A sensorimotor basis for facial expressivity differences in autism.
Bress KS, Quinde-Zilbut J, Zoltowski AR, Convery CA, Lewis B, Rogers BP, Vandekar S, Travers B, Cascio CJ.
Imaging Neurosci (Camb). 2025 Nov 10;3:IMAG.a.981. doi: 10.1162/IMAG.a.981. eCollection 2025.
PMID: 41230421 Free PMC article.
Abstract: In autism, differences in the appearance, timing, and intensity of facial expressions are a major barrier to social communication. While disrupted sensorimotor feedback has been proposed as a potential contributing factor, the neural pathways linking sensory input to facial motor control are poorly understood even in the general population. In this study, we provide novel characterization of resting-state functional connectivity (rs-FC) between the facial regions of the primary somatosensory (S1) and motor (M1) cortices in both nonautistic and autistic individuals. We identify that rs-FC is somatotopically patterned for the lower but not upper face in both groups, mirroring known anatomical differences in corticomotor inputs to the upper versus lower face musculature. We independently replicate this patterning in a large, open-source neuroimaging dataset. Critically, we demonstrate that upper face actions are selectively diminished in autism, and that the relationship between sensorimotor connectivity and facial behavior diverges between autistic and nonautistic individuals. These findings offer the first direct evidence of a sensorimotor basis for altered facial expressivity in autism, challenging long-held assumptions about the underlying mechanisms of this communication barrier and pointing toward new targets for therapeutic intervention.
Keywords: autism; facial expression; functional connectivity; primary motor cortex (M1); primary somatosensory cortex (S1); sensorimotor behavior.
Glutamine synthetase deficiency enhances CD8 T cell survival and stress resilience in the tumor microenvironment.
Fisher-Gupta EL, Hathaway ES, Perera JM, Jennings EQ, Chi C, Sewell AE, Stone SH, Muka JE, Sinard RC, DeCorte JA, Chen H, Wilson JT, Meiler J, Rathmell JC.
J Immunol. 2025 Oct 31:vkaf250. doi: 10.1093/jimmun/vkaf250. Online ahead of print.
PMID: 41171699
Abstract: Cellular immunotherapy has revolutionized the treatment of hematologic malignancies yet has had limited success in the solid tumor microenvironment (TME). While insufficient nutrients can lead to T cell metabolic stress in the TME, the glutamine antagonist DON can paradoxically enhance antitumor immunity. Because DON inhibits both essential and nonessential enzymes whose impairment may contribute to dose-limiting toxicities, mechanisms underlying DON-induced antitumor activity have remained unclear. Here, we aimed to identify specific DON targets that increase T cell antitumor activity and test if more selective inhibition of glutamine metabolism could replicate the effects of DON with reduced toxicity. CRISPR screening in the TME of DON-relevant glutamine metabolizing enzymes identified some targets that were essential in tumor-infiltrating CD8 T cells, but that tumor-infiltrating CD8 T cells lacking the DON target glutamine synthetase (GS) were enriched. Upon adoptive T cell transfers, GS-deficient CD8+ T cells displayed improved survival, a higher proportion TCF-1+ Tox- stem-like cells, and greater antitumor and memory function. GS converts glutamate to glutamine and GS-deficient cells exhibited increased intracellular glutamate and reduced glutathione levels, which correlated with enhanced mitochondrial respiration and resistance to reactive oxygen species. Pharmacological inhibition of GS reduced tumor burden in multiple orthotopic murine tumor models in a manner dependent on adaptive immunity. Our findings establish GS as a key metabolic regulator of CD8+ T cells stress resilience in the TME. By preserving intracellular glutamate, GS inhibition reprograms T cells for improved survival and function, offering a promising therapeutic strategy to enhance immune-based cancer treatments.
Keywords: T cell; antitumor immunity; glutamine; glutamine synthetase; immunometabolism.
Efficient kidney gene transfer and proximal tubule transduction using self-complementary AAV.cc47 vectors.
