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Heterozygous expression of a Kcnt1 gain-of-function variant has differential effects on somatostatin- and parvalbumin-expressing cortical GABAergic neurons
No full textMore than 20 recurrent missense gain-of-function (GOF) mutations have been identified in the sodium-activated potassium (K(Na)) channel gene KCNT1 in patients with severe developmental and epileptic encephalopathies (DEEs), most of which are resistant to current therapies. Defining the neuron types most vulnerable to KCNT1 GOF will advance our understanding of disease mechanisms and provide refined targets for precision therapy efforts. Here, we assessed the effects of heterozygous expression of a Kcnt1 GOF variant (Kcnt1(Y777H)) on K(Na) currents and neuronal physiology among cortical glutamatergic and GABAergic neurons in mice, including those expressing vasoactive intestinal polypeptide (VIP), somatostatin (SST), and parvalbumin (PV), to identify and model the pathogenic mechanisms of autosomal dominant KCNT1 GOF variants in DEEs. Although the Kcnt1(Y777H) variant had no effects on glutamatergic or VIP neuron function, it increased subthreshold K(Na) currents in both SST and PV neurons but with opposite effects on neuronal output; SST neurons became hypoexcitable with a higher rheobase current and lower action potential (AP) firing frequency, whereas PV neurons became hyperexcitable with a lower rheobase current and higher AP firing frequency. Further neurophysiological and computational modeling experiments showed that the differential effects of the Kcnt1(Y777H) variant on SST and PV neurons are not likely due to inherent differences in these neuron types, but to an increased persistent sodium current in PV, but not SST, neurons. The Kcnt1(Y777H) variant also increased excitatory input onto, and chemical and electrical synaptic connectivity between, SST neurons. Together, these data suggest differential pathogenic mechanisms, both direct and compensatory, contribute to disease phenotypes, and provide a salient example of how a pathogenic ion channel variant can cause opposite functional effects in closely related neuron subtypes due to interactions with other ionic conductances.The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication
Decreased Circulating Gonadotropin-Releasing Hormone Associated with Keratoconus
No full textKeratoconus (KC) is a corneal thinning dystrophy that leads to visual impairment. While the cause of KC remains poorly understood, changes in sex hormone levels have been correlated with KC development. This study investigated circulating gonadotropin-releasing hormone (GnRH) in control and KC subjects to determine if this master hormone regulator is linked to the KC pathology. Plasma and saliva were collected from KC subjects (n = 227 and n = 274, respectively) and non-KC controls (n = 58 and n = 101, respectively), in concert with patient demographics and clinical features. GnRH levels in both plasma and saliva were significantly lower in KC subjects compared to controls. This finding was retained in plasma when subjects were stratified based on age, sex, and KC severity. Control and KC corneal fibroblasts (HKCs) stimulated with recombinant GnRH protein in vitro revealed significantly increased luteinizing hormone receptor by HKCs and reduced expression of alpha-smooth muscle actin with treatment suggesting that GnRH may modulate hormonal and fibrotic responses in the KC corneal stroma. Further studies are needed to reveal the role of the hypothalamic-pituitary-gonadal axis in the onset and progression of KC and to explore this pathway as a novel therapeutic target.We would like to acknowledge funding from the National Institutes of Health: EY028888; National Institutes of Health: EY028949; National Institutes of Health: NIH 2U42 OD011158; National Institutes of Health: EY035510
The importance of education combined with tailored exercise in the health and wellness of older adults: a community case study
No full textCurrent literature states the importance of mental and physical health in combating the effects of metabolic syndrome; however, there is limited information on whether providing education on the syndrome along with mental and individualized physical exercises improves perceived confidence in the older adult population. A solution to this problem would be to provide a course to this population with a primary goal of education and exercise prescription. A community case study was implemented in the spring of 2024 with the purpose of measuring perceived confidence in metabolic syndrome, management of stress and anxiety, and how to move safely with exercise. Twenty-nine older adults with an average age of 76.1 years were recruited from a local senior citizen center. A course was given to the participants that included education and prescription of exercises tailored to the needs of the individual. Before and after the course, participants completed a confidence survey investigating their confidence in lowering the risk for metabolic syndrome, managing stress/anxiety, and understanding how to move safely with exercise. Regarding the post surveys, knowing how to lower the risk of metabolic syndrome increased by 46%, learning how to manage stress and anxiety increased by 50%, and understanding how to exercise safely increased by 41%. The data from this study suggests that providing education along with specific exercise prescription improved the participant's confidence in lowering their risk for metabolic syndrome, management of stress and anxiety, and how to move safely with exercise.The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article
