Citations

Abstract The impact of microglia antigen presentation on CNS infiltrating CD8 T cells responses during neurotropic virus infection has been difficult to define. Using Theiler’s murine encephalomyelitis virus (TMEV) infection of neurons as a model system, our laboratory has previously determined that H-2D b restricted, but not H-2K b restricted CD8 T cells are required for viral clearance, demonstrating the role of discrete MHC class I alleles. To determine the extent microglia antigen presentation impacts brain-infiltrating CD8 T cells, our laboratory generated novel single MHC class I conditional knockout mice in which H-2K b or H-2D b can be specifically deactivated in TMEM119+ microglia with tamoxifen administration. During TMEV infection, conditional knockout of H-2K b in microglia reduced antigen-specific CD8 T cell proliferation in the brain. Meanwhile, mice with deletion of D b in microglia had reduced levels of perforin in antigen-specific CD8 T cells. Furthermore, microglia specific deletion of H-2D b reduced CD8 T cell numbers in the brain and preserved blood-brain barrier (BBB) integrity. Microglial D b restricted antigen presentation was also essential for the reactivation of CD8 tissue resident memory (TRM) cells and BBB integrity during memory recall responses. These findings further our understanding of how brain infiltrating antiviral CD8 T cell responses are impacted by microglia, as well as define how this cellular interaction contributes to BBB disruption during neuroinflammation. These findings also have high significance to our understanding of how microglia impact CD8 TRM cell populations that reside in the brain long after virus infection is cleared. Graphical abstract

Aging is associated with increased aortic stiffness and exaggerated stress-induced blood pressure (BP) responsiveness, both of which contribute to the risk of cardiovascular disease. Supplementation with inorganic nitrate increases nitric oxide (NO) bioavailability and is a promising potential treatment to improve vascular function. While the acute effects of dietary inorganic nitrate supplementation on various measures of vascular function and BP have been demonstrated in several studies, the effects of increasing NO bioavailability through prolonged use (i.e. weeks) is unclear. Therefore, we tested the hypothesis that 4-weeks of inorganic nitrate supplementation will effectively increase NO bioavailability (as measured by plasma nitrate and nitrite) and reduce central BP, aortic stiffness, and BP responsiveness to a cold pressor test (CPT) in older adults. Thirteen older adults (67±3 years; 7 males and 6 females) completed a randomized, double-blind, placebo-controlled, crossover trial consisting of two 4-week supplementation periods (nitrate vs. placebo) separated by a 4-week washout. Central BP and carotid-femoral pulse wave velocity (cfPWV) were measured via applanation tonometry. Peripheral BP responses were assessed using beat-by-beat BP at baseline and during CPT. Plasma [nitrate] (40±24 to 76±46 µM, P< 0.01) and [nitrite] (289±94 to 413± 28 nM, P< 0.01) increased following inorganic nitrate supplementation, but remained unchanged after placebo ([nitrate] 39±20 to 39±16 µM, P=0.97; [nitrite] 303±108 to 302±87 nM, P=0.95). Four weeks of inorganic nitrate supplementation reduced resting measures of central systolic BP (cSBP; 116±12 to 113±10 mmHg, P< 0.05) and diastolic BP (cDBP; 79±8 to 74±6 mmHg, P< 0.05), as well as cfPWV (10.2±1.3 to 9.4±1.0 m/sec, P< 0.01), whereas no changes were observed following placebo (cSBP 112±10 to 115±10 mmHg; cDBP 75±7 to 78±7 mmHg; cfPWV 10.0±1.1 to 9.8±1.0 m/sec, P >0.05 for all). Additionally, the peak change (Δ from baseline) in peripheral SBP (28±10 to 23±6 mmHg, P< 0.05) and mean arterial pressure (MAP; 17±6 to 14±3 mmHg, P< 0.05) during the CPT were reduced following nitrate with no changes observed after placebo (SBP 25±8 to 26±12 mmHg, P=0.51; MAP 14±4 to 16±8 mmHg, P=0.19). Our findings demonstrate 4-weeks of inorganic dietary nitrate supplementation has favorable effects on central BP, aortic stiffness and BP responsiveness in older adults. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Abstract The lateral and medial meniscus play vital roles in load distribution across the knee joint and in the prevention of knee osteoarthritis. As such, every effort should be made to save and repair the meniscus when possible, as partial and total meniscectomies have been shown to impair the meniscus’ ability to effectively dissipate shock. Recently, an algorithm—coined the “ABCs of meniscal repair”—has emerged as a blueprint for optimizing the success of a meniscal repair. The “ABCs of meniscal repair” refer to anatomic reduction, biologic augmentation, and circumferential compression across the meniscus tear, respectively. In this technique, we describe a modified use of the arthroscopic skid that allows for access to difficult‐to‐reach peripheral meniscal tears while simultaneously aiding in the anatomic reduction of the tear.

