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Institution

Veterans Health Administration

GovernmentWashington D.C., District of Columbia, United States
About: Veterans Health Administration is a government organization based out in Washington D.C., District of Columbia, United States. It is known for research contribution in the topics: Population & Veterans Affairs. The organization has 63820 authors who have published 98417 publications receiving 4835425 citations. The organization is also known as: VHA.


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Journal ArticleDOI
TL;DR: The finding of pathogenic mutations in TARDBP implicates TDP-43 as an active mediator of neurodegeneration in TDP -43 proteinopathies, a class of disorder that includes ALS and FTLD-U.
Abstract: Summary Background TDP-43 is a major component of the ubiquitinated inclusions that characterise amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with ubiquitin inclusions (FTLD-U). TDP-43 is an RNA-binding and DNA-binding protein that has many functions and is encoded by the TAR DNA-binding protein gene ( TARDBP ) on chromosome 1. Our aim was to investigate whether TARDBP is a candidate disease gene for familial ALS that is not associated with mutations in superoxide dismutase 1 ( SOD1 ). Methods TARDBP was sequenced in 259 patients with ALS, FTLD, or both. We used TaqMan-based SNP genotyping to screen for the identified variants in control groups matched to two kindreds of patients for age and ethnic origin. Additional clinical, genetic, and pathological assessments were made in these two families. Findings We identified two variants in TARDBP , which would encode Gly290Ala and Gly298Ser forms of TDP-43, in two kindreds with familial ALS. The variants seem to be pathogenic because they co-segregated with disease in both families, were absent in controls, and were associated with TDP-43 neuropathology in both members of one of these families for whom CNS tissue was available. Interpretation The Gly290Ala and Gly298Ser mutations are located in the glycine-rich domain of TDP-43, which regulates gene expression and mediates protein–protein interactions such as those with heterogeneous ribonucleoproteins. Owing to the varied and important cellular functions of TDP-43, these mutations might cause neurodegeneration through both gains and losses of function. The finding of pathogenic mutations in TARDBP implicates TDP-43 as an active mediator of neurodegeneration in TDP-43 proteinopathies, a class of disorder that includes ALS and FTLD-U. Funding National Institutes of Health (AG10124, AG17586, AG005136-22, PO1 AG14382), Department of Veterans Affairs, Friedrich-Baur Stiftung (0017/2007), US Public Health Service, ALS Association, and Fundacio ‘la Caixa'.

693 citations

Journal ArticleDOI
TL;DR: The integration of sex steroid effects at distinct cellular locations of its receptor leads to important cellular physiological outcomes and are manifest in both reproductive and nonreproductive organs.
Abstract: Estrogen receptors (ERs) are localized to many sites within the cell, potentially contributing to overall estrogen action. In the nucleus, estrogen mainly modulates gene transcription, and the resulting protein products determine the cell biological actions of the sex steroid. In addition, a small pool of ERs localize to the plasma membrane and signal mainly though coupling, directly or indirectly, to G proteins. In response to steroid, signal transduction modulates both nontranscriptional and transcriptional events and impacts both the rapid and more prolonged actions of estrogen. Cross-talk from membrane-localized ERs to nuclear ERs can be mediated through growth factor receptor tyrosine kinases, such as epidermal growth factor receptor and IGF-I receptor. Growth factor receptors enact signal transduction to kinases such as ERK and phosphatidylinositol 3-kinase that phosphorylate and activate nuclear ERs, and this can also occur in the absence of sex steroid. A complex relationship between the membrane and nuclear effects of estrogen also involves membrane-initiated phosphorylation of coactivators, recruiting these proteins to the nuclear transcriptosome. Finally, large pools of cytoplasmic ERs exist, and some are localized to mitochondria. The integration of sex steroid effects at distinct cellular locations of its receptor leads to important cellular physiological outcomes and are manifest in both reproductive and nonreproductive organs.

