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Mathematical bounds on r² and the effect size in case-control genome-wide association studies

Theoretical Population Biology 2025年 164卷 1-11页

作者： Paye, Sanjana M. Edge, Michael D. Department of Quantitative and Computational Biology University of Southern California United States University of Michigan Medical Scientist Training Program United States

Case-control genome-wide association studies (GWAS) are often used to find associations between genetic variants and diseases. When case-control GWAS are conducted, researchers must make decisions regarding how many cases and how many controls to include in the study. Connections between variants and diseases are made using association statistics, including χ². Previous work in population genetics has shown that LD statistics, including r², are bounded by the allele frequencies in the population being studied. Since varying the case fraction changes sample allele frequencies, we use the known bounds on r² to explore how the fraction of cases included in a study can affect statistical power to detect associations. We analyze a simple mathematical model and use simulations to study a quantity proportional to the χ² noncentrality parameter, which is closely related to r², under various conditions. Varying the case fraction changes the χ² noncentrality parameter, and by extension the statistical power, with effects depending on the dominance, penetrance, and frequency of the risk allele. Our framework explains previously observed results, such as asymmetries in power to detect risk vs. protective alleles, and the fact that a balanced sample of cases and controls does not always give the best power to detect associations, particularly for highly penetrant minor risk alleles that are either dominant or recessive. We show by simulation that our results can be used as a rough guide to statistical power for association tests other than χ² tests of independence. © 2025 Elsevier Inc.

关键词： Case control studies Genome-wide association studies Linkage disequilibrium Mathematical bounds Population genetics

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Carcinogenetic mechanisms employed by the oral microbiome: A narrative review

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American Journal of the medical Sciences 2025年第5期369卷 556-561页

作者： Menghani, Sanjay V. University of Arizona College of Medicine – Tucson AZ United States Medical Scientist Training MD-PhD Program University of Arizona College of Medicine Tucson AZ United States

Cancers of the oral cavity, lip, salivary gland, and oropharynx cause substantial global disease burden. While tobacco-use and alcohol use are highly associated with oral cancers, the rising incidence of disease in patients who do not use tobacco or alcohol points to additional carcinogenic risk factors. Chronic inflammation, disruption of the oral microbiome, and dysbiosis are becoming more widely implicated in the pathogenesis of oral cancer. Several studies have identified specific bacterial species enriched in patients with oral cancer, including Porphyromonas gingivalis and Fusobacterium nucleatum. In this narrative review, we describe potential carcinogenic mechanisms exhibited by these species and other microbes in the development of oral cancer. © 2025

关键词： Carcinogenesis Fusobacterium nucleatum Immunology Oral cancer Oral microbiome Porphyromonas gingivalis

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Third-order entropy for spatiotemporal neural network characterization

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Journal of Neurophysiology 2025年第4期133卷 1234-1244页

作者： Deshpande, Sarita S. van Drongelen, Wim Medical Scientist Training Program University of Chicago Chicago IL United States Committee on Neurobiology University of Chicago Chicago IL United States Section of Pediatric Neurology University of Chicago Chicago IL United States Committee on Computational Neuroscience University of Chicago Chicago IL United States

The human brain comprises an intricate web of connections that generate complex neural networks capable of storing and processing information based on factors such as network structure, connectivity strength, and interactions. To further unravel and understand this information, we introduce third-order entropy, a new metric grounded in the Triple Correlation Uniqueness (TCU) theorem. Triple correlation, which provides a complete and unique characterization of the network, relates three nodes separated by up to two spatiotemporal lags. Based on these four lags, we evaluate third-order entropy from the spatiotemporal lag probability distribution function (PDF) of the network activity’s triple correlation. Given a spike raster, we compute triple correlation by iterating over time and space. Summing the contributions to the triple correlation over each of the spatial and temporal lag combinations generates a 4-D spatiotemporal frequency histogram, from which we estimate a PDF and compute entropy. To validate our approach, we first estimate third-order entropy from feedforward motifs in a simulated spike raster and then simulate the effects of adding increasing motif-class structure to a Poisson-modeled spike raster. Finally, we apply this methodology to spiking activity recorded from rat cortical cultures and compare our results to previously published results of pairwise entropy over time. Although first- and second-order metrics of activity (spike rate and cross-correlation) show agreement with previously published results, our TCU-based third-order entropy computation is a more complete tool for neural network characterization and reveals a greater depth of underlying network organization compared with pairwise entropy. NEW & NOTEWORTHY Here, we present third-order entropy built from triple correlation, which measures spatiotemporal interactions among up to three neurons. Per the Triple Correlation Uniqueness theorem, third-order entropy is based on a complete and un