Abstract Femoroacetabular impingement with cam morphology that fails nonoperative management can be addressed with hip arthroscopy and cam resection. There exists a wide variation of cam morphology due to various etiologies that can make some cam lesions more challenging to address. A thorough preoperative evaluation and the utilization of a variety of intraoperative techniques can allow for adequate arthroscopic resection of these otherwise challenging cam lesions. In this technique video, we describe a systematic approach for the preoperative assessment of femoroacetabular impingement due to a cam lesion and consideration of different approaches for arthroscopic resection based on cam‐specific morphology.

Background: Complex repairs of radial meniscal tears have shown increased fixation strength compared to conventional sutures. A simplified 2-suture hybrid and a novel dual tie-grip repair with interconnected vertical mattress sutures spanning the tear were tested and compared to all-inside double-horizontal and tie-grip repairs. Hypothesis: The dual tie-grip repair would increase the initial compression load across the tear and show the least cyclic displacement and highest failure strength. Study Design: Controlled laboratory study. Methods: A total of 40 porcine medial menisci were assigned to 4 repair groups: double-horizontal, hybrid, tie-grip, and dual tie-grip (10 per group). Results from tie-grip repairs were used to assess the effect of vertical mattress suture interconnection. After suture placement according to the described technique and fixation, the initial compressive load, stiffness, and relief displacement were measured. The repaired specimens underwent cyclic loading between 5 and 30 N over 1000 cycles (0.75 Hz), while cyclic stiffness and displacement were measured. Ultimate stiffness and load-to-failure were analyzed at 3.15 mm/s. Results: Analysis of variance revealed that dual tie-grip and hybrid repairs showed higher initial compressive load and relief displacement than the other techniques, with dual tie-grip repair reaching the highest values for both metrics (load: 19.3 ± 2.3 N [ P < .001]; displacement: 0.75 ± 0.19 mm [ P < .001]). The double-horizontal repair had the lowest initial stiffness ( P < .001). Cyclic displacement was lowest for the dual tie-grip repair and highest for the double-horizontal repair (both P < .001). All repaired specimens stiffened during cycling without intergroup differences. Analysis of covariance for stiffness over displacement revealed higher stabilization ( P < .040) with dual tie-grip repair and reduced stabilization ( P < .001) with double-horizontal repair. Despite comparable ultimate stiffness across groups, the dual tie-grip repair failed predominantly by suture rupture at the highest ultimate load (275.5 ± 26.2 N; P < .001), whereas the double-horizontal repair failed by tissue rupture the earliest (127.2 ± 15.9 N; P < .001). Conclusion: The dual tie-grip repair provided the highest initial compression across the radial meniscal tear, the lowest cyclic displacement, and the greatest load-to-failure among all techniques in a porcine cadaveric model. The simplified 2-suture hybrid repair showed higher initial compression than other repairs and comparable cyclic stability to the tie-grip repair. Clinical Relevance: The dual tie-grip repair provided high compression across the radial tear and strong resistance to cyclic displacement. Future clinical series assessing differences in healing rates among different repair groups are warranted.