691 citations

Journal ArticleDOI
TL;DR: Strength and muscle mass are increased following resistance training in older adults through a poorly understood series of events that appears to involve the recruitment of satellite cells to support hypertrophy of mature myofibres.
Abstract: Using an integrative approach, this review highlights the benefits of resistance training toward improvements in functional status, health and quality of life among older adults. Sarcopenia (i.e. muscle atrophy) and loss of strength are known to occur with age. While its aetiology is poorly understood, the multifactorial sequelae of sarcopenia are well documented and present a major public health concern to our aging population, as both the quality of life and the likelihood of age-associated declines in health status are influenced. These age-related declines in health include decreased energy expenditure at rest and during exercise, and increased body fat and its accompanying increased dyslipidaemia and reduced insulin sensitivity. Quality of life is affected by reduced strength and endurance and increased difficulty in being physically active. Strength and muscle mass are increased following resistance training in older adults through a poorly understood series of events that appears to involve the recruitment of satellite cells to support hypertrophy of mature myofibres. Muscle quality (strength relative to muscle mass) also increases with resistance training in older adults possibly for a number of reasons, including increased ability to neurally activate motor units and increased high-energy phosphate availability. Resistance training in older adults also increases power, reduces the difficulty of performing daily tasks, enhances energy expenditure and body composition, and promotes participation in spontaneous physical activity. Impairment in strength development may result when aerobic training is added to resistance training but can be avoided with training limited to 3 days/week.

691 citations

Journal ArticleDOI
TL;DR: Although complement undoubtedly plays a role in host defense against many microbial pathogens, it appears most important in protection against encapsulated bacteria, especially Neisseria meningitidis but also Streptococcus pneumoniae, Haemophilus influenzae, and, to a lesser extent, NeISSeria gonorrhoeae.
Abstract: The complement system consists of both plasma and membrane proteins. The former influence the inflammatory response, immune modulation, and host defense. The latter are complement receptors, which mediate the cellular effects of complement activation, and regulatory proteins, which protect host cells from complement-mediated injury. Complement activation occurs via either the classical or the alternative pathway, which converge at the level of C3 and share a sequence of terminal components. Four aspects of the complement cascade are critical to its function and regulation: (i) activation of the classical pathway, (ii) activation of the alternative pathway, (iii) C3 convertase formation and C3 deposition, and (iv) membrane attack complex assembly and insertion. In general, mechanisms evolved by pathogenic microbes to resist the effects of complement are targeted to these four steps. Because individual complement proteins subserve unique functional activities and are activated in a sequential manner, complement deficiency states are associated with predictable defects in complement-dependent functions. These deficiency states can be grouped by which of the above four mechanisms they disrupt. They are distinguished by unique epidemiologic, clinical, and microbiologic features and are most prevalent in patients with certain rheumatologic and infectious diseases. Ethnic background and the incidence of infection are important cofactors determining this prevalence. Although complement undoubtedly plays a role in host defense against many microbial pathogens, it appears most important in protection against encapsulated bacteria, especially Neisseria meningitidis but also Streptococcus pneumoniae, Haemophilus influenzae, and, to a lesser extent, Neisseria gonorrhoeae. The availability of effective polysaccharide vaccines and antibiotics provides an immunologic and chemotherapeutic rationale for preventing and treating infection in patients with these deficiencies.

691 citations


Authors

Showing all 63886 results

NameH-indexPapersCitations
Michael Karin236704226485
Paul M. Ridker2331242245097
Eugene Braunwald2301711264576
Ralph B. D'Agostino2261287229636
John Q. Trojanowski2261467213948
Fred H. Gage216967185732
Edward Giovannucci2061671179875
Rob Knight2011061253207
Frank E. Speizer193636135891
Stephen V. Faraone1881427140298
Scott M. Grundy187841231821
Paul G. Richardson1831533155912
Peter W.F. Wilson181680139852
Dennis S. Charney179802122408
Kenneth C. Anderson1781138126072
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Performance
Metrics
No. of papers from the Institution in previous years
YearPapers
202314
2022137
20216,161
20205,712
20195,171
20184,497