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https://www.readbyqxmd.com/read/28548640/efficacy-of-%C3%AE-lactam-%C3%AE-lactamase-inhibitor-combination-is-linked-to-whib4-mediated-changes-in-redox-physiology-of-mycobacterium-tuberculosis
#1
Saurabh Mishra, Prashant Shukla, Ashima Bhaskar, Kushi Anand, Priyanka Baloni, Rajiv Kumar Jha, Abhilash Mohan, Raju S Rajmani, Valakunja Nagaraja, Nagasuma Chandra, Amit Singh
Mycobacterium tuberculosis (Mtb) expresses a broad-spectrum β-lactamase (BlaC) that mediates resistance to one of the highly effective antibacterials, β-lactams. Nonetheless, β-lactams showed mycobactericidal activity in combination with β-lactamase inhibitor, clavulanate (Clav). However, the mechanistic aspects of how Mtb responds to β-lactams such as Amoxicillin in combination with Clav (referred as Augmentin [AG]) are not clear. Here, we identified cytoplasmic redox potential and intracellular redox sensor, WhiB4, as key determinants of mycobacterial resistance against AG...
May 26, 2017: ELife
https://www.readbyqxmd.com/read/28548639/rai1%C3%A2-frees-mice-from-the-repression-of-active-wake-behaviors-by-light
#2
Shanaz Diessler, Corinne Kostic, Yvan Arsenijevic, Aki Kawasaki, Paul Franken
Besides its role in vision, light impacts physiology and behavior through circadian and direct (aka 'masking') mechanisms. In Smith-Magenis Syndrome (SMS), the dysregulation of both sleep-wake behavior and melatonin production strongly suggest impaired non-visual light perception. We discovered that mice haploinsufficient for the SMS causal gene, Retinoic acid induced-1 (Rai1), were hypersensitive to light such that light eliminated alert and active-wake behaviors, while leaving time-spent-awake unaffected...
May 26, 2017: ELife
https://www.readbyqxmd.com/read/28548638/asymmetric-recognition-of-hiv-1-envelope-trimer-by-v1v2-loop-targeting-antibodies
#3
Haoqing Wang, Harry B Gristick, Louise Scharf, Anthony P West, Rachel P Galimidi, Michael S Seaman, Natalia T Freund, Michel C Nussenzweig, Pamela J Bjorkman
The HIV-1 envelope (Env) glycoprotein binds to host cell receptors to mediate membrane fusion. The prefusion Env trimer is stabilized by V1V2 loops that interact at the trimer apex. Broadly neutralizing antibodies (bNAbs) against V1V2 loops, exemplified by PG9, bind asymmetrically as a single Fab to the apex of the symmetric Env trimer using a protruding CDRH3 to penetrate the Env glycan shield. Here we characterized a distinct mode of V1V2 epitope recognition by the new bNAb BG1 in which two Fabs bind asymmetrically per Env trimer using a compact CDRH3...
May 26, 2017: ELife
https://www.readbyqxmd.com/read/28541184/the-step-wise-pathway-of-septin-hetero-octamer-assembly-in-budding-yeast
#4
Andrew D Weems, Michael A McMurray
Septin proteins bind guanine nucleotides and form rod-shaped hetero-oligomers. Cells choose from a variety of available septins to assemble distinct hetero-oligomers, but the underlying mechanism was unknown. Using a new in vivo assay, we find that a stepwise assembly pathway produces the two species of budding yeast septin hetero-octamers: Cdc11/Shs1-Cdc12-Cdc3-Cdc10-Cdc10-Cdc3-Cdc12-Cdc11/Shs1. Rapid GTP hydrolysis by monomeric Cdc10 drives assembly of the core Cdc10 homodimer. The extended Cdc3 N terminus autoinhibits Cdc3 association with Cdc10 homodimers until prior Cdc3-Cdc12 interaction...
May 25, 2017: ELife
https://www.readbyqxmd.com/read/28541183/pausing-guides-rna-folding-to-populate-transiently-stable-rna-structures-for-riboswitch-based-transcription-regulation
#5
Hannah Steinert, Florian Sochor, Anna Wacker, Janina Buck, Christina Helmling, Fabian Hiller, Sara Keyhani, Jonas Noeske, Steffen Kaspar Grimm, Martin M Rudolph, Heiko Keller, Rachel Anne Mooney, Robert Landick, Beatrix Suess, Boris Fürtig, Jens Wöhnert, Harald Schwalbe
In bacteria, the regulation of gene expression by cis-acting transcriptional riboswitches located in the 5'-untranslated regions of messenger RNA requires the temporal synchronization of RNA synthesis and ligand binding-dependent conformational refolding. Ligand binding to the aptamer domain of the riboswitch induces premature termination of the mRNA synthesis of ligand-associated genes due to the coupled formation of 3'-structural elements acting as terminators. To date, there has been no high resolution structural description of the concerted process of synthesis and ligand-induced restructuring of the regulatory RNA element...