Cancer Incidences And Outcomes In Adolescent And Young Adult Patients Living In Food Deserts - A Retrospective Study At Cook Children's Medical Center
No full textFood Deserts, as classified by the USDA, are areas of low access to nutritious foods. Access to nutritious food is inhibited by resources such as income, transportation, and/or distance to stores with healthy food options. The areas classified as food deserts are most commonly found in minority communities. Living in a food desert has been associated with several chronic diseases such as hypertension, coronary heart disease, chronic obstructive pulmonary disease, kidney disease, and cancer. This study evaluates adolescent and young adult data from the Cook Children's Cancer Registry for food desert status and its relationship between demographics and survival. The AYA oncology population is a growing area of research but remains understudied. Research looking into the health disparities caused by food deserts can impact future care by improving health and disease outcomes in the AYA community
Re-evaluating Person-Centeredness in Relation to the Workforce and Care for Older Adults
No full textBackground: The term “person-centeredness” has been widely referenced and identified as a gold standard practice, especially in the care for older adults. However, many inconsistencies exist regarding its definition and implementation. With the recognition of caregivers being paramount to the improvement of healthcare quality, a clearer understanding of the term and its application to the healthcare workforce is needed. To address this issue, we aimed to identify key themes regarding the role of person-centeredness as it relates the workforce and care for older adults. Methods: Six think-tank meetings (two in-person; four virtual) were convened. The 38 participants included nurses, direct care workers, and dining staff from long-term care (LTC) settings; leaders of LTC organizations; and academic researchers in aging and LTC policy. Qualitative methods were used to analyze notes and transcripts. Results: Four overarching themes were identified: (1) Staff attitudes and practices toward person-centeredness tend to vary by care setting, due to differences in each setting’s inherent characteristics and goals of care. (2) Person-centeredness at the care level is conveyed through concrete practices of individual care providers; barriers involve both interpersonal competencies and organizational structures. (3) Supportive leadership is critical for staff to be empowered to approach care in a person-centered manner. (4) The lack of operationalized person-centeredness definitions has created inconsistencies in implementation. Conclusion: The definition of person-centeredness has grown from its original interpretation. These think-tanks centered on the workforce and care for older adults identified four themes that both align with and expand the current literature on person-centeredness and its implementation.Research was supported by NIA R24AG065185 (LINC-AD: Leveraging an Interdisciplinary Consortium to Improve Care and Outcomes for Persons Living with Alzheimer’s and Dementia) and NIA T35 AG038047 (UNC Chapel Hill Summer Research Training in Aging for Medical Students; MSTAR
ANCA positivity in the case of acute bacterial endocarditis
No full textBackground: The case of ANCA positivity in an individual with bacterial endocarditis demonstrates the importance of thorough testing and labs prior to treatment. This case draws attention to a diagnostic conflict, as starting treatment on immunosuppressants, as would be the standard therapy for ANCA-associated vasculitis (AAV), could exacerbate the bacterial endocarditis and carry severe consequences. In this case of glomerulonephritis and associated endocarditis, the patient presented with several symptoms which mimicked AAV. Thus, it is important for providers to include cultures in routine assessments of ANCA-positive cases to allow for thorough evaluation and appropriate therapy.
Case information: A 60-year-old morbidly obese male presented for right knee pain. His medical history includes hypertension, congestive heart failure (CHF), osteoarthritis, atrial fibrillation, and stage IV chronic kidney disease (CKD). The patient denied history of smoking, drugs, or alcohol use. He has no family history of autoimmune disease. Upon evaluation, the patient was found to have a deep vein thrombosis (DVT) with leg pain, as well as paroxysmal atrial fibrillation. He was started on Coumadin for anticoagulation therapy. During his hospital stay, his creatinine levels climbed from 2.0 mg/dL to 6.3 mg/dL and was given a preliminary diagnosis of acute renal failure on top of his preexisting CKD. His renal decline prompted a kidney biopsy, which revealed focal necrotizing and crescentic glomerulonephritis with C3 dominant deposition. Urinalysis showed proteinuria and was positive for active urinary sediment. Bloodwork was remarkable for MPO-ANCA positivity (MPO-ANCA 1:640). Transesophageal echocardiogram (TEE) and blood culture revealed an aortic valve vegetation positive for methicillin-sensitive staphylococcus aureus (MSSA), and the patient was started on broad-spectrum antibiotic therapy.
