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Incident Hearing Loss and Subsequent Risk of Dementia: The Health and Retirement Study 2010-2018
No full textBackground and Objectives While hearing loss is a known risk factor for dementia, the impact of incident hearing loss on subsequent dementia risk remains underexplored. This study examined the association between newly reported hearing loss and dementia risk in U.S. adults, focusing on critical intervention periods for dementia prevention. Research Design and Methods Participants from the Health and Retirement Study who reported no hearing loss or hearing aid use in 2010 or 2012 were included. Incident hearing loss and dementia were assessed via self-report and proxy report. Pooled logistic regression models with inverse probability weighting estimated the cumulative incidence of dementia at 2, 4, 6, and 8 years after baseline. Risk ratios (RR) with 95% confidence intervals were calculated from 200 bootstrap samples. Subgroup analyses were conducted by age, sex, and cardiovascular disease (CVD) status. Results Among 13,599 participants, 1125 (8.3%) reported incident hearing loss. Dementia incidence was higher among those with hearing loss (6.6%) compared to those without (4.9%). Starting at 4 years, incident hearing loss was associated with a higher dementia risk, persisting at 8 years (RR = 1.34; 95% CI: 1.05, 1.59). This association was significant among individuals aged 50-64 years and those with CVD. Discussion and Implications Incident hearing loss is associated with a heightened dementia risk, particularly in midlife and among individuals with CVD. Future research should investigate the effectiveness of timely interventions aimed at preventing dementia in individuals with hearing loss
The Impact of Household Dysfunction on Dating Violence Perpetration Among Adolescents in the United States: A Scoping Review
Get PDFAdverse childhood experiences, such as household dysfunction (HD), play a central role in how adolescents establish, experience, and navigate the challenges of relationship formation, maintenance, and dissolution. HD exposures have been independently associated with dating violence (DV) perpetration in both adolescents and adults. However, research examining the association between the concurrent effect of HD on DV perpetration, especially among adolescents remains scarce. Thus, we conducted a scoping review to accumulate and summarize existing research regarding the impact of HD on DV perpetration among adolescents aged 10 to 17 years in the United States. We used three electronic databases, Medline (Ovid), PsycINFO, and EMBASE, to search for studies published in English between 2013 and August 2023. A total of 14 studies were retained for this review after full-text screening. Most of the included studies (64%) were longitudinal. Concerning HD measurement, 71% of studies evaluated witnessing intimate partner violence (IPV), and the remaining 29% assessed family conflict, both using different instruments. Regarding DV measurement, 43% of studies utilized the Safe Dates Abuse measures to assess various forms of DV perpetration. Findings from 3/4 (75%) studies that evaluated family conflict found it to be a significant predictor of DV perpetration. Additionally, 8/10 (80%) studies that assessed exposure to IPV reported significant associations with various forms of DV perpetration among adolescents. None of the included studies measured HD comprehensively; thus, measurement development is imperative. Findings from this review may help initiate the development of a more comprehensive HD measure, promote early intervention, and foster resilience among adolescents
Primary Care Telehealth in a Dynamic Healthcare Environment From Digital Divide to Healthcare Outcomes
No full textWith expanded telehealth availability in primary care, its impact on quality of care and associated costs remains debated. Analyzing 199,829 Medicare beneficiaries in Mississippi (2019-2021), we found telehealth utilization associated with significant sociodemographic disparities, reduced inpatient admissions, and lower 30-day readmissions. By accounting for primary care utilization, our findings suggest that the higher absolute costs observed among telehealth users may reflect underlying healthcare needs rather than telehealth utilization
Leptin Receptor Neurons in the Dorsomedial Hypothalamus Require Distinct Neuronal Subsets for Thermogenesis and Weight Loss