关键词： entropy neural network characterization Triple Correlation Uniqueness theorem

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A Novel Catheter-Based Method for Denervation of Afferent Renal Nerves in Sheep

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Cardiovascular Engineering and Technology 2025年 1-10页

作者： de la Cruz-Lynch, Arthur Dailey-Krempel, Brianna Dayton, Alex Nguyen, Duc T. Tyshynsky, Roman Van Helden, Dusty Lahti, Matthew Carney, John Evans, Louise Vulchanova, Lucy Osborn, John Department of Surgery University of Minnesota MinneapolisMN55455 United States Department of Integrative Biology & Physiology University of Minnesota MinneapolisMN55455 United States Medical Scientist Training Program University of Minnesota MinneapolisMN55455 United States Department of Neuroscience University of Minnesota MinneapolisMN55455 United States Experimental Surgical Services Laboratory University of Minnesota MinneapolisMN55455 United States

Purpose: Catheter-based total renal denervation (TRDN) has recently gained FDA approval to lower blood pressure in patients with treatment-resistant hypertension. Current TRDN technologies indiscriminately destroy efferent (sympathetic) and afferent (sensory) renal nerves. However, preclinical studies suggest that the beneficial effects of TRDN may be due to ablation of afferent, rather than efferent, renal nerves. We developed a novel method for chemical ablation of afferent renal nerves by periaxonal application of capsaicin which has been employed in mouse and rat models of hypertension. In certain rodent models afferent-specific renal denervation (ARDN) has been shown to lower arterial pressure to the same degree as TRDN. The objective of the present study was to develop a catheter-based method for ARDN in a large animal model with the long-term goal of translating this treatment to humans. We tested the feasibility of using the Peregrine™ catheter infusion system, currently used to perform TRDN in humans by injection of ethanol, to perform catheter-based afferent renal denervation in sheep by periaxonal application of capsaicin. Methods: Castrated, adult, male, Friesen sheep underwent Sham RDN (saline, n = 2), TRDN (ethanol, n = 4), or ARDN (capsaicin, n = 4) with the Peregrine™ catheter before termination > 2 weeks after the procedure. Denervation of renal efferents was verified by measurement of renal cortical norepinephrine (NE) content and anti-tyrosine hydroxylase (TH) staining;denervation of renal afferents was verified with anti-calcitonin gene-related peptide (CGRP) staining. Results: There was a significant decrease in TH + and CGRP + fibers in TRDN kidneys and in CGRP + but not TH + fibers in ARDN kidneys. TRDN significantly reduced renal cortical norepinephrine (NE) content by 89% while ARDN had similar NE content to Sham RDN kidneys. Conclusions: This study establishes the feasibility of performing catheter-based afferent renal denervation in a larg

关键词： Rats

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Pathognomonic

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Journal of General Internal Medicine 2025年第5期40卷 1200-1200页

作者： Zhu, David T. Medical Scientist Training Program School of Medicine Virginia Commonwealth University Richmond VA United States

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Incidence and risk factors for rejection after conversion from calcineurin inhibitor to sirolimus-based immunosuppression in orthotopic heart transplant recipients

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Journal of Heart and Lung Transplantation 2025年第6期44卷 975-983页

作者： Inglis, Sara S. Abbas, Mohsin Asleh, Rabea Garmany, Armin Smith, Byron H. Kushwaha, Sudhir Pereira, Naveen Clavell, Alfredo L. Villavicencio, Mauricio A. Spencer, Philip J. Daly, Richard C. Behfar, Atta Rosenbaum, Andrew N. Van Cleve Cardiac Regenerative Medicine Program Mayo Clinic Rochester MN United States Deparment of Cardiovascular Medicine Mayo Clinic Rochester MN United States of Biomedical Sciences Alix School of Medicine Medical Scientist Training Program Mayo Clinic Rochester MN United States Department of Biostatistics Mayo Clinic Rochester MN United States Department of Cardiovascular Surgery Mayo Clinic Rochester MN United States

