Modeling Genetic Networks from Clonal Analysis

In this report a systematic approach is used to determine the approximate genetic network and robust dependencies underlying differentiation. The data considered is in the form of a binary matrix and represent the expression of the nine genes across the ninety-nine colonies. The report is divided into two parts: the first part identifies significant pair-wise dependencies from the given binary matrix using linear correlation and mutual information. A new method is proposed to determine statistically significant dependencies estimated using the mutual information measure. In the second, a Bayesian approach is used to obtain an approximate description (equivalence class) of network structures. The robustness of linear correlation, mutual information and the equivalence class of networks is investigated with perturbation and decreasing colony number. Perturbation of the data was achieved by generating bootstrap realizations. The results are refined with biological knowledge. It was found that certain dependencies in the network are immune to perturbation and decreasing colony number and may represent robust features, inherent in the differentiation program of osteoblast progenitor cells. The methods to be discussed are generic in nature and not restricted to the experimental paradigm addressed in this study.Comment: 59 pahes, 11 figures, 3 table

Myonuclear Domain Flexibility Challenges Rigid Assumptions on Satellite Cell Contribution to Skeletal Muscle Fiber Hypertrophy

Satellite cell-mediated myonuclear accretion is thought to be required for skeletal muscle fiber hypertrophy, and even drive hypertrophy by preceding growth. Recent studies in humans and rodents provide evidence that challenge this axiom. Specifically, Type 2 muscle fibers reliably demonstrate a substantial capacity to hypertrophy in the absence of myonuclear accretion, challenging the notion of a tightly regulated myonuclear domain (i.e., area that each myonucleus transcriptionally governs). In fact, a “myonuclear domain ceiling”, or upper limit of transcriptional output per nucleus to support hypertrophy, has yet to be identified. Satellite cells respond to muscle damage, and also play an important role in extracellular matrix remodeling during loading-induced hypertrophy. We postulate that robust satellite cell activation and proliferation in response to mechanical loading is largely for these purposes. Future work will aim to elucidate the mechanisms by which Type 2 fibers can hypertrophy without additional myonuclei, the extent to which Type 1 fibers can grow without myonuclear accretion, and whether a true myonuclear domain ceiling exists

Mycobacterium leprae in Armadillo Tissues from Museum Collections, United States

We examined armadillos from museum collections in the United States using molecular assays to detect leprosy-causing bacilli. We found Mycobacterium leprae bacilli in samples from the United States, Bolivia, and Paraguay; prevalence was 14.8% in nine-banded armadillos. US isolates belonged to subtype 3I-2, suggesting long-term circulation of this genotype

Myonuclear Transcriptional Dynamics in Response to Exercise Following Satellite Cell Depletion

Skeletal muscle is composed of post-mitotic myofibers that form a syncytium containing hundreds of myonuclei. Using a progressive exercise training model in the mouse and single nucleus RNA-sequencing (snRNA-seq) for high-resolution characterization of myonuclear transcription, we show myonuclear functional specialization in muscle. After 4 weeks of exercise training, snRNA-seq reveals that resident muscle stem cells, or satellite cells, are activated with acute exercise but demonstrate limited lineage progression while contributing to muscle adaptation. In the absence of satellite cells, a portion of nuclei demonstrates divergent transcriptional dynamics associated with mixed-fate identities compared with satellite cell replete muscles. These data provide a compendium of information about how satellite cells influence myonuclear transcription in response to exercise

Myogenic Progenitor Cells Control Extracellular Matrix Production by Fibroblasts during Skeletal Muscle Hypertrophy

Satellite cells, the predominant stem cell population in adult skeletal muscle, are activated in response to hypertrophic stimuli and give rise to myogenic progenitor cells (MPCs) within the extracellular matrix (ECM) that surrounds myofibers. This ECM is composed largely of collagens secreted by interstitial fibrogenic cells, which influence satellite cell activity and muscle repair during hypertrophy and aging. Here we show that MPCs interact with interstitial fibrogenic cells to ensure proper ECM deposition and optimal muscle remodeling in response to hypertrophic stimuli. MPC-dependent ECM remodeling during the first week of a growth stimulus is sufficient to ensure long-term myofiber hypertrophy. MPCs secrete exosomes containing miR-206, which represses Rrbp1, a master regulator of collagen biosynthesis, in fibrogenic cells to prevent excessive ECM deposition. These findings provide insights into how skeletal stem and progenitor cells interact with other cell types to actively regulate their extracellular environments for tissue maintenance and adaptation

The influence of left ventricular hypertrophyon survival in patients with coronaryartery disease: do race and gender matter?

