The relationship between ciliary neurotrophic factor (CNTF) genotype and motor unit physiology: preliminary studies

BACKGROUND: Ciliary neurotrophic factor (CNTF) is important for neuronal and muscle development, and genetic variation in the CNTF gene has been associated with muscle strength. The effect of CNTF on nerve development suggests that CNTF genotype may be associated with force production via its influence on motor unit size and firing patterns. The purpose of this study is to examine whether CNTF genotype differentially affects motor unit activation in the vastus medialis with increasing isometric force during knee extension. RESULTS: Sixty-nine healthy subjects were genotyped for the presence of the G and A (null) alleles in the CNTF gene (n = 57 G/G, 12 G/A). They were tested using a dynamometer during submaximal isometric knee extension contractions that were from 10–50% of their maximal strength. During the contractions, the vastus medialis was studied using surface and intramuscular electromyography with spiked triggered averaging to assess surface-detected motor unit potential (SMUP) area and mean firing rates (mFR) from identified motor units. CNTF genotyping was performed using standard PCR techniques from DNA obtained from leucocytes of whole blood samples. The CNTF G/A genotype was associated with smaller SMUP area motor units and lower mFR at higher force levels, and fewer but larger units at lower force levels than G/G homozygotes. The two groups used motor units with different size and activation characteristics with increasing force generation. While G/G subjects tended to utilize larger motor units with increasing force, G/A subjects showed relatively less increase in size by using relatively larger units at lower force levels. At higher force levels, G/A subjects were able to generate more force per motor unit size suggesting more efficient motor unit function with increasing muscle force. CONCLUSION: Differential motor unit responses were observed between CNTF genotypes at force levels utilized in daily activities

Nanoscale protein architecture of the kidney glomerular basement membrane

In multicellular organisms, proteins of the extracellular matrix (ECM) play structural and functional roles in essentially all organs, so understanding ECM protein organization in health and disease remains an important goal. Here, we used sub-diffraction resolution stochastic optical reconstruction microscopy (STORM) to resolve the in situ molecular organization of proteins within the kidney glomerular basement membrane (GBM), an essential mediator of glomerular ultrafiltration. Using multichannel STORM and STORM-electron microscopy correlation, we constructed a molecular reference frame that revealed a laminar organization of ECM proteins within the GBM. Separate analyses of domains near the N- and C-termini of agrin, laminin, and collagen IV in mouse and human GBM revealed a highly oriented macromolecular organization. Our analysis also revealed disruptions in this GBM architecture in a mouse model of Alport syndrome. These results provide the first nanoscopic glimpse into the organization of a complex ECM. DOI: http://dx.doi.org/10.7554/eLife.01149.00

Sibling Spillovers

It is notoriously difficult to identify peer effects within the family, because of the common shocks and reflection problems. We make use of a novel identification strategy and unique data in order to gain some purchase on this problem. We employ data from the universe of children born in Florida between 1994 and 2002 and in Denmark between 1990 and 2001, which we match to school and medical records. To address the identification problem, we examine the effects of having a sibling with a disability. Utilizing three-plus-child families, we employ a differences-in-differences research design which makes use of the fact that birth order influences the amount of time which a child spends in early childhood with their siblings, disabled or not. We observe consistent evidence in both locations that the second child in a family is differentially affected when the third child is disabled. We also provide evidence which suggests that the sibling spillovers are working at least in part through the relative exposure to parental time and financial resources

Results of the 2016 Indianapolis Biodiversity Survey, Marion County, Indiana

Surprising biodiversity can be found in cities, but urban habitats are understudied. We report on a bioblitz conducted primarily within a 24-hr period on September 16 and 17, 2016 in Indianapolis, Indiana, USA. The event focused on stretches of three waterways and their associated riparian habitat: Fall Creek (20.6 ha; 51 acres), Pleasant Run (23.5 ha; 58 acres), and Pogue’s Run (27.1 ha; 67 acres). Over 75 scientists, naturalists, students, and citizen volunteers comprised 14 different taxonomic teams. Five hundred ninety taxa were documented despite the rainy conditions. A brief summary of the methods and findings are presented here. Detailed maps of survey locations and inventory results are available on the Indiana Academy of Science website (https://www.indianaacademyofscience.org/)

Navier-Stokes Analysis of a High Wing Transport High-Lift Configuration with Externally Blown Flaps

Insights and lessons learned from the aerodynamic analysis of the High Wing Transport (HWT) high-lift configuration are presented. Three-dimensional Navier-Stokes CFD simulations using the OVERFLOW flow solver are compared with high Reynolds test data obtained in the NASA Ames 12 Foot Pressure Wind Tunnel (PWT) facility. Computational analysis of the baseline HWT high-lift configuration with and without Externally Blown Flap (EBF) jet effects is highlighted. Several additional aerodynamic investigations, such as nacelle strake effectiveness and wake vortex studies, are presented. Technical capabilities and shortcomings of the computational method are discussed and summarized