No full textThe dorsomedial hypothalamus (DMH) receives inputs from the preoptic area (POA), where ambient temperature mediates physiological adaptations of energy expenditure and food intake. Warm-activated POA neurons suppress energy expenditure via brown adipose tissue (BAT) projecting neurons in the dorsomedial hypothalamus/dorsal hypothalamic area (dDMH/DHA). Our earlier work identified leptin receptor (Lepr)-expressing, BAT-projecting dDMH/DHA neurons that mediate metabolic leptin effects. Yet, the neurotransmitter (glutamate or GABA) used by dDMH/DHALepr neurons remains unexplored and was investigated in this study using mice. We report that dDMH/DHALepr neurons represent equally glutamatergic and GABAergic neurons. Surprisingly, chemogenetic activation of glutamatergic and/or GABAergic dDMH/DHA neurons were capable to increase energy expenditure and locomotion, but neither reproduced the beneficial metabolic effects observed after chemogenetic activation of dDMH/DHALepr neurons. We clarify that BAT-projecting dDMH/DHA neurons that innervate the raphe pallidus (RPa) are exclusively glutamatergic Lepr neurons. In contrast, projections of GABAergic or dDMH/DHALepr neurons overlapped in the ventromedial arcuate nucleus (vmARC), suggesting distinct energy expenditure pathways. Brain slice patch clamp recordings further demonstrate a considerable proportion of leptin-inhibited dDMH/DHALepr neurons, while removal of pre-synaptic (indirect) effects with synaptic blocker increased the proportion of leptin-activated dDMH/DHALepr neurons, suggesting that pre-synaptic Lepr neurons inhibit dDMH/DHALepr neurons. We conclude that stimulation of BAT-related, GABA- and glutamatergic dDMH/DHALepr neurons in combination mediate the beneficial metabolic effects. Our data support the idea that dDMH/DHALepr neurons integrate upstream Lepr neurons (e.g., originating from POA and ARC). We speculate that these neurons manage dynamic adaptations to a variety of environmental changes including ambient temperature and energy state. SIGNIFICANCE STATEMENT: Our earlier work identified leptin receptor expressing neurons in the dDMH/DHA as an important thermoregulatory site. Dorsomedial hypothalamus (DMH) Lepr neurons participate in processing and integration of environmental exteroceptive signals like ambient temperature and circadian rhythm, as well as interoceptive signals including leptin and the gut hormone glucagon-like-peptide-1 (GLP1). The present work further characterizes dDMH/DHALepr neurons as a mixed glutamatergic and GABAergic population, but with distinct axonal projection sites. Surprisingly, select activation of glutamatergic and/or GABAergic populations are all able to increase energy expenditure, but are unable to replicate the beneficial metabolic effects observed by Lepr activation. These findings highlighting dDMH/DHA Lepr neurons as a distinct subgroup of glutamatergic and GABAergic neurons that are under indirect and direct influence of the interoceptive hormone leptin and if stimulated are uniquely capable to mediate beneficial metabolic effects. Our work significantly expands our knowledge of thermoregulatory circuits and puts a spotlight onto DMH-Lepr neurons for the integration into whole body energy and body weight homeostasis
A Comprehensive Uhplc-Ms/Ms and Extraction Method Reveals Flavonoid Profile and Concentration Are Diverse in Spinach (Spinacia oleracea L.)
No full textINTRODUCTION: Spinach produces an array of unique flavonoids not commonly found in other fruits and vegetables. These molecules likely serve as defense agents against biotic and abiotic stress and may have health beneficial properties for humans. Current methods to analyze spinach flavonoids are incomplete and only capture a portion of this uncharacterized pathway. A comprehensive analysis method is needed to determine how genetics, environmental conditions, and other factors influence spinach flavonoid biosynthesis.
METHODS: We developed and validated a high-throughput extraction and ultra high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method to separate and quantify 39 spinach flavonoid species in 11.5 minutes. Spinach flavonoids without authentic standards were putatively identified using MS/MS fragmentation experiments, precursor scans, and matches to high-resolution MS literature reports.
RESULTS: Our extraction method enables up to 48 samples to be extracted in 60 minutes with recovery estimates between 100.5 - 107.8%. To assess the suitability of our method and generate benchmark estimates for 39 spinach flavonoids, we grew a panel of 30 genetically diverse spinach accessions and compared quantification data generated with a traditional or our high-throughput approach. Data generated by either approach were comparable, estimating total flavonoid averages of 75.1 - 170.1 or 93.1 - 187.26 mg/100 g fresh weight for the high-throughput and traditional method, respectively.