Background: Although recommended in International Society for Heart and Lung Transplantation (ISHLT) guidelines, transition to mammalian targets of rapamycin (mTOR) inhibitors in heart transplant recipients is not routinely performed, in part due to perceived risk of rejection. This study sought to evaluate the incidence and risk factors for biopsy-proven, clinically relevant rejection following conversion from calcineurin inhibitor (CNI) to sirolimus (SRL) immunosuppression. Methods: A single center retrospective study was conducted of all consecutive adult patients who underwent orthotopic heart transplantation (OHT) and CNI-free SRL conversion from January 1999 to January 2023. All post-OHT biopsy data were obtained and graded per ISHLT criteria (antibody-mediated rejection [pAMR] or acute cellular rejection [ACR]). The primary endpoint was early rejection, defined as grade 2R ACR, pAMR 1, or greater, within 6 months after conversion. Results: Three hundred and seventeen patients (72% male, mean age 51.5 ± 12.6 years) were included. Median time to SRL conversion following OHT was 0.76 years (IQR 0.49, 1.42). Median time from conversion to rejection was 0.51 years (IQR 0.31, 1.05). Thirty eight patients (12%) experienced early rejection. Following multivariate analysis, both timing to SRL conversion following OHT (OR 0.94 per month, 95% CI: 0.89–0.99, p-value = 0.0054) and age at transplantation (OR 0.96, 95% CI: 0.93–0.99, p-value = 0.0071) were independently associated with early rejection. Rejection following SRL conversion was not associated with increased risk of cardiac allograft vasculopathy (CAV) grade 2-3. Conclusions: In a CNI-free SRL conversion protocol, both earlier SRL conversion following OHT and younger age at transplant are independently associated with early rejection, but rejection is not associated with a net increased risk of prognostically important CAV. Individualization of transition is necessary to mitigate risk, and these findings may aid

关键词： cardiac allograft vasculopathy cardiac transplantation MTOR inhibitor rejection sirolimus

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An innate drive to save a life

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Science (New York, N.Y.) 2025年第6736期387卷 827-828页

作者： William M Sheeran Zoe R Donaldson Department of Molecular Cellular and Developmental Biology University of Colorado Boulder Boulder CO USA. Medical Scientist Training Program University of Colorado School of Medicine Aurora CO USA. Department of Psychology and Neuroscience University of Colorado Boulder Boulder CO USA.

In mice, two brain regions drive the impulse to revive an unconscious companion.

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Impact of adjuvant interstitial brachytherapy on lengths of stay, discharge disposition, and 30-/90-day readmission for malignant brain tumor patients: a national readmission database analysis

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Discover Medicine 2025年第1期2卷 1-11页

作者： Sun, Kevin W. Zhu, Ping Do, Truong H. Chen, Clark C. Medical Scientist Training Program University of Cincinnati Cincinnati USA Department of Neurosurgery University of Minnesota Minneapolis USA Department of Neurosurgery Warren Alpert School of Medicine Rhode Island Hospital Brown University Providence USA

Advances in interstitial brachytherapy for brain cancers have revived interest in this treatment platform. However, the impact of this therapy on hospital quality measures remains poorly characterized. Here, we utilized the National Readmission Database (NRD) to address this gap in knowledge by identifying associations between interstitial brachytherapy and hospital course, discharge disposition, and readmission rates. We identified patients in the United States of America with malignant brain tumors who had undergone either craniotomies (C) for tumor resection or craniotomies augmented with adjuvant interstitial brachytherapy (C + IB) in the National Readmission Database (NRD, 2010–2018). Propensity-score weighting and survey regression techniques were used for analysis. Over the study period, the number of craniotomies with adjuvant interstitial brachytherapy (C + IB) steadily decreased. For brain metastasis (BM) patients, C + IB and C patients exhibited comparable length of hospital stay (aIRR: 1.01, CI95 0.86–1.18, p = 0.918) and routine discharge to home or self-care (aOR:0.95, CI95:0.61–1.50, p = 0.838). However, primary brain tumor (PBT) patients who underwent C + IB showed longer hospital stay (aIRR:1.43, CI95:1.03–1.99, p = 0.032) and were less likely to undergo routine discharge (aOR: 0.38, CI95:0.20–0.74, p = 0.005) relative to the C cohort. Despite these differences, C + IB and C patients showed comparable 30- or 90- day readmission risks. The profile of readmission diagnoses was also similar. Cost-analysis suggests that IB increased the median total charge by $19,184 (p = 0.003). Our NRD analysis suggests that adjuvant interstitial brachytherapy did not alter hospital course/readmission risk for brain metastasis patients. However, primary brain tumor patients who underwent this therapy showed longer hospitalization and an increased likelihood of non-routine discharge.