May 25, 2017: ELife
https://www.readbyqxmd.com/read/28541182/chemotactic-network-responses-to-live-bacteria-show-independence-of-phagocytosis-from-chemo-receptor-sensing
#6
Netra Pal Meena, Alan R Kimmel
Aspects of innate immunity derive from characteristics inherent to phagocytes, including chemotaxis toward and engulfment of unicellular organisms or cell debris. Ligand chemotaxis has been biochemically investigated using mammalian and model systems, but precision of chemotaxis towards ligands being actively secreted by live bacteria is not well studied, nor has there been systematic analyses of interrelationships between chemotaxis and phagocytosis. The genetic/molecular model Dictyostelium and mammalian phagocytes share mechanistic pathways for chemotaxis and phagocytosis; Dictyostelium chemotax toward bacteria and phagocytose them as food sources...
May 25, 2017: ELife
https://www.readbyqxmd.com/read/28537559/enforcement-of-developmental-lineage-specificity-by-transcription-factor-oct1
#7
Zuolian Shen, Jinsuk Kang, Arvind Shakya, Marcin Tabaka, Elke A Jarboe, Aviv Regev, Dean Tantin
Embryonic stem cells co-express Oct4 and Oct1, a related protein with similar DNA binding specificity. To study the role of Oct1 in ESC pluripotency and transcriptional control, we constructed germline and inducible-conditional Oct1 deficient ESC lines. ESCs lacking Oct1 show normal appearance, self-renewal and growth, but manifest defects upon differentiation. They fail to form beating cardiomyocytes, generate neurons poorly, form small, poorly differentiated teratomas, and cannot generate chimeric mice. Upon RA-mediated differentiation, Oct1 deficient cells induce lineage-appropriate developmentally poised genes poorly while lineage-inappropriate genes, including extra-embryonic genes, are inappropriately expressed...
May 24, 2017: ELife
https://www.readbyqxmd.com/read/28537558/rapid-short-term-reorganization-in-the-language-network
#8
Gesa Hartwigsen, Danilo Bzdok, Maren Klein, Max Wawrzyniak, Anika Stockert, Katrin Wrede, Joseph Classen, Dorothee Saur
The adaptive potential of the language network to compensate for lesions remains elusive. We show that perturbation of a semantic region in the healthy brain induced suppression of activity in a large semantic network and upregulation of neighbouring phonological areas. After perturbation, the disrupted area increased its inhibitory influence on another semantic key node. The inhibitory influence predicted the individual delay in response speed, indicating that inhibition at remote nodes is functionally relevant...
May 24, 2017: ELife
https://www.readbyqxmd.com/read/28537557/apol1-renal-risk-variants-have-contrasting-resistance-and-susceptibility-associations-with-african-trypanosomiasis-renal-risk-variants-have-contrasting-resistance-and-susceptibility-associations-with-african-trypanosomiasis
#9
Anneli Cooper, Hamidou Ilboudo, V Pius Alibu, Sophie Ravel, John Enyaru, William Weir, Harry Noyes, Paul Capewell, Mamadou Camara, Jacqueline Milet, Vincent Jamonneau, Oumou Camara, Enock Matovu, Bruno Bucheton, Annette MacLeod
Reduced susceptibility to infectious disease can increase the frequency of otherwise deleterious alleles. In populations of African ancestry, two apolipoprotein-L1 (APOL1) variants with a recessive kidney disease risk, named G1 and G2, occur at high frequency. APOL1 is a trypanolytic protein that confers innate resistance to most African trypanosomes, but not Trypanosoma brucei rhodesiense or T.b. gambiense, which cause human African trypanosomiasis. In this case-control study we test the prevailing hypothesis that these APOL1 variants reduce trypanosomiasis susceptibility, resulting in their positive selection in sub-Saharan Africa...
May 24, 2017: ELife
https://www.readbyqxmd.com/read/28537556/the-dynamic-three-dimensional-organization-of-the-diploid-yeast-genome
#10
Seungsoo Kim, Ivan Liachko, Donna G Brickner, Kate Cook, William S Noble, Jason H Brickner, Jay Shendure, Maitreya J Dunham
The budding yeast Saccharomyces cerevisiae is a long-standing model for the three-dimensional organization of eukaryotic genomes. However, even in this well-studied model, it is unclear how homolog pairing in diploids or environmental conditions influence overall genome organization. Here, we performed high-throughput chromosome conformation capture on diverged Saccharomyces hybrid diploids to obtain the first global view of chromosome conformation in diploid yeasts. After controlling for the Rabl-like orientation using a polymer model, we observe significant homolog proximity that increases in saturated culture conditions...