Autoimmune diseases arise when B and T lymphocytes lose tolerance to self. Yet in most disorders, the underlying molecular determinants, including autoantibodies, epitopes and lymphocyte clones that drive tissue injury remain undefined. Rapid-onset obesity with hypothalamic dysfunction, hypoventilation and autonomic dysregulation (ROHHAD) is a rare and often fatal pediatric neuroendocrine syndrome with strong evidence of antigen-driven paraneoplastic autoimmunity, including association with the intracellular autoantigen ZSCAN1. However, the effector immune circuit and the epitope-level determinants operating within the hypothalamus and brainstem have remained unknown. To address this challenge in ROHHAD and more broadly in autoimmune disease, we developed the Autoimmune Epitope and immunoGlobulin/Immune-receptor identification System (AEGIS), an integrated framework that links immune repertoires to their cognate self-epitopes. AEGIS combines B cell and T cell receptor profiling from sites of tissue injury with high-resolution epitope mapping, direct sequencing of antigen-specific autoantibodies, in silico antibody-antigen folding, selection, and T cell antigen discovery. Applied to a deeply phenotyped child with ROHHAD, AEGIS revealed a compartmentalized, clonally restricted immune response in which brain-deposited IgG and expanded cerebrospinal fluid B cell and CD4 T cell clonotypes converged on shared ZSCAN1 epitopes, resolved to minimal determinants and peptide-MHC ligands. These findings provide a clone- and epitope-linked mechanistic map of ROHHAD autoimmunity and establish a generalizable framework for identifying candidate pathogenic clones and antigens across diverse autoimmune diseases.

Abstract Medial meniscus root tears are among the most painful and disabling injuries in knee preservation practice, frequently presenting with substantial functional decline, particularly in female patients. Recent research associates increased posterior tibial slope with both root tears and worse pain scores. Although biomechanically plausible, posterior tibial slope should be interpreted as an association rather than a primary causal driver, as small variations in slope alone are unlikely to fully account for symptom burden or structural progression. Pain and functional decline in this population more likely reflects a multifactorial mechanical environment, in which posterior tibial slope interacts with other determinants of joint loading, including meniscal extrusion, limb alignment, cartilage health, body mass index, subchondral bone response, and degenerative meniscal changes. In our view, posterior tibial slope is one contributor within a broader mechanical environment rather than the primary driver. However, the key clinical message is clear: root tears represent a critical joint‐failure event that demands early recognition and treatment.

Abstract This work presents a first-of-its-kind artificial intelligence (AI-)integrated MR pulse sequence that detects out-of-voxel (OOV) artifacts in real-time (within-TR) and responds prospectively by updating the crusher gradient scheme. Per Excitation Real-time Execution & Guided Responses with Integrated Neural-network Evaluation (PEREGRINE), allows for deployment of deep learning models and pulse sequence updates. In this study, PEREGRINE operated a time-domain (TD) and frequency-domain (FD) convolutional autoencoder that detect OOV artifacts. Scans without (AI-off) and with (AI-on) updates were collected from the medial prefrontal cortex of healthy volunteers using a MEGA-edited MRS experiment. The degree of OOV contamination (OOV Score) was quantified per transient based upon the prevalence of OOV signals in the TD and FD data. OOV Scores above a user-defined threshold triggered an update of the crusher gradient scheme, iterating through 48 permutations (6 axis transpositions × 8 polarity flips). Within each 2-second TR, PEREGRINE successfully provided single-transient OOV Scores and updated gradients accordingly. No difference was observed between the OOV Scores from the full (“Full” condition) AI-on and AI-off sessions due to the AI-on scan cycling over better and worse gradient permutations relative to the AI-off scan. However, the AI-on scan had significantly lower OOV Scores than the AI-off scan when selecting the transients where PEREGRINE persisted (“Dwell” condition) on a given gradient permutation. Ultimately, Fit Quality Number (FQN) from linear combination modeling improved significantly for the AI-on compared to the AI-off scan. PEREGRINE enabled an adaptive and AI-integrated sequence allowing for real-time evaluation and response to OOV artifacts, identifying gradient modifications that produced less OOV contamination. Graphical Abstract Graphical Abstract Summary PEREGRINE, Per Excitation Real-time Execution & Guided Responses with Integrated Neural-network Evaluation, allows for pulse sequence updates using on-scanner deployed neural networks. To demonstrate the utility, PEREGRINE was used to operate two neural networks (time/frequency domain), trained to detect out-of-voxel artifacts, during a MEGA-edited MRS experiment in the prefrontal cortex. When artifacts were detected, PEREGRINE updated the crusher gradients within the same TR. Real-time, adaptive, and AI-driven MR will provide a long-awaited solution for combatting artifacts and poor data quality. Graphical Abstract Figure