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Glymphatics and meningeal lymphatics unlock the brain-immune code

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Immunity 2025年第5期58卷 1040-1051页

作者： Kim, Min Woo Kipnis, Jonathan Brain Immunology and Glia (BIG) Center Washington University in St. Louis School of Medicine St. Louis MO United States Department of Pathology and Immunology Washington University in St. Louis School of Medicine St. Louis MO United States Medical Scientist Training Program Washington University in St. Louis School of Medicine St. Louis MO United States

The central nervous system (CNS) was once perceived as entirely shielded from the immune system, protected behind the blood-brain barrier and thought to lack lymphatic drainage. However, recent evidence has challenged many dogmas in neuroimmunology. Indeed, by means of glymphatics, brain-derived “waste” from deep within the CNS mobilizes toward immunologically active brain borders, where meningeal lymphatic vessels are appropriately positioned to drain antigens from the brain to the periphery. Accordingly, the presentation of brain-derived self-peptides emerges at the brain's borders and drives T cell responses with suppressive properties, critical in allowing active immunosurveillance while limiting aberrant immune reactivity. Taking into consideration these concepts, we further discuss how inflammation, aging, and neurodegenerative diseases potentially reshape the repertoire of self-antigens and immune cells, disrupting the healthy dialogue between the CNS and immune system. Collectively, this evolving perspective unveils new therapeutic avenues for CNS pathologies. © 2025 The Author(s)

关键词： glymphatics meningeal immunity meningeal lymphatics neuroimmunology

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δ-Containing GABA_A receptors on parvalbumin interneurons modulate neuronal excitability and network dynamics in the mouse medial prefrontal cortex

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Journal of neurophysiology 2025年第4期133卷 1003-1013页

作者： Lu, Xinguo Shu, Hong-Jin Lambert, Peter M. Benz, Ann Zorumski, Charles F. Mennerick, Steven Department of Psychiatry Washington University in St. Louis School of Medicine St. Louis MO United States Medical Scientist Training Program Washington University in St. Louis School of Medicine St. Louis MO United States Taylor Family Institute for Innovative Psychiatric Research Washington University in St. Louis School of Medicine St. Louis MO United States

In medial prefrontal cortex (mPFC), fast-spiking parvalbumin (PV) interneurons regulate excitability and microcircuit oscillatory activity important for cognition. Although PV interneurons inhibit pyramidal neurons, they themselves express δ subunits of GABAA receptors important for slow inhibition. However, the specific contribution of δ-containing GABAA receptors to the function of PV interneurons in mPFC is unclear. We explored cellular, synaptic, and local-circuit activity in PV interneurons and pyramidal neurons in mouse mPFC after selectively deleting δ subunits in PV interneurons (cKO mice). In current-clamp recordings, cKO PV interneurons exhibited a higher frequency of action potentials and higher input resistance than wild-type (WT) PV interneurons. Picrotoxin increased firing and GABA decreased firing in WT PV interneurons but not in cKO PV interneurons. The δ-preferring agonist THIP reduced spontaneous inhibitory postsynaptic currents disproportionately in WT pyramidal neurons compared with cKO pyramidal neurons. In WT slices, depolarizing the network with 400 nM kainate increased firing of pyramidal neurons but had little effect on PV interneuron firing. In contrast, kainate application in cKO slices preferentially activated PV interneurons rather than pyramidal neurons. At the population level, kainate induced broadband increases in local field potentials in WT but not in cKO slices. These results on cells and network activity can be understood through increased excitability of cKO PV interneurons. In summary, our study demonstrates that δ-containing GABAA receptors in mPFC PV interneurons play a crucial role in regulating their excitability and the phasic inhibition of pyramidal neurons, elucidating intricate mechanisms governing cortical *** & NOTEWORTHY We reveal the critical role of δ-containing GABAA receptors in parvalbumin interneurons in the medial prefrontal cortex, important for human neuropsychiatric disorders. We demonstrate these

关键词： medial prefrontal cortex neuronal excitability parvalbumin interneurons δ-containing GABAA receptors

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