Service evaluation of weight outcomes as a function of initial BMI in 34,271 adults referred to a primary care/commercial weight management partnership scheme

Peer reviewedPublisher PD

A [4Fe-4S]-Fe(CO)(CN)-L-cysteine intermediate is the first organometallic precursor in [FeFe] hydrogenase H-cluster bioassembly.

Biosynthesis of the [FeFe] hydrogenase active site (the 'H-cluster') requires the interplay of multiple proteins and small molecules. Among them, the radical S-adenosylmethionine enzyme HydG, a tyrosine lyase, has been proposed to generate a complex that contains an Fe(CO)2(CN) moiety that is eventually incorporated into the H-cluster. Here we describe the characterization of an intermediate in the HydG reaction: a [4Fe-4S][(Cys)Fe(CO)(CN)] species, 'Complex A', in which a CO, a CN- and a cysteine (Cys) molecule bind to the unique 'dangler' Fe site of the auxiliary [5Fe-4S] cluster of HydG. The identification of this intermediate-the first organometallic precursor to the H-cluster-validates the previously hypothesized HydG reaction cycle and provides a basis for elucidating the biosynthetic origin of other moieties of the H-cluster

GPX4 regulates cellular necrosis and host resistance in Mycobacterium tuberculosis infection

Cellular necrosis during Mycobacterium tuberculosis (Mtb) infection promotes both immunopathology and bacterial dissemination. Glutathione peroxidase-4 (Gpx4) is an enzyme that plays a critical role in preventing iron-dependent lipid peroxidation–mediated cell death (ferroptosis), a process previously implicated in the necrotic pathology seen in Mtb-infected mice. Here, we document altered GPX4 expression, glutathione levels, and lipid peroxidation in patients with active tuberculosis and assess the role of this pathway in mice genetically deficient in or overexpressing Gpx4. We found that Gpx4-deficient mice infected with Mtb display substantially increased lung necrosis and bacterial burdens, while transgenic mice overexpressing the enzyme show decreased bacterial loads and necrosis. Moreover, Gpx4-deficient macrophages exhibited enhanced necrosis upon Mtb infection in vitro, an outcome suppressed by the lipid peroxidation inhibitor, ferrostatin-1. These findings provide support for the role of ferroptosis in Mtb-induced necrosis and implicate the Gpx4/GSH axis as a target for host-directed therapy of tuberculosis

An observational prospective study of topical acidified nitrite for killing methicillin-resistant Staphylococcus aureus (MRSA) in contaminated wounds

Background Endogenous nitric oxide (NO) kills bacteria and other organisms as part of the innate immune response. When nitrite is exposed to low pH, NO is generated and has been used as an NO delivery system to treat skin infections. We demonstrated eradication of MRSA carriage from wounds using a topical formulation of citric acid (4.5%) and sodium nitrite (3%) creams co-applied for 5 days to 15 wounds in an observational prospective pilot study of 8 patients. Findings Following treatment with topical citric acid and sodium nitrite, 9 of 15 wounds (60%) and 3 of 8 patients (37%) were cleared of infection. MRSA isolates from these patients were all sensitive to acidified nitrite in vitro compared to methicillin-sensitive S. aureus and a reference strain of MRSA. Conclusions Nitric oxide and acidified nitrite offer a novel therapy for control of MRSA in wounds. Wounds that were not cleared of infection may have been re-contaminated or the bioavailability of acidified nitrite impaired by local factors in the tissue

Microscopic Description of Super Heavy Nuclei

The results of extensive microscopic Relativistic Mean Field (RMF) calculations for the nuclei appearing in the alpha - decay chains of recently discovered superheavy elements with Z = 109 to 118 are presented and discussed. The calculated ground state properties like total binding energies, Q values, deformations, radii and densities closely agree with the corresponding experimental data, where available. The double folding (t-rho-rho) approximation is used to calculate the interaction potential between the daughter and the alpha, using RMF densities along with the density dependent nucleon - nucleon interaction (M3Y). This in turn, is employed within the WKB approximation to estimate the half lives without any additional parameter for alpha - decay. The half lives are highly sensitive to the Q values used and qualitatively agree with the corresponding experimental values. The use of experimental Q values in the WKB approximation improves the agreement with the experiment, indicating that the resulting interaction potential is reliable and can be used with confidence as the real part of the optical potential in other scattering and reaction processes.Comment: Accepted for publication in Annals of Physics (NY