DISCUSSION: Many estimates generated by our analysis method represent the first quantitative literature reports of these compounds. These experiments indicate that our extraction and analysis method is efficient, robust, and an important tool needed to study the biosynthesis and biological role of spinach flavonoids
New Genetic Tools To Define the Pathophysiology of Inborn Errors of Cobalamin Metabolism Impacting Mammalian Development
No full textThe congenital, autosomal recessive disorder combined methylmalonic acidemia and homocystinuria - cblC type, is the most common inborn error of cobalamin (vitamin B12) metabolism. In its early onset form, cblC profoundly impacts fetal development of the central nervous system, hematopoietic system, and other tissues. Previously, mutations in the MMACHC gene, which encodes a protein required for the intracellular trafficking and enzymatic processing of free cobalamin into active coenzyme forms, were found to cause cblC. These coenzymes are required in two metabolic pathways which produce either succinyl-CoA in the mitochondria or methionine in the cytosol. However, due to a lack of sufficient animal models, the exact pathophysiology of cblC remains unknown. Moreover, there is evidence to suggest that MMACHC may have roles outside of cobalamin metabolism and that cobalamin itself may be required for additional, unknown metabolic pathways. Here, we report the generation and characterization of three new mouse lines aimed at further defining the role of MMACHC and cobalamin in mammalian development. CRISPR/Cas9 genome editing was used to develop an HA-tagged version of Mmachc, which will aid in affinity purification and spatiotemporal localization of the MMACHC protein. To clarify which metabolic perturbations downstream of Mmachc loss give rise to tissue-specific developmental defects, we also created floxed alleles for both methionine synthase (Mtr) and methylmalonyl-CoA mutase (Mmut), which are the only known cobalamin dependent enzymes in mammals. In total, these new mouse models significantly expand upon the repertoire of genetic reagents to clarify the pathophysiology of cblC as well as define both the canonical and hypothesized noncanonical roles of MMACHC in mammalian development
Mitral Valve Repair During CABG Surgery: Navigating the Gray Area of Moderate Ischemic Mitral Regurgitation
No full textIschemic mitral regurgitation is a consequence of prior myocardial infarction, resulting in regional wall motion abnormalities, leaflet tethering, papillary muscle displacement, and annular dilatation. In patients with multivessel coronary artery disease, approximately 30-50% develop moderate to severe ischemic mitral regurgitation, associated with a threefold increase in the incidence of congestive heart failure and cardiac death. We present a case involving a 66-year-old male with multivessel coronary artery disease, heart failure with reduced ejection fraction (30-35%), and diabetes who was found to have moderate ischemic mitral regurgitation at the time of coronary artery bypass graft surgery. The decision to pursue mitral valve repair was deferred. Despite revascularization, the patient had persistent mitral regurgitation and a low ejection fraction, leading to an inability to wean off cardiopulmonary bypass. Subsequently, an intra-aortic balloon pump was deployed, and due to further deterioration, mechanical cardiac support was escalated to an Impella 5.5 (Abiomed). After a prolonged hospital course, the patient was ultimately discharged to a skilled nursing facility. This case highlights the complex decision-making involved in pursuing mitral valve repair in patients with moderate ischemic mitral regurgitation and reduced ejection fraction, given the extended aortic cross-clamping time and the associated increase in perioperative risks. Considering these challenges, there needs to be careful selection of patients who should undergo mitral valve repair in addition to revascularization versus revascularization alone. Selecting these patients requires the assessment of multiple factors, including viability, scar burden, scar location, left ventricular size, and careful pre-operative grading of the severity of mitral regurgitation. In this case report, we highlight the significance of scar in the coronary distribution that supplies the posteromedial papillary muscle, leading to persistent ischemic mitral regurgitation after coronary artery bypass grafting despite having over 75% of myocardial viability on positron emission tomography imaging
