The Oklahoma Medical Research Foundation (OMRF), located in Oklahoma City, Oklahoma, is an independent, nonprofit biomedical research institute. Established in 1946, OMRF is dedicated to understanding and developing more effective treatments for human disease. Andrew S. Weyrich, Ph.D. serves as president of OMRF, which employs more than 500 scientific and administrative staff members.OMRF's scientists, who include a member of the National Academy of Sciences, hold more than 700 U.S. and international patents and have spun off 11 biotech companies. Discoveries at OMRF led to Xigris, the first FDA-approved drug for the treatment of severe sepsis, and Ceprotin, a therapy for people suffering from a rare and life-threatening blood disorder known as protein C deficiency. Research at OMRF also identified the enzyme believed responsible for Alzheimer's disease and laid the groundwork for OncoVue, a breast cancer risk assessment test.S.D.
People with multiple sclerosis (pwMS) have an increased risk of infections. There are limited data characterizing who initially diagnoses infections in pwMS and how these are communicated among healthcare providers. Retrospective US claims data from January 1, 2017 to August 31, 2024 were used to identify newly diagnosed pwMS aged 18–64 years who were taking any disease-modifying therapy (DMT) for ≥ 90 days. Index date was the earliest date of the first DMT claim. Infections were based on International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes. Severe infections included events requiring hospitalization and/or intravenous antibiotics. Overall, 69,148 pwMS who were treatment-naïve met eligibility criteria. Mean age was 44.1 years; 72
OBJECTIVE:Using a hydroxychloroquine (HCQ) dose of 5 mg/kg/day in systemic lupus erythematosus (SLE) is associated with a higher risk of flares; HCQ blood level monitoring could be a better way to adjust the HCQ dose. We studied the upper threshold for a reference range of HCQ levels to inform routine monitoring. METHODS:This observational study included patients (N = 2,010) across the Systemic Lupus International Collaborating Clinics, Wisconsin, international, and French studies who underwent HCQ blood level measurements. Using adjusted spline and logistic regression analyses on the cross-sectional data, we first identified an HCQ blood level associated with higher HCQ toxicity. Next, we tested if this upper threshold level was supratherapeutic (no further risk reduction for the Systemic Lupus Erythematosus Disease Activity Index 2000 [score ≥6]). Finally, we examined associations between chronic kidney disease (CKD) stage and supratherapeutic (toxic) HCQ blood levels. RESULTS:Among 1,842 patients (excluding 168 patients with very low HCQ blood levels), 4.9% had HCQ-related toxicity. Odds of toxicity were 2.1-fold higher with blood levels ≥1,150 ng/mL and 1.7-fold higher with the cumulative HCQ dose per 1,000-g increase. Blood levels ≥1,150 ng/mL were associated with a saturation in therapeutic effect, indicating supratherapeutic levels. Patients with CKD stage ≥3 had 2.3-fold higher odds of having supratherapeutic levels (≥1,150 ng/mL). CONCLUSION:The therapeutic reference range for HCQ blood level monitoring is 750 to <1,150 ng/mL. HCQ level monitoring could optimize HCQ use, particularly in patients with CKD stage ≥3. Future longitudinal studies are needed to validate the use of HCQ blood level monitoring in optimizing dosing.
Senescent cells have been implicated in the pathogenesis of metabolic dysfunction-associated liver disease (MASLD), which can negatively affect female fertility. Senolytic drugs are reported to eliminate senescent cells in various tissues, including the ovary. However, the efficacy of senolytic drugs in reducing liver damage and preserving fertility in female mice with MASLD remains unclear. Therefore, this study aimed to evaluate the protective effect of senolytic drugs on liver damage and fertility in reproductive-aged female mice with MASLD. Three-month-old female mice were fed a standard diet (SD) or Western diet (WD) to induce MASLD until 9 months of age. Starting at 6 months of age, mice were also randomized to receive senolytic treatment (dasatinib + quercetin, D + Q) or vehicle within each diet. We observed that mice fed the WD exhibited liver damage characteristic of MASLD, with increased liver size, triglyceride accumulation, and fibrosis. These mice also exhibited increased liver senescence and inflammation. Senolytic treatment slightly reduced liver mass and modulated some liver senescence and inflammation-related genes, suggesting limited efficacy in controlling WD-induced liver damage. Pregnancy rates were reduced in mice with MASLD and improved by senolytic treatment. Mice with MASLD had increased ovarian senescence, inflammation, and fibrosis, which was attenuated by senolytic treatment, despite having no effect on the ovarian follicle reserve. We conclude that senolytic treatment has potential for improving reproductive function in aged female mice with MASLD, despite limited impact in liver and systemic indicators.
Mitochondria regulate cellular processes through direct and indirect interactions with other organelles. A well-studied example has been contact with the endoplasmic reticulum at mitochondrial-associated endoplasmic reticulum membranes1, which control pathways including redox and calcium homeostasis2,3. Recent studies have also reported direct mitochondria-nuclear membrane contacts in cancer cells and yeast that promote pro-survival signalling4,5. Here we identify direct interactions between mitochondria and nuclear pores. Using two unbiased proteomic screens, GST pulldown and BioID, we found that VDAC1 was the top mitochondrial candidate that interacts with the filamentous nuclear pore protein RANBP2. In vitro RANBP2 CRISPR knockout, RANBP2 truncation or site-directed mutagenesis of RANBP2-VDAC1 interacting amino acids resulted in reduced mitochondria-nucleus proximity and decreased nuclear ATP and phosphocreatine levels. This was accompanied by a decline in the levels of the nuclear phosphoproteome and downregulation of pathways involved in histone modification, cellular differentiation and transcriptional regulation in vitro. Moreover, deletion of the RANBP2 C-terminal domain in vivo in mice resulted in embryonic lethality due to cardiac and neural crest differentiation defects. Collectively, these results describe a mechanism by which mitochondria directly interact with the nuclear pore complex, a phenomenon critical for regulation of nuclear energetics and cellular differentiation. Undoubtedly, additional roles of this interaction remain to be revealed.
ABSTRACT 2‐oxyglutarate dehydrogenase ( OGDH ) encodes an E1 component of α‐ketoglutarate dehydrogenase complex that plays a pivotal role in the Krebs cycle. Biallelic variants in OGDH have been reported to cause an early‐onset neurodevelopmental and mitochondrial disorder. However, monoallelic OGDH variants have not been associated with human disease. Here, we identified de novo c.1909C>T (p.Arg637Trp) and heterozygous c.162T>G (p.Ser54Arg) variants in OGDH in unrelated individuals exhibiting late‐onset neurological phenotypes, characterized by cerebellar ataxia, peripheral neuropathy and optic atrophy. In silico protein structure predictions suggest that the p.Arg637Trp mutation might influence protein function. To determine the functional effects of the OGDH variants in vivo, we generated Drosophila models harboring UAS‐dOgdh ( p.Arg639Trp ) and UAS‐dOgdh ( p.Thr58Arg ) mutations, homologous to the human variants. While the mutant OGDH expression did not lead to defects in development, it did lead to age‐dependent locomotion defects. Further, we found that p.Arg639Trp mutant leads to defective OGDH activity, while p.Thr58Arg causes abnormal proteolytic cleavage and impaired mitochondrial import. These findings suggest that the variants act as dominant‐negative and toxic gain‐of‐function mutations, respectively. Our data provide evidence that monoallelic OGDH variants are involved in late‐onset neurological disease in humans.
