UPDATED: Torrent Pharmaceuticals Limited Issues Voluntary Nationwide Recall of Losartan Potassium Tablets, USP and Losartan Potassium and Hydrochlorothiazide Tablets, USP

Audience: Consumer, Health Professional, Pharmacy. Torrent Pharmaceuticals Limited is expanding its voluntary recall from 10 lots of Losartan potassium tablets USP to include 6 lots of Losartan potassium and hydrochlorothiazide tablets, USP, to the...

http://bit.ly/2S5vCY4

Auxin-Inducible Depletion of the Essentialome Suggests Inhibition of TORC1 by Auxins and Inhibition of Vrg4 by SDZ 90-215, a Natural Antifungal Cyclopeptide

Gene knockout and knockdown strategies have been immensely successful probes of gene function, but small molecule inhibitors (SMIs) of gene products allow much greater time resolution and are particularly useful when the targets are essential for cell replication or survival. SMIs also serve as lead compounds for drug discovery. However, discovery of selective SMIs is costly and inefficient. The action of SMIs can be modeled simply by tagging gene products with an auxin-inducible degron (AID) that triggers rapid ubiquitylation and proteasomal degradation of the tagged protein upon exposure of live cells to auxin. To determine if this approach is broadly effective, we AID-tagged over 750 essential proteins in Saccharomyces cerevisiae and observed growth inhibition by low concentrations of auxin in over 66% of cases. Polytopic transmembrane proteins in the plasma membrane, Golgi complex, and endoplasmic reticulum were efficiently depleted if the AID-tag was exposed to cytoplasmic OsTIR1 ubiquitin ligase. The auxin analog 1-napthylacetic acid (NAA) was as potent as auxin on AID-tags, but surprisingly NAA was more potent than auxin at inhibiting target of rapamycin complex 1 (TORC1) function. Auxin also synergized with known SMIs when acting on the same essential protein, indicating that AID-tagged strains can be useful for SMI screening. Auxin synergy, resistance mutations, and cellular assays together suggest the essential GMP/GDP-mannose exchanger in the Golgi complex (Vrg4) as the target of a natural cyclic peptide of unknown function (SDZ 90-215). These findings indicate that AID-tagging can efficiently model the action of SMIs before they are discovered and can facilitate SMI discovery.

http://bit.ly/2FWQk5Q

Genome-Wide Studies of Rho5-Interacting Proteins That Are Involved in Oxidant-Induced Cell Death in Budding Yeast

Rho GTPases play critical roles in cell proliferation and cell death in many species. As in animal cells, cells of the budding yeast Saccharomyces cerevisiae undergo regulated cell death under various physiological conditions and upon exposure to external stress. The Rho5 GTPase is necessary for oxidant-induced cell death, and cells expressing a constitutively active GTP-locked Rho5 are hypersensitive to oxidants. Yet how Rho5 regulates yeast cell death has been poorly understood. To identify genes that are involved in the Rho5-mediated cell death program, we performed two complementary genome-wide screens: one screen for oxidant-resistant deletion mutants and another screen for Rho5-associated proteins. Functional enrichment and interaction network analysis revealed enrichment for genes in pathways related to metabolism, transport, and plasma membrane organization. In particular, we find that ATG21, which is known to be involved in the CVT (Cytoplasm-to-Vacuole Targeting) pathway and mitophagy, is necessary for cell death induced by oxidants. Cells lacking Atg21 exhibit little cell death upon exposure to oxidants even when the GTP-locked Rho5 is expressed. Moreover, Atg21 interacts with Rho5 preferentially in its GTP-bound state, suggesting that Atg21 is a downstream target of Rho5 in oxidant-induced cell death. Given the high degree of conservation of Rho GTPases and autophagy from yeast to human, this study may provide insight into regulated cell death in eukaryotes in general.

http://bit.ly/2FIFAZJ

Development of a Novel Mule Deer Genomic Assembly and Species-Diagnostic SNP Panel for Assessing Introgression in Mule Deer, White-Tailed Deer, and Their Interspecific Hybrids

