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https://www.readbyqxmd.com/read/28262353/remnants-of-an-ancient-metabolism-without-phosphate
#1
Joshua E Goldford, Hyman Hartman, Temple F Smith, Daniel Segrè
Phosphate is essential for all living systems, serving as a building block of genetic and metabolic machinery. However, it is unclear how phosphate could have assumed these central roles on primordial Earth, given its poor geochemical accessibility. We used systems biology approaches to explore the alternative hypothesis that a protometabolism could have emerged prior to the incorporation of phosphate. Surprisingly, we identified a cryptic phosphate-independent core metabolism producible from simple prebiotic compounds...
March 2, 2017: Cell
https://www.readbyqxmd.com/read/28238471/structural-basis-of-substrate-recognition-by-the-multidrug-resistance-protein-mrp1
#2
Zachary Lee Johnson, Jue Chen
The multidrug resistance protein MRP1 is an ATP-binding cassette (ABC) transporter that confers resistance to many anticancer drugs and plays a role in the disposition and efficacy of several opiates, antidepressants, statins, and antibiotics. In addition, MRP1 regulates redox homeostasis, inflammation, and hormone secretion. Using electron cryomicroscopy, we determined the molecular structures of bovine MRP1 in two conformations: an apo form at 3.5 Å without any added substrate and a complex form at 3.3 Å with one of its physiological substrates, leukotriene C4...
February 22, 2017: Cell
https://www.readbyqxmd.com/read/28431254/hypothalamic-agrp-neurons-drive-stereotypic-behaviors-beyond-feeding
#3
Marcelo O Dietrich, Marcelo R Zimmer, Jeremy Bober, Tamas L Horvath
No abstract text is available yet for this article.
April 20, 2017: Cell
https://www.readbyqxmd.com/read/28431253/crispr-based-technologies-for-the-manipulation-of-eukaryotic-genomes
#4
Alexis C Komor, Ahmed H Badran, David R Liu
No abstract text is available yet for this article.
April 20, 2017: Cell
https://www.readbyqxmd.com/read/28431252/engineered-regulatory-systems-modulate-gene-expression-of-human-commensals-in-the-gut
#5
Bentley Lim, Michael Zimmermann, Natasha A Barry, Andrew L Goodman
The gut microbiota is implicated in numerous aspects of health and disease, but dissecting these connections is challenging because genetic tools for gut anaerobes are limited. Inducible promoters are particularly valuable tools because these platforms allow real-time analysis of the contribution of microbiome gene products to community assembly, host physiology, and disease. We developed a panel of tunable expression platforms for the prominent genus Bacteroides in which gene expression is controlled by a synthetic inducer...
April 20, 2017: Cell
https://www.readbyqxmd.com/read/28431251/tunable-expression-tools-enable-single-cell-strain-distinction-in-the-gut-microbiome
#6
Weston R Whitaker, Elizabeth Stanley Shepherd, Justin L Sonnenburg
Applying synthetic biology to engineer gut-resident microbes provides new avenues to investigate microbe-host interactions, perform diagnostics, and deliver therapeutics. Here, we describe a platform for engineering Bacteroides, the most abundant genus in the Western microbiota, which includes a process for high-throughput strain modification. We have identified a novel phage promoter and translational tuning strategy and achieved an unprecedented level of expression that enables imaging of fluorescent-protein-expressing Bacteroides stably colonizing the mouse gut...
April 20, 2017: Cell
https://www.readbyqxmd.com/read/28431250/nuclear-proximity-of-mtr4-to-rna-exosome-restricts-dna-mutational-asymmetry
#7
Junghyun Lim, Pankaj Kumar Giri, David Kazadi, Brice Laffleur, Wanwei Zhang, Veronika Grinstein, Evangelos Pefanis, Lewis M Brown, Erik Ladewig, Ophélie Martin, Yuling Chen, Raul Rabadan, François Boyer, Gerson Rothschild, Michel Cogné, Eric Pinaud, Haiteng Deng, Uttiya Basu
The distribution of sense and antisense strand DNA mutations on transcribed duplex DNA contributes to the development of immune and neural systems along with the progression of cancer. Because developmentally matured B cells undergo biologically programmed strand-specific DNA mutagenesis at focal DNA/RNA hybrid structures, they make a convenient system to investigate strand-specific mutagenesis mechanisms. We demonstrate that the sense and antisense strand DNA mutagenesis at the immunoglobulin heavy chain locus and some other regions of the B cell genome depends upon localized RNA processing protein complex formation in the nucleus...
