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51.
Kristen E. Rennoll-Bankert M. Sayeedur Rahman Joseph J. Gillespie Mark L. Guillotte Simran J. Kaur Stephanie S. Lehman Magda Beier-Sexton Abdu F. Azad 《PLoS pathogens》2015,11(8)
Bacterial Sec7-domain-containing proteins (RalF) are known only from species of Legionella and Rickettsia, which have facultative and obligate intracellular lifestyles, respectively. L. pneumophila RalF, a type IV secretion system (T4SS) effector, is a guanine nucleotide exchange factor (GEF) of ADP-ribosylation factors (Arfs), activating and recruiting host Arf1 to the Legionella-containing vacuole. In contrast, previous in vitro studies showed R. prowazekii (Typhus Group) RalF is a functional Arf-GEF that localizes to the host plasma membrane and interacts with the actin cytoskeleton via a unique C-terminal domain. As RalF is differentially encoded across Rickettsia species (e.g., pseudogenized in all Spotted Fever Group species), it may function in lineage-specific biology and pathogenicity. Herein, we demonstrate RalF of R. typhi (Typhus Group) interacts with the Rickettsia T4SS coupling protein (RvhD4) via its proximal C-terminal sequence. RalF is expressed early during infection, with its inactivation via antibody blocking significantly reducing R. typhi host cell invasion. For R. typhi and R. felis (Transitional Group), RalF ectopic expression revealed subcellular localization with the host plasma membrane and actin cytoskeleton. Remarkably, R. bellii (Ancestral Group) RalF showed perinuclear localization reminiscent of ectopically expressed Legionella RalF, for which it shares several structural features. For R. typhi, RalF co-localization with Arf6 and PI(4,5)P2 at entry foci on the host plasma membrane was determined to be critical for invasion. Thus, we propose recruitment of PI(4,5)P2 at entry foci, mediated by RalF activation of Arf6, initiates actin remodeling and ultimately facilitates bacterial invasion. Collectively, our characterization of RalF as an invasin suggests that, despite carrying a similar Arf-GEF unknown from other bacteria, different intracellular lifestyles across Rickettsia and Legionella species have driven divergent roles for RalF during infection. Furthermore, our identification of lineage-specific Arf-GEF utilization across some rickettsial species illustrates different pathogenicity factors that define diverse agents of rickettsial diseases. 相似文献
52.
Deidre A. Winnier Marcel Fourcaudot Luke Norton Muhammad A. Abdul-Ghani Shirley L. Hu Vidya S. Farook Dawn K. Coletta Satish Kumar Sobha Puppala Geetha Chittoor Thomas D. Dyer Rector Arya Melanie Carless Donna M. Lehman Joanne E. Curran Douglas T. Cromack Devjit Tripathy John Blangero Ravindranath Duggirala Harald H. H. G?ring Ralph A. DeFronzo Christopher P. Jenkinson 《PloS one》2015,10(4)
Type 2 diabetes (T2D) is a complex metabolic disease that is more prevalent in ethnic groups such as Mexican Americans, and is strongly associated with the risk factors obesity and insulin resistance. The goal of this study was to perform whole genome gene expression profiling in adipose tissue to detect common patterns of gene regulation associated with obesity and insulin resistance. We used phenotypic and genotypic data from 308 Mexican American participants from the Veterans Administration Genetic Epidemiology Study (VAGES). Basal fasting RNA was extracted from adipose tissue biopsies from a subset of 75 unrelated individuals, and gene expression data generated on the Illumina BeadArray platform. The number of gene probes with significant expression above baseline was approximately 31,000. We performed multiple regression analysis of all probes with 15 metabolic traits. Adipose tissue had 3,012 genes significantly associated with the traits of interest (false discovery rate, FDR ≤ 0.05). The significance of gene expression changes was used to select 52 genes with significant (FDR ≤ 10-4) gene expression changes across multiple traits. Gene sets/Pathways analysis identified one gene, alcohol dehydrogenase 1B (ADH1B) that was significantly enriched (P < 10-60) as a prime candidate for involvement in multiple relevant metabolic pathways. Illumina BeadChip derived ADH1B expression data was consistent with quantitative real time PCR data. We observed significant inverse correlations with waist circumference (2.8 x 10-9), BMI (5.4 x 10-6), and fasting plasma insulin (P < 0.001). These findings are consistent with a central role for ADH1B in obesity and insulin resistance and provide evidence for a novel genetic regulatory mechanism for human metabolic diseases related to these traits. 相似文献
53.
