Homology modeling of Ferredoxin-nitrite reductase from Arabidopsis thaliana

Different subtypes of Influenza A virus are associated with species specific, zoonotic or pandemic Influenza. The cause of its severity underlies in complicated evolution of its segmented RNA genome. Although genetic shift and genetic drift are well known in the evolution of this virus, we reported the significant role of unique RNA palindromes in its evolution. Our computational approach identified the existence of unique palindromes in each subtype of Influenza A virus with its absence in Influenza B relating the fact of virulence and vigorous genetic hitchhiking in Influenza A. The current study focused on the re-assortment event responsible for the emergence of pandemic-2009 H1N1 virus, which is associated with outgrow of new palindrome and in turn, changing its RNA structure. We hypothesize that the change in RNA structure due to the presence of palindrome facilitates the event of re-assortment in Influenza A. Thus the evolutionary process of Influenza A is much more complicated as previously known, and that has been demonstrated in this study.     

Relationships between magmatism and lithosphere-asthenosphere structure in the Western Mediterranean and implications for geodynamics

Shear-wave (V _S ) tomography along transects across the Western-Central Mediterranean area reveals heterogeneous lateral and vertical physical characteristics in the lithosphere-asthenosphere system (LAS). A 50 km thick low velocity layer (LVL), with V _S ∼ 4.0–4.2 km/sec, typical of low rigidity fluid-bearing mantle material, is observed at a depth of about 70–120 km from offshore Provence, to Sardinia and the Central Tyrrhenian Sea. This LVL, enclosed between higher velocity mantle rocks, rises to a depth of less than 30 km below the recent and active volcanoes of Central Italy and the Southern Tyrrhenian Sea, where a maximum in the heath flow is observed. The LVL is absent beneath Southeastern France and the northern border of the African foreland. In the Balearic Sea-Sardinia-Central Tyrrhenian section, the depth of LVL corresponds to pressure conditions of minimum temperature of peridotite+CO₂+H₂O solidus, consistent with conditions where fluid loss from the slab and mantle flow over the subducting plate favor significant melt generation above steep, west-dipping subduction zones. It is suggested that LVL in the Balearic-Tyrrhenian domains is the result of mantle contamination and melting left behind by the eastward retreating Adriatic-Ionian subducting plates from Oligo-Miocene to present. This layer also marks a discontinuity between the lithospere and underlying mantle behind the subduction zone, favoring detachment and westward drift of the lithosphere, and consequent opening of backarc basins. These data support the hypothesis that the orogenic Oligocene to Quaternary volcanism in the Western Mediterranean area is the effect of shallow mantle processes, and argue against the presence of deep mantle plumes. A shallow-mantle origin is also suggested for the EM1-type Plio-Quaternary anorogenic magmatism in Sardinia and for the FOZO-DMM-type magmatism on the northern margin of the African foreland.      

The mechano‐activated K+ channels TRAAK and TREK‐1 control both warm and cold perception

The sensation of cold or heat depends on the activation of specific nerve endings in the skin. This involves heat‐ and cold‐sensitive excitatory transient receptor potential (TRP) channels. However, we show here that the mechano‐gated and highly temperature‐sensitive potassium channels of the TREK/TRAAK family, which normally work as silencers of the excitatory channels, are also implicated. They are important for the definition of temperature thresholds and temperature ranges in which excitation of nociceptor takes place and for the intensity of excitation when it occurs. They are expressed with thermo‐TRP channels in sensory neurons. TRAAK and TREK‐1 channels control pain produced by mechanical stimulation and both heat and cold pain perception in mice. Expression of TRAAK alone or in association with TREK‐1 controls heat responses of both capsaicin‐sensitive and capsaicin‐insensitive sensory neurons. Together TREK‐1 and TRAAK channels are important regulators of nociceptor activation by cold, particularly in the nociceptor population that is not activated by menthol.     

Dispersal history of a globally introduced carnivore,the small Indian mongoose Urva auropunctata,with an emphasis on the Caribbean region

Biological Invasions - The small Indian mongoose has been introduced into several important hotspots of biodiversity and is considered the wild carnivore with the greatest negative impact on...     

Identification of Four New Chemical Series of Small Drug-Like Natural Products as Potential Neuropilin-1 Inhibitors by Structure-Based Virtual Screening: Pharmacophore-Based Molecular Docking and Dynamics Simulation

Neuropilin-1 (NRP-1), a surface transmembrane glycoprotein, is one of the most important co-receptors of VEGF-A165 (vascular endothelial growth factor) responsible for pathological angiogenesis. In general, NRP-1 overexpression in cancer correlates with poor prognosis and more tumor aggressiveness. NRP-1 role in cancer has been mainly explained by mediating VEGF-A165-induced effects on tumor angiogenesis. NRP-1 was recently identified as a co-receptor and an independent gateway for SARS-CoV-2 through binding subunit S2 of Spike protein in the same way as VEGF-A165. Thus, NRP-1 is of particular value as a target for cancer therapy and other angiogenesis-dependent diseases as well as for SARS-CoV-2 antiviral intervention. Herein, The Super Natural II, the largest available database of natural products (∼0.33 M), pre-filtered with drug-likeness criteria (absorption, distribution, metabolism and excretion/toxicity), was screened against NRP-1. NRP-1/VEGF-A165 interaction is one of protein-protein interfaces (PPIs) known to be challenging when approached in-silico. Thus, a PPI-suited multi-step virtual screening protocol, incorporating a derived pharmacophore with molecular docking and followed by MD (molecular dynamics) simulation, was designed. Two stages of pharmacophorically constrained molecular docking (standard and extra precisions), a mixed Torsional/Low-mode conformational search and MM-GBSA ΔG binding affinities calculation, resulted in the selection of 100 hits. These 100 hits were subjected to 20 ns MD simulation, that was extended to 100 ns for top hits (20) and followed by post-dynamics analysis (atomic ligand-protein contacts, RMSD, RMSF, MM-GBSA ΔG, Rg, SASA and H-bonds). Post-MD analysis showed that 19 small drug-like nonpeptide natural molecules, grouped in four chemical scaffolds (purine, thiazole, tetrahydropyrimidine and dihydroxyphenyl), well verified the derived pharmacophore and formed stable and compact complexes with NRP-1. The discovered molecules are promising and can serve as a base for further development of new NRP-1 inhibitors.     

