Structures of Streptococcus pneumoniae PiaA and Its Complex with Ferrichrome Reveal Insights into the Substrate Binding and Release of High Affinity Iron Transporters

Iron scarcity is one of the nutrition limitations that the Gram-positive infectious pathogens Streptococcus pneumoniae encounter in the human host. To guarantee sufficient iron supply, the ATP binding cassette (ABC) transporter Pia is employed to uptake iron chelated by hydroxamate siderophore, via the membrane-anchored substrate-binding protein PiaA. The high affinity towards ferrichrome enables PiaA to capture iron at a very low concentration in the host. We presented here the crystal structures of PiaA in both apo and ferrichrome-complexed forms at 2.7 and 2.1 Å resolution, respectively. Similar to other class III substrate binding proteins, PiaA is composed of an N-terminal and a C-terminal domain bridged by an α-helix. At the inter-domain cleft, a molecule of ferrichrome is stabilized by a number of highly conserved residues. Upon ferrichrome binding, two highly flexible segments at the entrance of the cleft undergo significant conformational changes, indicating their contribution to the binding and/or release of ferrichrome. Superposition to the structure of Escherichia coli ABC transporter BtuF enabled us to define two conserved residues: Glu119 and Glu262, which were proposed to form salt bridges with two arginines of the permease subunits. Further structure-based sequence alignment revealed that the ferrichrome binding pattern is highly conserved in a series of PiaA homologs encoded by both Gram-positive and negative bacteria, which were predicted to be sensitive to albomycin, a sideromycin antibiotic derived from ferrichrome.     

Long COVID and its Management

The pandemic of COVID-19 is the biggest public health crisis in 21^st Century. Besides the acute symptoms after infection, patients and society are also being challenged by the long-term health complications associated with COVID-19, commonly known as long COVID. While health professionals work hard to find proper treatments, large amount of knowledge has been accumulated in recent years. In order to deal with long COVID efficiently, it is important for people to keep up with current progresses and take proactive actions on long COVID. For this purpose, this review will first introduce the general background of long COVID, and then discuss its risk factors, diagnostic indicators and management strategies. This review will serve as a useful resource for people to understand and prepare for long COVID that will be with us in the foreseeable future.     

Vascular dysfunction in type 2 diabetic TallyHo mice: role for an increase in the contribution of PGH2/TxA2 receptor activation and cytochrome p450 products

In this study, we tested the hypothesis that spontaneously diabetic TallyHo (TH) mice, a novel polygenic model for type 2 diabetes, will exhibit endothelial dysfunction associated with an increased contribution from endothelium-derived contractile factors (EDCF). The cellular mechanisms underlying the increased contribution of EDCF were explored in 16 and 30-week-old male TH and age-matched male C57BL/6J mice (n=4-9). Blood glucose and serum lipid profiles were markedly increased in the TH mice. Superoxide generation, assessed with a lucigenin chemiluminescence assay, was markedly increased in the aortae of TH mice. Endothelium-dependent vascular relaxations and contractions to acetylcholine (ACh), but not endothelium-independent relaxations to sodium nitroprusside, were impaired and vascular contractions to phenylephrine were significantly enhanced in aortae from TH mice. Nomega-nitro-L-arginine methyl ester markedly increased the ACh-induced contractions in TH mice, whereas SQ29548, a thromboxane receptor antagonist, and cytochrome P450 (CYP) inhibitors 17-octadecynoic acid and sulfaphenazole, the latter being specific for CYP2C6 and 2C9, decreased and (or) normalized the contractile response to ACh in TH mice. The present study indicates that enhanced contribution of prostaglandin H2/thromboxane A2 receptor and CYP, likely CYP2C6 and 2C9, play a critical role in the pathogenesis of increased EDCF in the aortae of type 2 diabetic TH mice.     

SIDD: A Semantically Integrated Database towards a Global View of Human Disease

Background

A number of databases have been developed to collect disease-related molecular, phenotypic and environmental features (DR-MPEs), such as genes, non-coding RNAs, genetic variations, drugs, phenotypes and environmental factors. However, each of current databases focused on only one or two DR-MPEs. There is an urgent demand to develop an integrated database, which can establish semantic associations among disease-related databases and link them to provide a global view of human disease at the biological level. This database, once developed, will facilitate researchers to query various DR-MPEs through disease, and investigate disease mechanisms from different types of data.

