Supporting Career Development and Employment: Benefits Planning, Assistance and Outreach (BPA&O) and Protection and Advocacy for Beneficiaries of Social Security (PABSS)

This training curriculum is dedicated to increasing knowledge and understanding of the Social Security Administration\u27s disability and return to work programs and work incentive provisions as prescribed in the Social Security Act and Ticket to Work and Work Incentives Improvement Act of 1999 as well as other federal benefit programs. These informational resources were compiled and edited to provide continuing education and print materials for benefits specialists and protection and advocacy personnel on the interplay of these benefit programs and impact or employment

Mass spectrometry techniques to assess the metabolism and toxicity of pharmaceutical and dietary nitrates

Nitric oxide (NO) is a signaling molecule that regulates blood pressure and vascular tone. Humans produce NO by endothelial nitric oxide synthase (eNOS), which is impaired in patients with cardiovascular disease leading to increased blood pressure, endothelial dysfunction, and an increased risk of adverse cardiovascular outcomes. Maintaining optimal levels of NO is critical for human health. Inorganic nitrate (NO3-) is reduced to NO and can be an alternate pathway to restore NO production. Diets high in nitrate reduce blood pressure and improve exercise performance in humans. In patients with advanced cardiovascular disease, organic nitrates such as nitroglycerin (glyceryl trinitrate, GTN) release NO and are essential for managing symptoms. This dissertation emphasizes mass spectrometry techniques to elucidate novel mechanisms for the effects of both organic and inorganic nitrate on cardiovascular health and exercise performance.Pharmaceutical Nitrate. Patients develop tolerance to GTN after several weeks of continuous use, limiting the potential for long-term therapy. The cause of nitrate tolerance is relatively unknown. I developed a cell culture model of nitrate tolerance that utilizes stable isotopes to measure metabolism of 15N3-GTN into 15N-nitrite. I performed global metabolomics to identify the mechanism of GTN-induced nitrate tolerance and to elucidate the protective role of vitamin C. Metabolomics demonstrated that GTN impaired purine metabolism and depleted intracellular ATP and GTP. GTN inactivated the enzyme xanthine oxidase (XO), an enzyme that is critical for the metabolism of GTN into NO. Vitamin C prevented inactivation of XO, resulting in increased NO production from GTN. Vitamin C supplementation should be further investigated as a simple and inexpensive strategy to prevent nitrate tolerance.Dietary Nitrate. Inorganic nitrate improves exercise performance by reducing the oxygen cost of exercise. Although previous research has suggested that nitrate improves mitochondrial efficiency and stimulates mitochondrial biogenesis, we have an incomplete understanding of the mechanism. In a zebrafish (Danio rerio) model, nitrate reduced the oxygen cost of exercise during a vigorous 2-hour exercise test. Although there were no significant differences in mitochondrial function between control and nitrate-treated zebrafish, nitrate treatment increased resting ADP, ATP, and cyclic AMP levels. Metabolomics analysis of whole fish illustrated that nitrate stimulated glycolysis and ketogenesis. I conclude that nitrate reduces the oxygen cost of exercise by favoring glycolysis for energy production, thereby producing more ATP while consuming less oxygen. Nitrate-stimulated alteration of metabolic fuels for energy production is a novel mechanism for the improvement in exercise performance.Summary. This dissertation is a significant contribution to scientific knowledge because of the development of a novel assay to measure 15N-labeled nitrate and nitrite, which I have applied to study the metabolism of pharmaceutical and dietary nitrates. Using metabolomics, I elucidated the novel mechanism that vitamin C prevents nitrate tolerance by protecting XO from inactivation. Furthermore, I demonstrated that nitrate alters the utilization of metabolic fuels, leading to reduced oxygen consumption during exercise.Keywords: pharmacology, zebrafish, toxicology, metabolomics, nitric oxide, nitrat

Plants poisonous to livestock

1 online resource (PDF, 14 pages)This archival publication may not reflect current scientific knowledge or recommendations. Current information available from the University of Minnesota Extension: https://www.extension.umn.edu

A role for mospd1 in mesenchymal stem cell proliferation and differentiation

Mesenchymal stem cells (MSCs) isolated from many tissues including bone marrow and fat can be expanded in vitro and can differentiate into a range of different cell types such as bone, cartilage, and adipocytes. MSCs can also exhibit immunoregulatory properties when transplanted but, although a number of clinical trials using MSCs are in progress, the molecular mechanisms that control their production, proliferation, and differentiation are poorly understood. We identify MOSPD1 as a new player in this process. We generated MOSPD1‐null embryonic stem cells (ESCs) and demonstrate that they are deficient in their ability to differentiate into a number of cell lineages including osteoblasts, adipocytes, and hematopoietic progenitors. The self‐renewal capacity of MOSPD1‐null ESCs was normal and they exhibited no obvious defects in early germ layer specification nor in epithelial to mesenchymal transition (EMT), indicating that MOSPD1 functions after these key steps in the differentiation process. Mesenchymal stem cell (MSC)‐like cells expressing CD73, CD90, and CD105 were generated from MOSPD1‐null ESCs but their growth rate was significantly impaired implying that MOSPD1 plays a role in MSC proliferation. Phenotypic deficiencies exhibited by MOSPD1‐null ESCs were rescued by exogenous expression of MOSPD1, but not MOSPD3 indicating distinct functional properties of these closely related genes. Our in vitro studies were supported by RNA‐sequencing data that confirmed expression of Mospd1 mRNA in cultured, proliferating perivascular pre‐MSCs isolated from human tissue. This study adds to the growing body of knowledge about the function of this largely uncharacterized protein family and introduces a new player in the control of MSC proliferation and differentiation. Stem Cells 2015;33:3077–308