In Silico Design of Novel Tetra-Substituted Pyridinylimidazoles Derivatives as c-Jun N-Terminal Kinase-3 Inhibitors,Using 2D/3D-QSAR Studies,Molecular Docking and ADMET Prediction

The c-Jun N-terminal Kinase 3 (JNK3) is a family of protein kinases that plays an important role in the neurodegenerative diseases such as Alzheimer’     

Autoantibodies against cardiac β(1)-adrenoceptor do not affect the low-affinity state β(1)-adrenoceptor-mediated inotropy in rat cardiomyocytes

Circulating autoantibodies directed against the 2nd extracellular loop (EL-2) of β(1)-adrenoceptors (β(1)-AABs) have been detected in the serum of patients with various cardiovascular pathologies. β(1)-AABs induce agonistic, positive inotropic effects via β(1)-adrenoceptors (β(1)ARs). In the mammalian heart, β(1)-AR can exist in 2 distinct activated configurations (the so-called high- and low-affinity states). The aim of the present study was to investigate whether the action of β(1)-AAB is dependent on the affinity state of β(1)AR in isolated ventricular cardiomyocytes of adult Wistar rats. Immunoglobulin G (IgG) containing β(1)-AAB obtained from animals immunized with a peptide corresponding to the EL-2 of human β(1)-AR, caused a dose-dependent increase in cell shortening. Isoproterenol-induced inotropy was significantly reduced in cardiomyocytes that had been preincubated with IgG containing β(1)-AAB and in cardiomyocytes isolated from immunized rats. The negative effects of preincubation with IgG containing β(1)-AAB on the response to isoproterenol was inhibited in the presence of bisoprolol. CGP 12177A and pindolol-induced inotropy was not affected by IgG preincubation or immunization. No detectable inotropic effect of cell shortening was obtained with IgG containing β(1)-AAB in the presence of propranolol and 3-isobutyl-1-methylxanthine. The present study demonstrates that β(1)-AABs have no agonist/antagonist-like effects upon low-affinity state β(1)-ARs. This result indicates that β(1)-AABs recognize and stabilize the high-affinity state, but are unable to stabilize and (or) induce the low-affinity state receptor.     

Luminescence Study of Silver Nanoparticles Obtained by Annealed Ionic Exchange Silicate Glasses

The photoluminescence of silver nanoparticles glasses obtained by ionic exchange and annealing is investigated for various ionic exchange times. These glasses are prepared by immersion of silicate glass samples in a molten salt bath of molar concentration 10% AgNO₃ in NaNO₃ at T = 320 °C. Scanning electron microscopy measurement in electron diffraction scattering (EDS) configuration confirms the silver presence in the various glasses, and the UV/visible absorption gives the evolution of the spectra after ionic exchange and plasmon resonance apparition after annealing. After annealing at 450 °C, both diagnostics inform us about the particles’ formation and the silver rediffusion. Silver nanoparticle growth after annealing prior leads to photoluminescence exaltation and quenching for the longest exchange samples. Subsequently, we propose potential mechanisms of the nanoparticle formation with an initial depolymerization of the silicate network during the ionic exchange and repolymerization during annealing.     

Nitric oxide mediates the survival action of IGF-1 and insulin in pancreatic beta cells

Generation of low levels of nitric oxide (NO) contributes to beta cell survival in vitro. The purpose of this study was to explore the link between NO and the survival pathway triggered by insulin-like growth factor-1 (IGF-1) and insulin in insulin producing RINm5F cells and in pancreatic islets. Results show that exposure of cells to IGF-1/insulin protects against serum deprivation-induced apoptosis. This action is prevented with inhibitors of NO generation, PI3K and Akt. Moreover, transfection with the negative dominant form of the tyrosine kinase c-Src abrogates the effect of IGF-1 and insulin on DNA fragmentation. An increase in the expression level of NOS3 protein and in the enzyme activity is observed following exposure of serum-deprived RINm5F cells to IGF-1 and insulin. Phosphorylation of IRS-1, IRS-2 and to less extent IRS-3 takes place when serum-deprived RINm5F cells and rat pancreatic islets are exposed to either IGF-1, insulin, or diethylenetriamine nitric oxide adduct (DETA/NO). In human islets, IRS-1 and IRS-2 proteins are present and tyrosine phosphorylated upon exposure to IGF-1, insulin and DETA/NO. Both rat and human pancreatic islets undergo DNA fragmentation when cultured in serum-free medium and IGF-1, insulin and DETA/NO protect efficiently from this damage. We then conclude that generation of NO participates in the activation of survival pathways by IGF-1 and insulin in beta cells.