Clara?D. van?Karnebeek William?S. Sly Colin?J. Ross Ramona Salvarinova Joy Yaplito-Lee Saikat Santra Casper Shyr Gabriella?A. Horvath Patrice Eydoux Anna?M. Lehman Virginie Bernard Theresa Newlove Henry Ukpeh Anupam Chakrapani Mary?Anne Preece Sarah Ball James Pitt Hilary?D. Vallance Marion Coulter-Mackie Hien Nguyen Lin-Hua Zhang Amit?P. Bhavsar Graham Sinclair Abdul Waheed Wyeth?W. Wasserman Sylvia Stockler-Ipsiroglu 《American journal of human genetics》2014,94(3):453-461
Four children in three unrelated families (one consanguineous) presented with lethargy, hyperlactatemia, and hyperammonemia of unexplained origin during the neonatal period and early childhood. We identified and validated three different CA5A alterations, including a homozygous missense mutation (c.697T>C) in two siblings, a homozygous splice site mutation (c.555G>A) leading to skipping of exon 4, and a homozygous 4 kb deletion of exon 6. The deleterious nature of the homozygous mutation c.697T>C (p.Ser233Pro) was demonstrated by reduced enzymatic activity and increased temperature sensitivity. Carbonic anhydrase VA (CA-VA) was absent in liver in the child with the homozygous exon 6 deletion. The metabolite profiles in the affected individuals fit CA-VA deficiency, showing evidence of impaired provision of bicarbonate to the four enzymes that participate in key pathways in intermediary metabolism: carbamoylphosphate synthetase 1 (urea cycle), pyruvate carboxylase (anaplerosis, gluconeogenesis), propionyl-CoA carboxylase, and 3-methylcrotonyl-CoA carboxylase (branched chain amino acids catabolism). In the three children who were administered carglumic acid, hyperammonemia resolved. CA-VA deficiency should therefore be added to urea cycle defects, organic acidurias, and pyruvate carboxylase deficiency as a treatable condition in the differential diagnosis of hyperammonemia in the neonate and young child. 相似文献
54.
Shixin Yang Lucian Barbu-Tudoran Marek Orzechowski Roger Craig John Trinick Howard White William Lehman 《Biophysical journal》2014,106(4):855-864
Muscle contraction is regulated by troponin-tropomyosin, which blocks and unblocks myosin binding sites on actin. To elucidate this regulatory mechanism, the three-dimensional organization of troponin and tropomyosin on the thin filament must be determined. Although tropomyosin is well defined in electron microscopy helical reconstructions of thin filaments, troponin density is mostly lost. Here, we determined troponin organization on native relaxed cardiac muscle thin filaments by applying single particle reconstruction procedures to negatively stained specimens. Multiple reference models led to the same final structure, indicating absence of model bias in the procedure. The new reconstructions clearly showed F-actin, tropomyosin, and troponin densities. At the 25 Å resolution achieved, troponin was considerably better defined than in previous reconstructions. The troponin density closely resembled the shape of troponin crystallographic structures, facilitating detailed interpretation of the electron microscopy density map. The orientation of troponin-T and the troponin core domain established troponin polarity. Density attributable to the troponin-I mobile regulatory domain was positioned where it could hold tropomyosin in its blocking position on actin, thus suggesting the underlying structural basis of thin filament regulation. Our previous understanding of thin filament regulation had been limited to known movements of tropomyosin that sterically block and unblock myosin binding sites on actin. We now show how troponin, the Ca2+ sensor, may control these movements, ultimately determining whether muscle contracts or relaxes. 相似文献
55.