Conclusions: The details of this case prompt reflection on the diagnostic steps taken by providers when presented with an ANCA-positive patient. The standard protocol taken in the treatment of ANCA vasculitis differs tremendously from and could even have devastating consequences in the case of infectious endocarditis. Therefore, careful evaluation for bacterial endocarditis in the case of ANCA positivity should be incorporated into the diagnostic process. Most of the current literature represents cases of c-ANCA positivity in subacute infectious endocarditis (IE), often with Streptococcus viridans responsible. This case is unique in that the patient was positive for MPO-ANCA and not PR3 and the causative organism was MSSA. While several cases of MSSA IE with ANCA positivity have been reported, this combination of MSSA endocarditis and isolated MPO-ANCA positivity has only been represented one other time in the literature to our knowledge
Chronic intermittent hypoxia-induced hypertension: the impact of sex hormones
Get PDFObstructive sleep apnea, a common form of sleep-disordered breathing, is characterized by intermittent cessations of breathing that reduce blood oxygen levels and contribute to the development of hypertension. Hypertension is a major complication of obstructive sleep apnea that elevates the risk of end-organ damage. Premenopausal women have a lower prevalence of obstructive sleep apnea and cardiovascular disease than men and postmenopausal women, suggesting that sex hormones play a role in the pathophysiology of sleep apnea-related hypertension. The lack of protection in men and postmenopausal women implicates estrogen and progesterone as protective agents but testosterone as a permissive agent in sleep apnea-induced hypertension. A better understanding of how sex hormones contribute to the pathophysiology of sleep apnea-induced hypertension is important for future research and possible hormone-based interventions. The effect of sex on the pathophysiology of sleep apnea and associated intermittent hypoxia-induced hypertension is of important consideration in the screening, diagnosis, and treatment of the disease and its cardiovascular complications. This review summarizes our current understanding of the impact of sex hormones on blood pressure regulation in sleep apnea with a focus on sex differences.This review was supported by National Heart, Lung, and BloodInstitute Grant R01 HL155977 (to J.T.C., G.E.F., and R.L.C.) andNational Institute of Neurological Disorders and Stroke Grant R01NS0091359 (to R.L.C.
Neuroinflammation and gut diversity effects due to opioid self-administration
No full textPurpose: Opioids are a great resource to treat pain in humans, but prolonged use can lead users to physical dependence and opioid use disorders (OUD). The use of opioids increases the risk of developing OUDs in humans via activation ofμ-opioid receptors. OUD is extensively studied for its effects in the central nervous system including the brain; however, Gut-Brain Axis (GBA) research will potentially expand our understanding of addiction and provide a new paradigm for developing new substance use disorder (SUD) therapeutics. GBA in animal models of OUDs can elucidate the complex interactions between the brain and gut that lead to pathological drug seeking and consumption and their relation to GBA components (i.e., bacterial populations, gut peptides, and gut signaling). In this study, we will share the determining temporal hallmarks of gut alterations in rats self-administering morphine for 15 days and relate it to neuroinflammatory features in the brain. One of our hypotheses is that abuse of drugs, such as morphine, starts by inducing inflammation of the brain and gut taxonomic changes similar to those observed in human opioid users. Methods: In this project, we used Sprague Dawley (SD) rats, and both the experimental and control groups were surgically implanted with intravenous (IV) catheters. The control group was exposed to the self-administration box, but only received sucrose pellets instead of morphine to avoid differences in behavior due to instrument learning or exposure to self-administration chambers. The experimental group was trained to self-administer morphine dosed to their body weight of 0.4 mg/kg for 14 days. The experimental timeline was (1) baseline: 7 days after catheter implantation, (2) acute: 24 hours after the second day of self-administration, and (3) chronic: 24 hours after completion of the 12 days of self-administration. Fecal samples were acquired at the three-time points and analyzed with 16s DNA sequencing to determine the relative abundance of microbial species at the time points. After the last day, we collected the brains from all animals and prepared tissue FFPE for immunohistochemistry and spatial transcriptomics analysis. Concurrently we acquired MRI diffusion-weighted scans in a 7.0 T preclinical scanner. Rats were restrained under sedation (isoflurane 5% induction, 2% maintenance) reducing the stressor of noise and restriction while scanning. This project will help us identify whether neuroinflammation markers occur due to large doses of morphine repetitively in rodents. Results: Preliminary analysis points out that chronic and voluntary administration of morphine leads to a neuroinflammatory response in the habenula possibly detected with diffusion MRI. Our preliminary16s DNA sequencing analysis has shown some key microbiome differences in our experimental drug group versus our control pellet group. Conclusion: As we continue analyzing our data, we hope to provide more insight on early effects of chronic drug use on gut-brain axis.BBRF Young Investigator Gran