Summary Cancer genome sequencing is essential for understanding tumor evolution and advancing precision medicine. 1 However, reference gaps and germline variants obscure detection of small and large somatic variants and methylation in repetitive regions. 1–3 It is common for tumor cells to gain or lose chromosome arms due to somatic structural changes that occur inside highly repetitive satellite DNA sequences in the centromeres. 4 To identify the full spectrum of somatic variants, including complex rearrangements, we construct and curate near-complete, haplotype-resolved assemblies of the most recent common ancestor of an early-passage broadly-consented hypodiploid pancreatic cancer cell line and matched normal tissues. The tumor assembly completely recapitulates all 35 tumor chromosomes observed with karyotyping, with multiple translocation-induced hybrid chromosomes. The hybrid chromosomes contain putative functional dicentric and fused centromeres, nested foldback inversions causing 14 breakpoints with a haplotype switch in a single event, and centromeric satellite tandem duplications up to 136 kbp. Direct comparison of tumor and normal assembly haplotypes uncovers >7,000 variants altering >1 Mbp of sequence in repetitive regions that have been hidden by reference gaps and germline variants. 44 % of somatic small variants change representation because they alter germline variants on GRCh38, impacting mutational signatures and kataegis/omikli clusters. Most somatic LINE insertions originate from two hypomethylated non-reference germline LINE insertions, highlighting their impact on insertion mutation burden. These assemblies demonstrate that centromeric, acrocentric, and telomeric regions conventionally excluded from analysis harbor extensive somatic and epigenetic changes. Resolving complete tumor genomes enables a deeper understanding of cancer structural plasticity and the endpoints of breakage-fusion-bridge cycles. These assembled, curated paired normal-tumor benchmarks will serve as a critical foundation for developing future algorithms to characterize the most intractable regions of cancer genomes.

Background: Several special tests for detecting medial ulnar collateral ligament (MUCL) injuries of the elbow have been described, but data on the clinical utility of these tests are limited. Purpose: To determine the clinical utility of selected elbow special tests to detect MUCL injuries in an athletic population. Study Design: Cross-sectional study; Level of evidence, 3. Methods: A total of 84 consecutive patients with sports-related elbow pain underwent a standardized clinical examination. Overall, 6 special tests (moving valgus stress test, static valgus stress test, modified valgus stress test, milking maneuver, pronation flexion resistance test, and temple/cheek press test) were performed. Sensitivity, specificity, accuracy, positive/negative predictive value, and positive/negative likelihood ratio (LR+ and LR–, respectively) were calculated for individual tests and combinations of tests to detect MUCL injuries. Higher values for the LR+ and lower values for the LR– represent stronger clinical utility. Results: For detecting MUCL injuries, the moving valgus stress test resulted in the highest sensitivity (98%) and accuracy (93%) with the lowest LR– (2%). The milking maneuver had the highest LR+ (5.1) with the second highest sensitivity (77%) and accuracy (79%). The pronation flexion resistance test and the temple/cheek press test had the lowest LR+ (1.5 and 1.8, respectively) and highest LR– (94% and 95%, respectively) in addition to the lowest sensitivity (16% and 9%, respectively) and accuracy (33% and 30%, respectively). No combination of tests resulted in increased clinical utility. Conclusion: The moving valgus stress test and milking maneuver demonstrated acceptable clinical utility in which the moving valgus stress test was better for ruling out MUCL injuries and the milking maneuver was better at ruling in MUCL injuries. There was no added value when combining the 2 tests together or with other maneuvers.