April 20, 2017: Cell
https://www.readbyqxmd.com/read/28431249/macrophages-facilitate-electrical-conduction-in-the-heart
#8
Maarten Hulsmans, Sebastian Clauss, Ling Xiao, Aaron D Aguirre, Kevin R King, Alan Hanley, William J Hucker, Eike M Wülfers, Gunnar Seemann, Gabriel Courties, Yoshiko Iwamoto, Yuan Sun, Andrej J Savol, Hendrik B Sager, Kory J Lavine, Gregory A Fishbein, Diane E Capen, Nicolas Da Silva, Lucile Miquerol, Hiroko Wakimoto, Christine E Seidman, Jonathan G Seidman, Ruslan I Sadreyev, Kamila Naxerova, Richard N Mitchell, Dennis Brown, Peter Libby, Ralph Weissleder, Filip K Swirski, Peter Kohl, Claudio Vinegoni, David J Milan, Patrick T Ellinor, Matthias Nahrendorf
Organ-specific functions of tissue-resident macrophages in the steady-state heart are unknown. Here, we show that cardiac macrophages facilitate electrical conduction through the distal atrioventricular node, where conducting cells densely intersperse with elongated macrophages expressing connexin 43. When coupled to spontaneously beating cardiomyocytes via connexin-43-containing gap junctions, cardiac macrophages have a negative resting membrane potential and depolarize in synchrony with cardiomyocytes. Conversely, macrophages render the resting membrane potential of cardiomyocytes more positive and, according to computational modeling, accelerate their repolarization...
April 20, 2017: Cell
https://www.readbyqxmd.com/read/28431248/spontaneous-chitin-accumulation-in-airways-and-age-related-fibrotic-lung-disease
#9
Steven J Van Dyken, Hong-Erh Liang, Ram P Naikawadi, Prescott G Woodruff, Paul J Wolters, David J Erle, Richard M Locksley
The environmentally widespread polysaccharide chitin is degraded and recycled by ubiquitous bacterial and fungal chitinases. Although vertebrates express active chitinases from evolutionarily conserved loci, their role in mammalian physiology is unclear. We show that distinct lung epithelial cells secrete acidic mammalian chitinase (AMCase), which is required for airway chitinase activity. AMCase-deficient mice exhibit premature morbidity and mortality, concomitant with accumulation of environmentally derived chitin polymers in the airways and expression of pro-fibrotic cytokines...
April 20, 2017: Cell
https://www.readbyqxmd.com/read/28431247/the-ubiquitin-ligase-chip-integrates-proteostasis-and-aging-by-regulation-of-insulin-receptor-turnover
#10
Riga Tawo, Wojciech Pokrzywa, Éva Kevei, Melek E Akyuz, Vishnu Balaji, Svenja Adrian, Jörg Höhfeld, Thorsten Hoppe
Aging is attended by a progressive decline in protein homeostasis (proteostasis), aggravating the risk for protein aggregation diseases. To understand the coordination between proteome imbalance and longevity, we addressed the mechanistic role of the quality-control ubiquitin ligase CHIP, which is a key regulator of proteostasis. We observed that CHIP deficiency leads to increased levels of the insulin receptor (INSR) and reduced lifespan of worms and flies. The membrane-bound INSR regulates the insulin and IGF1 signaling (IIS) pathway and thereby defines metabolism and aging...
April 20, 2017: Cell
https://www.readbyqxmd.com/read/28431246/fatty-acids-regulate-germline-sex-determination-through-acs-4-dependent-myristoylation
#11
Hongyun Tang, Min Han
Fat metabolism has been linked to fertility and reproductive adaptation in animals and humans, and environmental sex determination potentially plays a role in the process. To investigate the impact of fatty acids (FA) on sex determination and reproductive development, we examined and observed an impact of FA synthesis and mobilization by lipolysis in somatic tissues on oocyte fate in Caenorhabditis elegans. The subsequent genetic analysis identified ACS-4, an acyl-CoA synthetase and its FA-CoA product, as key germline factors that mediate the role of FA in promoting oocyte fate through protein myristoylation...
April 20, 2017: Cell
https://www.readbyqxmd.com/read/28431245/host-microbe-co-metabolism-dictates-cancer-drug-efficacy-in-c-%C3%A2-elegans
#12
Timothy A Scott, Leonor M Quintaneiro, Povilas Norvaisas, Prudence P Lui, Matthew P Wilson, Kit-Yi Leung, Lucia Herrera-Dominguez, Sonia Sudiwala, Alberto Pessia, Peter T Clayton, Kevin Bryson, Vidya Velagapudi, Philippa B Mills, Athanasios Typas, Nicholas D E Greene, Filipe Cabreiro
Fluoropyrimidines are the first-line treatment for colorectal cancer, but their efficacy is highly variable between patients. We queried whether gut microbes, a known source of inter-individual variability, impacted drug efficacy. Combining two tractable genetic models, the bacterium E. coli and the nematode C. elegans, we performed three-way high-throughput screens that unraveled the complexity underlying host-microbe-drug interactions. We report that microbes can bolster or suppress the effects of fluoropyrimidines through metabolic drug interconversion involving bacterial vitamin B6, B9, and ribonucleotide metabolism...