Intratumoral Neutrophil-to-Lymphocyte Ratio Is Mirrored by Circulating Neutrophil-to-Lymphocyte Ratio in Non-Small Cell Lung Cancer
No full textTumor-initiated emergency granulopoiesis results in expansion of the circulating neutrophil compartment and neutrophil recruitment into the tumor microenvironment (TME), which may in turn promote tumor progression. Although an elevated circulating neutrophil-to-lymphocyte ratio (cNLR) has repeatedly been demonstrated to be an adverse prognostic factor in patients with non-small cell lung cancer (NSCLC), whether this neutrophil expansion in circulation reflects a similar relative neutrophil abundance in the TME remains unclear. We sought to characterize the relationships between cNLR and the intratumoral neutrophil-to-lymphocyte ratio (tNLR), between tNLR and proteogenomic and immune features of NSCLC tumors, and between tNLR and prognosis.We analyzed tNLR (transcriptomic signatures) and cNLR in a prospectively-enrolled cohort of patients with NSCLC (stage IA-III) that was subjected to multifaceted immunoprofiling (ImmunogenomiC prOfiling of early-stage Non-small cell lung cancer (ICON), N=150). We examined the relationship between tNLR and genomic, transcriptomic, and proteomic features of NSCLC tumors in The Cancer Genome Atlas (TCGA) and ICON. Finally, tNLR was analyzed for associations with postoperative recurrence-free survival (ICON) and overall survival (TCGA).In the ICON cohort, tNLR was significantly positively correlated with cNLR, but there was no association between intratumoral and circulating neutrophils or lymphocytes alone. High tNLR was associated with poor postoperative recurrence-free survival, and multivariate analysis indicated tNLR was a stronger driver of outcomes than cNLR. Mutations in KEAP1, STK11, PTEN, PI3K, and TSC2 were associated with an increased tNLR. Tumors with elevated tNLR were marked by proteomic and transcriptomic features indicative of increased cell cycle, receptor tyrosine kinase, and YAP signaling, as well as immunosuppression (reduced IFNG and GZMB expression). Flow cytometry and multiplex immunofluorescence confirmed reduced CD8+granzyme B+ T cells in the TME of tumors with high tNLR. Finally, TCGA confirmed associations between tNLR with prognosis, mutational status, and proteomic/transcriptomic features, and further showed that tNLR is prognostically relevant in multiple solid cancers.tNLR is mirrored by NLR in circulation (cNLR) in NSCLCs. High tNLR is associated with an immunosuppressed TME phenotype and poor prognosis across multiple cancers. These findings support ongoing investigations of the utility of cNLR and tNLR as clinical biomarkers in the context of patients with NSCLC treated with immune checkpoint inhibitor therapies
Targeting Stromal-Mediated Resistance Mechanisms in Oncogenic KRAS-Driven Pancreatic Ductal Adenocarcinoma
No full textPancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with oncogenic KRAS mutations driving both tumor initiation and maintenance. Despite recent breakthroughs in KRAS-targeted therapies, the rapid emergence of resistance mechanisms limits their clinical efficacy. This dissertation investigates three interconnected aspects of PDAC biology and therapeutic targeting in the context of oncogenic KRAS. First, the thesis demonstrates that stromal-derived Neuregulin 1 (NRG1) activates upregulated ERBB2/3 receptors on cancer cells following KRAS inhibition, establishing a critical resistance pathway. Second, optimize tissue dissociation methodology was proposed for PDAC specimens, overcoming barriers created by the dense desmoplastic stroma to enable more effective isolation and characterization of tumor and stromal components. Last, the therapeutic potential of targeting the Hedgehog pathway in KRAS-mutant PDAC was investigated. Collectively, these findings advance understanding of tumor-microenvironment interactions in PDAC and provide a framework for novel combination therapeutic strategies targeting both oncogenic drivers and stromal resistance mechanisms
Functions of RNA exosome and tRNA splicing ligase in Mendelian and Infectious diseases
No full textFunctions of RNA exosome and tRNA splicing ligase in Mendelian and Infectious diseases
Khondakar Sayef Ahammed, M.S.
Advisory Professor: Ambro van Hoof, Ph.D.
