Extraislet expression of islet antigen boosts T cell exhaustion to partially prevent autoimmune diabetes.

Persistent antigen exposure results in the differentiation of functionally impaired, also termed exhausted, T cells which are maintained by a distinct population of precursors of exhausted T (TPEX) cells. T cell exhaustion is well studied in the context of chronic viral infections and cancer, but it is unclear whether and how antigen-driven T cell exhaustion controls progression of autoimmune diabetes and whether this process can be harnessed to prevent diabetes. Using nonobese diabetic (NOD) mice, we show that some CD8+ T cells specific for the islet antigen, islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) displayed terminal exhaustion characteristics within pancreatic islets but were maintained in the TPEX cell state in peripheral lymphoid organs (PLO). More IGRP-specific T cells resided in the PLO than in islets. To examine the impact of extraislet antigen exposure on T cell exhaustion in diabetes, we generated transgenic NOD mice with inducible IGRP expression in peripheral antigen-presenting cells. Antigen exposure in the extraislet environment induced severely exhausted IGRP-specific T cells with reduced ability to produce interferon (IFN)γ, which protected these mice from diabetes. Our data demonstrate that T cell exhaustion induced by delivery of antigen can be harnessed to prevent autoimmune diabetes.

Standardized indolent systemic mastocytosis evaluations across a health care system: implications for screening accuracy.

ABSTRACT: Timely diagnosis of systemic mastocytosis (SM) remains challenging because of care heterogeneity. We implemented a standardized approach for SM screening and diagnosis using a novel health care system-wide international screening registry. A retrospective analysis assessed rates of SM, cutaneous mastocytosis (CM), and molecular diagnoses before and 2 years after care standardization. The accuracy of individual and combined SM screening tests, basal serum tryptase (BST) ≥11.5 and ≥20.0 ng/mL, REMA ≥2, monomorphic maculopapular CM (MPCM), and elevated BST based upon tryptase genotype, was analyzed. Tryptase genotyping and high-sensitivity KIT p.D816V testing increased substantially 2 years after care standardization. SM diagnoses doubled from 47 to 94, and KIT p.D816V molecular diagnoses increased from 24 to 79. Mean BST and KIT p.D816V variant allele frequency values were significantly lower in patients diagnosed after standardization. Hereditary-alpha tryptasemia prevalence was increased in SM before care standardization (4/30 [13.3%]) but reflected the general population prevalence 2 years later at (5/76 [6.6%]). Elevated BST based upon genotype and BST ≥11.5 ng/mL had the highest sensitivities at 84.2% and 88.3%, respectively. The presence of monomorphic MPCM, elevated BST based upon tryptase genotype, and the combination of REMA ≥2 with elevated BST based upon tryptase genotype had specificities >90%. BST >20.0 ng/mL had low sensitivity and specificity and was not required to establish any indolent SM (ISM) diagnosis. Care standardization increased SM diagnosis rates, particularly in patients with low BSTs. Stratifying BST based upon genotype had the best overall sensitivity and specificity of any ISM screening test and improved the REMA score specificity.

Deficiency of the innate immune adaptor STING promotes autoreactive T cell expansion in NOD mice.

AIMS/HYPOTHESIS: Stimulator of IFN genes (STING) is a central hub for cytosolic nucleic acid sensing and its activation results in upregulation of type I IFN production in innate immune cells. A type I IFN gene signature seen before the onset of type 1 diabetes has been suggested as a driver of disease initiation both in humans and in the NOD mouse model. A possible source of type I IFN is through activation of the STING pathway. Recent studies suggest that STING also has antiproliferative and proapoptotic functions in T cells that are independent of IFN. To investigate whether STING is involved in autoimmune diabetes, we examined the impact of genetic deletion of STING in NOD mice. METHODS: CRISPR/Cas9 gene editing was used to generate STING-deficient NOD mice. Quantitative real-time PCR was used to assess the level of type I IFN-regulated genes in islets from wild-type and STING-deficient NOD mice. The number of islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)206-214-specific CD8+ T cells was determined by magnetic bead-based MHC tetramer enrichment and flow cytometry. The incidence of spontaneous diabetes and diabetes after adoptive transfer of T cells was determined. RESULTS: STING deficiency partially attenuated the type I IFN gene signature in islets but did not suppress insulitis. STING-deficient NOD mice accumulated an increased number of IGRP206-214-specific CD8+ T cells (2878 ± 642 cells in NOD.STING-/- mice and 728.8 ± 196 cells in wild-type NOD mice) in peripheral lymphoid tissue, associated with a higher incidence of spontaneous diabetes (95.5% in NOD.STING-/- mice and 86.2% in wild-type NOD mice). Splenocytes from STING-deficient mice rapidly induced diabetes after adoptive transfer into irradiated NOD recipients (median survival 75 days for NOD recipients of NOD.STING-/- mouse splenocytes and 121 days for NOD recipients of NOD mouse splenocytes). CONCLUSIONS/INTERPRETATION: Data suggest that sensing of endogenous nucleic acids through the STING pathway may be partially responsible for the type I IFN gene signature but not autoimmunity in NOD mice. Our results show that the STING pathway may play an unexpected intrinsic role in suppressing the number of diabetogenic T cells.

