV max thresholds 2.0, 2.5, 3.0, TBR of contralateral breast less than or equal to 1, and TBR of liver less than or equal to 1 was 8.4, 15.1, 21.8, 5.1, and 28.6%, respectively for [ 18 F]FDG PET/CT and 16.1, 19.4, 29.0, 6.9, and 35.5% for [ 18 F]FDG PET/MRI. Clinically tumour status (cT-status), histology type, and tumour grade were associated with the presence of a hypometabolic tumour. No PET-derived variables were associated with recurrence-free survival. A considerable proportion of estrogen receptor-positive breast tumours showed low SUV max , indicating potential suboptimal staging on [ 18 F]FDG PET. In patients with lower cT-status, lobular histology and low-grade estrogen receptor-positive tumour, [ 18 F]FDG PET may be less reliable as staging procedure. Further research is necessary to determine the optimal metabolic threshold for defining a hypometabolic tumour.