Wake Forest School of Medicine
  • Winston-Salem, NC, United States
Recent publications
Muscular dystrophies are a heterogeneous group of inherited progressive disorders of muscle characterized pathologically by destruction of muscle and its replacement by fatty and fibrous tissue. The most common muscular dystrophies are Duchenne muscular dystrophy, myotonic dystrophy types 1 and 2, and facioscapulohumeral dystrophy. Muscle weakness is a major manifestation and often has an early onset, but initial symptoms may also be reported in early or even late adulthood. Genes with mutations causing muscular dystrophies typically play major roles in muscle development and maintenance of muscle function, including the reinforcement and repair of the plasma membrane. The considerable mechanical forces involved in contractility and the energy demands for metabolism and regeneration significantly affect the physiology of muscle fibers. Recent scientific advances have improved our diagnostic abilities and enabled experimental studies of gene therapy and conventional pharmacological treatments that should eventually lead to effective treatment of these hereditary disorders.
Anti-SSA/Ro antibodies, while strongly linked to fetal cardiac injury and neonatal rash, can associate with a spectrum of disease in the mother, ranging from completely asymptomatic to overt Systemic Lupus Erythematosus (SLE) or Sjögren's Syndrome (SS). This study was initiated to test the hypothesis that the microbiome, influenced in part by genetics, contributes to disease state. The stool microbiome of healthy controls (HC) was compared to that of anti-SSA/Ro positive women whose children had neonatal lupus. At the time of sampling, these women were either asymptomatic (Asym), had minor rheumatic symptoms or signs considered as an undifferentiated autoimmune syndrome (UAS), or were diagnosed with SLE or SS. Differences in microbial relative abundances among these three groups were tested assuming an ordering in clinical severity (HC<Asym/UAS<SS/SLE) and then again without the ordinal assumption. Those taxa that showed differential relative abundances were then tested for whether the effect size differed depending on the women's HLA SLE-risk allele genotype (DRB1*03:01, DRB1*15:01, DQB1*02:01 and DQB1*06:02) or anti-SSA/Ro autoantibody levels. Multiple genera within the families Ruminococcaceae and Lachnospiraceae showed evidence of an HLA-by-genus interaction (P < .05). Four genera exhibited evidence of an interaction with anti-Ro52 IgA: Lachnoclostridium, Romboutsia, Bacteroides and Actinomyces (P < .01). In addition to documenting differences in microbial relative abundances across clinical severity of disease, these data provide a first-time demonstration that microbial differences are correlated with HLA SLE-risk alleles. Taken together, these data suggest that the clinical spectrum from benign to overt clinical autoimmunity may partially result from or trigger a complex interplay among specific microbial profiles, anti-Ro autoantibodies, and genetics.
Background Cellular senescence is a complex stress response that impacts cellular function and organismal health. Multiple developmental and environmental factors, such as intrinsic cellular cues, radiation, oxidative stress, oncogenes, and protein accumulation, activate genes and pathways that can lead to senescence. Enormous efforts have been made to identify and characterize senescence genes (SnGs) in stress and disease systems. However, the prevalence of senescent cells in healthy human tissues and the global SnG expression signature in different cell types are poorly understood. Methods This study performed an integrative gene network analysis of bulk and single-cell RNA-seq data in non-diseased human tissues to investigate SnG co-expression signatures and their cell-type specificity. Results Through a comprehensive transcriptomic network analysis of 50 human tissues in the Genotype-Tissue Expression Project (GTEx) cohort, we identified SnG-enriched gene modules, characterized SnG co-expression patterns, and constructed aggregated SnG networks across primary tissues of the human body. Our network approaches identified 51 SnGs highly conserved across the human tissues, including CDKN1A ( p21 )-centered regulators that control cell cycle progression and the senescence-associated secretory phenotype (SASP). The SnG-enriched modules showed remarkable cell-type specificity, especially in fibroblasts, endothelial cells, and immune cells. Further analyses of single-cell RNA-seq and spatial transcriptomic data independently validated the cell-type specific SnG signatures predicted by the network analysis. Conclusions This study systematically revealed the co-regulated organizations and cell type specificity of SnGs in major human tissues, which can serve as a blueprint for future studies to map senescent cells and their cellular interactions in human tissues.
