Structural and biochemical characterization of a quinol binding site of Escherichia coli nitrate reductase A

The crystal structure of Escherichia coli nitrate reductase A (NarGHI) in complex with pentachlorophenol has been determined to 2.0 A of resolution. We have shown that pentachlorophenol is a potent inhibitor of quinol:nitrate oxidoreductase activity and that it also perturbs the EPR spectrum of one of the hemes located in the membrane anchoring subunit (NarI). This new structural information together with site-directed mutagenesis data, biochemical analyses, and molecular modeling provide the first molecular characterization of a quinol binding and oxidation site (Q-site) in NarGHI. A possible proton conduction pathway linked to electron transfer reactions has also been defined, providing fundamental atomic details of ubiquinol oxidation by NarGHI at the bacterial membrane.     

Circulating NOD1 Activators and Hematopoietic NOD1 Contribute to Metabolic Inflammation and Insulin Resistance

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Biodegradable Monocrystalline Silicon Photovoltaic Microcells as Power Supplies for Transient Biomedical Implants

Bioresorbable electronic materials serve as foundations for implantable devices that provide active diagnostic or therapeutic function over a timeframe matched to a biological process, and then disappear within the body to avoid secondary surgical extraction. Approaches to power supply in these physically transient systems are critically important. This paper describes a fully biodegradable, monocrystalline silicon photovoltaic (PV) platform based on microscale cells (microcells) designed to operate at wavelengths with long penetration depths in biological tissues (red and near infrared wavelengths), such that external illumination can provide realistic levels of power. Systematic characterization and theoretical simulations of operation under porcine skin and fat establish a foundational understanding of these systems and their scalability. In vivo studies of a representative platform capable of generating ≈60 µW of electrical power under 4 mm of porcine skin and fat illustrate an ability to operate blue light‐emitting diodes (LEDs) as subdermal implants in rats for 3 d. Here, the PV system fully resorbs after 4 months. Histological analysis reveals that the degradation process introduces no inflammatory responses in the surrounding tissues. The results suggest the potential for using silicon photovoltaic microcells as bioresorbable power supplies for various transient biomedical implants.     

The immunomodulatory effects of tachykinins and their receptors

Tachykinins (TKs) are a family of neuropeptides mainly expressed by neuronal and non-neuronal cell types, especially immune cells. Expression of TKs receptors on immune cell surfaces, their involvement in immune-related disorders, and therefore, understanding their immunomodulatory roles have become of particular interest to researchers. In fact, the precise understanding of TKs intervention in the immune system would help to design novel therapeutic approaches for patients suffering from immune disorders. The present review summarizes studies on TKs function as modulators of the immune system by reviewing their roles in generation, activation, development, and migration of immune cells. Also, it discusses TKs involvement in three main cellular mechanisms including inflammation, apoptosis, and proliferation.     

Molecular Docking studies of FKBP12-mTOR inhibitors using binding predictions

Mammalian target of rapamycin (mTOR) is a key regulator of cell growth, proliferation and angiogenesis. mTOR signaling is frequently hyper activated in a broad spectrum of human cancers thereby making it a potential drug target. The current drugs available have been successful in inhibiting the mTOR signaling, nevertheless, show low oral bioavailability and suboptimal solubility. Considering the narrow therapeutic window of the available inhibitors, through computational approaches, the present study pursues to identify a compound with optimal oral bioavailability and better solubility properties in addition ensuing high affinity between FKBP12 and FRB domain of mTOR. Current mTOR inhibitors; Everolimus, Temsirolimus Deforolimus and Echinomycin served as parent molecules for similarity search with a threshold of 95%. The query molecules and respective similar molecules were docked at the binding cleft of FKBP12 protein. Aided by MolDock algorithm, high affinity compounds against FKBP12 were retrieved. Patch Dock supervised protein-protein interactions were established between FRB domain of mTOR and ligand (query and similar) bound and free states of FKBP12. All the similar compounds thus retrieved showed better solubility properties and enabled better complex formation of mTOR and FKBP12. In particular Everolimus similar compound PubChem ID: 57284959 showed appreciable drugs like properties bestowed with better solubility higher oral bioavailability. In addition this compound brought about enhanced interaction between FKBP12 and FRB domain of mTOR. In the study, we report Everolimus similar compound PubChem ID: 57284959 to be potential inhibitor for mTOR pathway which can overcome the affinity and solubility concerns of current mTOR drugs.

Abbreviations

mTOR - Mammalian Target of Rapamycin, FRB domain - FKBP12-rapamycin associated protein, FKBP12 - FK506-binding protein 12, OPLS - Optimized Potentials for Liquid Simulations, Akt - RAC-alpha serine/threonine-protein kinase, PI3K - phosphatidylinositide 3-kinases.     

Association between rs3088440 (G > A) polymorphism at 9p21.3 locus with the occurrence and severity of coronary artery disease in an Iranian population

Molecular Biology Reports - Several genome-wide association studies showed that a series of genetic variants located at the chromosome 9p21 locus are strongly associated with coronary artery...