557 research outputs found
Pneumolysin Is Responsible for Differential Gene Expression and Modifications in the Epigenetic Landscape of Primary Monocyte Derived Macrophages
α-d-Tagatopyranose
The title compound, C6H12O6, also known as d-Tagatose, occurs in its furanose and pyranose forms in solution, but only the α-pyranose form crystallizes out. In the crystal, the molecules form hydrogen bonded chains propagating in [100] linked by O—H⋯O interactions. Further O—H⋯O bonds cross-link the chains
Preparation of azide biosynthetic surrogates of myo-Inositol
As a prelude to biomolecular incorporation studies, practical routes to a series of four regioisomeric azido-deoxy derivatives of inositol that mimic the natural myo-stereochemistry are described. Starting from commercially available myo-inositol, the regioselective and stereoselective introduction of azide functionality was achieved at the C-2, C-3, C-4 and C-5 positions via azide displacement of the corresponding O-sulfonates of suitably protected scyllo-, chiro-, epi- and neo-inositols, respectively. Notably, a final one-pot acetolysis method conveniently allowed for rapid access to pentaacetate azido-deoxy inositols. Investigations on the metabolic incorporation of these myo-inositol azide surrogates in both acetate and free alcohol forms are in progress
TMEM203 is a binding partner and regulator of STING-mediated inflammatory signaling in macrophages
Regulation of IFN signaling is critical in host recognition and response to pathogens while its dysregulation underlies the pathogenesis of several chronic diseases. STimulator of IFN Genes (STING) has been identified as a critical mediator of IFN inducing innate immune pathways, but little is known about direct coregulators of this protein. We report here that TMEM203, a conserved putative transmembrane protein, is an intracellular regulator of STING-mediated signaling. We show that TMEM203 interacts, functionally cooperates, and comigrates with STING following cell stimulation, which in turn leads to the activation of the kinase TBK1, and the IRF3 transcription factor. This induces target genes in macrophages, including IFN-β. Using Tmem203 knockout bone marrow-derived macrophages and transient knockdown of TMEM203 in human monocyte-derived macrophages, we show that TMEM203 protein is required for cGAMPinduced STING activation. Unlike STING, TMEM203 mRNA levels are elevated in T cells from patients with systemic lupus erythematosus, a disease characterized by the overexpression of type I interferons. Moreover, TMEM203 mRNA levels are associated with disease activity, as assessed by serum levels of the complement protein C3. Identification of TMEM203 sheds light into the control of STING-mediated innate immune responses, providing a potential novel mechanism for therapeutic interventions in STING-associated inflammatory diseases
Sodium ion interactions with aqueous glucose: Insights from quantum mechanics, molecular dynamics, and experiment
In the last several decades, significant efforts have been conducted to understand the fundamental reactivity of glucose derived from plant biomass in various chemical environments for conversion to renewable fuels and chemicals. For reactions of glucose in water, it is known that inorganic salts naturally present in biomass alter the product distribution in various deconstruction processes. However, the molecular-level interactions of alkali metal ions and glucose are unknown. These interactions are of physiological interest as well, for example, as they relate to cation-glucose cotransport. Here, we employ quantum mechanics (QM) to understand the interaction of a prevalent alkali metal, sodium, with glucose from a structural and thermodynamic perspective. The effect on B-glucose is subtle: a sodium ion perturbs bond lengths and atomic partial charges less than rotating a hydroxymethyl group. In contrast, the presence of a sodium ion significantly perturbs the partial charges of α-glucose anomeric and ring oxygens. Molecular dynamics (MD) simulations provide dynamic sampling in explicit water, and both the QM and the MD results show that sodium ions associate at many positions with respect to glucose with reasonably equivalent propensity. This promiscuous binding nature of Na + suggests that computational studies of glucose reactions in the presence of inorganic salts need to ensure thorough sampling of the cation positions, in addition to sampling glucose rotamers. The effect of NaCl on the relative populations of the anomers is experimentally quantified with light polarimetry. These results support the computational findings that Na + interacts similarly with a- and B-glucose
CFTR function is impaired in a subset of patients with pancreatitis carrying rare CFTR variants
Background: Many affected by pancreatitis harbor rare variants of the cystic fibrosis (CF) gene, CFTR, which encodes an epithelial chloride/bicarbonate channel. We investigated CFTR function and the effect of CFTR modulator drugs in pancreatitis patients carrying CFTR variants. Methods: Next-generation sequencing was performed to identify CFTR variants. Sweat tests and nasal potential difference (NPD) assays were performed to assess CFTR function in vivo. Intestinal current measurement (ICM) was performed on rectal biopsies. Patient-derived intestinal epithelial monolayers were used to evaluate chloride and bicarbonate transport and the effects of a CFTR modulator combination: elexacaftor, tezacaftor and ivacaftor (ETI). Results: Of 32 pancreatitis patients carrying CFTR variants, three had CF-causing mutations on both alleles and yielded CF-typical sweat test, NPD and ICM results. Fourteen subjects showed a more modest elevation in sweat chloride levels, including three that were provisionally diagnosed with CF. ICM indicated impaired CFTR function in nine out of 17 non-CF subjects tested. This group of nine included five carrying a wild type CFTR allele. In epithelial monolayers, a reduction in CFTR-dependent chloride transport was found in six out of 14 subjects tested, whereas bicarbonate secretion was reduced in only one individual. In epithelial monolayers of four of these six subjects, ETI improved CFTR function. Conclusions: CFTR function is impaired in a subset of pancreatitis patients carrying CFTR variants. Mutations outside the CFTR locus may contribute to the anion transport defect. Bioassays on patient-derived intestinal tissue and organoids can be used to detect such defects and to assess the effect of CFTR modulators