Population genetic diversity and fitness in multiple environments

<p>Abstract</p> <p>Background</p> <p>When a large number of alleles are lost from a population, increases in individual homozygosity may reduce individual fitness through inbreeding depression. Modest losses of allelic diversity may also negatively impact long-term population viability by reducing the capacity of populations to adapt to altered environments. However, it is not clear how much genetic diversity within populations may be lost before populations are put at significant risk. Development of tools to evaluate this relationship would be a valuable contribution to conservation biology. To address these issues, we have created an experimental system that uses laboratory populations of an estuarine crustacean, <it>Americamysis bahia </it>with experimentally manipulated levels of genetic diversity. We created replicate cultures with five distinct levels of genetic diversity and monitored them for 16 weeks in both permissive (ambient seawater) and stressful conditions (diluted seawater). The relationship between molecular genetic diversity at presumptive neutral loci and population vulnerability was assessed by AFLP analysis.</p> <p>Results</p> <p>Populations with very low genetic diversity demonstrated reduced fitness relative to high diversity populations even under permissive conditions. Population performance decreased in the stressful environment for all levels of genetic diversity relative to performance in the permissive environment. Twenty percent of the lowest diversity populations went extinct before the end of the study in permissive conditions, whereas 73% of the low diversity lines went extinct in the stressful environment. All high genetic diversity populations persisted for the duration of the study, although population sizes and reproduction were reduced under stressful environmental conditions. Levels of fitness varied more among replicate low diversity populations than among replicate populations with high genetic diversity. There was a significant correlation between AFLP diversity and population fitness overall; however, AFLP markers performed poorly at detecting modest but consequential losses of genetic diversity. High diversity lines in the stressful environment showed some evidence of relative improvement as the experiment progressed while the low diversity lines did not.</p> <p>Conclusions</p> <p>The combined effects of reduced average fitness and increased variability contributed to increased extinction rates for very low diversity populations. More modest losses of genetic diversity resulted in measurable decreases in population fitness; AFLP markers did not always detect these losses. However when AFLP markers indicated lost genetic diversity, these losses were associated with reduced population fitness.</p

Application of a Mechanistic Model to Evaluate Putative Mechanisms of Tolvaptan Drug-Induced Liver Injury and Identify Patient Susceptibility Factors

Tolvaptan is a selective vasopressin V2 receptor antagonist, approved in several countries for the treatment of hyponatremia and autosomal dominant polycystic kidney disease (ADPKD). No liver injury has been observed with tolvaptan treatment in healthy subjects and in non-ADPKD indications, but ADPKD clinical trials showed evidence of drug-induced liver injury (DILI). Although all DILI events resolved, additional monitoring in tolvaptan-treated ADPKD patients is required. In vitro assays identified alterations in bile acid disposition and inhibition of mitochondrial respiration as potential mechanisms underlying tolvaptan hepatotoxicity. This report details the application of DILIsym software to determine whether these mechanisms could account for the liver safety profile of tolvaptan observed in ADPKD clinical trials. DILIsym simulations included physiologically based pharmacokinetic estimates of hepatic exposure for tolvaptan and2 metabolites, and their effects on hepatocyte bile acid transporters and mitochondrial respiration. The frequency of predicted alanine aminotransferase (ALT) elevations, following simulated 90/30 mg split daily dosing, was 7.9% compared with clinical observations of 4.4% in ADPKD trials. Toxicity was multifactorial as inhibition of bile acid transporters and mitochondrial respiration contributed to the simulated DILI. Furthermore, simulation analysis identified both pre-treatment risk factors and on-treatment biomarkers predictive of simulated DILI. The simulations demonstrated that in vivo hepatic exposure to tolvaptan and the DM-4103 metabolite, combined with these 2 mechanisms of toxicity, were sufficient to account for the initiation of tolvaptan-mediated DILI. Identification of putative risk-factors and potential novel biomarkers provided insight for the development of mechanism-based tolvaptan risk-mitigation strategies

Ab initio coupled-cluster and configuration interaction calculations for 16-O using V_UCOM

Using the ground-state energy of 16-O obtained with the realistic V_UCOM interaction as a test case, we present a comprehensive comparison of different configuration interaction (CI) and coupled-cluster (CC) methods, analyzing the intrinsic advantages and limitations of each of the approaches. In particular, we use the importance-truncated (IT) CI and no-core shell model (NCSM) schemes with up to 4-particle-4-hole (4p4h) excitations as well as the size extensive CC methods with a complete treatment of one- and two-body clusters (CCSD) and a non-iterative treatment of connected three-body clusters via the completely renormalized correction to the CCSD energy defining the CR-CC(2,3) approach. We discuss the impact of the center-of-mass contaminations, the choice of the single-particle basis, and size-extensivity on the resulting energies. When the IT-CI and IT-NCSM methods include the 4p4h excitations and when the CC calculations include the 1p1h, 2p2h, and 3p3h clusters, as in the CR-CC(2,3) approach, we observe an excellent agreement among the different methodologies. This shows that despite their individual limitations, the IT-CI, IT-NCSM, and CC methods can provide precise and consistent ab initio nuclear structure predictions. Furthermore, the IT-CI, IT-NCSM, and CC ground-state energy values obtained with 16-O are in good agreement with the experimental value, proving that the V_UCOM two-body interaction allows for a realistic description of binding energies for heavier nuclei and that all of the methods used in this study account for most of the relevant particle correlation effects.Comment: 20 pages, 4 figures, 1 table (v2: extended version in response to referees' comments

Global Kidney Exchange Should Expand Wisely.

We read with great interest and appreciation the careful consideration and analysis by Ambagtsheer et al. of the most critical ethical objections to Global Kidney Exchange (GKE). Ambagtsheer et al. conclude that implementation of GKE is a means to increase access to transplantation ethically and effectively