Alzheimer’s disease (AD) is the most common form of dementia, characterized by progressive cognitive impairment and neurodegeneration. Extensive clinical and genomic studies have revealed biomarkers, risk factors, pathways, and targets of AD in the past decade. However, the exact molecular basis of AD development and progression remains elusive. The emerging single-cell sequencing technology can potentially provide cell-level insights into the disease. Here we systematically review the state-of-the-art bioinformatics approaches to analyze single-cell sequencing data and their applications to AD in 14 major directions, including 1) quality control and normalization, 2) dimension reduction and feature extraction, 3) cell clustering analysis, 4) cell type inference and annotation, 5) differential expression, 6) trajectory inference, 7) copy number variation analysis, 8) integration of single-cell multi-omics, 9) epigenomic analysis, 10) gene network inference, 11) prioritization of cell subpopulations, 12) integrative analysis of human and mouse sc-RNA-seq data, 13) spatial transcriptomics, and 14) comparison of single cell AD mouse model studies and single cell human AD studies. We also address challenges in using human postmortem and mouse tissues and outline future developments in single cell sequencing data analysis. Importantly, we have implemented our recommended workflow for each major analytic direction and applied them to a large single nucleus RNA-sequencing (snRNA-seq) dataset in AD. Key analytic results are reported while the scripts and the data are shared with the research community through GitHub. In summary, this comprehensive review provides insights into various approaches to analyze single cell sequencing data and offers specific guidelines for study design and a variety of analytic directions. The review and the accompanied software tools will serve as a valuable resource for studying cellular and molecular mechanisms of AD, other diseases, or biological systems at the single cell level.
Septic shock remains a health care concern associated with significant morbidity and mortality. The Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock recommend early fluid resuscitation and antimicrobials. Beyond initial management, the guidelines do not provide clear recommendations on appropriate time to initiate vasoactive therapies and corticosteroids in patients who develop shock. This review summarizes the literature regarding time of initiation of these interventions. Clinical data regarding time of initiation of these therapies in relation to shock onset, sequence of treatments with regard to each other, and clinical markers evaluated to guide initiation are summarized. Early-high vasopressor initiation within first 6 h of shock onset is associated with lower mortality. Following norepinephrine initiation, the exact dose and timing of escalation to adjunctive vasopressor agents are not well elucidated in the literature. However, recent data indicate that timing may be an important factor in initiating vasopressors and adjunctive therapies, such as corticosteroids. Norepinephrine-equivalent dose and lactate concentration can aid in determining when to initiate vasopressin and angiotensin II in patients with septic shock. Future guidelines with clear recommendations on the time of initiation of septic shock therapies are warranted.
Alpha(α)Klotho, a soluble transmembrane protein, facilitates calcium-phosphorus homeostasis through feedback between bone and kidney and is a potential systemic biomarker for bone-kidney health during spaceflight. We determined if: (1) plasma αKlotho was reduced after both spaceflight aboard the ISS and hindlimb unloading (HU); and (2) deficiency could be reversed with exercise. Both spaceflight and HU lowered circulating plasma αKlotho: plasma αKlotho recovered with exercise after HU.
Background We determine the predictive value of transthoracic echocardiographic (TTE) metrics for clinical deterioration within 5 days in adults with intermediate-risk pulmonary embolism (PE). Methods This was a prospective observational study of intermediate-risk PE patients. To determine associations of TTE and clinical predictors with clinical deterioration, we used univariable analysis, Youden’s index for optimal thresholds, and multivariable analyses to report odds ratios (ORs) or area under the curve (AUC). Results Of 306 intermediate-risk PE patients, 115 (37.6%) experienced clinical deterioration. PE patients who had clinical deterioration within 5 days had greater baseline right ventricle (RV) dilatation and worse systolic function than the group without clinical deterioration as indicated by the following: RV basal diameter 4.46 ± 0.77 versus 4.20 ± 0.77 cm; RV/LV basal width ratio 1.14 ± 0.29 versus 1.02 ± 0.24; tricuspid annular plane systolic excursion (TAPSE) 1.56 ± 0.55 versus 1.80 ± 0.52 cm; and RV systolic excursion velocity 10.40 ± 3.58 versus 12.1 ± 12.5 cm/s, respectively. Optimal thresholds for predicting clinical deterioration were: RV basal width 3.9 cm (OR 2.85 [1.64, 4.97]), RV-to-left ventricle (RV/LV) ratio 1.08 (OR 3.32 [2.07, 5.33]), TAPSE 1.98 cm (OR 3.3 [2.06, 5.3]), systolic excursion velocity 10.10 cm/s (OR 2.85 [1.75, 4.63]), and natriuretic peptide 190 pg/mL (OR 2.89 [1.81, 4.62]). Significant independent predictors were: transient hypotension 6.1 (2.2, 18.9), highest heart rate 1.02 (1.00, 1.03), highest respiratory rate 1.02 (1.00, 1.04), and RV/LV ratio 1.29 (1.14, 1.47). By logistic regression and random forest analyses, AUCs were 0.80 (0.73, 0.87) and 0.78 (0.70, 0.85), respectively. Conclusions Basal RV, RV/LV ratio, and RV systolic function measurements were significantly different between intermediate-risk PE patients grouped by subsequent clinical deterioration.
