Survey of Human Mitochondrial Diseases Using New Genomic/Proteomic Tools

BACKGROUND. We have constructed Bayesian prior-based, amino-acid sequence profiles for the complete yeast mitochondrial proteome and used them to develop methods for identifying and characterizing the context of protein mutations that give rise to human mitochondrial diseases. (Bayesian priors are conditional probabilities that allow the estimation of the likelihood of an event - such as an amino-acid substitution - on the basis of prior occurrences of similar events.) Because these profiles can assemble sets of taxonomically very diverse homologs, they enable identification of the structurally and/or functionally most critical sites in the proteins on the basis of the degree of sequence conservation. These profiles can also find distant homologs with determined three-dimensional structures that aid in the interpretation of effects of missense mutations. RESULTS. This survey reports such an analysis for 15 missense mutations one insertion and three deletions involved in Leber's hereditary optic neuropathy, Leigh syndrome, mitochondrial neurogastrointestinal encephalomyopathy, Mohr-Tranebjaerg syndrome, iron-storage disorders related to Friedreich's ataxia, and hereditary spastic paraplegia. We present structural correlations for seven of the mutations. CONCLUSIONS. Of the 19 mutations analyzed, 14 involved changes in very highly conserved parts of the affected proteins. Five out of seven structural correlations provided reasonable explanations for the malfunctions. As additional genetic and structural data become available, this methodology can be extended. It has the potential for assisting in identifying new disease-related genes. Furthermore, profiles with structural homologs can generate mechanistic hypotheses concerning the underlying biochemical processes - and why they break down as a result of the mutations.United States Department of Energy (DE-FG02-98ER62558); National Science Foundation (DBI-9807993

Higher-Order Demand-Driven Program Analysis

We explore a novel approach to higher-order program analysis that brings ideas of on-demand lookup from first-order CFL-reachability program analyses to higher-order programs. The analysis needs to produce only a control-flow graph; it can derive all other information including values of variables directly from the graph. Several challenges had to be overcome, including how to build the control-flow graph on-the-fly and how to deal with non-local variables in functions. The resulting analysis is flow- and context-sensitive with a provable polynomial-time bound. The analysis is formalized and proved correct and terminating, and an initial implementation is described

Cosmic Neutrino Last Scattering Surface

Neutrinos decoupled from the rest of the cosmic plasma when the Universe was less than one second old, far earlier than the photons which decoupled at t=380,000 years. Surprisingly, though, the last scattering surface of the neutrinos is much closer to us than that of the photons. Here we calculate the properties of the last scattering surfaces of the three species of neutrinos.Comment: Important reference to earlier work of Bisnovatyi-Kogan and Seidov added, and mis-spelling of Opher reference correcte

Wind turbine generator interaction with conventional diesel generators on Block Island, Rhode Island. Volume 1: Executive summary

Primary results are summarized for a three-part study involving the effects of connecting a MOD-OA wind turbine generator to an isolated diesel power system. The MOD-OA installation considered was the third of four experimental nominal 200 kW wind turbines connected to various utilities under the Federal Wind Energy Program and was characterized by the highest wind energy penetration levels of four sites. The study analyses address: fuel displacement, dynamic interaction, and three modes of reactive power control. These analyses all have as their basis the results of the data acquisition program conducted on Block Island, Rhode Island

Wind turbine generator interaction with conventional diesel generators on Block Island, Rhode Island. Volume 2: Data analysis

Assessing the performance of a MOD-OA horizontal axis wind turbine connected to an isolated diesel utility, a comprehensive data measurement program was conducted on the Block Island Power Company installation on Block Island, Rhode Island. The detailed results of that program focusing on three principal areas of (1) fuel displacement (savings), (2) dynamic interaction between the diesel utility and the wind turbine, (3) effects of three models of wind turbine reactive power control are presented. The approximate two month duration of the data acquisition program conducted in the winter months (February into April 1982) revealed performance during periods of highest wind energy penetration and hence severity of operation. Even under such conditions fuel savings were significant resulting in a fuel reduction of 6.7% while the MOD-OA was generating 10.7% of the total electrical energy. Also, electrical disturbance and interactive effects were of an acceptable level

