Heterobimetallic [NiFe] complexes containing mixed CO/CN− ligands: analogs of the active site of the [NiFe] hydrogenases

The development of synthetic analogs of the active sites of [NiFe] hydrogenases remains challenging and, in spite of the number of complexes featuring a [NiFe] center, those featuring CO and CN− ligands at the Fe center are under-represented. We report herein the synthesis of three bimetallic [NiFe] complexes [Ni(N2S2)Fe(CO)2(CN)2], [Ni(S4)Fe(CO)2(CN)2] and [Ni(N2S3)Fe(CO)2(CN)2] that each contain a Ni center that bridges through two thiolato S donors to a {Fe(CO)2(CN)2} unit. X-ray crystallographic studies on [Ni(N2S3)Fe(CO)2(CN)2], supported by DFT calculations, are consistent with a solid state structure containing distinct molecules in the singlet (S = 0) and triplet (S = 1) states. Each cluster exhibits irreversible reduction processes between −1.45 to −1.67 V vs Fc+/Fc and [Ni(N2S3)Fe(CO)2(CN)2] possesses a reversible oxidation process at 0.17 V vs Fc+/Fc. Spectroelectrochemical infrared (IR) and electron paramagnetic resonance (EPR) studies, supported by density functional theory (DFT) calculations, are consistent with a NiIIIFeII formulation for [Ni(N2S3)Fe(CO)2(CN)2]+. The SOMO in [Ni(N2S3)Fe(CO)2(CN)2]+ is based on Ni 3dz² and 3p S with the S contributions deriving principally from the apical S-donor. The nature of the SOMO corresponds to that proposed for the Ni-C state of the [NiFe] hydrogenases for which a NiIIIFeII formulation has also been proposed. A comparison of the experimental structures, and the electrochemical and spectroscopic properties of [Ni(N2S3)Fe(CO)2(CN)2] and its [Ni(N2S3)] precursor, together with calculations on the oxidized [Ni(N2S3)Fe(CO)2(CN)2]+ and [Ni(N2S3)]+ forms suggests that the binding of the {Fe(CO)(CN)2} unit to the {Ni(CysS)4} center at the active site of the [NiFe] hydrogenases suppresses thiolate-based oxidative chemistry involving the bridging thiolate S donors. This is in addition to the role of the Fe center in modulating the redox potential and geometry, and supporting a bridging hydride species between the Ni and Fe centers in the Ni-C state.

Migration and "Low-Skilled" Workers in Destination Countries

In the fourth article in a six-part PLoS Medicine series on Migration & Health, Joan Benach and colleagues discuss the specific health risks and policy needs associated with migration in destination countries, especially for low-skilled and illegal migrant workers

Heterobimetallic [NiFe] complexes containing mixedCO/CN− ligands: analogs of the active site of the [NiFe]hydrogenases

The development of synthetic analogs of the active sites of [NiFe] hydrogenases remains challenging and, in spite of the number of complexes featuring a [NiFe] center, those featuring CO and CN− ligands at the Fe center are under-represented. We report herein the synthesis of three bimetallic [NiFe] complexes [Ni(N2S2)Fe(CO)2(CN)2], [Ni(S4)Fe(CO)2(CN)2] and [Ni(N2S3)Fe(CO)2(CN)2] that each contain a Ni center that bridges through two thiolato S donors to a {Fe(CO)2(CN)2} unit. X-ray crystallographic studies on [Ni(N2S3)Fe(CO)2(CN)2], supported by DFT calculations, are consistent with a solid state structure containing distinct molecules in the singlet (S = 0) and triplet (S = 1) states. Each cluster exhibits irreversible reduction processes between −1.45 to −1.67 V vs Fc+/Fc and [Ni(N2S3)Fe(CO)2(CN)2] possesses a reversible oxidation process at 0.17 V vs Fc+/Fc. Spectroelectrochemical infrared (IR) and electron paramagnetic resonance (EPR) studies, supported by density functional theory (DFT) calculations, are consistent with a NiIIIFeII formulation for [Ni(N2S3)Fe(CO)2(CN)2]+. The SOMO in [Ni(N2S3)Fe(CO)2(CN)2]+ is based on Ni 3dz² and 3p S with the S contributions deriving principally from the apical S-donor. The nature of the SOMO corresponds to that proposed for the Ni-C state of the [NiFe] hydrogenases for which a NiIIIFeII formulation has also been proposed. A comparison of the experimental structures, and the electrochemical and spectroscopic properties of [Ni(N2S3)Fe(CO)2(CN)2] and its [Ni(N2S3)] precursor, together with calculations on the oxidized [Ni(N2S3)Fe(CO)2(CN)2]+ and [Ni(N2S3)]+ forms suggests that the binding of the {Fe(CO)(CN)2} unit to the {Ni(CysS)4} center at the active site of the [NiFe] hydrogenases suppresses thiolate-based oxidative chemistry involving the bridging thiolate S donors. This is in addition to the role of the Fe center in modulating the redox potential and geometry, and supporting a bridging hydride species between the Ni and Fe centers in the Ni-C state.