Elagolix is an FDA-approved treatment for moderate-to-severe pain associated with endometriosis but has been associated with increased acute porphyric attacks in women with the acute hepatic porphyrias (AHPs). A fluorescence-based screening assay for drug porphyrogenicity in LMH cells indicates that elagolix is porphyrogenic; thus, elagolix should be avoided or used with caution in patients with the AHPs.
Purpose Studies of early depth of sedation in mixed critically ill populations have suggested benefit to light sedation; however, the relationship of early depth of sedation with outcomes in patients with acute respiratory distress syndrome (ARDS) is unknown. Materials and methods We performed a propensity-score matched analysis of early light sedation (Richmond Agitation Sedation Scale Score, RASS 0 to −1 or equivalent) versus deep sedation (RASS −2 or lower) in patients enrolled in the non-intervention group of The Reevaluation of Systemic Early Neuromuscular Blockade trial. Primary outcome was 90 day mortality. Secondary outcomes included days free of mechanical ventilation, days not in ICU, days not in hospital at day 28. Results 137 of 486 participants (28.2%) received early light sedation. Vasopressor usage and Apache III scores significantly differed between groups. Prior to matching, 90-day mortality was higher in the early deep sedation (45.3%) compared to light sedation (34.2%) group. In the propensity score matched cohort, there was no difference in 90-day mortality (Odds Ratio (OR) 0.72, 95% CI 0.41, 1.27, p = 0.26) or secondary outcomes between the groups. Conclusions We did not find an association between early depth of sedation and clinical outcomes in this cohort of patients with moderate-to-severe ARDS.
Lung cancer is one of the leading causes of cancer-related death, with a five-year survival rate of 18%. It is a priority for us to understand the underlying mechanisms affecting lung cancer therapeutics' implementation and effectiveness. In this study, we combine the power of Bioinformatics and Systems Biology to comprehensively uncover functional and signaling pathways of drug treatment using bioinformatics inference and multiscale modeling of both scRNA-seq data and proteomics data. Based on a time series of lung adenocarcinoma derived A549 cells after DEX treatment, we first identified the differentially expressed genes (DEGs) in those lung cancer cells. Through the interrogation of regulatory network of those DEGs, we identified key hub genes including TGFβ, MYC, and SMAD3 varied underlie DEX treatment. Further gene set enrichment analysis revealed the TGFβ signaling pathway as the top enriched term. Those genes involved in the TGFβ pathway and their crosstalk with the ERBB pathway presented a strong survival prognosis in clinical lung cancer samples. With the basis of biological validation and literature-based curation, a multiscale model of tumor regulation centered on both TGFβ-induced and ERBB-amplified signaling pathways was developed to characterize the dynamic effects of DEX therapy on lung cancer cells. Our simulation results were well matched to available data of SMAD2, FOXO3, TGFβ1, and TGFβR1 over the time course. Moreover, we provided predictions of different doses to illustrate the trend and therapeutic potential of DEX treatment. The innovative and cross-disciplinary approach can be further applied to other computational studies in tumorigenesis and oncotherapy. We released the approach as a user-friendly tool named BIMM (Bioinformatic Inference and Multiscale Modeling), with all the key features available at https://github.com/chenm19/BIMM.
Reactive oxygen species (ROS) serve as second messengers in plant signaling pathways to remodel plant growth and development. New insights into how enzymatic ROS-producing machinery is regulated by hormones or localized during development have provided a framework for understanding the mechanisms that control ROS accumulation patterns. Signaling-mediated increases in ROS can then modulate the activity of proteins through reversible oxidative modification of specific cysteine residues. Plants also control the synthesis of antioxidants, including plant-specialized metabolites, to further define when, where, and how much ROS accumulate. The availability of sophisticated imaging capabilities, combined with a growing tool kit of ROS detection technologies, particularly genetically encoded biosensors, sets the stage for improved understanding of ROS as signaling molecules.
Cardiovascular disease is the leading cause of mortality in diabetes, necessitating biomarkers beyond traditional methods to stratify risk in these populations. Glycemic variability and prolonged hyperglycemia have been linked to diabetic complications and increased risk of mortality. Early in the disease process, pathologic changes to the heart occur and can be captured with noninvasive methods including an electrocardiogram (ECG). Prolonged repolarization of cardiac myocytes, represented by a prolonged QT interval on ECG, predisposes the heart to arrhythmias and sudden cardiac death. Notably, variations in the QT interval such as prolonged QT interval and increased QT dispersion have been linked to increased all-cause mortality in those with diabetes.
