Defining Optimal Aerobic Exercise Parameters to Affect Complex Motor and Cognitive Outcomes after Stroke: A Systematic Review and Synthesis

Although poststroke aerobic exercise (AE) increases markers of neuroplasticity and protects perilesional tissue, the degree to which it enhances complex motor or cognitive outcomes is unknown. Previous research suggests that timing and dosage of exercise may be important. We synthesized data from clinical and animal studies in order to determine optimal AE training parameters and recovery outcomes for future research. Using predefined criteria, we included clinical trials of stroke of any type or duration and animal studies employing any established models of stroke. Of the 5,259 titles returned, 52 articles met our criteria, measuring the effects of AE on balance, lower extremity coordination, upper limb motor skills, learning, processing speed, memory, and executive function. We found that early-initiated low-to-moderate intensity AE improved locomotor coordination in rodents. In clinical trials, AE improved balance and lower limb coordination irrespective of intervention modality or parameter. In contrast, fine upper limb recovery was relatively resistant to AE. In terms of cognitive outcomes, poststroke AE in animals improved memory and learning, except when training was too intense. However, in clinical trials, combined training protocols more consistently improved cognition. We noted a paucity of studies examining the benefits of AE on recovery beyond cessation of the intervention

Financing drug discovery for orphan diseases

Recently proposed ‘megafund’ financing methods for funding translational medicine and drug development require billions of dollars in capital per megafund to de-risk the drug discovery process enough to issue long-term bonds. Here, we demonstrate that the same financing methods can be applied to orphan drug development but, because of the unique nature of orphan diseases and therapeutics (lower development costs, faster FDA approval times, lower failure rates and lower correlation of failures among disease targets) the amount of capital needed to de-risk such portfolios is much lower in this field. Numerical simulations suggest that an orphan disease megafund of only US$575 million can yield double-digit expected rates of return with only 10–20 projects in the portfolio.MIT Laboratory for Financial Engineerin

Abnormal Trafficking of Endogenously Expressed BMPR2 Mutant Allelic Products in Patients with Heritable Pulmonary Arterial Hypertension

More than 200 heterozygous mutations in the type 2 BMP receptor gene, BMPR2, have been identified in patients with Heritable Pulmonary Arterial Hypertension (HPAH). More severe clinical outcomes occur in patients with BMPR2 mutations by-passing nonsense-mediated mRNA decay (NMD negative mutations). These comprise 40% of HPAH mutations and are predicted to express BMPR2 mutant products. However expression of endogenous NMD negative BMPR2 mutant products and their effect on protein trafficking and signaling function have never been described. Here, we characterize the expression and trafficking of an HPAH-associated NMD negative BMPR2 mutation that results in an in-frame deletion of BMPR2 EXON2 (BMPR2ΔEx2) in HPAH patient-derived lymphocytes and in pulmonary endothelial cells (PECs) from mice carrying the same in-frame deletion of Exon 2 (Bmpr2 (ΔEx2/+) mice). The endogenous BMPR2ΔEx2 mutant product does not reach the cell surface and is retained in the endoplasmic reticulum. Moreover, chemical chaperones 4-PBA and TUDCA partially restore cell surface expression of Bmpr2ΔEx2 in PECs, suggesting that the mutant product is mis-folded. We also show that PECs from Bmpr2 (ΔEx2/+) mice have defects in the BMP-induced Smad1/5/8 and Id1 signaling axis, and that addition of chemical chaperones restores expression of the Smad1/5/8 target Id1. These data indicate that the endogenous NMD negative BMPRΔEx2 mutant product is expressed but has a folding defect resulting in ER retention. Partial correction of this folding defect and restoration of defective BMP signaling using chemical chaperones suggests that protein-folding agents could be used therapeutically in patients with these NMD negative BMPR2 mutations

Evaluation of the Group Lifestyle Balance Program in a Military Setting: An Investment Worth Expanding

Introduction: The Diabetes Prevention Program (DPP) demonstrated that lifestyle intervention programs were effective in preventing or delaying the onset of diabetes. The Group Lifestyle Balance (GLB) program translated the DPP curriculum into a 12-wk group intervention for those at risk for diabetes. This retrospective evaluation examined clinical outcomes for patients in the Diabetes Center of Excellence GLB program located at Wilford Hall Ambulatory Surgical Center from 2009 to 2013. Objectives included determining rates of retention, demographic characteristics of program completers, and changes in metabolic surrogates of disease prevalence. Study Design: Adults with prediabetes or metabolic syndrome (MetS) were referred to the GLB program. Updated participant metabolic data were collected at regular intervals during their participation. Results: During the 5-yr study, 704 patients attended the initial class. Overall, 52% of all participants completed the program with the greatest decline in participation occurring by the fourth week (30%). Baseline prevalence of conditions of interest for those who completed the program was prediabetes (93.2%), obesity (56.1%), and MetS (31.5%). GLB completers were older and retired (p \u3c 0.05). A significant number of active duty military members (44.9%, p \u3c 0.01, n = 53) dropped out of the program before the fourth week. Furthermore, those who completed the program saw a 2.0% reduction in prediabetes prevalence (p \u3c 0.001), obesity decreased by 8.7% (p \u3c 0.001), and MetS decreased by 6.8% (p \u3c 0.01). Significant differences were found for central obesity, triglycerides, and fasting blood sugar (p \u3c 0.001). Conclusions: The GLB program is a valuable DPP and was effective at improving clinical outcomes and reducing the incidence of prediabetes, obesity, and MetS for participants who completed the program. Every effort should be made to support and encourage GLB participants to complete the program

CcpA regulates arginine biosynthesis in Staphylococcus aureus through repression of proline catabolism.