Spatial heterogeneity and peptide availability determine CTL killing efficiency in vivo

The rate at which a cytotoxic T lymphocyte (CTL) can survey for infected cells is a key ingredient of models of vertebrate immune responses to intracellular pathogens. Estimates have been obtained using in vivo cytotoxicity assays in which peptide-pulsed splenocytes are killed by CTL in the spleens of immunised mice. However the spleen is a heterogeneous environment and splenocytes comprise multiple cell types. Are some cell types intrinsically more susceptible to lysis than others? Quantitatively, what impacts are made by the spatial distribution of targets and effectors, and the level of peptide-MHC on the target cell surface? To address these questions we revisited the splenocyte killing assay, using CTL specific for an epitope of influenza virus. We found that at the cell population level T cell targets were killed more rapidly than B cells. Using modeling, quantitative imaging and in vitro killing assays we conclude that this difference in vivo likely reflects different migratory patterns of targets within the spleen and a heterogeneous distribution of CTL, with no detectable difference in the intrinsic susceptibilities of the two populations to lysis. Modeling of the stages involved in the detection and killing of peptide-pulsed targets in vitro revealed that peptide dose influenced the ability of CTL to form conjugates with targets but had no detectable effect on the probability that conjugation resulted in lysis, and that T cell targets took longer to lyse than B cells. We also infer that incomplete killing in vivo of cells pulsed with low doses of peptide may be due to a combination of heterogeneity in peptide uptake and the dissociation, but not internalisation, of peptide-MHC complexes. Our analyses demonstrate how population-averaged parameters in models of immune responses can be dissected to account for both spatial and cellular heterogeneity

Evolutionary variation in the expression of phenotypically plastic color vision in Caribbean mantis shrimps, genus Neogonodactylus

Author Posting. © The Author(s), 2006. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Marine Biology 150 (2006): 213-220, doi:10.1007/s00227-006-0313-5.Many animals have color vision systems that are well suited to their local environments. Changes in color vision can occur over long periods (evolutionary time), or over relatively short periods such as during development. A select few animals, including stomatopod crustaceans, are able to adjust their systems of color vision directly in response to varying environmental stimuli. Recently, it has been shown that juveniles of some stomatopod species that inhabit a range of depths can spectrally tune their color vision to local light conditions through spectral changes in filters contained in specialized photoreceptors. The present study quantifies the potential for spectral tuning in adults of three species of Caribbean Neogonodactylus stomatopods that differ in their depth ranges to assess how ecology and evolutionary history influence the expression of phenotypically plastic color vision in adult stomatopods. After 12 weeks in either a full-spectrum “white” or a narrow-spectrum “blue” light treatment, each of the three species evidenced distinctive tuning abilities with respect to the light environment that could be related to its natural depth range. A molecular phylogeny generated using mitochondrial cytochrome oxidase C subunit 1 (CO-1) was used to determine whether tuning abilities were phylogenetically or ecologically constrained. Although the sister taxa N. wennerae and N. bredini both exhibited spectral tuning, their ecology (i.e. preferred depth range) strongly influenced the expression of the phenotypically plastic color vision trait. Our results indicate that adult stomatopods have evolved the ability to undergo habitat-specific spectral tuning, allowing rapid facultative physiological modification to suit ecological constraints.This research was funded partially by NSF grant (IBN-0235820) to TWC and Sigma Xi Grants-in-Aid to AGC and by the National Coral Reef Institute through a subaward to PHB and RL Caldwell through the NOAA Coastal Ocean Program under award #NA16OA2413, to Nova Southeastern University

Eosinophils are part of the granulocyte response in tuberculosis and promote host resistance in mice

Host resistance to Mycobacterium tuberculosis (Mtb) infection requires the activities of multiple leukocyte subsets, yet the roles of the different innate effector cells during tuberculosis are incompletely understood. Here we uncover an unexpected association between eosinophils and Mtb infection. In humans, eosinophils are decreased in the blood but enriched in resected human tuberculosis lung lesions and autopsy granulomas. An influx of eosinophils is also evident in infected zebrafish, mice, and nonhuman primate granulomas, where they are functionally activated and degranulate. Importantly, using complementary genetic models of eosinophil deficiency, we demonstrate that in mice, eosinophils are required for optimal pulmonary bacterial control and host survival after Mtb infection. Collectively, our findings uncover an unexpected recruitment of eosinophils to the infected lung tissue and a protective role for these cells in the control of Mtb infection in mice