Soil health -- a new challenge for microbiologists and chemists.

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The Metallo-β-lactamase GOB Is a Mono-Zn(II) Enzyme with a Novel Active Site

Metallo-β-lactamases (MβLs) are zinc-dependent enzymes able to hydrolyze and inactivate most β-lactam antibiotics. The large diversity of active site structures and metal content among MβLs from different sources has limited the design of a pan-MβL inhibitor. Here we report the biochemical and biophysical characterization of a novel MβL, GOB-18, from a clinical isolate of a Gram-negative opportunistic pathogen, Elizabethkingia meningoseptica. Different spectroscopic techniques, three-dimensional modeling, and mutagenesis experiments, reveal that the Zn(II) ion is bound to Asp120, His121, His263, and a solvent molecule, i.e. in the canonical Zn2 site of dinuclear MβLs. Contrasting all other related MβLs, GOB-18 is fully active against a broad range of β-lactam substrates using a single Zn(II) ion in this site. These data further enlarge the structural diversity of MβLs

Comparative Analysis of Different Definitions of Amyloid-beta Positivity to Detect Early Downstream Pathophysiological Alterations in Preclinical Alzheimer

Amyloid-β (Aβ) positivity is defined using different biomarkers and different criteria. Criteria used in symptomatic patients may conceal meaningful early Aβ pathology in preclinical Alzheimer. Therefore, the description of sensitive cutoffs to study the pathophysiological changes in early stages of the Alzheimer’s continuum is critical. Here, we compare different Aβ classification approaches and we show their performance in detecting pathophysiological changes downstream Aβ pathology. We studied 368 cognitively unimpaired individuals of the ALFA+ study, many of whom in the preclinical stage of the Alzheimer’s continuum. Participants underwent Aβ PET and CSF biomarkers assessment. We classified participants as Aβ -positive using five approaches: (1) CSF Aβ42 12; (4) Aβ PET Centiloid > 30 or (5) Aβ PET Positive visual read. We assessed the correlations between Aβ biomarkers and compared the prevalence of Aβ positivity. We determined which approach significantly detected associations between Aβ pathology and tau/neurodegeneration CSF biomarkers. We found that CSF-based approaches result in a higher Aβ-positive prevalence than PET-based ones. There was a higher number of discordant participants classified as CSF Aβ-positive but PET Aβ-negative than CSF Aβ-negative but PET Aβ-positive. The CSF Aβ 42/40 approach allowed optimal detection of significant associations with CSF p-tau and t-tau in the Aβ-positive group. Altogether, we highlight the need for sensitive Aβ -classifications to study the preclinical Alzheimer’s continuum. Approaches that define Aβ positivity based on optimal discrimination of symptomatic Alzheimer’s disease patients may be suboptimal for the detection of early pathophysiological alterations in preclinical Alzheimer

Molecular mechanisms of atherosclerosis in metabolic syndrome: role of reduced IRS2-dependent signaling

OBJECTIVE: The mechanisms underlying accelerated atherosclerosis in metabolic syndrome (MetS) patients remain poorly defined. In the mouse, complete disruption of insulin receptor substrate-2 (Irs2) causes insulin resistance, MetS-like manifestations, and accelerates atherosclerosis. Here, we performed human, mouse, and cell culture studies to gain insight into the contribution of defective Irs2 signaling to MetS-associated alterations. METHODS AND RESULTS: In circulating leukocytes from insulin-resistant MetS patients, Irs2 and Akt2 mRNA levels inversely correlate with plasma insulin levels and HOMA index and are reduced compared to insulin-sensitive MetS patients. Notably, a moderate reduction in Irs2 expression in fat-fed apolipoprotein E-null mice lacking one allele of Irs2 (apoE(-/-)Irs2(+/-)) accelerates atherosclerosis compared to apoE-null controls, without affecting plaque composition. Partial Irs2 inactivation also increases CD36 and SRA scavenger receptor expression and modified LDL uptake in macrophages, diminishes Akt2 and Ras expression in aorta, and enhances expression of the proatherogenic cytokine MCP1 in aorta and primary vascular smooth muscle cells (VSMCs) and macrophages. Inhibition of AKT or ERK1/2, a downstream target of RAS, upregulates Mcp1 in VSMCs. CONCLUSIONS: Enhanced levels of MCP1 resulting from reduced IRS2 expression and accompanying defects in AKT2 and Ras/ERK1/2 signaling pathways may contribute to accelerated atherosclerosis in MetS states

