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181.
Reto Guler Suraj P. Parihar Suzana Savvi Erin Logan Anita Schwegmann Sugata Roy Natalie E. Nieuwenhuizen Mumin Ozturk Sebastian Schmeier Harukazu Suzuki Frank Brombacher 《PloS one》2015,10(3)
Classical activation of macrophages (caMph or M1) is crucial for host protection against Mycobacterium tuberculosis (Mtb) infection. Evidence suggests that IL-4/IL-13 alternatively activated macrophages (aaMph or M2) are exploited by Mtb to divert microbicidal functions of caMph. To define the functions of M2 macrophages during tuberculosis (TB), we infected mice deficient for IL-4 receptor α on macrophages (LysMcreIL-4Rα-/lox) with Mtb. We show that absence of IL-4Rα on macrophages does not play a major role during infection with Mtb H37Rv, or the clinical Beijing strain HN878. This was demonstrated by similar mortality, bacterial burden, histopathology and T cell proliferation between infected wild-type (WT) and LysMcreIL-4Rα-/lox mice. Interestingly, we observed no differences in the lung expression of inducible nitric oxide synthase (iNOS) and Arginase 1 (Arg1), well-established markers for M1/M2 macrophages among the Mtb-infected groups. Kinetic expression studies of IL-4/IL-13 activated bone marrow-derived macrophages (BMDM) infected with HN878, followed by gene set enrichment analysis, revealed that the MyD88 and IL-6, IL-10, G-CSF pathways are significantly enriched, but not the IL-4Rα driven pathway. Together, these results suggest that IL-4Rα-macrophages do not play a central role in TB disease progression. 相似文献
182.
Joy Gardner Penny A. Rudd Natalie A. Prow Essia Belarbi Pierre Roques Thibaut Larcher Lionel Gresh Angel Balmaseda Eva Harris Wayne A. Schroder Andreas Suhrbier 《PloS one》2015,10(10)
Chikungunya virus (CHIKV) is a reemerging, ordinarily mosquito-transmitted, alphavirus that occasionally produces hemorrhagic manifestations, such as nose bleed and bleeding gums, in human patients. Interferon response factor 3 and 7 deficient (IRF3/7-/-) mice, which are deficient for interferon α/β responses, reliably develop hemorrhagic manifestations after CHIKV infection. Here we show that infectious virus was present in the oral cavity of CHIKV infected IRF3/7-/- mice, likely due to hemorrhagic lesions in the olfactory epithelium that allow egress of infected blood into the nasal, and subsequently, oral cavities. In addition, IRF3/7-/- mice were more susceptible to infection with CHIKV via intranasal and oral routes, with IRF3/7-/- mice also able to transmit virus mouse-to-mouse without an arthropod vector. Cynomolgus macaques often show bleeding gums after CHIKV infection, and analysis of saliva from several infected monkeys also revealed the presence of viral RNA and infectious virus. Furthermore, saliva samples collected from several acute CHIKV patients with hemorrhagic manifestations were found to contain viral RNA and infectious virus. Oral fluids can therefore be infectious during acute CHIKV infections, likely due to hemorrhagic manifestations in the oral/nasal cavities. 相似文献
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184.
Detelina Grozeva Keren Carss Olivera Spasic-Boskovic Michael?J. Parker Hayley Archer Helen?V. Firth Soo-Mi Park Natalie Canham Susan?E. Holder Meredith Wilson Anna Hackett Michael Field James?A.B. Floyd UKK Consortium Matthew Hurles F.?Lucy Raymond 《American journal of human genetics》2014,94(4):618-624
To identify further Mendelian causes of intellectual disability (ID), we screened a cohort of 996 individuals with ID for variants in 565 known or candidate genes by using a targeted next-generation sequencing approach. Seven loss-of-function (LoF) mutations—four nonsense (c.1195A>T [p.Lys399∗], c.1333C>T [p.Arg445∗], c.1866C>G [p.Tyr622∗], and c.3001C>T [p.Arg1001∗]) and three frameshift (c.2177_2178del [p.Thr726Asnfs∗39], c.3771dup [p.Ser1258Glufs∗65], and c.3856del [p.Ser1286Leufs∗84])—were identified in SETD5, a gene predicted to encode a methyltransferase. All mutations were compatible with de novo dominant inheritance. The affected individuals had moderate to severe ID with additional variable features of brachycephaly; a prominent high forehead with synophrys or striking full and broad eyebrows; a long, thin, and tubular nose; long, narrow upslanting palpebral fissures; and large, fleshy low-set ears. Skeletal anomalies, including significant leg-length discrepancy, were a frequent finding in two individuals. Congenital heart defects, inguinal hernia, or hypospadias were also reported. Behavioral problems, including obsessive-compulsive disorder, hand flapping with ritualized behavior, and autism, were prominent features. SETD5 lies within the critical interval for 3p25 microdeletion syndrome. The individuals with SETD5 mutations showed phenotypic similarity to those previously reported with a deletion in 3p25, and thus loss of SETD5 might be sufficient to account for many of the clinical features observed in this condition. Our findings add to the growing evidence that mutations in genes encoding methyltransferases regulating histone modification are important causes of ID. This analysis provides sufficient evidence that rare de novo LoF mutations in SETD5 are a relatively frequent (0.7%) cause of ID. 相似文献
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187.