April 20, 2017: Cell
https://www.readbyqxmd.com/read/28431244/bacterial-metabolism-affects-the-c-%C3%A2-elegans-response-to-cancer-chemotherapeutics
#13
Aurian P García-González, Ashlyn D Ritter, Shaleen Shrestha, Erik C Andersen, L Safak Yilmaz, Albertha J M Walhout
The human microbiota greatly affects physiology and disease; however, the contribution of bacteria to the response to chemotherapeutic drugs remains poorly understood. Caenorhabditis elegans and its bacterial diet provide a powerful system to study host-bacteria interactions. Here, we use this system to study how bacteria affect the C. elegans response to chemotherapeutics. We find that different bacterial species can increase the response to one drug yet decrease the effect of another. We perform genetic screens in two bacterial species using three chemotherapeutic drugs: 5-fluorouracil (5-FU), 5-fluoro-2'-deoxyuridine (FUDR), and camptothecin (CPT)...
April 20, 2017: Cell
https://www.readbyqxmd.com/read/28431243/cryo-em-structure-of-the-open-human-ether-%C3%A3-go-go-related-k-channel-herg
#14
Weiwei Wang, Roderick MacKinnon
The human ether-à-go-go-related potassium channel (hERG, Kv11.1) is a voltage-dependent channel known for its role in repolarizing the cardiac action potential. hERG alteration by mutation or pharmacological inhibition produces Long QT syndrome and the lethal cardiac arrhythmia torsade de pointes. We have determined the molecular structure of hERG to 3.8 Å using cryo-electron microscopy. In this structure, the voltage sensors adopt a depolarized conformation, and the pore is open. The central cavity has an atypically small central volume surrounded by four deep hydrophobic pockets, which may explain hERG's unusual sensitivity to many drugs...
April 20, 2017: Cell
https://www.readbyqxmd.com/read/28431242/structural-and-functional-analysis-of-a-%C3%AE-2-adrenergic-receptor-complex-with-grk5
#15
Konstantin E Komolov, Yang Du, Nguyen Minh Duc, Robin M Betz, João P G L M Rodrigues, Ryan D Leib, Dhabaleswar Patra, Georgios Skiniotis, Christopher M Adams, Ron O Dror, Ka Young Chung, Brian K Kobilka, Jeffrey L Benovic
The phosphorylation of agonist-occupied G-protein-coupled receptors (GPCRs) by GPCR kinases (GRKs) functions to turn off G-protein signaling and turn on arrestin-mediated signaling. While a structural understanding of GPCR/G-protein and GPCR/arrestin complexes has emerged in recent years, the molecular architecture of a GPCR/GRK complex remains poorly defined. We used a comprehensive integrated approach of cross-linking, hydrogen-deuterium exchange mass spectrometry (MS), electron microscopy, mutagenesis, molecular dynamics simulations, and computational docking to analyze GRK5 interaction with the β2-adrenergic receptor (β2AR)...
April 20, 2017: Cell
https://www.readbyqxmd.com/read/28431241/akt-pkb-signaling-navigating-the-network
#16
REVIEW
Brendan D Manning, Alex Toker
The Ser and Thr kinase AKT, also known as protein kinase B (PKB), was discovered 25 years ago and has been the focus of tens of thousands of studies in diverse fields of biology and medicine. There have been many advances in our knowledge of the upstream regulatory inputs into AKT, key multifunctional downstream signaling nodes (GSK3, FoxO, mTORC1), which greatly expand the functional repertoire of AKT, and the complex circuitry of this dynamically branching and looping signaling network that is ubiquitous to nearly every cell in our body...
April 20, 2017: Cell
https://www.readbyqxmd.com/read/28431240/building-a-translational-microbiome-toolbox
#17
Payal Joglekar, Julia A Segre
Designing successful microbiota-based therapies requires in-depth understanding of the ecological foundations of this community. In this issue, two studies by Whitaker et al. and Lim et al. provide refined genetic tools for dissecting the spatial organization and temporal dynamics of bacterial communities at the single-cell and -gene levels.
April 20, 2017: Cell
https://www.readbyqxmd.com/read/28431239/resident-macrophages-near-and-dear-to-your-heart
#18
Nikhil V Munshi
In this issue of Cell, Hulsmans et al. identify a subset of macrophages residing within the cardiac conduction system, which orchestrates cardiac rhythm. Macrophages directly couple with cardiomyocytes, and their perturbation alters cardiac conduction, suggesting that pharmacological manipulation of resident macrophages might represent a new strategy to combat cardiac arrhythmias.
April 20, 2017: Cell
https://www.readbyqxmd.com/read/28431238/reducing-recurrence-of-c-difficile-infection
#19
Michael G Dieterle, Vincent B Young
Clostridium difficile infection (CDI) is facilitated by alteration of the microbiome following antibiotic administration. Antimicrobial therapy directed against the pathogen can treat CDI. Unfortunately, ∼20% of successfully treated patients will suffer recurrence. Bezlotoxumab, a human monoclonal antibody, binds to C. difficile toxin B (TcdB), reducing recurrence presumably by limiting epithelial damage and facilitating microbiome recovery.
April 20, 2017: Cell
https://www.readbyqxmd.com/read/28431237/bringing-culture-to-bacteria
#20
Mirna Kvajo
No abstract text is available yet for this article.
April 20, 2017: Cell
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