Peek JL, Rosales A, Qi J, Feleke L, Menshikh A, Welch RC, Woodard LE, Asokan A, Wilson MH.
Mol Ther Methods Clin Dev. 2025 Oct 6;33(4):101606. doi: 10.1016/j.omtm.2025.101606. eCollection 2025 Dec 11.
PMID: 41146875 Free PMC article.
Abstract: Gene delivery to critical cell types within the kidney can enable preclinical evaluation of gene therapies for kidney disease. The novel adeno-associated virus AAV.cc47 was discovered after sequential evolution in mice, pigs, and macaques and improved transduction in multiple tissues but without in-depth exploration of the kidney. We observed robust kidney transduction by AAV.cc47 vectors in mice in vivo and in human kidney organoids compared to AAV9, mostly within the proximal tubule (PT) epithelium. We then developed a quantitative analysis method of transgene expression utilizing automated classification of nephron cell types coupled with cellular expression. Despite exhibiting similar biodistribution to AAV9 in renal and extrarenal tissues, AAV.cc47 consistently transduced the kidney at higher efficiency, with >80% of PT epithelium transduced at low, systemically administered vector dose. Self-complementary AAV.cc47 vectors appear to transduce a subset of PT epithelium, with undetectable transduction of non-PT cells. This method could be adapted to evaluate different AAV vectors transducing other kidney cell types. We also demonstrate the utility of dual AAV.cc47 vectors to increase genome payload capacity for kidney gene transfer. AAV.cc47 represents a promising vector for use as a research tool and possibly clinical application for kidney disease.
Keywords: AAV; gene therapy; kidney; proximal tubule.
Implementation of a Physician Assistant-Led Recovery Model for Heart Transplantation: Clinical Outcomes and Programmatic Benefits at a High-Volume Center.
Petrovic M, Williams AM, Lowman J, DeVries S, Trahanas JM, Quintana E, Ahmad A, Wang CC, McGann K, Absi T, Bacchetta M, Schlendorf KH, Lima B, Shah AS, Bommareddi S.
Am J Transplant. 2025 Nov 12:S1600-6135(25)03102-8. doi: 10.1016/j.ajt.2025.11.003. Online ahead of print.
PMID: 41238023
Abstract: Physician assistant (PA)-led donor recovery models have been shown to be safe and effective in lung transplantation, but data on their application in heart transplantation (HT) are limited. We conducted an observational cohort study at a high-volume heart transplant center to compare outcomes of adult HTs between 2020 and 2024 using allografts recovered by PA-led vs non-PA-led recovery teams. A total of 497 adult HTs were included: 130 in the PA group and 367 in the non-PA group. The incidence of severe PGD was not significantly different (7.7% vs 5.2%; P = .28). Thirty-day survival was 96.9% in the PA group and 96.3% in the non-PA group (P = .99). Implementation of a PA-led recovery model reduced attending surgeon presence on donor runs by 62.4% (P = .054) and reduced attending surgeon time commitment from 57.5 to 10.8 hours/month (P = .045). Following implementation, the number of HTs for high sequence number recipients (>50) increased at a rate of approximately 0.89 transplants per month (P = .04), compared to a prior rate of 0.03/month. In this single-center study, implementation of a physician assistant-led recovery model for heart allograft recovery showed no significant differences in early and medium-term patient outcomes following HT.
Keywords: heart transplant; organ procurement; organ recovery; physician assistant recovery model; thoracoabdominal normothermic regional perfusion.
Altered Interictal Bed Nucleus of Stria Terminalis Connectivity in Patients With Temporal Lobe Epilepsy.
Reda A, Doss DJ, Makhoul GS, Monroy Lerma BH, Johnson G, Sainburg LE, Cavender AC, Sundrani S, Liao E, Roche A, Long I, Kang H, Dawant B, Chang C, Bick SK, Nobis WP, Morgan V, Englot DJ.
Neurology. 2025 Dec 9;105(11):e214385. doi: 10.1212/WNL.0000000000214385. Epub 2025 Nov 13.