Genomic epidemiology and population structure of Neisseria gonorrhoeae from remote highly endemic Western Australian populations

Background: Neisseria gonorrhoeae causes gonorrhoea, the second most commonly notified sexually transmitted infection in Australia. One of the highest notification rates of gonorrhoea is found in the remote regions of Western Australia (WA). Unlike isolates from the major Australian population centres, the remote community isolates have low rates of antimicrobial resistance (AMR). Population structure and whole-genome comparison of 59 isolates from the Western Australian N. gonorrhoeae collection were used to investigate relatedness of isolates cultured in the metropolitan and remote areas. Core genome phylogeny, multilocus sequencing typing (MLST), N. gonorrhoeae multi-antigen sequence typing (NG-MAST) and N. gonorrhoeae sequence typing for antimicrobial resistance (NG-STAR) in addition to hierarchical clustering of sequences were used to characterize the isolates. Results: Population structure analysis of the 59 isolates together with 72 isolates from an international collection, revealed six population groups suggesting that N. gonorrhoeae is a weakly clonal species. Two distinct population groups, Aus1 and Aus2, represented 63% of WA isolates and were mostly composed of the remote community isolates that carried no chromosomal AMR genotypes. In contrast, the Western Australian metropolitan isolates were frequently multi-drug resistant and belonged to population groups found in the international database, suggesting international transmission of the isolates. Conclusions: Our study suggests that the population structure of N. gonorrhoeae is distinct between the communities in remote and metropolitan WA. Given the high rate of AMR in metropolitan regions, ongoing surveillance is essential to ensure the enduring efficacy of the empiric gonorrhoea treatment in remote WA

Enhancer Remodeling during Adaptive Bypass to MEK Inhibition Is Attenuated by Pharmacologic Targeting of the P-TEFb Complex

Targeting the dysregulated BRaf-MEK-ERK pathway in cancer has increasingly emerged in clinical trial design. Despite clinical responses in specific cancers using inhibitors targeting BRaf and MEK, resistance develops often involving non-genomic adaptive bypass mechanisms. Inhibition of MEK1/2 by trametinib in triple negative breast cancer (TNBC) patients induced dramatic transcriptional responses, including upregulation of receptor tyrosine kinases (RTKs) comparing tumor samples before and after one week of treatment. In preclinical models MEK inhibition induced genome-wide enhancer formation involving the seeding of BRD4, MED1, H3K27 acetylation and p300 that drives transcriptional adaptation. Inhibition of P-TEFb associated proteins BRD4 and CBP/p300 arrested enhancer seeding and RTK upregulation. BRD4 bromodomain inhibitors overcame trametinib resistance, producing sustained growth inhibition in cells, xenografts and syngeneic mouse TNBC models. Pharmacological targeting of P-TEFb members in conjunction with MEK inhibition by trametinib is an effective strategy to durably inhibit epigenomic remodeling required for adaptive resistance

Population Genomics Related to Adaptation in Elite Oat Germplasm

Six hundred thirty five oat ( L.) lines and 4561 single-nucleotide polymorphism (SNP) loci were used to evaluate population structure, linkage disequilibrium (LD), and genotype–phenotype association with heading date. The first five principal components (PCs) accounted for 25.3% of genetic variation. Neither the eigenvalues of the first 25 PCs nor the cross-validation errors from = 1 to 20 model-based analyses suggested a structured population. However, the PC and = 2 model-based analyses supported clustering of lines on spring oat vs. southern United States origin, accounting for 16% of genetic variation ( < 0.0001). Single-locus -statistic () in the highest 1% of the distribution suggested linkage groups that may be differentiated between the two population subgroups. Population structure and kinship-corrected LD of = 0.10 was observed at an average pairwise distance of 0.44 cM (0.71 and 2.64 cM within spring and southern oat, respectively). On most linkage groups LD decay was slower within southern lines than within the spring lines. A notable exception was found on linkage group Mrg28, where LD decay was substantially slower in the spring subpopulation. It is speculated that this may be caused by a heterogeneous translocation event on this chromosome. Association with heading date was most consistent across location-years on linkage groups Mrg02, Mrg12, Mrg13, and Mrg24

SNP Discovery and Chromosome Anchoring Provide the First Physically-Anchored Hexaploid Oat Map and Reveal Synteny with Model Species