Harnessing CD8+ T-cell exhaustion to treat type 1 diabetes.

Although immune interventions have shown great promise in type 1 diabetes mellitus (T1D) clinical trials, none are yet in routine clinical use or able to achieve insulin independence in patients. In addition to this, the principles of T1D treatment remain essentially unchanged since the isolation of insulin, almost a century ago. T1D is characterized by insulin deficiency as a result of destruction of insulin-producing beta cells mediated by autoreactive T cells. Therapies that target beta-cell antigen-specific T cells are needed to prevent T1D. CD8+ T-cell exhaustion is an emerging area of research in chronic infection, cancer immunotherapy, and more recently, autoimmunity. Recent data suggest that exhausted T-cell populations are associated with improved markers of T1D. T-cell exhaustion is both characterized and mediated by inhibitory receptors. This review aims to identify which inhibitory receptors may prove useful to induce T-cell exhaustion to treat T1D and identify limitations and gaps in the current literature.

Sports interest mediating exercise and compulsive internet use among undergraduates.

With the massive growth in Internet technologies, people have become wary of excessive Internet usage, known as compulsive Internet usage or Internet addiction. This study looks into how exercise is related to compulsive Internet usage. Previous research showed varying results regarding the relationship between sports habit and Internet usage; this project clarifies the relationship by investigating mediating variables in terms of interest in different aspects of sports, such as physical education, mastering sport skills, sports participation, and watching sports. Two survey studies were conducted. The participants were 232 male and 107 female Taiwanese undergraduate students in the first survey, totaling 339 students. The second survey had 233 males, 98 female students, and 2 who did not disclose their gender, with a final total of 333. The results reveal that interest in physical education (IPE) mediates sports habit and compulsive Internet usage. As long as the student had a habit of doing sports that increased IPE, this would in turn decrease compulsive Internet use. The importance of igniting students' IPE is discussed.

Effect of hydraulic retention time on electricity generation using a solid plain-graphite plate microbial fuel cell anoxic/oxic process for treating pharmaceutical sewage.

Treatment efficiency and electricity generation were evaluated using a solid plain-graphite plate microbial fuel cell (MFC) anoxic/oxic (A/O) process that treated pharmaceutical sewage using different hydraulic retention times (HRT). Short HRTs increased the volumetric organic loading rate, thereby reducing the MFC performance due to rapid depletion of the substrate (carbon/nitrogen source). The COD removal efficiency decreased from 96.28% at a HRT of 8 h to 90.67% at a HRT of 5 h. The removal efficiency of total nitrogen was reduced from 74.16% at a HRT of 8 h to 53.42% at a HRT of 5 h. A shorter HRT decreased the efficiency in treatment of the pharmaceutical products (PPs), which included acetaminophen, ibuprofen and sulfamethoxazole in an aerobic reactor because these antibiotic compounds inhibited the microbial activity of the aerobic activated sludge in the MFC A/O system. The average power density and coulombic efficiency values were 162.74 mW m-2 and 7.09% at a HRT of 8 h and 29.12 mW m-2 and 2.23% at a HRT of 5 h, respectively. The dominant bacterial species including Hydrogenophaga spp., Rubrivivax spp. and Leptothrix spp., which seem to be involved in PP biodegradation; these were identified in the MFC A/O system under all HRT conditions for the first time using next generation sequencing. Bacterial nanowires were involved in accelerating the transfer of electrons and served as mediators in the SPGRP biofilm. In conclusion, a SPGRP MFC A/O system at a HRT of 8 h gave better removal of COD, T-N and PPs, as well as generated more electricity.