PMID: 41232063
Abstract: Background and objectives: Temporal lobe epilepsy (TLE) is a highly prevalent neurologic disorder, with 30%-50% of patients developing drug-resistant epilepsy. Pharmacoresistant seizures remodel critical arousal and respiratory networks, impairing autonomic function and chemoreception and putting patients at increased risk of adverse respiratory events and sudden unexpected death (SUDEP). Given that the bed nucleus of stria terminalis (BNST) serves as a key relay between brainstem respiratory nuclei and cortical arousal networks, we characterized interictal BNST connectivity alterations in patients with TLE.
Methods: We conducted a case-control study of patients with drug-resistant TLE evaluated for epilepsy surgery at Vanderbilt University Medical Center, compared with healthy controls with no history of neurologic disease. Inclusion criteria for patients included clinical TLE diagnosis and age 18-65 years. Using resting-state fMRI (multiband factor = 3, repetition time [TR] = 1.3 seconds), we measured functional connectivity (FC) and effective connectivity through Granger causality (GC) between BNST and whole-brain cortical networks, and brainstem nuclei. Graph theoretical network metrics assessed BNST hub properties. Statistical analyses used multiple comparison corrections and age-corrected z-scores.
Results: Thirty-seven patients with TLE (mean age 42.5 ± 12.1 years, 43.2% female) and 33 healthy controls (mean age 36.2 ± 12.0 years, 54.5% female) were studied. Patients demonstrated bilateral reductions in BNST connectivity and causal influence with the whole brain (FC: -2.31 ± 2.87, p = 0.0032; GC: -0.18 ± 0.08, p = 0.0025). While FC showed preserved BNST-brainstem connectivity, GC revealed ipsilateral disruptions in BNST influence over ventral tegmental area (0.023 ± 0.026, p = 0.0067), median raphe (-0.009 ± 0.029, p = 0.0038), and cuneiform nuclei (0.012 ± 0.062, p = 0.0153). Critical respiratory circuits showed divergent reorganization: dorsal raphe-parabrachial complex pathways exhibited 57.2% efferent reduction (p = 0.0028), with 204.6% compensatory afferent increase (p = 0.0020), while dorsal raphe-locus coeruleus circuits showed bilateral deterioration (66.2% reduction in dorsal raphe-locus coeruleus [DR→LC], p = 0.0015; 56.4% reduction in LC→DR, p = 0.0189). Graph analyses confirmed compromised BNST network integration bilaterally (p < 0.05).
Discussion: Our findings reveal network reorganization in TLE that compromises autonomic and arousal circuit integrity, leading to failed respiratory-autonomic integration that may underlie respiratory vulnerability and increased SUDEP risk; however, we did not directly study SUDEP cases.
Clonal Hematopoiesis of Indeterminate Potential Influences Breast Cancer Outcomes in a Genotype-Specific Manner.
Reed SC, Potts CR, Luo LY, Davidson BA, Bergman RE, Kemp JDJ, Fox EK, Thomas BA, Ha L, Arora V, Cartailler J, Sanders ME, Sanchez V, Gonzalez-Ericsson P, Croessmann S, Hurley PJ, Bick AG, Ferrell PB, Park BH.
Clin Cancer Res. 2025 Nov 14;31(22):4707-4719. doi: 10.1158/1078-0432.CCR-25-2009.
PMID: 40970771
Abstract
Purpose: Clonal hematopoiesis of indeterminate potential (CHIP) has been associated with adverse outcomes in some solid tumor settings, but its impact on breast cancer remains unclear. We sought to investigate the genotype-specific effects of CHIP on breast cancer outcomes and the tumor microenvironment.
Experimental design: We examined a retrospective cohort of 125 patients with breast cancer, using targeted sequencing to identify CHIP. Metastatic events were recorded, and distant metastasis-free survival probability was analyzed. In parallel, we developed chimeric mouse models of the two most mutated CHIP genes, DNMT3A and TET2. CHIP and control mice were orthotopically injected with syngeneic breast cancer cells. Tumor growth was measured, and immune infiltrate was profiled via mass cytometry.