44 Quantitative PCR demonstrates the underestimated burden of Streptococcus pyogenes as a cause of paediatric pyoderma in The Gambia
Sn-Beta zeolites with borate salts catalyse the epimerization of carbohydrates via an intramolecular carbon shift
Carbohydrate epimerization is an essential technology for the widespread production of rare sugars. In contrast to other enzymes, most epimerases are only active on sugars substituted with phosphate or nucleotide groups, thus drastically restricting their use. Here we show that Sn-Beta zeolite in the presence of sodium tetraborate catalyses the selective epimerization of aldoses in aqueous media. Specifically, a 5 wt% aldose (for example, glucose, xylose or arabinose) solution with a 4:1 aldose:sodium tetraborate molar ratio reacted with catalytic amounts of Sn-Beta yields near-equilibrium epimerization product distributions. The reaction proceeds by way of a 1,2 carbon shift wherein the bond between C-2 and C-3 is cleaved and a new bond between C-1 and C-3 is formed, with C-1 moving to the C-2 position with an inverted configuration. This work provides a general method of performing carbohydrate epimerizations that surmounts the main disadvantages of current enzymatic and inorganic processes.National Science Foundation (U.S.). Materials Research Science and Engineering Centers (Program) (Award DMR-0819762)DuPont MIT Alliance (Graduate Research Fellowship)National Institutes of Health (U.S.) (Grant EB-001960)National Institutes of Health (U.S.) (Grant EB-002026)National Science Foundation (U.S.). Graduate Research Fellowship Program (Grant 1122374
Local- versus broad-scale environmental drivers of continental β-diversity patterns in subterranean spider communities across Europe
Macroecologists seek to identify drivers of community turnover (β-diversity) through broad spatial scales. However, the influence of local habitat features in driving broad-scale β-diversity patterns remains largely untested, owing to the objective challenges of associating local-scale variables to continental-framed datasets. We examined the relative contribution of local- versus broad-scale drivers of continental β-diversity patterns, using a uniquely suited dataset of cave-dwelling spider communities across Europe (35–70° latitude). Generalized dissimilarity modelling showed that geographical distance, mean annual temperature and size of the karst area in which caves occurred drove most of β-diversity, with differential contributions of each factor according to the level of subterranean specialization. Highly specialized communities were mostly influenced by geographical distance, while less specialized communities were mostly driven by mean annual temperature. Conversely, local-scale habitat features turned out to be meaningless predictors of community change, which emphasizes the idea of caves as the human accessible fraction of the extended network of fissures that more properly represents the elective habitat of the subterranean fauna. To the extent that the effect of local features turned to be inconspicuous, caves emerge as experimental model systems in which to study broad biological patterns without the confounding effect of local habitat features
Characterization of methyl-, 3-deoxy-, and methyl-deoxysugars in marine high molecular weight dissolved organic matter
Author Posting. © Elsevier B.V., 2007. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Organic Geochemistry 38 (2007): 884-896, doi:10.1016/j.orggeochem.2007.02.005.Nuclear magnetic resonance spectroscopy of marine high molecular weight
dissolved organic matter (HMWDOM) in surface waters show that >50% of the carbon is
a compositionally well-defined family of acylated-polysaccharides that are conserved
across ocean basins. However, acid hydrolysis of HMWDOM followed by
chromatographic analyses recover only 10-20% of the carbon as neutral, amino, and
acidic sugars. Most carbohydrate in HMWDOM therefore remains uncharacterized.
Here we use acid hydrolysis followed by Ag+ and Pb2+ cation exchange chromatography
to separate HMWDOM hydrolysis products for characterization by 1-D and 2-D NMR
spectroscopy. In addition to neutral sugars identified in past studies, we find 3-Omethylglucose,
3-O-methylrhamnose, 2-O-methylrhamnose and 2-O-methylfucose. We
also find 3-deoxysugars to be present, although their complete structures could not be
determined. Methyl sugars are widely distributed in plant and bacterial structural
carbohydrates, such as cell wall polysaccharides, and their presence in HMWDOM
suggests that structural carbohydrates may contribute to DOM in surface seawater. We
find most HMWDOM carbohydrate is not depolymerized by acid hydrolysis, and that the
nonhydrolyzable component includes 6-deoxysugars.Funding was provided by the Ocean Carbon Sequestration Research
Program, Biological and Environmental Research (BER), U.S. Department of Energy
grant DEFG0200ER62999 and the National Sciences Foundation Chemical
Oceanography Program grant OCE 9818654. Christos Panagiotopoulos received support
through the Postdoctoral Fellowship Program of the Woods Hole Oceanographic
Institution, and DJR received support through the Stanley Watson Chair in
Oceanography
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