Worldwide incidence of cervical lesions: a systematic review.

We conducted a systematic review summarizing data on incidence of high- and low-grade lesions in women with normal baseline cervical cytology, stratified by age (<30 and ⩾30 years), and baseline human papillomavirus (HPV) infection. Incidence of high- and low-grade lesions in women aged ⩾30 years with a baseline HPV infection increased over follow-up time (5-127 months), although incidence generally remained <10%. Without baseline HPV infection, incidence of high-grade lesions remained low over follow-up time (<5% over 5-122 months). Incidence of high-grade lesions in women aged ⩾30 years with baseline HPV infection appeared similar to that in women aged <30 years. In some women aged <30 years, high-grade lesions can develop relatively shortly after initial HPV infection. We observed an increase in low-grade lesions over time in women aged ⩾30 years with baseline HPV infection, potentially indicative of an HPV infection that is potentially progressing to higher grade lesions.

Condition dependence of female choosiness in a field cricket.

Females generally choose mates that produce the loudest, brightest or most elaborate sexual displays, and these costly male displays are predicted to be condition dependent. However, mate choice itself is a costly behaviour also expected to be condition dependent. Male fall field crickets, Gryllus pennsylvanicus, produce a conspicuous long-distance calling song that attracts females and is condition dependent. In this study, we tested the condition dependence of female preferences (preference function and choosiness) for male calling effort in G. pennsylvanicus. We manipulated female condition by raising crickets from hatching on either a low- or high-quality diet. In a series of two-speaker phonotaxis trials, both low- and high-condition females preferred playbacks reflecting greater calling effort. However, relative to low-condition females, high-condition females took significantly longer to make a choice, were more likely to fail to choose within the time allotted for a phonotaxis trial and significantly increased their latency to choose over the course of multiple trials. We discuss these results with respect to the possibility that female G. pennsylvanicus may be foraging for direct benefits when they choose their mates.

Critical Bone Defect Affecting the Outcome of Management in Anatomical Type IV Chronic Osteomyelitis.

Background: The Cierny and Mader classification assists with decision-making by stratifying host status and the pathoanatomy of the disease. However, the anatomical type IV represents a heterogenous group with regard to treatment requirements and outcomes. We propose that modification of the Cierny and Mader anatomical classification with an additional type V classifier (diffuse corticomedullary involvement with an associated critical bone defect) will allow more accurate stratification of patients and tailoring of treatment strategies. Methods: A retrospective review of 83 patients undergoing treatment for Cierny and Mader anatomical type IV osteomyelitis of the appendicular skeleton at a single centre was performed. Results: Risk factors for the presence of a critical bone defect were female patients [OR 3.1 (95% CI, 1.08-8.92)] and requirement for soft tissue reconstruction [OR 3.35 (95% CI, 1.35-8.31)]; osteomyelitis of the femur was negatively associated with the presence of a critical bone defect [OR 0.13 (95% CI, 0.03-0.66)]. There was no statistically significant risk of adverse outcomes (failure to eradicate infection or achieve bone union) associated with the presence of a critical-sized bone defect. The median time to the bone union was ten months (95% CI, 7.9-12.1 months). There was a statistically significant difference in the median time to bone union between cases with a critical bone defect [12.0 months (95% CI, 10.2-13.7 months)] and those without [6.0 months (95% CI, 4.8-7.1 months)]. Conclusion: This study provided evidence to support the introduction of a new subgroup of the Cierny and Mader anatomical classification (Type V). Using a standardised approach to management, comparable early outcomes can be achieved in patients with Cierny and Mader anatomical type V osteomyelitis. However, to achieve a successful outcome, there is a requirement for additional bone and soft tissue reconstruction procedures with an associated increase in treatment time. How to cite this article: Tsang STJ, Epstein GZ, Ferreira N. Critical Bone Defect Affecting the Outcome of Management in Anatomical Type IV Chronic Osteomyelitis. Strategies Trauma Limb Reconstr 2024;19(1):26-31.