RNA maturation and degradation reactions are important for health and survival of all organisms. In humans, defects in these processes cause various Mendelian diseases, while drugs that inhibit pathogen-specific RNA processing enzymes promise to be effective treatment options for infectious diseases. The RNA exosome complex is a major 3’ RNase in eukaryotes that catalyzes the processing and degradation of a wide range of substrates in the nucleus and cytoplasm. Single amino acid mutations in RNA exosome subunits cause a range of Mendelian diseases collectively referred to as exosomopathies. However, distinguishing these disease-causing variants from non-pathogenic ones remains challenging, and the mechanism by which these variants cause disease is largely unknown.
Here, I developed a hybrid yeast/mammalian RNA exosome model of exosomopathies by systematically replacing the individual yeast subunits with their corresponding human or mouse orthologs. This allows us to unambiguously assess the damaging effects of the exact patient variant in budding yeast. Functional analysis of the disease-associated variants utilizing this genetic tool revealed defects in RNA exosome function caused by previously known as well as uncharacterized variants in several replaceable subunits, including EXOSC1, EXOSC2, EXOSC4, EXOSC7, and EXOSC9. Further detailed investigation of the two damaging EXOSC1 variants, using orthologous mutations in the corresponding yeast subunit Csl4, revealed malfunction in the nuclear and cytoplasmic functions of RNA exosome. These two patient-derived mutations are located in functionally redundant domains of Csl4, and each variant partially impaired RNA exosome function by disrupting its corresponding domain. Genetic and transcriptome analysis of these csl4 variants implied that the N- and C-terminal domains of Cs4 have distinct and overlapping in vivo functions. Furthermore, these Csl4 domains maintain a ‘bipartite functional interaction’ with nuclear cofactors (Rrp6, Mpp6, and Mtr4), where one of the interactions is required for the essential function of the exosome. Thus, analyzing disease variants in the budding yeast model provides important insights into RNA exosome defects caused by patient-derived variants and elucidates the subunit-specific role of Csl4/EXOSC1 in nuclear RNA exosome function.
Another aspect of my thesis was dedicated to understanding the function of fungal tRNA ligase that is involved in the processing of intron-containing pre-tRNAs. The first step of the pre-tRNA splicing mechanism is conserved and involves cleavage by tRNA splicing endonuclease (TSEN), resulting in 5’ exon, 3’ exon, and intron fragments. Fungi use a “heal and seal” pathway that requires three distinct catalytic domains of the tRNA ligase enzyme, Trl1. In contrast, humans use a “direct ligation” pathway carried out by RTCB, an enzyme completely unrelated to Trl1. Because of these mechanistic differences, Trl1 has been proposed as a promising drug target for fungal infections.
In this study, I systematically tested whether Trl1 meets the key criteria for a viable antifungal drug target candidate. To validate Trl1 as a broad-spectrum drug target, I showed that fungi from three different phyla contain Trl1 orthologs with all three catalytic domains. This includes the major invasive human fungal pathogens, and these proteins can each functionally replace yeast Trl1. In contrast, species from the order Mucorales, including the pathogens Rhizopus arrhizus and Mucor circinelloides, have an atypical Trl1 that contains the sealing domain but lacks both healing domains. These sealing-only Trl1 orthologs can functionally complement defects in the corresponding domain of yeast Trl1 and use a conserved catalytic lysine residue. Thus, Mucorales use a sealing-only enzyme together with unidentified non-orthologous healing enzymes for their heal and seal pathway. Functional investigation of the individual domains of Trl1 in pathogenic fungi species revealed that the ligase domain is the domain to target for antifungal development.
One of the key challenges in developing Trl1 inhibitors is the lack of a robust, sensitive, and rapid in vivo drug screening assay system for screening Trl1 inhibitors. To enable the discovery of Trl1 inhibitors, I designed a cell-based assay system that can be used in a high-throughput setting to identify compounds that specifically inhibit fungal Trl1. Furthermore, while validating Trl1 as a potential drug target, I uncovered several species-specific biological aspects of fungal Trl1, which provide new insights into our understanding of the tRNA splicing pathway in fungi