Hydroxylamine Complexes of Cytochrome c': Influence of Heme Iron Redox State on Kinetic and Spectroscopic Properties.

Hydroxylamine (NH2OH or HA) is a redox-active nitrogen oxide that occurs as a toxic intermediate in the oxidation of ammonium by nitrifying and methanotrophic bacteria. Within ammonium containing environments, HA is generated by ammonia monooxygenase (nitrifiers) or methane monooxygenase (methanotrophs). Subsequent oxidation of HA is catalyzed by heme proteins, including cytochromes P460 and multiheme hydroxylamine oxidoreductases, the former contributing to emissions of N2O, an ozone-depleting greenhouse gas. A heme-HA complex is also a proposed intermediate in the reduction of nitrite to ammonia by cytochrome c nitrite reductase. Despite the importance of heme-HA complexes within the biogeochemical nitrogen cycle, fundamental aspects of their coordination chemistry remain unknown, including the effect of the Fe redox state on heme-HA affinity, kinetics, and spectroscopy. Using stopped-flow UV-vis and resonance Raman spectroscopy, we investigated HA complexes of the L16G distal pocket variant of Alcaligenes xylosoxidans cytochrome c'-α (L16G AxCP-α), a pentacoordinate c-type cytochrome that we show binds HA in its Fe(III) (Kd ∼ 2.5 mM) and Fe(II) (Kd = 0.0345 mM) states. The ∼70-fold higher HA affinity of the Fe(II) state is due mostly to its lower koff value (0.0994 s-1 vs 11 s-1), whereas kon values for Fe(II) (2880 M-1 s-1) and Fe(III) (4300 M-1 s-1) redox states are relatively similar. A comparison of the HA and imidazole affinities of L16G AxCP-α was also used to predict the influence of Fe redox state on HA binding to other proteins. Although HA complexes of L16G AxCP-α decompose via redox reactions, the lifetime of the Fe(II)HA complex was prolonged in the presence of excess reductant. Spectroscopic parameters determined for the Fe(II)HA complex include the N-O stretching vibration of the NH2OH ligand, ν(N-O) = 906 cm-1. Overall, the kinetic trends and spectroscopic benchmarks from this study provide a foundation for future investigations of heme-HA reaction mechanisms.

Prevention of Knee and Anterior Cruciate Ligament Injuries Through the Use of Neuromuscular and Proprioceptive Training: An Evidence-Based Review.

Reference/Citation: Donnell-Fink LA, Klara K, Collins JE, et al. Effectiveness of knee injury and anterior cruciate ligament tear prevention programs: a meta-analysis. PLoS One. 2015;10(12)e0144063. CLINICAL QUESTION: Is neuromuscular and proprioceptive training effective in preventing knee and anterior cruciate ligament (ACL) injuries? DATA SOURCES: The authors searched CINAHL, Cochrane Central Register of Controlled Trials, MEDLINE/EMBASE, PubMed, and Web of Science databases from 1996 through December 2014 and limited the results to peer-reviewed manuscripts published in English. Search terms for all databases were knee injury OR knee injuries; OR anterior cruciate ligament injury OR anterior cruciate ligament injuries; OR ACL injury OR ACL injuries; OR lower limb injury OR lower limb injuries AND prevention. STUDY SELECTION: Inclusion criteria were (1) English language, (2) published from 1996 through 2014, (3) the intervention used neuromuscular or proprioceptive training to prevent knee or ACL injuries, (4) human participants, (5) the incidence of knee or ACL injury was provided. DATA EXTRACTION: For the articles that met the inclusion criteria, 2 authors worked independently using the Jadad scale to extract the first author, year of publication, title, sport type, participant sex, participant age, country in which the study was conducted, number of participants in the control and intervention groups, intervention characteristics or components, and knee or ACL injury outcome. MAIN RESULTS: A total of 24 studies with 1093 participants were included in this review. Intervention efficacy was determined from weighted incidence rate ratios. After the intervention of neuromuscular and proprioceptive training exercises, the incidence ratio (frequency of a disease or injury occurrence in a population over a specific time frame) was calculated at 0.731 (95% confidence interval = 0.614, 0.871) for knee injury and at 0.493 (95% confidence interval = 0.285, 0.854) for ACL injury. This indicated a link between neuromuscular and proprioceptive training programs and injury reduction. No significant correlation was present between more components added to training and a greater decrease in injury to either the knee or ACL. CONCLUSIONS: Neuromuscular and proprioceptive training appeared to decrease the incidence of injury to the knee and specifically the ACL. However, no evidence suggested that a specific group of exercises was better than others.

The PCSK6 gene is associated with handedness, the autism spectrum, and magical ideation in a non-clinical population.

Common polymorphisms in the gene PCSK6, whose protein product mediates the development of brain and body asymmetry through the NODAL pathway, have recently been associated with handedness in three studies, making it a key candidate gene for understanding the developmental and expression of human lateralization. We tested the hypothesis that the PCSK6 VNTR polymorphism rs1053972 influences the expression of handedness and aspects of dimensional schizotypy and autism. For a sample of 709 healthy individuals, rs1053972 genotype was significantly associated with categorical measures of handedness, and with dimensional handedness in subsets of the population with high schizotypy and magical ideation or a lack of strong right-handedness. Both findings showed evidence of stronger or exclusive effects among females, compared to males. Genotypes of PCSK6 also showed significant sex-limited associations with magical ideation, a component of positive schizotypal cognition measured using the Schizotypal Personality Questionnaire, and total autism score, measured using the Autism Spectrum Quotient. These results partially replicate previous studies on effects of PCSK6 rs1053972 genetic variation on handedness phenotypes, link the PCSK6 gene with the dimensional expression of neurodevelopmental conditions in healthy individuals, and show that associations of this gene with handedness and psychological phenotypes exhibit evidence of sex-limited effects.