A Rare Case of Extranodal Natural Killer/T-cell Lymphoma, Nasal Type Associated With Hemophagocytic Lymphohistiocytosis in a Patient With Recurrent Sinusitis.

We present a rare case of hemophagocytic lymphohistiocytosis (HLH) secondary to nasal-type extranodal natural killer/T-cell lymphoma (ENKL). Nasal-type ENKL is a rare subtype of non-Hodgkin's lymphoma usually associated with Epstein-Barr virus (EBV). The patient was a 19-year-old woman who presented with facial numbness, diminished hearing, and dysgeusia. She was febrile with palatal necrosis, loss of gag reflex, and cranial nerve palsies. Labs revealed neutropenia. Broad-spectrum antimicrobials, including amphotericin, were started. Given concern for invasive fungal disease, she underwent surgical debridement, which revealed inflamed fibrous tissue and extensive necrosis. Pathology showed no fungal elements or malignancy. Lack of clinical improvement and worsening palatal necrosis prompted additional debridement. Histology identified an atypical CD3+/CD56+ cellular infiltrate. Bone marrow biopsy showed prominent hemophagocytosis, but no malignancy. She met the criteria for HLH and high-dose dexamethasone was started. Her fevers resolved. Additional labs and nasal tissue sampling with EBV-encoded RNA staining were recommended. Flow cytometry was negative, but histology revealed ENKL nasal-type, with positive EBV-encoded RNA in situ hybridization. Plasma EBV DNA level was 11,518 IU/mL. The M-SMILE (dexamethasone, methotrexate, ifosfamide, l-asparaginase, and etoposide) regimen was initiated; one cycle led to marked improvement. EBV level returned to zero. Subsequent radiation and chemotherapy, followed by autologous stem cell transplant consolidation, led to complete remission. We conclude that ENKL may mimic invasive sinusitis clinically. Fibrinoid necrosis in vessels and surrounding tissues often leads to diagnostic delay. It is important to have a high degree of clinical suspicion for malignancy in cases of HLH and sinusitis unresponsive to appropriate therapy. Obtaining proper tissue, communication with the pathologist, and prompt initiation of therapy are crucial.

A Case of Non-Seminomatous Germ Cell Tumor Complicated by Tumor Thrombus in an Active Duty Soldier.

Testicular malignancies commonly affect adolescent and young adult males. Although they tend to respond well to cisplatin-based chemotherapy with excellent overall survival, complications such as inferior vena cava tumor thrombus are rare and can be associated with high morbidity and mortality. We present a case of tumor thrombus in a 21-year-old active duty male with a newly diagnosed stage IIIB non-seminomatous germ cell tumor presenting with extensive left lower extremity swelling. Ultrasound with Doppler was notable for significant thrombus of the left common femoral, femoral, and popliteal vein. Computed tomography imaging revealed extensive thrombus of the inferior vena cava, left iliac veins, and left gonadal vein with sparing of the left renal vein. Endovascular thrombectomy was performed with pathologic analysis confirming the presence of malignant cells consistent with tumor thrombus. The patient continued subsequent non-seminomatous germ cell tumor treatment without complications.

Neuronal morphology in MeCP2 mouse models is intrinsically variable and depends on age, cell type, and Mecp2 mutation.

Rett Syndrome (RTT), a progressive neurological disorder characterized by developmental regression and loss of motor and language skills, is caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MECP2). Neurostructural phenotypes including decreased neuronal size, dendritic complexity, and spine density have been reported in postmortem RTT brain tissue and in Mecp2 animal models. How these changes in neuronal morphology are related to RTT-like phenotype and MeCP2 function, and the extent to which restoration of neuronal morphology can be used as a cellular readout in therapeutic studies, however, remain unclear. Here, we systematically examined neuronal morphology in vivo across three Mecp2 mouse models representing Mecp2 loss-of-function, partial loss-of-function, and gain-of-function mutations, at developmental time points corresponding to early- and late-symptomatic RTT-like behavioral phenotypes. We found that in Mecp2 loss-of-function mouse models, dendritic complexity is reduced in a mild, age-dependent, and brain region-specific manner, whereas soma size is reduced consistently throughout development. Neither phenotype, however, is altered in Mecp2 gain-of-function mice. Our results suggest that, in the cell types we examined, the use of dendritic morphology as a cellular readout of RTT phenotype and therapeutic efficacy should be cautioned, as it is intrinsically variable. In contrast, soma size may be a robust and reliable marker for evaluation of MeCP2 function in Mecp2 loss-of-function studies.