Physical properties of two low-luminosity z ~ 1.9 galaxies behind the lensing cluster AC 114

We present VLT/ISAAC near-infrared spectroscopy of two gravitationally-lensed z ~ 1.9 galaxies, A2 and S2, located behind the cluster AC 114. Thanks to large magnification factors, we have been successful in detecting rest-frame optical emission lines in star-forming galaxies 1 to 2 magnitudes fainter than in previous studies of Lyman break galaxies (LBGs) at z ~ 3. From the Ha luminosity, we estimate star formation rates (SFRs) which are 7 to 15 times higher than those inferred from the UV continuum flux at 1500 ang without dust extinction correction. The behavior of S2 and A2 in terms of O/H and N/O abundance ratios are very different, and they are also different from typical LBGs at z ~ 3. S2 is a low-metallicity object (Z ~ 0.03 Zsun) with a low N/O ratio, similar to those derived in the most metal-poor nearby HII galaxies. In contrast, A2 is a high-metallicity galaxy (Z ~ 1.3 Zsun) with a high N/O abundance ratio, similar to those derived in the most metal-rich starburst nucleus galaxies. The virial masses, derived from emission-line widths, are 0.5 and 2.4 x 10^10 Msun, for S2 and A2 respectively. Thanks to the gravitational amplification, the line profiles of S2 are spatially resolved, leading to a velocity gradient of +- 240 km/s, which yields a dynamical mass of ~ 1.3 x 10^10 Msun within the inner 1 kpc radius. Combining these new data with the sample of LBGs at z ~ 3, we conclude that these three galaxies exhibit different physical properties in terms of SFRs, abundance and mass-to-light ratios, and reddening. High-redshift galaxies of different luminosities could thus have quite different star formation histories (abridged version).Comment: 11 pages, 8 figures. Accepted for publication in A&

Potential common radiation problems for components and diagnostics in future magnetic and inertial confinement fusion devices

This work aims at identifying common potential problems that future fusion devices will encounter for both magnetic (MC) and inertial (IC) confinement approaches in order to promote joint efforts and to avoid duplication of research

Study of vascular risk in Navarre: objectives and design. Prevalence of metabolic syndrome and of vascular risk factors

BACKGROUND: To determine in a representative sample of the population the prevalence of risk factors and metabolic syndrome; their association with sub-clinical atherosclerotic lesions and their impact on cardiocerebrovascular disease 10 years after. MATERIAL AND METHODS: (Phase 1) Cross sectional survey of a random sample stratified by age and sex of the population of Navarre aged between 35 and 84. Antecedents, risk factors, physical and analytical exploration. (Phase II) Ten year follow-up cohort study, in 500 exposed to MS and 500 not exposed persons, aged between 45 and 74 years; with an 82.25% power to detect a risk ratio of 2; with analytical and image markers of sub-clinical atherosclerosis. (Phase III) Follow up of vascular events at ten years. RESULTS: The subjects recruited were 6,553; excluded or not found 871; the final sample was 5,682 (2,644 men and 3,038 women); 4,168 (73,4%) took part in the study. The prevalence of MS was 22.1% (95%CI 20.5 - 23.7) for men and 17,2% (95%CI 15.8 - 18.5) for women. The main cardiovascular RF were high compared to other geographical areas except for HDL cholesterol. The rate was 8.5% (95%CI 7.4 - 9.6) for men and 1.7% (95%CI 1.3 - 2.2) CONCLUSIONS: There are important differences in risk between sex, being worst for men. The high figures for HDL cholesterol and the low prevalence of MS might mean a lower risk of vascular events in Navarra