Alan Birchall M. Puncher J. Harrison A. Riddell M. R. Bailey V. Khokryakov S. Romanov 《Radiation and environmental biophysics》2010,49(2):203-212
Epidemiological studies of the relationship between risk and internal exposure to plutonium are clearly reliant on the dose
estimates used. The International Commission on Radiological Protection (ICRP) is currently reviewing the latest scientific
information available on biokinetic models and dosimetry, and it is likely that a number of changes to the existing models
will be recommended. The effect of certain changes, particularly to the ICRP model of the respiratory tract, has been investigated
for inhaled forms of 239Pu and uncertainties have also been assessed. Notable effects of possible changes to respiratory tract model assumptions are
(1) a reduction in the absorbed dose to target cells in the airways, if changes under consideration are made to the slow clearing
fraction and (2) a doubling of absorbed dose to the alveolar region for insoluble forms, if evidence of longer retention times
is taken into account. An important factor influencing doses for moderately soluble forms of 239Pu is the extent of binding of dissolved plutonium to lung tissues and assumptions regarding the extent of binding in the
airways. Uncertainty analyses have been performed with prior distributions chosen for application in epidemiological studies.
The resulting distributions for dose per unit intake were lognormal with geometric standard deviations of 2.3 and 2.6 for
nitrates and oxides, respectively. The wide ranges were due largely to consideration of results for a range of experimental
data for the solubility of different forms of nitrate and oxides. The medians of these distributions were a factor of three
times higher than calculated using current default ICRP parameter values. For nitrates, this was due to the assumption of
a bound fraction, and for oxides due mainly to the assumption of slower alveolar clearance. This study highlights areas where
more research is needed to reduce biokinetic uncertainties, including more accurate determination of particle transport rates
and long-term dissolution for plutonium compounds, a re-evaluation of long-term binding of dissolved plutonium, and further
consideration of modeling for plutonium absorbed to blood from the lungs. 相似文献
188.
N. P. Aksenova L. A. Wasserman L. I. Sergeeva T. N. Konstantinova S. A. Golyanovskaya A. V. Krivandin I. G. Plashchina W. Blaszczak J. Fornal G. A. Romanov 《Russian Journal of Plant Physiology》2010,57(5):656-663
Wild-type (WT) plants of potato (Solanum tuberosum L.) and their transgenic forms carrying agrobacterial genes rolB or rolC under the control of B33 class I patatin promoter were cultured in vitro on MS medium with 2% sucrose in a controlled-climate chamber at 16-h illumination
and 22°C. These plants were used as a source of single-node stem cuttings, which were cultured in darkness on the same medium
supplemented with 8% sucrose. The tubers formed on them were used for determination of the structure of native starch using
the methods of differential scanning microcalorimetry (DSC), X-ray scattering, and scanning electron microscopy. It was found
that, in starch from the tubers of rolB-plants, the temperature of crystalline lamella melting was lower and their thickness was less than in WT potato. In tubers
of rolC plants, starch differed from starch in WT plants by a higher melting temperature, considerably reduced melting enthalpy,
and a greater thickness of crystalline lamellae. Deconvolution of DSC thermogram makes it possible to interpret the melting
of starch from the tubers of rolC plants as the melting of two independent crystalline structures with melting temperatures of 65.0 and 69.8°C. Electron microscopic
examination confirmed the earlier obtained data indicating that, in the tubers of rolC plants, starch granules are smaller and in the tubers of rolB plants larger than in WT plants. Possible ways of influence of rol transgenes on structural properties of starch in amyloplasts of potato tubers are discussed. 相似文献
189.
Robert Lam Vladimir Romanov Kathy Johns Kevin P. Battaile Jean Wu‐Brown Jennifer L. Guthrie Robert P. Hausinger Emil F. Pai Nickolay Y. Chirgadze 《Proteins》2010,78(13):2839-2848
Urease plays a central role in the pathogenesis of Helicobacter pylori in humans. Maturation of this nickel metalloenzyme in bacteria requires the participation of the accessory proteins UreD (termed UreH in H. pylori), UreF, and UreG, which form sequential complexes with the urease apoprotein as well as UreE, a metallochaperone. Here, we describe the crystal structure of C‐terminal truncated UreF from H. pylori (residues 1–233), the first UreF structure to be determined, at 1.55 Å resolution using SAD methods. UreF forms a dimer in vitro and adopts an all‐helical fold congruent with secondary structure prediction. On the basis of evolutionary conservation analysis, the structure reveals a probable binding surface for interaction with other urease components as well as key conserved residues of potential functional relevance. Proteins 2010. © 2010 Wiley‐Liss, Inc. 相似文献
190.
Discovery and synthesis of 6,7,8,9-tetrahydro-5H-pyrimido-[4,5-d]azepines as novel TRPV1 antagonists
Hawryluk NA Merit JE Lebsack AD Branstetter BJ Hack MD Swanson N Ao H Maher MP Bhattacharya A Wang Q Freedman JM Scott BP Wickenden AD Chaplan SR Breitenbucher JG 《Bioorganic & medicinal chemistry letters》2010,20(23):7137-7141
Utilization of a tetrahydro-pyrimdoazepine core as a bioisosteric replacement for a piperazine-urea resulted in the discovery a novel series of potent antagonists of TRPV1. The tetrahydro-pyrimdoazepines have been identified as having good in vitro and in vivo potency and acceptable physical properties. 相似文献