A physically anchored consensus map is foundational to modern genomics research; however, construction of such a map in oat (Avena sativa L., 2n = 6x = 42) has been hindered by the size and complexity of the genome, the scarcity of robust molecular markers, and the lack of aneuploid stocks. Resources developed in this study include a modified SNP discovery method for complex genomes, a diverse set of oat SNP markers, and a novel chromosome-deficient SNP anchoring strategy. These resources were applied to build the first complete, physically-anchored consensus map of hexaploid oat. Approximately 11,000 high-confidence in silico SNPs were discovered based on nine million inter-varietal sequence reads of genomic and cDNA origin. GoldenGate genotyping of 3,072 SNP assays yielded 1,311 robust markers, of which 985 were mapped in 390 recombinant-inbred lines from six bi-parental mapping populations ranging in size from 49 to 97 progeny. The consensus map included 985 SNPs and 68 previously-published markers, resolving 21 linkage groups with a total map distance of 1,838.8 cM. Consensus linkage groups were assigned to 21 chromosomes using SNP deletion analysis of chromosome-deficient monosomic hybrid stocks. Alignments with sequenced genomes of rice and Brachypodium provide evidence for extensive conservation of genomic regions, and renewed encouragement for orthology-based genomic discovery in this important hexaploid species. These results also provide a framework for high-resolution genetic analysis in oat, and a model for marker development and map construction in other species with complex genomes and limited resources

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

A Retrospective Overview of Enterovirus Infection Diagnosis and Molecular Epidemiology in the Public Hospitals of Marseille, France (1985–2005)

Human enteroviruses (HEV) are frequent human pathogens and, associated in particular with large outbreaks of aseptic meningitis. Here, we have compiled a database of clinical HEV isolates from the Public Hospitals of Marseille, from 1985 to 2005. Amongst 654 isolates that could be characterized by complete sequencing of the VP1 gene, 98% belonged to species HEV-B; the most frequently isolated serotypes were Echovirus E30, E11, E7, E6 and E4. The high incidence of E30 and the recent emergence of E13 are consistent with reports worldwide and peak HEV isolation occurred mostly in the late spring and summer months. The proportion of echoviruses has decreased across the years, while that of coxsackieviruses has increased. Stool (the most frequent sample type) allowed detection of all identified serotypes. MRC5 (Human lung fibroblasts) cell line was the most conducive cell line for HEV isolation (84.9% of 10 most common serotype isolates, 96.3% in association with BGM (Buffalo green monkey kidney cells)). Previous seroneutralization-based serotype identification demonstrated 55.4% accuracy when compared with molecular VP1 analysis. Our analysis of a large number of clinical strains over 20 years reinforced the validity of VP1 serotyping and showed that comparative p-distance scores can be coupled with phylogenetic analysis to provide non-ambiguous serotype identification. Phylogenetic analysis in the VP1, 2C and 3D regions also provided evidence for recombination events amongst clinical isolates. In particular, it identified isolates with dissimilar VP1 but almost identical nonstructural regions

Shared genetic contribution to ischemic stroke and Alzheimer's disease

Objective Increasing evidence suggests epidemiological and pathological links between Alzheimer's disease (AD) and ischemic stroke (IS). We investigated the evidence that shared genetic factors underpin the two diseases. Methods Using genome-wide association study (GWAS) data from METASTROKE + (15,916 IS cases and 68,826 controls) and the International Genomics of Alzheimer's Project (IGAP; 17,008 AD cases and 37,154 controls), we evaluated known associations with AD and IS. On the subset of data for which we could obtain compatible genotype-level data (4,610 IS cases, 1,281 AD cases, and 14,320 controls), we estimated the genome-wide genetic correlation (rG) between AD and IS, and the three subtypes (cardioembolic, small vessel, and large vessel), using genome-wide single-nucleotide polymorphism (SNP) data. We then performed a meta-analysis and pathway analysis in the combined AD and small vessel stroke data sets to identify the SNPs and molecular pathways through which disease risk may be conferred. Results We found evidence of a shared genetic contribution between AD and small vessel stroke (rG [standard error] = 0.37 [0.17]; p = 0.011). Conversely, there was no evidence to support shared genetic factors in AD and IS overall or with the other stroke subtypes. Of the known GWAS associations with IS or AD, none reached significance for association with the other trait (or stroke subtypes). A meta-analysis of AD IGAP and METASTROKE + small vessel stroke GWAS data highlighted a region (ATP5H/KCTD2/ICT1) associated with both diseases (p = 1.8 × 10-8). A pathway analysis identified four associated pathways involving cholesterol transport and immune response. Interpretation Our findings indicate shared genetic susceptibility to AD and small vessel stroke and highlight potential causal pathways and loci. Ann Neurol 2016;79:739-74