R. Michael Lehman Shannon L. Osborne Deirdre A. Prischmann-Voldseth Kurt A. Rosentrater 《Plant and Soil》2010,333(1-2):481-490
The relative decomposability of corn (Zea mays L.) residues from insect (Bt)-protected hybrids and conventional hybrids cultivated under insect pressure was investigated in two studies. Above-ground biomass, residue macromolecular composition, and stalk physical strength were also measured. In the first decomposition study, chopped residues (stalks and leaves) were used from a corn rootworm-protected (Cry3Bb1) hybrid and its non-Bt near isoline that were grown in replicated plots infested with corn rootworms (Diabrotica spp.). In the second study, residue (intact stalk sections) was used from three European corn borer (ECB, Ostrinia nubilalis Hübner)-resistant (Cry1Ab) hybrids representing different seed manufacturer/maturity date series, their non-Bt near isolines, two Cry3Bb1-protected isolines, and three additional conventional hybrids, all cultivated in replicated plots under conditions of elevated ECB pressure. In both studies, insect-resistant residues decomposed at rates similar to their non-protected near isolines. No evidence was found that insect-protected hybrids produced more above-ground biomass or had distinct residue composition. While some measures of mechanical stalk strength indicated that ECB-damaged stalks were not as stiff as protected stalks, these physical differences did not translate into differences in residue decomposition. We conclude that while individual hybrids may vary in their production of biomass, residue composition or residue decomposability, these characteristics do not systematically vary with the presence of the Bt gene conferring insect resistance, even under conditions of insect pressure. 相似文献
56.
Hammock Bruce G. Hartman Rosemary Dahlgren Randy A. Johnston Catherine Kurobe Tomofumi Lehman Peggy W. Lewis Levi S. Van Nieuwenhuyse Erwin Ramrez-Duarte Wilson F. Schultz Andrew A. Teh Swee J. 《Hydrobiologia》2022,849(3):675-695
Hydrobiologia - Condition indices are key predictors of health and fitness in wild fish populations. Variation in body condition, therefore, can be used to identify stressful conditions that may... 相似文献
57.
Steffens Travis S. Ramsay Malcolm S. Andriatsitohaina Bertrand Cosby Alexandria E. Lehman Shawn M. Rakotondravony Romule Razafitsalama Mamy Teixeira Helena Radespiel Ute 《International journal of primatology》2022,43(4):636-656
International Journal of Primatology - It is important to understand how sympatric congeners can co-occur within the same landscapes to better understand niche differentiation and how each species... 相似文献
58.
Identification of the amino acids essential for LytSR‐mediated signal transduction in Staphylococcus aureus and their roles in biofilm‐specific gene expression
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60.
In many economies, wealth is strikingly concentrated. Entrepreneurs--individuals with ownership in for-profit enterprises--comprise a large portion of the wealthiest individuals, and their behavior may help explain patterns in the national distribution of wealth. Entrepreneurs are less diversified and more heavily invested in their own companies than is commonly assumed in economic models. We present an intentionally simplified individual-based model of wealth generation among entrepreneurs to assess the role of chance and determinism in the distribution of wealth. We demonstrate that chance alone, combined with the deterministic effects of compounding returns, can lead to unlimited concentration of wealth, such that the percentage of all wealth owned by a few entrepreneurs eventually approaches 100%. Specifically, concentration of wealth results when the rate of return on investment varies by entrepreneur and by time. This result is robust to inclusion of realities such as differing skill among entrepreneurs. The most likely overall growth rate of the economy decreases as businesses become less diverse, suggesting that high concentrations of wealth may adversely affect a country's economic growth. We show that a tax on large inherited fortunes, applied to a small portion of the most fortunate in the population, can efficiently arrest the concentration of wealth at intermediate levels. 相似文献