May 24, 2017: ELife
https://www.readbyqxmd.com/read/28537555/identification-of-a-novel-spinal-nociceptive-motor-gate-control-for-a%C3%AE-pain-stimuli-in-rats
#11
Dvir Blivis, Gal Haspel, Philip Z Mannes, Michael James O'Donovan, Michael J Iadarola
Physiological responses to nociceptive stimuli are initiated within tens of milliseconds, but the corresponding sub-second behavioral responses have not been adequately explored in awake, unrestrained animals. A detailed understanding of these responses is crucial for progress in pain neurobiology. Here, high-speed videography during nociceptive Aδ fiber stimulation demonstrated engagement of a multi-segmental motor program coincident with, or even preceding, withdrawal of the stimulated paw. The motor program included early head orientation and adjustments of the torso and un-stimulated paws...
May 24, 2017: ELife
https://www.readbyqxmd.com/read/28537554/pioneer-neurog1-expressing-cells-ingress-into-the-otic-epithelium-and-instruct-neuronal-specification
#12
Esteban Hoijman, Laura Fargas, Patrick Blader, Berta Alsina
Neural patterning involves regionalised cell specification. Recent studies indicate that cell dynamics play instrumental roles in neural pattern refinement and progression, but the impact of cell behaviour and morphogenesis on neural specification is not understood. Here we combine 4D analysis of cell behaviours with dynamic quantification of proneural expression to uncover the construction of the zebrafish otic neurogenic domain. We identify pioneer cells expressing neurog1 outside the otic primordium that migrate and ingress into the epithelialising placode to become the first otic neuronal progenitors...
May 24, 2017: ELife
https://www.readbyqxmd.com/read/28537553/longitudinal-imaging-of-caenorhabditis-elegans-in-a-microfabricated-device-reveals-variation-in-behavioral-decline-during-aging
#13
Matthew A Churgin, Sang-Kyu Jung, Chih-Chieh Yu, Xiangmei Chen, David M Raizen, Christopher Fang-Yen
The roundworm C. elegans is a mainstay of aging research due to its short lifespan and easily manipulable genetics. Current, widely used methods for long-term measurement of C. elegans are limited by low throughput and the difficulty of performing longitudinal monitoring of aging phenotypes. Here we describe the WorMotel, a microfabricated device for long-term cultivation and automated longitudinal imaging of large numbers of C. elegans confined to individual wells. Using the WorMotel, we find that short-lived and long-lived strains exhibit patterns of behavioral decline that do not temporally scale between individuals or populations, but rather resemble the shortest and longest lived individuals in a wild type population...
May 24, 2017: ELife
https://www.readbyqxmd.com/read/28537552/structure-analyses-reveal-a-regulated-oligomerization-mechanism-of-the-plexind1-gipc-myosin-vi-complex
#14
Guijun Shang, Chad A Brautigam, Rui Chen, Defen Lu, Jesús Torres-Vázquez, Xuewu Zhang
The GIPC family adaptor proteins mediate endocytosis by tethering cargo proteins to the myosin VI motor. The structural mechanisms for the GIPC/cargo and GIPC/myosin VI interactions remained unclear. PlexinD1, a transmembrane receptor that regulates neuronal and cardiovascular development, is a cargo of GIPCs. GIPC-mediated endocytic trafficking regulates PlexinD1 signaling. Here we unravel the mechanisms of the interactions among PlexinD1, GIPCs and myosin VI by a series of crystal structures of these proteins in apo or bound states...
May 24, 2017: ELife
https://www.readbyqxmd.com/read/28537551/rna-dependent-chromatin-association-of-transcription-elongation-factors-and-pol-ii-ctd-kinases
#15
Sofia Battaglia, Michael Lidschreiber, Carlo Baejen, Phillipp Torkler, Seychelle M Vos, Patrick Cramer
For transcription through chromatin, RNA polymerase (Pol) II associates with elongation factors (EFs). Here we show that many EFs crosslink to RNA emerging from transcribing Pol II in the yeast Saccharomyces cerevisiae. Most EFs crosslink preferentially to mRNAs, rather than unstable non-coding RNAs. RNA contributes to chromatin association of many EFs, including the Pol II serine 2 kinases Ctk1 and Bur1 and the histone H3 methyltransferases Set1 and Set2. The Ctk1 kinase complex binds RNA in vitro, consistent with direct EF-RNA interaction...