Mule deer (Odocoileus hemionus) are endemic to a wide variety of habitats in western North America, many of which are shared in sympatry with their closely related sister-species white-tailed deer (Odocoileus virginianus), whom they hybridize with in wild populations. Although mule deer meet many ideal conditions for a molecular ecological research species, such as high abundance, ecological importance, and broad dispersal and gene flow, conservation genetic studies have been limited by a relative lack of existing genomic resources and inherent difficulties caused by introgression with white-tailed deer. Many molecular tools currently available for the study of cervids were designed using reference assemblies of divergent model species, specifically cattle (Bos taurus). Bovidae and Cervidae diverged approximately 28 million years ago, therefore, we sought to ameliorate the available resources by contributing the first mule deer whole genome sequence draft assembly with an average genome-wide read depth of 25X, using the white-tailed genome assembly (Ovir.te_1.0) as a reference. Comparing the two assemblies, we identified ~33 million single nucleotide polymorphisms (SNPs) and insertion/deletion variants. We then verified fixed SNP differences between the two species and developed a 40-loci SNP assay capable of identifying pure mule deer, white-tailed deer, and interspecific hybrids. Assignment capacity of the panel, which was tested on simulated datasets, is reliable up to and including the third backcross hybrid generation. Identification of post-F1 hybrids will be necessary for hybrid zone population studies going forward, and the new mule deer assembly will be a valuable resource for genetic and comparative genomics studies.

http://bit.ly/2FWQcTU

Transcriptional Basis of Copper-Induced Olfactory Impairment in the Sea Lamprey, a Primitive Invasive Fish

Olfaction mediates behaviours necessary for survival and reproduction in fishes. Anthropogenic inputs of contaminants into aquatic environments, specifically copper, are known to disrupt a broad range of olfactory-mediated behaviours and can cause long-lasting damage even at low concentrations that have profound impacts on the biology of aquatic organisms. The sea lamprey (Petromyzon marinus) is a primitive fish species invasive to the North American Great Lakes that relies on olfaction to navigate during natal homing and in mate choice during reproduction. To investigate effects of copper on sea lamprey olfaction and the potential for maintenance of olfactory function during copper exposure, we exposed juvenile sea lamprey to environmentally ecologically relevant copper concentrations (0, 5, 10 and 30 µg/L) for 24 hours and characterized gene transcription response in olfactory tissue (i.e. peripheral olfactory organ and olfactory bulb) and forebrain using whole transcriptome sequencing. Copper exposure induced a pattern of positive dose-dependent transcriptional response. Expression changes primarily reflected up-regulation of genes involved in apoptosis and wound healing. Unlike higher vertebrates, genes specifically related to the olfactory senses of the sea lamprey, e.g. olfactory receptors, exhibited little transcriptional response to copper exposure, suggesting the mechanism of copper-induced olfactory impairment is through necrosis of the olfactory bulb and not copper-selective inhibition of olfactory receptors. Fully two-thirds of the differentially expressed genes at higher doses of copper have no known function and thus represent important candidates for further study of the responses to copper-induced olfactory injury. Our results shed light on the evolution of vertebrate olfactory repair mechanisms and have important implications for the conservation and management of both invasive and native populations of lamprey.

http://bit.ly/2FIFykz

Aegilops tauschii Genome Sequence: A Framework for Meta-analysis of Wheat QTLs

Numerous quantitative trait loci (QTLs) have been mapped in tetraploid and hexaploid wheat and wheat relatives, mostly with simple sequence repeat (SSR) or single nucleotide polymorphism (SNP) markers. To conduct meta-analysis of QTLs requires projecting them onto a common genomic framework, either a consensus genetic map or genomic sequence. The latter strategy is pursued here. Of 774 QTLs mapped in wheat and wheat relatives found in the literature, 585 (75.6%) were successfully projected onto the Aegilops tauschii pseudomolecules. QTLs mapped with SNP markers were more successfully projected (92.2%) than those mapped with SSR markers (66.2%). The QTLs were not distributed homogeneously along chromosome arms. Their frequencies increased in the proximal-to-distal direction but declined in the most distal regions and were weakly correlated with recombination rates along the chromosome arms. Databases for projected SSR markers and QTLs were constructed and incorporated into the Ae. tauschii JBrowse. To facilitate meta-QTL analysis, eight clusters of QTLs were used to estimate standard deviations (ô) of independently mapped QTLs projected onto the Ae. tauschii genome sequence. The standard deviations ô were modeled as an exponential decay function of recombination rates along the Ae. tauschii chromosomes. We implemented four hypothesis tests for determining the membership of query QTLs. The hypothesis tests and estimation procedure for were implemented in a web portal for meta-analysis of projected QTLs. Twenty-one QTLs for fusarium head blight resistance mapped on wheat chromosomes 3A, 3B, and 3D were analyzed to illustrate the use of the portal for meta-QTL analyses.

http://bit.ly/2FWQ9HI

Desmoid Tumors Respond to Sorafenib [News in Brief]

Phase III trial finds that the TKI nearly doubles progression-free survival.

http://bit.ly/2FEJzGA