Life Sciences | Open Access Articles | Digital Commons Network™

Genetic And Acute Cpeb1 Depletion Ameliorate Fragile X Pathophysiology, Tsuyoshi Udagawa, Natalie Farny, Mira Jakovcevski, Hanoch Kaphzan, Juan Alarcon, Shobha Anilkumar, Maria Ivshina, Jessica Hurt, Kentaro Nagaoka, Vijayalaxmi Nalavadi, Lori Lorenz, Gary Bassell, Schahram Akbarian, Sumantra Chattarji, Eric Klann, Joel Richter

Natalie G. Farny

Fragile X syndrome (FXS), the most common cause of inherited mental retardation and autism, is caused by transcriptional silencing of FMR1, which encodes the translational repressor fragile X mental retardation protein (FMRP). FMRP and cytoplasmic polyadenylation element-binding protein (CPEB), an activator of translation, are present in neuronal dendrites, are predicted to bind many of the same mRNAs and may mediate a translational homeostasis that, when imbalanced, results in FXS. Consistent with this possibility, Fmr1(-/y); Cpeb1(-/-) double-knockout mice displayed amelioration of biochemical, morphological, electrophysiological and behavioral phenotypes associated with FXS. Acute depletion of CPEB1 in the hippocampus of adult Fmr1(-/y) mice …

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Control Of Stem Cell Self-Renewal And Differentiation By The Heterochronic Genes And The Cellular Asymmetry Machinery In Caenorhabditis Elegans, Omid F. Harandi, Victor Ambros

Victor R. Ambros

Transitions between asymmetric (self-renewing) and symmetric (proliferative) cell divisions are robustly regulated in the context of normal development and tissue homeostasis. To genetically assess the regulation of these transitions, we used the postembryonic epithelial stem (seam) cell lineages of Caenorhabditis elegans. In these lineages, the timing of these transitions is regulated by the evolutionarily conserved heterochronic pathway, whereas cell division asymmetry is conferred by a pathway consisting of Wnt (Wingless) pathway components, including posterior pharynx defect (POP-1)/TCF, APC related/adenomatosis polyposis coli (APR-1)/APC, and LIT-1/NLK (loss of intestine/Nemo-like kinase). Here we explore the genetic regulatory mechanisms underlying stage-specific transitions between self-renewing …

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Mir-14 Regulates Autophagy During Developmental Cell Death By Targeting Ip3-Kinase 2, Charles Nelson, Victor Ambros, Eric Baehrecke

Victor R. Ambros

Macroautophagy (autophagy) is a lysosome-dependent degradation process that has been implicated in age-associated diseases. Autophagy is involved in both cell survival and cell death, but little is known about the mechanisms that distinguish its use during these distinct cell fates. Here, we identify the microRNA miR-14 as being both necessary and sufficient for autophagy during developmentally regulated cell death in Drosophila. Loss of miR-14 prevented induction of autophagy during salivary gland cell death, but had no effect on starvation-induced autophagy in the fat body. Moreover, misexpression of miR-14 was sufficient to prematurely induce autophagy in salivary glands, but not in …

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Drug-Resistant Hiv-1 Protease Regains Functional Dynamics Through Cleavage Site Coevolution, Nevra Ozer, Aysegul Ozen, Celia Schiffer, Turkan Haliloglu

Celia A. Schiffer

Drug resistance is caused by mutations that change the balance of recognition favoring substrate cleavage over inhibitor binding. Here, a structural dynamics perspective of the regained wild-type functioning in mutant HIV-1 proteases with coevolution of the natural substrates is provided. The collective dynamics of mutant structures of the protease bound to p1-p6 and NC-p1 substrates are assessed using the Anisotropic Network Model (ANM). The drug-induced protease mutations perturb the mechanistically crucial hinge axes that involve key sites for substrate binding and dimerization and mainly coordinate the intrinsic dynamics. Yet with substrate coevolution, while the wild-type dynamic behavior is restored in …

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Evolution Of The Influenza A Virus Genome During Development Of Oseltamivir Resistance In Vitro, Nicholas Renzette, Daniel Caffrey, Konstantin Zeldovich, Ping Liu, Glen Gallagher, Daniel Aiello, Alyssa Porter, Evelyn Kurt-Jones, Daniel Bolon, Yu-Ping Poh, Jeffrey Jensen, Celia Schiffer, Timothy Kowalik, Robert Finberg, Jennifer Wang

Glen R. Gallagher

Influenza A virus (IAV) is a major cause of morbidity and mortality throughout the world. Current antiviral therapies include oseltamivir, a neuraminidase inhibitor that prevents the release of nascent viral particles from infected cells. However, the IAV genome can evolve rapidly, and oseltamivir resistance mutations have been detected in numerous clinical samples. Using an in vitro evolution platform and whole-genome population sequencing, we investigated the population genomics of IAV during the development of oseltamivir resistance. Strain A/Brisbane/59/2007 (H1N1) was grown in Madin-Darby canine kidney cells with or without escalating concentrations of oseltamivir over serial passages. Following drug treatment, the H274Y …

