Improved estimation of starting times of human activities using Hidden Markov modeling based activity classification?

Automated classification of human activities should help the researcher, or the physician, with the interpretation of data. In a previous study a novel activity classifier based on Hidden Markov Models was successfully implemented and tested on ambulatory obtained of human activities. The estimated starting times were not accurate. Here the addition of timing information to perform isolated activity training as initialization of the HMM's is proposed to more accurately estimate the starting times of activities

Redox properties and electron paramagnetic resonance spectroscopy of the transition state complex of Azotobacter vinelandii nitrogenase

AbstractNitrogenase is a two-component metalloenzyme that catalyzes a MgATP hydrolysis driven reduction of substrates. Aluminum fluoride plus MgADP inhibits nitrogenase by stabilizing an intermediate of the on-enzyme MgATP hydrolysis reaction. We report here the redox properties and electron paramagnetic resonance (EPR) signals of the aluminum fluoride-MgADP stabilized nitrogenase complex of Azotobacter vinelandii. Complex formation lowers the midpoint potential of the [4Fe-4S] cluster in the Fe protein. Also, the two-electron reaction of the unique [8Fe-7S] cluster in the MoFe protein is split in two one-electron reactions both with lower midpoint potentials. Furthermore, a change in spin-state of the two-electron oxidized [8Fe-7S] cluster is observed. The implications of these findings for the mechanism of MgATP hydrolysis driven electron transport within the nitrogenase protein complex are discussed

The natural history and genotype–phenotype correlations of TMPRSS3 hearing loss:an international, multi-center, cohort analysis

TMPRSS3-related hearing loss presents challenges in correlating genotypic variants with clinical phenotypes due to the small sample sizes of previous studies. We conducted a cross-sectional genomics study coupled with retrospective clinical phenotype analysis on 127 individuals. These individuals were from 16 academic medical centers across 6 countries. Key findings revealed 47 unique TMPRSS3 variants with significant differences in hearing thresholds between those with missense variants versus those with loss-of-function genotypes. The hearing loss progression rate for the DFNB8 subtype was 0.3 dB/year. Post-cochlear implantation, an average word recognition score of 76% was observed. Of the 51 individuals with two missense variants, 10 had DFNB10 with profound hearing loss. These 10 all had at least one of 4 TMPRSS3 variants predicted by computational modeling to be damaging to TMPRSS3 structure and function. To our knowledge, this is the largest study of TMPRSS3 genotype–phenotype correlations. We find significant differences in hearing thresholds, hearing loss progression, and age of presentation, by TMPRSS3 genotype and protein domain affected. Most individuals with TMPRSS3 variants perform well on speech recognition tests after cochlear implant, however increased age at implant is associated with worse outcomes. These findings provide insight for genetic counseling and the on-going design of novel therapeutic approaches.</p

An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge

There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. RESULTS: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. CONCLUSIONS: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups

Bioreduction of carboxylic acids by Pyrococcus furiosus in batch cultures

The reduction of aromatic and aliphatic (di)carboxylic acids to their corresponding aldehydes and alcohols by the hyperthermophilic organism Pyrococcus furiosus was investigated. The reduction was performed with P. furiosus cells growing in the presence of 1 mM acid with starch as a carbon and energy source at 90oC. The aromatic acids t-cinnamic and 3-phenylpropionic acid were reduced to their corresponding alcohols with the highest yields in the described batch cultures: 67 and 69%, respectively. The aliphatic acid reduced with the highest yield was hexanoic acid (yield: 38%). No aldehydes were detected during the reduction of acids, indicating that the reduction of aldehydes to alcohols is faster than the reduction of acids to aldehydes. Some aldehydes were both reduced to the corresponding alcohol and oxidized to the corresponding acid. Besides reduction of the unsaturated t-cinnamaldehyde to t-cinnamyl alcohol (63%), the double bond of t-cinnamaldehyde was also reduced by P. furiosus