Electron tunneling in biological molecules

Electron transfers in photosynthesis and respiration commonly occur between protein-bound prosthetic groups that are separated by large molecular distances (often greater than 10Å). Although the electron donors and acceptors are expected to be weakly coupled, the reactions are remarkably fast and proceed with high specificity. Tunneling timetables based on analyses of Fe^(2+)/Cu^+ to Ru^(3+) electron-transfer rates for Ru-modified heme and copper proteins reveal that the structure of the intervening polypeptide can control these distant donor-acceptor couplings. Multistep tunneling can account for the relatively rapid Cu^+ to Re^(2+) electron transfer observed in Re-modified azurin

Secondary and tertiary budbreak release is enhanced by extended dormancy chilling in 'Shiraz' grapevines

Limited information exists regarding the dormancy of secondary and tertiary buds within the compound bud of grapevines. We were interested to evaluate how extended chilling duration would affect the budbreak percentage of all three bud orders within the compound bud. Dormant potted 'Shiraz' grapevines, with thirty retained buds per vine, were placed in a cool room at 4 °C over a 20-month period to extend dormancy. Vines were then systematically removed over five dates and placed in a controlled growth environment to assess budbreak percentages and cane tissue concentrations of abscisic acid and cytokinins. Budbreak was hastened by at least 13 d with vines receiving any extra chilling compared to no initial chilling. Furthermore, the firstly observed correlative inhibition of basal buds was apparently removed with chilling. Removal of correlative inhibition within the compound bud with increased chilling duration was also observed with the increases of secondary (doubles) and tertiary (triples) buds breaking simultaneously with the primary bud at each node. This resulted in 91 % of the nodes having two developing shoots and 56 % of the nodes presenting three developing shoots by the end of the experiment. Furthermore, a sigmoidal relationship between percent secondary buds and chilling duration was observed. Possible phytohormone connections were observed with the decline of ABA as secondary and tertiary buds broke at 414 d of chilling and depletion of the CKs, which coincided with the greatest rate of primary bud break after 242 d of chilling. Other possible involvement of ABA and Cis-type cytokinin interactions with secondary and tertiary bud dormancy is discussed. The results suggest future investigations into secondary and tertiary bud release within the grapevine using similar techniques may help to better understand the biochemical mechanisms associated with dormancy

De novoframeshift mutation in ASXL3 in a patient with global developmental delay, microcephaly, and craniofacial anomalies

BACKGROUND: Currently, diagnosis of affected individuals with rare genetic disorders can be lengthy and costly, resulting in a diagnostic odyssey and in many patients a definitive molecular diagnosis is never achieved despite extensive clinical investigation. The recent advent and use of genomic medicine has resulted in a paradigm shift in the clinical molecular genetics of rare diseases and has provided insight into the causes of numerous rare genetic conditions. In particular, whole exome and genome sequencing of families has been particularly useful in discovering de novo germline mutations as the cause of both rare diseases and complex disorders. CASE PRESENTATION: We present a six year old, nonverbal African American female with microcephaly, autism, global developmental delay, and metopic craniosynostosis. Exome sequencing of the patient and her two parents revealed a heterozygous two base pair de novo deletion, c.1897_1898delCA, p.Gln633ValfsX13 in ASXL3, predicted to result in a frameshift at codon 633 with substitution of a valine for a glutamine and introduction of a premature stop codon. CONCLUSIONS: We provide additional evidence that, truncating and frameshifting mutations in the ASXL3 gene are the cause of a newly recognized disorder characterized by severe global developmental delay, short stature, microcephaly, and craniofacial anomalies. Furthermore, we expand the knowledge about disease causing mutations and the genotype-phenotype relationships in ASXL3 and provide evidence that rare, nonsynonymous, damaging mutations are not associated with developmental delay or microcephaly

Functional validation of novel compound heterozygous variants in B3GAT3 resulting in severe osteopenia and fractures: expanding the disease phenotype