The incidence, aetiology and outcome of acute seizures in children admitted to a rural Kenyan district hospital

<p>Abstract</p> <p>Background</p> <p>Acute seizures are a common cause of paediatric admissions to hospitals in resource poor countries and a risk factor for neurological and cognitive impairment and epilepsy. We determined the incidence, aetiological factors and the immediate outcome of seizures in a rural malaria endemic area in coastal Kenya.</p> <p>Methods</p> <p>We recruited all children with and without seizures, aged 0–13 years and admitted to Kilifi District hospital over 2 years from 1^stDecember 2004 to 30^thNovember 2006. Only incident admissions from a defined area were included. Patients with epilepsy were excluded. The population denominator, the number of children in the community on 30^thNovember 2005 (study midpoint), was modelled from a census data.</p> <p>Results</p> <p>Seizures were reported in 900/4,921(18.3%) incident admissions and at least 98 had status epilepticus. The incidence of acute seizures in children 0–13 years was 425 (95%CI 386, 466) per 100,000/year and was 879 (95%CI 795, 968) per 100,000/year in children <5 years. This incidence data may however be an underestimate of the true incidence in the community. Over 80% of the seizures were associated with infections. Neonatal infections (28/43 [65.1%]) and falciparum malaria (476/821 [58.0%]) were the main diseases associated with seizures in neonates and in children six months or older respectively. Falciparum malaria was also the main illness (56/98 [57.1%]) associated with status epilepticus. Other illnesses associated with seizures included pyogenic meningitis, respiratory tract infections and gastroenteritis. Twenty-eight children (3.1%) with seizures died and 11 surviving children (1.3%) had gross neurological deficits on discharge. Status epilepticus, focal seizures, coma, metabolic acidosis, bacteraemia, and pyogenic meningitis were independently associated with mortality; while status epilepticus, hypoxic ischaemic encephalopathy and pyogenic meningitis were independently associated with neurological deficits on discharge.</p> <p>Conclusion</p> <p>There is a high incidence of acute seizures in children living in this malaria endemic area of Kenya. The most important causes are diseases that are preventable with available public health programs.</p

Molecular Evolution of Phosphoprotein Phosphatases in Drosophila

Phosphoprotein phosphatases (PPP), these ancient and important regulatory enzymes are present in all eukaryotic organisms. Based on the genome sequences of 12 Drosophila species we traced the evolution of the PPP catalytic subunits and noted a substantial expansion of the gene family. We concluded that the 18–22 PPP genes of Drosophilidae were generated from a core set of 8 indispensable phosphatases that are present in most of the insects. Retropositons followed by tandem gene duplications extended the phosphatase repertoire, and sporadic gene losses contributed to the species specific variations in the PPP complement. During the course of these studies we identified 5, up till now uncharacterized phosphatase retrogenes: PpY+, PpD5+, PpD6+, Pp4+, and Pp6+ which are found only in some ancient Drosophila. We demonstrated that all of these new PPP genes exhibit a distinct male specific expression. In addition to the changes in gene numbers, the intron-exon structure and the chromosomal localization of several PPP genes was also altered during evolution. The G−C content of the coding regions decreased when a gene moved into the heterochromatic region of chromosome Y. Thus the PPP enzymes exemplify the various types of dynamic rearrangements that accompany the molecular evolution of a gene family in Drosophilidae

The FAIR Guiding Principles for scientific data management and stewardship

There is an urgent need to improve the infrastructure supporting the reuse of scholarly data. A diverse set of stakeholders—representing academia, industry, funding agencies, and scholarly publishers—have come together to design and jointly endorse a concise and measureable set of principles that we refer to as the FAIR Data Principles. The intent is that these may act as a guideline for those wishing to enhance the reusability of their data holdings. Distinct from peer initiatives that focus on the human scholar, the FAIR Principles put specific emphasis on enhancing the ability of machines to automatically find and use the data, in addition to supporting its reuse by individuals. This Comment is the first formal publication of the FAIR Principles, and includes the rationale behind them, and some exemplar implementations in the community

Model for screening of resonant magnetic perturbations by plasma in a realistic tokamak geometry and its impact on divertor strike points

This work addresses the question of the relation between strike-point splitting and magnetic stochasticity at the edge of a poloidally diverted tokamak in the presence of externally imposed magnetic perturbations. More specifically, ad-hoc helical current sheets are introduced in order to mimic a hypothetical screening of the external resonant magnetic perturbations by the plasma. These current sheets, which suppress magnetic islands, are found to reduce the amount of splitting expected at the target, which suggests that screening effects should be observable experimentally. Multiple screening current sheets reinforce each other, i.e. less current relative to the case of only one current sheet is required to screen the perturbation.Comment: Accepted in the Proceedings of the 19th International Conference on Plasma Surface Interactions, to be published in Journal of Nuclear Materials. Version 2: minor formatting and text improvements, more results mentioned in the conclusion and abstrac

Modelling of the effect of ELMs on fuel retention at the bulk W divertor of JET

Effect of ELMs on fuel retention at the bulk W target of JET ITER-Like Wall was studied with multi-scale calculations. Plasma input parameters were taken from ELMy H-mode plasma experiment. The energetic intra-ELM fuel particles get implanted and create near-surface defects up to depths of few tens of nm, which act as the main fuel trapping sites during ELMs. Clustering of implantation-induced vacancies were found to take place. The incoming flux of inter-ELM plasma particles increases the different filling levels of trapped fuel in defects. The temperature increase of the W target during the pulse increases the fuel detrapping rate. The inter-ELM fuel particle flux refills the partially emptied trapping sites and fills new sites. This leads to a competing effect on the retention and release rates of the implanted particles. At high temperatures the main retention appeared in larger vacancy clusters due to increased clustering rate