Regenerative medicine (RM) is changing how we think and practice transplant medicine. In regenerative medicine, the aim is to develop and employ methods to regenerate, restore or replace damaged/diseased tissues or organs. Regenerative medicine investigates using tools such as novel technologies or techniques, extracellular vesicles, cell-based therapies, and tissue-engineered constructs to design effective patient-specific treatments. This review illustrates current advancements in regenerative medicine that may pertain to transplant medicine. We highlight progress made and various tools designed and employed specifically for each tissue or organ, such as the kidney, heart, liver, lung, vasculature, gastrointestinal tract, and pancreas. By combing both fields of transplant and regenerative medicine, we can harbor a successful collaboration that would be beneficial and efficacious for the repair and design of de novo engineered whole organs for transplantations.
Introduction: Choledocholithiasis is a disease process that can be managed by laparoscopic common bile duct exploration at the time of cholecystectomy. However, it can be negatively perceived by surgeons as lengthening procedure time and adding technical complexity. Materials and Methods: We have created a dual balloon biliary intervention catheter designed to make common duct exploration efficient, simple, and safe. The device consists of two balloons, one compliant and one noncompliant, to perform initial cholangiography, dilate the sphincter, and occlude the proximal duct for distal power flushing of stones. The catheter design facilitates a stepwise, over the wire progression of interventions with a singular device. Results: The catheter has been successfully deployed in a porcine feasibility model and the dual balloon concepts reduced to practice using currently available devices. Conclusion: Laparoscopic common bile duct exploration is a safe and effective way to treat choledocolithiasis. The Dual Balloon Catheter is a novel device that allows for duct occlusion for cholangiogram and power flushing in conjunction with duct and sphincter dilation.
Objective Determine the long-term health-related quality-of-life (HRQoL), work limitation, physical activity, health/economic cost and disease burden of traumatic ACL and/or meniscal injury. Findings will inform OPTIKNEE evidence-based consensus recommendations. Design Random-effects meta-analysis evaluated HRQoL (SF-36/SF-12/VR-12 Physical Component Scores (PCS) and Mental Component Scores (MCS), EuroQol-5D (EQ-5D)) stratified by time postinjury, and pooled mean differences (95% CI) between ACL-injured and uninjured controls. Other outcomes were synthesised descriptively. Risk-of-bias (RoB) and certainty of evidence (Grading of Recommendations Assessment, Development and Evaluation) were assessed. Data sources MEDLINE, EMBASE, CENTRAL, SPORTDiscus, CINAHL searched inception: 22 November 2021. Eligibility Studies reporting HRQoL, work limitations, physical activity levels, health/economic costs or disease burden, ≥2 years post-ACL and/or meniscal injury. Results Fifty studies were included (10 high-RoB, 28 susceptible-to-some-bias and 12 low-RoB). Meta-analysis (27 studies, very low certainty of evidence) estimated a pooled mean (95% CI) PCS of 52.4 (51.4 to 53.4) and MCS of 54.0 (53.0 to 55.0) 2–14 years post-ACL injury. Pooled PCS scores were worse >10 years (50.8 (48.7 to 52.9)) compared with 2–5 years (53.9 (53.1 to 54.7)) postinjury. Excluding high-RoB studies, PCS scores were worse in ACL-injured compared with uninjured controls (−1.5 (−2.9 to –0.1)). Six studies (low certainty of evidence) informed a pooled EQ-5D score of 0.83 (0.81 to 0.84). Some individuals experienced prolonged work absenteeism and modified activities ≥2 years post-ACL injury. ACL injury was associated with significant direct and indirect costs, and early ACL reconstruction may be less cost-effective than rehabilitation. Only three studies evaluated meniscal injury outcomes (all evaluated HRQoL). Conclusion There is a very-low certainty of evidence that PCS scores ≥2 years post-ACL injury are worse than uninjured controls and decline over time, whereas MCS scores remain high. ACL injury can result in prolonged work absenteeism and high health/economic costs. Further studies are needed to determine the long-term burden of traumatic meniscal injury.
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2,005 members
oguz akbilgic
  • Section on Cardiology
Dhanendra Tomar
  • Section on Cardiology
Lance Miller
  • Department of Cancer Biology
Michael Tytell
  • Department of Neurobiology and Anatomy
Karl-Erik Andersson
  • Institute for Regenerative Medicine
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