Background A new disease class of syndromes, described as linkeropathies, which are derived from defects in the glycosaminoglycan-linker region as well as glycosaminoglycan-side chains of proteoglycans is increasingly being recognized as a cause of human disease. Proteoglycans are an essential component of the extracellular matrix. Defects in the enzymatic process of proteoglycan synthesis broadly occur due to the incorrect addition of side chains. Previously, homozygous missense variants within the B3GAT3 gene encoding beta 1,3 glucuronyltransferase 3(GlcAT-I) responsible for the biosynthesis of glycosaminoglycans have been described in 7 individuals. Case presentation In this study, a 4-year-old patient with a severe phenotype of osteoporosis, hypotonia, joint laxity, fractures, scoliosis, biscuspid aortic valve and myopia was referred for next generation sequencing after extensive negative clinical testing. Whole exome sequencing was performed on the proband and his unaffected parents to identify the molecular basis of his disease. Sequencing revealed compound heterozygous variants in B3GAT3: c.1A > G (p.Met1?) and c.671 T > A (p.L224Q). Clinical and in vitro functional studies were then completed to verify the pathogenicity of the genotype and further characterize the functional basis of the patient’s disease demonstrating the patient had a decrease both in the protein level of B3GAT3 and in the glucuronyltransferase activity when compared to control samples. Independent in vitro assessment of each variant confirmed the B3GAT3: c.1A > G (p.Met1?) variant is functionally null and the c.671 T > A (p.L224Q) missense variant has significantly reduced glucuronyltransferase activity (~3% of control). Conclusions This is the first report of a patient with compound heterozygosity for a null variant in trans with a missense in B3GAT3 resulting in a severe phenotype, expanding both the genotypic and phenotypic spectrum of B3GAT3-related disease

Euglena International Network (EIN):Driving euglenoid biotechnology for the benefit of a challenged world

Euglenoids (Euglenida) are unicellular flagellates possessing exceptionally wide geographical and ecological distribution. Euglenoids combine a biotechnological potential with a unique position in the eukaryotic tree of life. In large part these microbes owe this success to diverse genetics including secondary endosymbiosis and likely additional sources of genes. Multiple euglenoid species have translational applications and show great promise in production of biofuels, nutraceuticals, bioremediation, cancer treatments and more exotically as robotics design simulators. An absence of reference genomes currently limits these applications, including development of efficient tools for identification of critical factors in regulation, growth or optimization of metabolic pathways. The Euglena International Network (EIN) seeks to provide a forum to overcome these challenges. EIN has agreed specific goals, mobilized scientists, established a clear roadmap (Grand Challenges), connected academic and industry stakeholders and is currently formulating policy and partnership principles to propel these efforts in a coordinated and efficient manner

The Methyltransferase WBSCR22/Merm1 Enhances Glucocorticoid Receptor Function and Is Regulated in Lung Inflammation and Cancer

Glucocorticoids (GC) regulate cell fate and immune function. We identified the metastasis-promoting methyltransferase, metastasis-related methyltransferase 1 (WBSCR22/Merm1) as a novel glucocorticoid receptor (GR) regulator relevant to human disease. Merm1 binds the GR co-activator GRIP1 but not GR. Loss of Merm1 impaired both GR transactivation and transrepression by reducing GR recruitment to its binding sites. This was accompanied by loss of GR-dependent H3K4Me3 at a well characterized promoter. Inflammation promotes GC resistance, in part through the actions of TNFα and IFNγ. These cytokines suppressed Merm1 protein expression by driving ubiquitination of two conserved lysine residues. Restoration of Merm1 expression rescued GR transactivation. Cytokine suppression of Merm1 and of GR function was also seen in human lung explants. In addition, striking loss of Merm1 protein was observed in both inflammatory and neoplastic human lung pathologies. In conclusion, Merm1 is a novel regulator of chromatin structure affecting GR recruitment and function, contributing to loss of GC sensitivity in inflammation, with suppressed expression in pulmonary disease

Defining elite athletes: Issues in the study of expert performance in sport psychology

© 2014 Elsevier Ltd. Objectives: There has been considerable inconsistency and confusion in the definition of elite/expert athletes in sport psychology research, which has implications for studies conducted in this area and for the field as a whole. This study aimed to: (i) critically evaluate the ways in which recent research in sport psychology has defined elite/expert athletes; (ii) explore the rationale for using such athletes; and (iii) evaluate the conclusions that research in this field draws about the nature of expertise. Design: Conventional systematic review principles were employed to conduct a rigorous search and synthesise findings. Methods: A comprehensive literature search of SPORTDiscus, Academic Search Complete, PsycINFO, and PsycARTICLES was completed in September, 2013 which yielded 91 empirical studies published between 2010 and 2013. The primarily qualitative findings were analysed thematically. Results: Eight ways of defining elite/expert athletes were identified, ranging from Olympic champions to regional level competitors and those with as little as two years of experience in their sport. Three types of rationale were evident in these studies (i.e., "necessity", "exploratory" and "superior"); while findings also indicated that some elite athletes are psychologically idiosyncratic and perhaps even dysfunctional in their behaviour. Finally, only 19 of the 91 included studies provided conclusions about the nature of expertise in sport. Conclusions: This study suggests that the definitions of elite athletes vary on a continuum of validity, and the findings are translated into a taxonomy for classifying expert samples in sport psychology research in future. Recommendations are provided for researchers in this area