Aero to the heart: A case of aortic valve endocarditis caused by Aerococcus Urinae in an elderly woman.

Aerococcus urinae (A. urinae) is an infrequent cause of infective endocarditis (IE) and few cases have been reported especially in older women. As of this publication, there are 31 reported cases of IE caused by aerococcus urinae, and of these, 4 are of women, 3 of which are aged > 75 years. Here, we describe a case of A. urinae endocarditis in an 80-year-old woman presenting with worsening fatigue. A diagnosis of native aortic valve endocarditis was established based on characteristic findings of aortic valvular vegetation on transesophageal echocardiogram along with isolation of A. urinae on blood cultures.

An atypical presentation of CNS tuberculosis manifesting with meningoencephalitis and tuberculoma in a New York taxi driver.

Mycobacterium Tuberculous (MTb) meningitis is a rare manifestation of extrapulmonary tuberculosis (Tb) but remains the most common form of Central Nervous System (CNS) manifestation of tuberculosis. It is associated with significant morbidity and mortality yet difficult to diagnose given the low sensitivity and specificity of diagnostic testing with cerebral spinal fluid (CSF) analysis which typically shows CSF findings of lymphocytic pleocytosis, elevated protein, and low glucose and is confirmed by acid fast bacillus (AFB) culture. Here, we describe a case of severe meningoencephalopathy in the setting of disseminated tuberculosis with atypical radiological findings of tuberculoma.

The potential advantages and workflow challenges of long axial field of view PET/CT.

Recently developed Long (≥100 cm) axial field of view (AFOV) PET/CT scanners are capable of producing images with higher signal-to-noise ratio, or performing faster whole-body acquisitions, or scanning with lower radiation dose to the patient, compared with conventional PET/CT scanners. These benefits, which arise due to their substantially higher, by more than an order of magnitude, geometric efficiency, have been well described in the recent literature. The introduction of Long AFOV PET/CT technology into the clinic also has important implications for the design and workflow of PET/CT facilities and their effects on radiation exposure to staff and patients. Maximising the considerable benefits of this technology requires a thorough understanding of the relationships between these factors to optimise workflows while appropriately managing radiation exposure. This article reviews current knowledge on PET/CT facility design, workflows and their effects on radiation exposure, identifies gaps in the literature and discusses the challenges that need to be considered with the introduction of Long AFOV PET/CT into the clinic.

Familial Essential Thrombocythemia With Novel MPL L502G and G208K Mutations.

Familial essential thrombocythemia is characterized by the inheritance of germline mutations to progeny, thereby increasing the risk for the development of essential thrombocythemia. Here, we present two cases of young women who developed thromboembolic phenomena, one of whom with an ischemic event despite adequate anticoagulation. Through extended mutational testing, both were characterized as having novel mutations in the myeloproliferative leukemia virus (MPL) gene, and both individuals have fathers being treated for essential thrombocythemia. This case provides insight that in familial essential thrombocythemia, there remain uncharacterized mutations in this inherited conditional landscape.

The Use of Orlistat in an Adult with Lipoprotein Lipase Deficiency: A Case Report.

Background: Patients with lipoprotein lipase (LPL) deficiency, an inherited disorder, develop hypertriglyceridemia, which can lead to recurrent pancreatitis. The mainstay of therapy is medical nutritional therapy. Case Report: We present the case of a 35-year-old woman with LPL deficiency who experienced recurrent hospitalizations for hypertriglyceridemia-induced pancreatitis, which was effectively treated with orlistat. Discussion: Other agents that have been studied for the treatment of LPL deficiency are costly and have limiting side effects. Studies have shown orlistat to be safe and effective for the treatment of LPL deficiency in children. No studies have been performed in adults with LPL deficiency. Conclusion: Orlistat may be a potential adjunctive treatment option for LPL deficiency in adults, given its availability and favorable safety profile. Further research regarding orlistat in the setting of LPL deficiency is needed.

Use of a Chemotherapy Toxicity Prediction Tool to Decrease Risks for Hospitalization in Older Patients.