Identification of Family-Specific Features in Cas9 and Cas12 Proteins: A Machine Learning Approach Using Complete Protein Feature Spectrum
Get PDFThe recent development of CRISPR-Cas technology holds promise to correct gene-level defects for genetic diseases. The key element of the CRISPR-Cas system is the Cas protein, a nuclease that can edit the gene of interest assisted by guide RNA. However, these Cas proteins suffer from inherent limitations like large size, low cleavage efficiency, and off-target effects, hindering their widespread application as a gene editing tool. Therefore, there is a need to identify novel Cas proteins with improved editing properties, for which it is necessary to understand the underlying features governing the Cas families. In the current study, we aim to elucidate the unique protein attributes associated with Cas9 and Cas12 families and identify the features that distinguish each family from the other. Here, we built Random Forest (RF) binary classifiers to distinguish Cas12 and Cas9 proteins from non-Cas proteins, respectively, using the complete protein feature spectrum (13,495 features) encoding various physiochemical, topological, constitutional, and coevolutionary information of Cas proteins. Furthermore, we built multiclass RF classifiers differentiating Cas9, Cas12, and Non-Cas proteins. All the models were evaluated rigorously on the test and independent datasets. The Cas12 and Cas9 binary models achieved a high overall accuracy of 95% and 97% on their respective independent datasets, while the multiclass classifier achieved a high F1 score of 0.97. We observed that Quasi-sequence-order descriptors like Schneider-lag descriptors and Composition descriptors like charge, volume, and polarizability are essential for the Cas12 family. More interestingly, we discovered that Amino Acid Composition descriptors, especially the Tripeptide Composition (TPC) descriptors, are important for the Cas9 family. Four of the identified important descriptors of Cas9 classification are tripeptides PWN, PYY, HHA, and DHI, which are seen to be conserved across all the Cas9 proteins and were located within different catalytically important domains of the Cas9 protein structure. Among these four tripeptides, tripeptides DHI and HHA are well-known to be involved in the DNA cleavage activity of the Cas9 protein. We therefore propose the the other two tripeptides, PWN and PYY, may also be essential for the Cas9 family. Our identified important descriptors enhanced the understanding of the catalytic mechanisms of Cas9 and Cas12 proteins and provide valuable insights into design of novel Cas systems to achieve enhanced gene-editing properties.This work was supported by a grant from National Institute of General Medical Sciences of the National Institutes of Health (R35GM133657). We thank our collaborator professor Shouyi Wang and his group from the University of Texas Arlington (UTA) for their continuous and valuable research support all along this study
Oxidative stress induces release of mitochondrial DNA into the extracellular space in human placental villous trophoblast BeWo cells
No full textCirculating cell-free mitochondrial DNA (ccf-mtDNA) is an indicator of cell death, inflammation, and oxidative stress. ccf-mtDNA in pregnancies with placental dysfunction differs from that in healthy pregnancies, and the direction of this difference depends on gestational age and method of mtDNA quantification. Reactive oxygen species (ROS) trigger release of mtDNA, yet it is unknown whether trophoblast cells release mtDNA in response to oxidative stress, a common feature of pregnancies with placental pathology. We hypothesized that oxidative stress would induce cell death and release of mtDNA from trophoblast cells. BeWo cells were treated with antimycin A (10-320 microM) or rotenone (0.2-50 microM) to induce oxidative stress. A multiplex real-time quantitative PCR (qPCR) assay was used to quantify mtDNA and nuclear DNA in membrane-bound, non-membrane-bound, and vesicle-bound forms in cell culture supernatants and cell lysates. Treatment with antimycin A increased ROS (P < 0.0001), induced cell necrosis (P = 0.0004) but not apoptosis (P = 0.6471), and was positively associated with release of membrane-bound and non-membrane-bound mtDNA (P < 0.0001). Antimycin A increased mtDNA content in exosome-like extracellular vesicles (vesicle-bound form; P = 0.0019) and reduced autophagy marker expression (LC3A/B, P = 0.0002; p62, P < 0.001). Rotenone treatment did not influence mtDNA release or cell death (P > 0.05). Oxidative stress induces release of mtDNA into the extracellular space and causes nonapoptotic cell death and a reduction in autophagy markers in BeWo cells, an established in vitro model of human trophoblast cells. Intersection between autophagy and necrosis may mediate the release of mtDNA from the placenta in pregnancies exposed to oxidative stress.NEW & NOTEWORTHY This is the first study to test whether trophoblast cells release mitochondrial (mt)DNA in response to oxidative stress and to identify mechanisms of release and biological forms of mtDNA from this cellular type. This research identifies potential cellular mechanisms that can be used in future investigations to establish the source and biomarker potential of circulating mtDNA in preclinical experimental models and humans.This study was supported by NIH R01 HL146562 andHL146562-S2 to S.G., AHA 18PRE33960162 and NIH T32AG020494 to S.C.C., AHA 19TPA-34850131 to S.G., AHA22POST-903250 to J.L.B., AHA 22PRE-900431 to J.J.G., andAHA 23PRE-1012811 to S.M.T