Methodology

To establish an integrated disease-associated database, disease vocabularies used in different databases are mapped to Disease Ontology (DO) through semantic match. 4,284 and 4,186 disease terms from Medical Subject Headings (MeSH) and Online Mendelian Inheritance in Man (OMIM) respectively are mapped to DO. Then, the relationships between DR-MPEs and diseases are extracted and merged from different source databases for reducing the data redundancy.

Conclusions

A semantically integrated disease-associated database (SIDD) is developed, which integrates 18 disease-associated databases, for researchers to browse multiple types of DR-MPEs in a view. A web interface allows easy navigation for querying information through browsing a disease ontology tree or searching a disease term. Furthermore, a network visualization tool using Cytoscape Web plugin has been implemented in SIDD. It enhances the SIDD usage when viewing the relationships between diseases and DR-MPEs. The current version of SIDD (Jul 2013) documents 4,465,131 entries relating to 139,365 DR-MPEs, and to 3,824 human diseases. The database can be freely accessed from: http://mlg.hit.edu.cn/SIDD.     

Triacylglycerol Synthesis Enzymes Mediate Lipid Droplet Growth by Relocalizing from the ER to Lipid Droplets

1. Download : Download high-res image (442KB)
2. Download : Download full-size image

Highlights? Triacylglyceride (TG) synthesis is coupled with lipid droplet (LD) growth ? Two LD populations exist: growing LDs, containing TG enzymes, and small LDs ? Specific TG synthesis enzymes move from the ER to LDs through membrane bridges ? LD localization of TG enzymes mediates expansion of a subset of LDs     

Factors Influencing Formation of Sclerotia in Grifola umbellate （Pers.） Pilaet Under Artificial Conditions

The effects of substrate composition and temperature on myceilal growth and sclerotium production in Grlfola umbellate （Pers.） Pilaet were Investigated In the present study. The Induction of sclerotla of G. umbellate was affected greatly by the type of medium, as well as the type of carbon source. Malt-extract agar was able to induce the production of sclerotia. The production of sclerotia was also observed when the carbon source in the GPC agar medium （glucose 20 g/L, peptone 6 g/L, corn steep liquor 10 g/L, and agar 15 g/L） was replaced with glycerol or mannitol. Altering the composition of the GPC medium with milk powder, thiamine hydrochlorlde, extract of Armlllarla mellea, active clay, dlatomite, kaolin, or arginlne did not induce the production of sclerotla. A temperature range of 18-25 ℃ was suitable for both mycellai growth and sclerotium formation. Glycerol significantly Induced slerotium formation on nutrient supplemented with sawdust substrates In bottle culture. 24S-Polyporusterone A and polyporusterone B were assayed In samples of natural and cultured sclerotla. Both natural and cultured sclerotla contained 24S- polyporusterone A and polyporusterone B.     

Modification of alternative splicing in bovine somatic cell nuclear transfer embryos using engineered CRISPR-Cas13d

Animal cloning can be achieved by somatic cell nuclear transfer(SCNT), but the resulting live birth rate is relatively low. We previously improved the efficiency of bovine SCNT by exogenous melatonin treatment or by overexpression of lysine-specific demethylase 4D(KDM4D) and 4E(KDM4E). In this study, we revealed abundant alternative splicing(AS) transitions during fertilization and embryonic genome activation, and demonstrated abnormal AS in bovine SCNT embryos compared with in vitro fertilized ...     

Mitochondrial genome nucleotide substitution pattern between domesticated silkmoth, Bombyx mori, and its wild ancestors, Chinese Bombyx mandarina and Japanese Bombyx mandarina

Bombyx mori and Bombyx mandarina are morphologically and physiologically similar. In this study, we compared the nucleotide variations in the complete mitochondrial (mt) genomes between the domesticated silkmoth, B. mori, and its wild ancestors, Chinese B. mandarina (ChBm) and Japanese B. mandarina (JaBm). The sequence divergence and transition mutation ratio between B. mori and ChBm are significantly smaller than those observed between B. mori and JaBm. The preference of transition by DNA strands between B. mori and ChBm is consistent with that between B. mori and JaBm, however, the regional variation in nucleotide substitution rate shows a different feature. These results suggest that the ChBm mt genome is not undergoing the same evolutionary process as JaBm, providing evidence for selection on mtDNA. Moreover, investigation of the nucleotide sequence divergence in the A+T-rich region of Bombyx mt genomes also provides evidence for the assumption that the A+T-rich region might not be the fastest evolving region of the mtDNA of insects.