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Supervillin Binds The Rac/Rho-Gef Trio And Increases Trio-Mediated Rac1 Activation, Kyonghee Son, Tara Smith, Elizabeth Luna

Elizabeth J. Luna

We investigated cross-talk between the membrane-associated, myosin II-regulatory protein supervillin and the actin-regulatory small GTPases Rac1, RhoA, and Cdc42. Supervillin knockdown reduced Rac1-GTP loading, but not the GTP loading of RhoA or Cdc42, in HeLa cells with normal levels of the Rac1-activating protein Trio. No reduction in Rac1-GTP loading was observed when supervillin levels were reduced in Trio-depleted cells. Conversely, overexpression of supervillin isoform 1 (SV1) or, especially, isoform 4 (SV4) increased Rac1 activation. Inhibition of the Trio-mediated Rac1 guanine nucleotide exchange (GEF) activity with ITX3 partially blocked the SV4-mediated increase in Rac1-GTP. Both SV4 and SV1 co-localized with Trio …

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Gamma-Sarcoglycan Is Required For The Response Of Archvillin To Mechanical Stimulation In Skeletal Muscle, Janelle Spinazzola, Tara Smith, Min Liu, Elizabeth Luna, Elisabeth Barton

Elizabeth J. Luna

Loss of gamma-sarcoglycan (gamma-SG) induces muscle degeneration and signaling defects in response to mechanical load, and its absence is common to both Duchenne and limb girdle muscular dystrophies. Growing evidence suggests that aberrant signaling contributes to the disease pathology; however, the mechanisms of gamma-SG-mediated mechanical signaling are poorly understood. To uncover gamma-SG signaling pathway components, we performed yeast two-hybrid screens and identified the muscle-specific protein archvillin as a gamma-SG and dystrophin interacting protein. Archvillin protein and message levels were significantly upregulated at the sarcolemma of murine gamma-SG-null (gsg-/-) muscle but delocalized in dystrophin-deficient mdx muscle. Similar elevation of archvillin protein …

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Differential Muscle Hypertrophy Is Associated With Satellite Cell Numbers And Akt Pathway Activation Following Activin Type Iib Receptor Inhibition In Mtm1 P.R69c Mice, Michael Lawlor, Marissa Viola, Hui Meng, Rachel Edelstein, Fujun Liu, Ke Yan, Elizabeth Luna, Alexandra Lerch-Gaggl, Raymond Hoffmann, Christopher Pierson, Anna Buj-Bello, Jennifer Lachey, Scott Pearsall, Lin Yang, Cecilia Hillard, Alan Beggs

Elizabeth J. Luna

X-linked myotubular myopathy is a congenital myopathy caused by deficiency of myotubularin. Patients often present with severe perinatal weakness, requiring mechanical ventilation to prevent death from respiratory failure. We recently reported that an activin receptor type IIB inhibitor produced hypertrophy of type 2b myofibers and modest increases of strength and life span in the severely myopathic Mtm1δ4 mouse model of X-linked myotubular myopathy. We have now performed a similar study in the less severely symptomatic Mtm1 p.R69C mouse in hopes of finding greater treatment efficacy. Activin receptor type IIB inhibitor treatment of Mtm1 p.R69C animals produced behavioral and histological evidence …

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Effects Of Direct-Fed Microbial Supplementation On Broiler Performance, Intestinal Nutrient Transport And Integrity Under Experimental Conditions With Increased Microbial Challenge, G. R. Murugesan, N. K. Gabler, M. E. Persia

G. R. Murugesan

1. The effects of Aspergillus oryzae- and Bacillus subtilis- based direct-fed microbials (DFM) were investigated on the performance, ileal nutrient transport and intestinal integrity of broiler chickens, raised under experimental conditions, with increased intestinal microbial challenge. 2. The first study was a 3 × 2 factorial experiment, with 3 dietary treatments (control (CON), CON + DFM and CON + antibiotic growth promoter) with and without challenge. Chicks were fed experimental diets from 1 to 28 d, while the challenge was provided by vaccinating with 10 times the normal dose of commercial coccidial vaccine on d 9. In a second experiment, …

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Alcohol-Induced Il-1beta In The Brain Is Mediated By Nlrp3/Asc Inflammasome Activation That Amplifies Neuroinflammation, Dora Lippai, Shashi Bala, Jan Petrasek, Timea Csak, Ivan Levin, Evelyn Kurt-Jones, Gyongyi Szabo