May 24, 2017: ELife
https://www.readbyqxmd.com/read/28534737/integration-of-tmc1-2-into-the-mechanotransduction-complex-in-zebrafish-hair-cells-is-regulated-by-transmembrane-o-methyltransferase-tomt
#16
Timothy Erickson, Clive P Morgan, Jennifer Olt, Katherine Hardy, Elisabeth M Busch-Nentwich, Reo Maeda, Rachel Clemens-Grisham, Jocelyn F Krey, Alex V Nechiporuk, Peter G Barr-Gillespie, Walter Marcotti, Teresa Nicolson
Transmembrane O-methyltransferase (TOMT / LRTOMT) is responsible for non-syndromic deafness DFNB63. However, the specific defects that lead to hearing loss have not been described. Using a zebrafish model of DFNB63, we show that the auditory and vestibular phenotypes are due to a lack of mechanotransduction (MET) in Tomt-deficient hair cells. GFP-tagged Tomt is enriched in the Golgi of hair cells, suggesting that Tomt might regulate the trafficking of other MET components to the hair bundle. We found that Tmc1/2 proteins are specifically excluded from the hair bundle in tomt mutants, whereas other MET complex proteins can still localize to the bundle...
May 23, 2017: ELife
https://www.readbyqxmd.com/read/28530549/a-genetic-basis-for-molecular-asymmetry-at-vertebrate-electrical-synapses
#17
Adam C Miller, Alex C Whitebirch, Arish N Shah, Kurt C Marsden, Michael Granato, John O'Brien, Cecilia B Moens
Neural network function is based upon the patterns and types of connections made between neurons. Neuronal synapses are adhesions specialized for communication and they come in two types, chemical and electrical. Communication at chemical synapses occurs via neurotransmitter release whereas electrical synapses utilize gap junctions for direct ionic and metabolic coupling. Electrical synapses are often viewed as symmetrical structures, with the same components making both sides of the gap junction. By contrast, we show that a broad set of electrical synapses in zebrafish, Danio rerio, require two gap-junction-forming Connexins for formation and function...
May 22, 2017: ELife
https://www.readbyqxmd.com/read/28527239/the-structure-of-a-lair1-containing-human-antibody-reveals-a-novel-mechanism-of-antigen-recognition
#18
Fu-Lien Hsieh, Matthew K Higgins
Antibodies are critical components of the human adaptive immune system, providing versatile scaffolds to display diverse antigen binding surfaces. Nevertheless, most antibodies have similar architectures, with the variable immunoglobulin domains of the heavy and light chain each providing three hypervariable loops, which are varied to generate diversity. The recent identification of a novel class of antibody in humans from malaria endemic regions of Africa was therefore surprising as one hypervariable loop contains the entire collagen-binding domain of human LAIR1...
May 20, 2017: ELife
https://www.readbyqxmd.com/read/28527238/a-widespread-family-of-serine-threonine-protein-phosphatases-shares-a-common-regulatory-switch-with-proteasomal-proteases
#19
Niels Bradshaw, Vladimir M Levdikov, Christina M Zimanyi, Rachelle Gaudet, Anthony J Wilkinson, Richard Losick
PP2C phosphatases control biological processes including stress responses, development, and cell division in all kingdoms of life. Diverse regulatory domains adapt PP2C phosphatases to specific functions, but how these domains control phosphatase activity was unknown. We present structures representing active and inactive states of the PP2C phosphatase SpoIIE from Bacillus subtilis. Based on structural analyses and genetic and biochemical experiments, we identify an α-helical switch that shifts a carbonyl oxygen into the active site to coordinate a metal cofactor...
May 20, 2017: ELife
https://www.readbyqxmd.com/read/28527237/the-n-terminus-of-the-prion-protein-is-a-toxic-effector-regulated-by-the-c-terminus
#20
Bei Wu, Alex J McDonald, Kathleen Markham, Celeste B Rich, Kyle P Mchugh, Jörg Tatzelt, David W Colby, Glenn L Millhauser, David A Harris
PrP(C), the cellular isoform of the prion protein, serves to transduce the neurotoxic effects of PrP(Sc), the infectious isoform, but how this occurs is mysterious. Here, using a combination of electrophysiological, cellular, and biophysical techniques, we show that the flexible, N-terminal domain of PrP(C) functions as a powerful toxicity-transducing effector whose activity is tightly regulated in cis by the globular C-terminal domain. Ligands binding to the N-terminal domain abolish the spontaneous ionic currents associated with neurotoxic mutants of PrP, and the isolated N-terminal domain induces currents when expressed in the absence of the C-terminal domain...
May 20, 2017: ELife
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