Results: CHIP was present in 18.4% of patients. High-burden CHIP and non-DNMT3A CHIP were associated with significantly shorter distant metastasis-free survival. In vivo, mice with Tet2-CHIP developed larger primary tumors and were more likely to experience lung metastasis, whereas Dnmt3a-CHIP did not differ from controls. The general immune subsets observed in both CHIP models were similar, but immunophenotyping revealed clonal expansion and immune cell subset skewing specific to the Tet2-CHIP model.
Conclusions: Our findings demonstrate a genotype-specific impact of CHIP on breast cancer across human and mouse data. Furthermore, the chimeric mouse models we generated offer a clinically relevant tool to study solid tumors in a CHIP background. This work underscores the need for further functional studies and personalized risk assessment to clearly define the impact of various CHIP genotypes on breast cancer.
Harmonizing 10,000 connectomes: site-invariant representation learning for multi-site analysis of network connectivity and cognitive impairment.
Newlin NR, Kim ME, Kanakaraj P, McMaster E, Cho C, Gao C, Hohman TJ, Beason-Held L, Resnick SM, O’Bryant SE, Phillips N, Barber RC, Bennett DA, Barnes LL, Biber S, Johnson S, Archer D, Li Z, Zuo L, Moyer D, Landman BA.
J Med Imaging (Bellingham). 2025 Nov;12(6):064001. doi: 10.1117/1.JMI.12.6.064001. Epub 2025 Nov 5.
PMID: 41210921 Free PMC article.
Reward circuit local field potential modulations precede risk taking.
Hughes NC, Qian H, Doss DJ, Makhoul GS, Zargari M, Zhao Z, Singh B, Wang Z, Fulton JN, Johnson GW, Li R, Dawant BM, Englot DJ, Constantinidis C, Williams Roberson S, Bick SK.
Brain. 2025 Nov 4;148(11):3958-3972. doi: 10.1093/brain/awaf107.
PMID: 40101145 Free PMC article.
Multipath cycleGAN for harmonization of paired and unpaired low-dose lung computed tomography reconstruction kernels.
Krishnan AR, Li TZ, Remedios LW, Kim ME, Gao C, Rudravaram G, McMaster EM, Saunders AM, Bao S, Xu K, Zuo L, Sandler KL, Maldonado F, Huo Y, Landman BA.
Med Phys. 2025 Nov;52(11):e70120. doi: 10.1002/mp.70120.
PMID: 41206352 Free PMC article.
IL-8 receptor signaling as a novel target for angiogenic retinopathies.
Garcia MJ, Beall AL, Morales MS, Beatty NJ, Palmer SA, Jhala M, Drmanovic A, Priest S, Zhang Y, Yang R, Arellano K, Penn JS, Padovani-Claudio DA.
Angiogenesis. 2025 Nov 1;29(1):2. doi: 10.1007/s10456-025-10015-7.
PMID: 41176546 Free PMC article.
Accurate and reliable detection of clonal hematopoiesis in plasma cell-free DNA.
Parker AC, Van Amburg J, Pershad Y, Ong DA, Hoey KJ, Farady CJ, Rauch PJ, Mendelson MM, Heimlich JB, Ferrell PB Jr, Bick AG.
Blood Adv. 2025 Oct 30:bloodadvances.2025017293. doi: 10.1182/bloodadvances.2025017293. Online ahead of print.
PMID: 41170909 No abstract available.
Ex Vivo Modulation of the BNST by Parabrachial CGRP Projections Is Decreased After a History of Stress-Induced Anxiety.
Kayat LS, Petersen N, Van Doorn CE, Nabit BP, Tyree JB, Centanni SW, Jaramillo AA.
Eur J Neurosci. 2025 Nov;62(9):e70268. doi: 10.1111/ejn.70268.
PMID: 41207872 Free PMC article.