Gyongyi Szabo

Alcohol-induced neuroinflammation is mediated by proinflammatory cytokines, including IL-1beta. IL-1beta production requires caspase-1 activation by inflammasomes-multiprotein complexes that are assembled in response to danger signals. We hypothesized that alcohol-induced inflammasome activation contributes to increased IL-1beta in the brain. WT and TLR4-, NLRP3-, and ASC-deficient (KO) mice received an ethanol-containing or isocaloric control diet for 5 weeks, and some received the rIL-1ra, anakinra, or saline treatment. Inflammasome activation, proinflammatory cytokines, endotoxin, and HMGB1 were measured in the cerebellum. Expression of inflammasome components (NLRP1, NLRP3, ASC) and proinflammatory cytokines (TNF-alpha, MCP-1) was increased in brains of alcohol-fed compared with control mice. Increased …

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Comparative Genomic Analysis Of 60 Mycobacteriophage Genomes: Genome Clustering, Gene Acquisition, And Gene Size, Graham Hatfull, Deborah Jacobs-Sera, Jeffrey Lawrence, Welkin Pope, Daniel Russell, Ching-Chung Ko, Rebecca Weber, Manisha Patel, Katherine Germane, Robert Edgar, Natasha Hoyte, Charles Bowman, Anthony Tantoco, Elizabeth Paladin, Marlana Myers, Alexis Smith, Molly Grace, Thuy Pham, Matthew O'Brien, Amy Vogelsberger, Andrew Hryckowian, Jessica Wynalek, Helen Donis-Keller, Matt Bogel, Craig Peebles, Steven Cresawn, Roger Hendrix

Helen Donis-Keller

Mycobacteriophages are viruses that infect mycobacterial hosts. Expansion of a collection of sequenced phage genomes to a total of 60—all infecting a common bacterial host—provides further insight into their diversity and evolution. Of the 60 phage genomes, 55 can be grouped into nine clusters according to their nucleotide sequence similarities, 5 of which can be further divided into subclusters; 5 genomes do not cluster with other phages. The sequence diversity between genomes within a cluster varies greatly; for example, the 6 genomes in Cluster D share more than 97.5% average nucleotide similarity with one another. In contrast, similarity between the …

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Alternative Temporal Control Systems For Hypodermal Cell Differentiation In Caenorhabditis Elegans, Zhongchi Liu, Victor Ambros

Victor R. Ambros

Beginning of article: In certain multicellular organisms, genetic regulatory systems that specify the timing of cell division, differentiation and morpho-genesis must accommodate environmental and physiological contingencies that perturb or arrest development. For example, Caenorhabditis elegans can either develop continuously through four larval stages (L1–L4) or arrest indefinitely as a 'dauer larva' at the second larval (L2) moult, and later resume L3 and L4 development. At the larva-to-adult (L4) moult of both con-tinuous and 'post-dauer' development, hypodermal cells switch (the 'L/A switch') from a proliferating state to the terminally differentiated state. Four temporal regulators, lin-4, lin-14, lin-28 and lin-29, have been …

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Full-Text Articles in Life Sciences

Natalie G. Farny

Control Of Stem Cell Self-Renewal And Differentiation By The Heterochronic Genes And The Cellular Asymmetry Machinery In Caenorhabditis Elegans, Omid F. Harandi, Victor Ambros

Victor R. Ambros

Mir-14 Regulates Autophagy During Developmental Cell Death By Targeting Ip3-Kinase 2, Charles Nelson, Victor Ambros, Eric Baehrecke

Victor R. Ambros

Drug-Resistant Hiv-1 Protease Regains Functional Dynamics Through Cleavage Site Coevolution, Nevra Ozer, Aysegul Ozen, Celia Schiffer, Turkan Haliloglu

Celia A. Schiffer

Glen R. Gallagher

Supervillin Binds The Rac/Rho-Gef Trio And Increases Trio-Mediated Rac1 Activation, Kyonghee Son, Tara Smith, Elizabeth Luna

Elizabeth J. Luna

Gamma-Sarcoglycan Is Required For The Response Of Archvillin To Mechanical Stimulation In Skeletal Muscle, Janelle Spinazzola, Tara Smith, Min Liu, Elizabeth Luna, Elisabeth Barton

Elizabeth J. Luna

Elizabeth J. Luna

Effects Of Direct-Fed Microbial Supplementation On Broiler Performance, Intestinal Nutrient Transport And Integrity Under Experimental Conditions With Increased Microbial Challenge, G. R. Murugesan, N. K. Gabler, M. E. Persia

G. R. Murugesan

Alcohol-Induced Il-1beta In The Brain Is Mediated By Nlrp3/Asc Inflammasome Activation That Amplifies Neuroinflammation, Dora Lippai, Shashi Bala, Jan Petrasek, Timea Csak, Ivan Levin, Evelyn Kurt-Jones, Gyongyi Szabo

Gyongyi Szabo

Helen Donis-Keller

Alternative Temporal Control Systems For Hypodermal Cell Differentiation In Caenorhabditis Elegans, Zhongchi Liu, Victor Ambros

Victor R. Ambros