AbstractObjectivesWe sought to determine the overall prognostic importance of left ventricular hypertrophy (LVH) among patients with coronary artery disease (CAD), as well as to determine whether this risk varies as a function of race or gender.BackgroundLeft ventricular hypertrophy is more prevalent among blacks and women than their counterparts. Blacks and women also have higher mortality with coronary disease.MethodsWe studied records of 2,461 patients (19% black, 42% women) diagnosed with CAD at cardiac catheterization between 1990 and 1998 from a single academic center. Left ventricular hypertrophy was defined using standard echocardiographic measures. Cox proportional hazards models were used for adjusted survival analyses. Mean patient follow-up was three years.ResultsPatients with LVH were older (68 vs. 65 years, p < 0.01), more often women (54% vs. 36%, p < 0.01), and black (25% vs. 16%, p < 0.01), and had higher unadjusted three-year mortality rates than patients without LVH (42% vs. 34%, p < 0.01). Left ventricular hypertrophy remained an independent predictor of mortality after adjusting for other clinical risk factors (hazard ratio 1.56, 95% confidence interval 1.35 to 1.80) with prognostic importance equivalent to that of left ventricular ejection fraction. Although the relative risk of LVH did not vary by race or gender, the attributable risk of LVH was greater in blacks and women.ConclusionsClinicians should consider the prognostic importance of LVH when assessing risk in patients with CAD. Because LVH is more common among black and women patients with CAD, it partially accounts for racial and gender differences in survival

Fusion and Beyond: Satellite Cell Contributions to Loading-Induced Skeletal Muscle Adaptation

Satellite cells support adult skeletal muscle fiber adaptations to loading in numerous ways. The fusion of satellite cells, driven by cell-autonomous and/or extrinsic factors, contributes new myonuclei to muscle fibers, associates with load-induced hypertrophy, and may support focal membrane damage repair and long-term myonuclear transcriptional output. Recent studies have also revealed that satellite cells communicate within their niche to mediate muscle remodeling in response to resistance exercise, regulating the activity of numerous cell types through various mechanisms such as secretory signaling and cell–cell contact. Muscular adaptation to resistance and endurance activity can be initiated and sustained for a period of time in the absence of satellite cells, but satellite cell participation is ultimately required to achieve full adaptive potential, be it growth, function, or proprioceptive coordination. While significant progress has been made in understanding the roles of satellite cells in adult muscle over the last few decades, many conclusions have been extrapolated from regeneration studies. This review highlights our current understanding of satellite cell behavior and contributions to adaptation outside of regeneration in adult muscle, as well as the roles of satellite cells beyond fusion and myonuclear accretion, which are gaining broader recognition

Potential Benefits of Combined Statin and Metformin Therapy on Resistance Training Response in Older Individuals

Metformin and statins are currently the focus of large clinical trials testing their ability to counter age-associated declines in health, but recent reports suggest that both may negatively affect skeletal muscle response to exercise. However, it has also been suggested that metformin may act as a possible protectant of statin-related muscle symptoms. The potential impact of combined drug use on the hypertrophic response to resistance exercise in healthy older adults has not been described. We present secondary statin analyses of data from the MASTERS trial where metformin blunted the hypertrophy response in healthy participants (\u3e65 years) following 14 weeks of progressive resistance training (PRT) when compared to identical placebo treatment (n = 94). Approximately one-third of MASTERS participants were taking prescribed statins. Combined metformin and statin resulted in rescue of the metformin-mediated impaired growth response to PRT but did not significantly affect strength. Improved muscle fiber growth may be associated with medication-induced increased abundance of CD11b+/CD206+ M2-like macrophages. Sarcopenia is a significant problem with aging and this study identifies a potential interaction between these commonly used drugs which may help prevent metformin-related blunting of the beneficial effects of PRT

Adipose Tissue Extracellular Matrix and Vascular Abnormalities in Obesity and Insulin Resistance

Context: Insulin resistance is associated with inflammation, fibrosis, and hypoxia in adipose tissue. Objective: This study was intended to better characterize the extracellular matrix (ECM) and vascularity of insulin-resistant adipose tissue. Design: Adipose expression of collagens, elastin, and angiogenic factors was assessed using realtime RT-PCR and immunohistochemistry (IHC) in abdominal sc adipose tissue. Adipocyte-macrophage coculture experiments examined the effects of polarized macrophages on adipose ECM gene expression, and the effects of collagens were measured in an angiogenesis assay. Participants and Setting: A total of 74 nondiabetic subjects participated at a University Clinical Research Center. Interventions: Interventions included baseline adipose biopsy and measurement of insulin sensitivity. Main Outcome Measures: Outcome measures included characterization of vascularity and ECM in adipose tissue. Results: CD31 (an endothelial marker) mRNA showed no significant correlation with body mass index or insulin sensitivity. In a subgroup of 17 subjects (nine obese, eight lean), CD31-positive capillary number in obese was decreased by 58%, whereas larger vessels were increased by 70%, accounting for the lack of change in CD31 expression with obesity. Using IHC, obese (compared with lean) subjects had decreased elastin and increased collagen V expression, and adipocytes cocultured with M2 macrophages had reduced elastin and increased collagen V expression. In obese subjects, collagen V was colocalized with large blood vessels, and the addition of collagen V to an angiogenesis assay inhibited endothelial budding. Conclusions: The adipose tissue from obese/insulin- resistant subjects has fewer capillaries and morelarge vessels as compared with lean subjects.The ECM of adipose tissue may play an important role in regulating the expandability as well as angiogenesis of adipose tissue. (J Clin Endocrinol Metab 96: E1990–E1998, 2011

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