Objectives Performance status (PS) scales such as the Eastern Cooperative Oncology Group (ECOG) PS and the Karnofsky Performance Index have limited utility in selecting therapies and predicting related adverse events in older patients with cancer. In July 2016, medical oncologists at our institution adopted the Cancer and Aging Research Group toxicity prediction score (CARG), a toxicity prediction tool, to identify patients who are "fit" for chemotherapy versus those who are "frail" and may experience severe complications. Methods Our retrospective review included referrals of beneficiaries 75 years of age and older who received standard systemic therapy and patients of the same age whose treatment was modified due to CARG. We compared the score's utilization six months before and after its incorporation and then assessed how its application impacted admissions, emergency department (ED) visits, and medical management. Results Thirty-eight patients with a mean age of 81 years met the inclusion criteria. Their diagnoses included gastrointestinal (37%), lung (21%), hematologic (18%), breast (10.5%), genitourinary (3%), and other (10.5%) malignancies. CARG was documented for 12.5% of systemic therapy recipients before its adoption and 41% of recipients after adoption. Its use was limited by the reliance on physicians to perform scoring during time-constrained patient encounters. Patients had fewer mean inpatient admissions (0.7 versus 2.3), admission days (4.3 versus 8), and ED visits (1.1 versus 2.5) when management was modified based on the score. Conclusion CARG assessment may facilitate a safer and more tailored approach to cancer care in older patients than conventional PS scales alone. Its integration into patient screening would increase its application and better define its potential predictive capacity to decrease risks for hospitalization.

MALDI-TOF mass spectrometry rapid pathogen identification and outcomes of patients with bloodstream infection: A systematic review and meta-analysis.

There was inconsistent evidence regarding the use of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) for microorganism identification with/without antibiotic stewardship team (AST) and the clinical outcome of patients with bloodstream infections (BSI). In a systematic review and meta-analysis, we evaluated the effectiveness of rapid microbial identification by MALDI-TOF MS with and without AST on clinical outcomes. We searched PubMed and EMBASE databases from inception to 1 February 2022 to identify pre-post and parallel comparative studies that evaluated the use of MALDI-TOF MS for microorganism identification. Pooled effect estimates were derived using the random-effects model. Twenty-one studies with 14,515 patients were meta-analysed. Compared with conventional phenotypic methods, MALDI-TOF MS was associated with a 23% reduction in mortality (RR = 0.77; 95% CI: 0.66; 0.90; I2  = 35.9%; 13 studies); 5.07-h reduction in time to effective antibiotic therapy (95% CI: -5.83; -4.31; I2  = 95.7%); 22.86-h reduction in time to identify microorganisms (95% CI: -23.99; -21.74; I2  = 91.6%); 0.73-day reduction in hospital stay (95% CI: -1.30; -0.16; I2  = 53.1%); and US$4140 saving in direct hospitalization cost (95% CI: $-8166.75; $-113.60; I2  = 66.1%). No significant heterogeneity sources were found, and no statistical evidence for publication bias was found. Rapid pathogen identification by MALDI-TOF MS with or without AST was associated with reduced mortality and improved outcomes of BSI, and may be cost-effective among patients with BSI.

Muscle 4EBP1 activation modifies the structure and function of the neuromuscular junction in mice.

Dysregulation of mTOR complex 1 (mTORC1) activity drives neuromuscular junction (NMJ) structural instability during aging; however, downstream targets mediating this effect have not been elucidated. Here, we investigate the roles of two mTORC1 phosphorylation targets for mRNA translation, ribosome protein S6 kinase 1 (S6K1) and eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1), in regulating NMJ structural instability induced by aging and sustained mTORC1 activation. While myofiber-specific deletion of S6k1 has no effect on NMJ structural integrity, 4EBP1 activation in murine muscle induces drastic morphological remodeling of the NMJ with enhancement of synaptic transmission. Mechanistically, structural modification of the NMJ is attributed to increased satellite cell activation and enhanced post-synaptic acetylcholine receptor (AChR) turnover upon 4EBP1 activation. Considering that loss of post-synaptic myonuclei and reduced NMJ turnover are features of aging, targeting 4EBP1 activation could induce NMJ renewal by expanding the pool of post-synaptic myonuclei as an alternative intervention to mitigate sarcopenia.