Apgar score and the risk of cause specific infant mortality: a population based cohort study of 1,029,207 livebirths

Background<p></p> The Apgar score has been used worldwide as an index of early neonatal condition for more than 60 years. With advances in health-care service provision, neonatal resuscitation, and infant care, its present relevance is unclear. The aim of the study was to establish the strength of the relation between Apgar score at 5 min and the risk of neonatal and infant mortality, subdivided by specific causes.<p></p> Methods<p></p> We linked routine discharge and mortality data for all births in Scotland, UK between 1992 and 2010. We restricted our analyses to singleton livebirths, in women aged over 10 years, with a gestational age at delivery between 22 and 44 weeks, and excluded deaths due to congenital anomalies or isoimmunisation. We calculated the relative risks (RRs) of neonatal and infant death of neonates with low (0–3) and intermediate (4–6) Apgar scores at 5 min referent to neonates with normal Apgar score (7–10) using binomial log-linear modelling with adjustment for confounders. Analyses were stratified by gestational age at birth because it was a significant effect modifier. Missing covariate data were imputed.<p></p> Findings<p></p> Complete data were available for 1 029 207 eligible livebirths. Across all gestational strata, low Apgar score at 5 min was associated with an increased risk of neonatal and infant death. However, the strength of the association (adjusted RR, 95% CI referent to Apgar 7–10) was strongest at term (p<0·0001). A low Apgar (0–3) was associated with an adjusted RR of 359·4 (95% CI 277·3–465·9) for early neonatal death, 30·5 (18·0–51·6) for late neonatal death, and 50·2 (42·8–59·0) for infant death. We noted similar associations of a lower magnitude for intermediate Apgar (4–6). The strongest associations were for deaths attributed to anoxia and low Apgar (0–3) for term infants (RR 961·7, 95% CI 681·3–1357·5) and preterm infants (141·7, 90·1–222·8). No association between Apgar score at 5 min and the risk of sudden infant death syndrome was noted at any gestational age (RR 0·6, 95% CI 0·1–4·6 at term; 1·2, 0·3–4·8 at preterm).<p></p> Interpretation<p></p> Low Apgar score at 5 min was strongly associated with the risk of neonatal and infant death. Our findings support its continued usefulness in contemporary practice

How Not to Invent a Patent Crisis

This short essay written for a broad audience addresses the problems that are at the center of current debates in academic and policy circles about the patent system. Most current patent reform proposals are designed to give officials and courts more power to weaken or eliminate ‘‘unworthy’’ patents and take primary aim at so-called patent trolls. This essay argues that in light of the rapid, and excessive, changes that have already occurred in the courts, what patent law needs is a tweaking of existing safety valves and processes - not opening the floodgates to more discretion and uncertainty

Beef Reproductive Technology Adoption- Impact of Production Risk and Capitals

Agriculture, Beef, Artificial insemination, Estrus synchronization, Social capital, Production risk, Technology adoption, Farm Management,

Higher-Order Demand-Driven Program Analysis (Artifact)

This artifact is a proof-of-concept implementation of DDPA, an on-demand program analysis for higher-order functional programs. The implementation, written in OCaml, includes a parser, evaluator, and DDPA analysis for the language defined in the companion paper (including the proper record semantics extension). The analysis may be performed using different levels of precision as specified by the user and is capable of rendering the control flow graphs and pushdown systems using the GraphViz language DOT. This artifact was used to verify the conclusions of the companion paper and produces visualizations matching those figures in the companion paper\u27s overview

Provide Support And Assistance Task 3.1.2.1.: Year 1 Report

Report describes the efforts undertaken by the Institute for Simulation and Training\u27s distributed interactive simulation (DIS) testbed team to assist organizations in the implementation of DIS