Autoregulation of RCO by Low-Affinity Binding Modulates Cytokinin Action and Shapes Leaf Diversity

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Discovery of a novel class of potent and selective tetrahydroindazole-based sigma-1 receptor ligands

The sigma-1 and sigma-2 receptors have been shown to play important roles in CNS diseases, cancer, and other disorders. These findings suggest that targeting these proteins with small-molecule modulators may be of important therapeutic value. Here we report the development of a new class of tetrahydroindazoles that are highly potent and selective ligands for sigma-1. Molecular modeling was used to rationalize the observed structure-activity relationships and identify key interactions responsible for increased potency of the optimized compounds. Assays for solubility and microsomal stability showed this series possesses favorable characteristics and is amenable to further therapeutic development. The compounds described herein will be useful in the development of new chemical probes for sigma-1 and to aid in future work therapeutically targeting this protein.     

Diverse paths to hybrid incompatibility in Arabidopsis

One of the most essential questions of biology is to understand how different species have evolved. Hybrid incompatibility, a phenomenon in which hybrids show reduced fitness in comparison with their parents, can result in reproductive isolation and speciation. Therefore, studying hybrid incompatibility provides an entry point in understanding speciation. Hybrid incompatibilities are known throughout taxa, and the underlying mechanisms have mystified scientists since the theory of evolution by means of natural selection was introduced. In plants, it is only in recent years that the high‐throughput genetic and molecular tools have become available for the Arabidopsis genus, thus helping to shed light on the different genes and molecular and evolutionary mechanisms that underlie hybrid incompatibilities. In this review, we highlight the current knowledge of diverse mechanisms that are known to contribute to hybrid incompatibility.     

Haematological and histological changes in fish Heteropneustes fossilis exposed to pesticides from industrial waste water

The present study investigated the potential changes in hematologic parameters and histology of fish Heteropneustes fossilis when exposed to industrial waste water of different concentrations. The toxicant enter into the fish body from different rout, inhalation, dermal oral, and other several rout for entering in the fish body. The blood parameters of fish H. fossilis control group and treatment were investigated on 1st, 5th, 10th, and 20th days of experiment, hematologic variation was observed in RBC, WBC, MCV, MCH, and MCHC count. Histopathologic changes in liver, intestine, gill, muscle, and heart showed increasing degrees of damage in the tissues in correlation with the accumulation pattern of pesticides, while liver, intestine, gill, muscle, and heart of control group exhibited a normal architecture. Toxic effects of pesticides vary in different organs of the fish H. fossilis significant. The fish exposed to higher concentration showed uncoordinated alterations in behavioral responses, especially erratic and jerky swimming, physiologic, malformation, histologic, hematologic and biochemical changes, frequent surfacing and in gulping, mucus secretion, an increase in opercular movement, and copious secretion of mucus of all over the body.     

The N-terminus and alpha-5, alpha-6 helices of the pro-apoptotic protein Bax,modulate functional interactions with the anti-apoptotic protein Bcl-x<Subscript>L</Subscript>

Background  

Bcl-2 family proteins are key regulators of mitochondrial integrity and comprise both pro- and anti-apoptotic proteins. Bax a pro-apoptotic member localizes as monomers in the cytosol of healthy cells and accumulates as oligomers in mitochondria of apoptotic cells. The Bcl-2 homology-3 (BH3) domain regulates interactions within the family, but regions other than BH3 are also critical for Bax function. Thus, the N-terminus has been variously implicated in targeting to mitochondria, interactions with BH3-only proteins as well as conformational changes linked to Bax activation. The transmembrane (TM) domains (α5-α6 helices in the core and α9 helix in the C-terminus) in Bax are implicated in localization to mitochondria and triggering cytotoxicity. Here we have investigated N-terminus modulation of TM function in the context of regulation by the anti-apoptotic protein Bcl-x_L.     

The Ribosome Biogenesis Protein Nol9 Is Essential for Definitive Hematopoiesis and Pancreas Morphogenesis in Zebrafish

Ribosome biogenesis is a ubiquitous and essential process in cells. Defects in ribosome biogenesis and function result in a group of human disorders, collectively known as ribosomopathies. In this study, we describe a zebrafish mutant with a loss-of-function mutation in nol9, a gene that encodes a non-ribosomal protein involved in rRNA processing. nol9 ^{sa1022/sa1022} mutants have a defect in 28S rRNA processing. The nol9 ^{sa1022/sa1022} larvae display hypoplastic pancreas, liver and intestine and have decreased numbers of hematopoietic stem and progenitor cells (HSPCs), as well as definitive erythrocytes and lymphocytes. In addition, ultrastructural analysis revealed signs of pathological processes occurring in endothelial cells of the caudal vein, emphasizing the complexity of the phenotype observed in nol9 ^{sa1022/sa1022} larvae. We further show that both the pancreatic and hematopoietic deficiencies in nol9 ^{sa1022/sa1022} embryos were due to impaired cell proliferation of respective progenitor cells. Interestingly, genetic loss of Tp53 rescued the HSPCs but not the pancreatic defects. In contrast, activation of mRNA translation via the mTOR pathway by L-Leucine treatment did not revert the erythroid or pancreatic defects. Together, we present the nol9 ^{sa1022/sa1022} mutant, a novel zebrafish ribosomopathy model, which recapitulates key human disease characteristics. The use of this genetically tractable model will enhance our understanding of the tissue-specific mechanisms following impaired ribosome biogenesis in the context of an intact vertebrate.     

Tyloxapol Niosomes as Prospective Drug Delivery Module for Antiretroviral Drug Nevirapine

With the aim of assuring more patient compliant pharmacotherapy for acquired immuno deficiency syndrome, a formulation of the first line anti-retroviral drug, nevirapine (NVP), has been developed by encapsulating it within niosomes. Biocompatible niosomes were fabricated using a biological surfactant, tyloxapol, with variable cholesterol concentrations. Formulation with surfactant/cholesterol molar ratio 1:0.1 exhibits maximum stability and optimum hydrophobicity. Thus, it is most suitable for the entrapment of NVP and has high entrapment efficiency of 94.3%. FTIR and DSC results indicate that NVP has sufficient compatibility with the excipients of the formulation. Photoluminescence quenching measurements were employed to elucidate the position of drug molecules in niosome bilayer along with the partition coefficient. Dissolution results indicate that the efflux of drug is sustained which creates a depot effect and decreases the fluctuations in drug release. Such a versatile and improved formulation of NVP is expected to increase its therapeutic index and alleviate toxic systemic side effects while improving the quality of life and duration of survival of the patients.KEY WORDS: cholesterol, encapsulation, nevirapine, sustained release, tyloxapol niosomes