Staphylococcus aureus is a leading cause of community-associated and nosocomial infections. Imperative to the success of S. aureus is the ability to adapt and utilize nutrients that are readily available. Genomic sequencing suggests that S. aureus has the genes required for synthesis of all twenty amino acids. However, in vitro experimentation demonstrates that staphylococci have multiple amino acid auxotrophies, including arginine. Although S. aureus possesses the highly conserved anabolic pathway that synthesizes arginine via glutamate, we demonstrate here that inactivation of ccpA facilitates the synthesis of arginine via the urea cycle utilizing proline as a substrate. Mutations within putA, rocD, arcB1, argG and argH abolished the ability of S. aureus JE2 ccpA::tetL to grow in the absence of arginine, whereas an interruption in argJBCF, arcB2, or proC had no effect. Furthermore, nuclear magnetic resonance demonstrated that JE2 ccpA::ermB produced (13)C(5) labeled arginine when grown with (13)C(5) proline. Taken together, these data support the conclusion that S. aureus synthesizes arginine from proline during growth on secondary carbon sources. Furthermore, although highly conserved in all sequenced S. aureus genomes, the arginine anabolic pathway (ArgJBCDFGH) is not functional under in vitro growth conditions. Finally, a mutation in argH attenuated virulence in a mouse kidney abscess model in comparison to wild type JE2 demonstrating the importance of arginine biosynthesis in vivo via the urea cycle. However, mutations in argB, argF, and putA did not attenuate virulence suggesting both the glutamate and proline pathways are active and they, or their pathway intermediates, can complement each other in vivo

Independent evolution of neurotoxin and flagellar genetic loci in proteolytic Clostridium botulinum

<p>Abstract</p> <p>Background</p> <p>Proteolytic <it>Clostridium botulinum </it>is the causative agent of botulism, a severe neuroparalytic illness. Given the severity of botulism, surprisingly little is known of the population structure, biology, phylogeny or evolution of <it>C. botulinum</it>. The recent determination of the genome sequence of <it>C. botulinum </it>has allowed comparative genomic indexing using a DNA microarray.</p> <p>Results</p> <p>Whole genome microarray analysis revealed that 63% of the coding sequences (CDSs) present in reference strain ATCC 3502 were common to all 61 widely-representative strains of proteolytic <it>C. botulinum </it>and the closely related <it>C. sporogenes </it>tested. This indicates a relatively stable genome. There was, however, evidence for recombination and genetic exchange, in particular within the neurotoxin gene and cluster (including transfer of neurotoxin genes to <it>C. sporogenes</it>), and the flagellar glycosylation island (FGI). These two loci appear to have evolved independently from each other, and from the remainder of the genetic complement. A number of strains were atypical; for example, while 10 out of 14 strains that formed type A1 toxin gave almost identical profiles in whole genome, neurotoxin cluster and FGI analyses, the other four strains showed divergent properties. Furthermore, a new neurotoxin sub-type (A5) has been discovered in strains from heroin-associated wound botulism cases. For the first time, differences in glycosylation profiles of the flagella could be linked to differences in the gene content of the FGI.</p> <p>Conclusion</p> <p>Proteolytic <it>C. botulinum </it>has a stable genome backbone containing specific regions of genetic heterogeneity. These include the neurotoxin gene cluster and the FGI, each having evolved independently of each other and the remainder of the genetic complement. Analysis of these genetic components provides a high degree of discrimination of strains of proteolytic <it>C. botulinum</it>, and is suitable for clinical and forensic investigations of botulism outbreaks.</p

Numerical simulations of string networks in the Abelian-Higgs model

We present the results of a field theory simulation of networks of strings in the Abelian Higgs model. Starting from a random initial configuration we show that the resulting vortex tangle approaches a self-similar regime in which the length density of lines of zeros of $\phi$ reduces as $t^{-2}$. We demonstrate that the network loses energy directly into scalar and gauge radiation. These results support a recent claim that particle production, and not gravitational radiation, is the dominant energy loss mechanism for cosmic strings. This means that cosmic strings in Grand Unified Theories are severely constrained by high energy cosmic ray fluxes: either they are ruled out, or an implausibly small fraction of their energy ends up in quarks and leptons.Comment: 4pp RevTeX, 3 eps figures, clarifications and new results included, to be published in Phys. Rev. Let