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11.
Jak2 is a 130 kDa tyrosine kinase that is important in a number of cellular signaling pathways. Its function is intrinsically regulated by the phosphorylation of a handful of its 49 tyrosines. Here, we report that tyrosine 972 (Y972) is a novel site of Jak2 phosphorylation and, hence, autoregulation. Specifically, we found that Y972 is phosphorylated and confirmed that this residue resides on the surface of the protein. Using expression plasmids that expressed either wild-type Jak2 or a full-length Jak2 cDNA containing a single Y972F substitution mutation, we investigated the consequences of losing Y972 phosphorylation on Jak2 function. We determined that the loss of Y972 phosphorylation significantly reduced the levels of both Jak2 total tyrosine phosphorylation and phosphorylation of Y1007/Y1008. Additionally, Y972 phosphorylation was shown to be important for maximal kinase function. Interestingly, in response to classical cytokine activation, the Jak2 Y972F mutant exhibited a moderately impaired level of activation when compared to the wild-type protein. However, when Jak2 was activated via a GPCR ligand, the ability of the Y972F mutant to be activated was completely lost, therefore suggesting a differential role of Y972 in Jak2 activation. Finally, we found that phosphorylation of Y972 enhances Jak2 kinase function via a mechanism that appears to stabilize the active conformation of the protein. Collectively, our results suggest that Y972 is a novel site of Jak2 phosphorylation and plays an important differential role in ligand-dependent Jak2 activation via a mechanism that involves stabilization of the Jak2 active conformation. 相似文献
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Chemical trapping of the dynamic MutS-MutL complex formed in DNA mismatch repair in Escherichia coli
Winkler I Marx AD Lariviere D Heinze RJ Cristovao M Reumer A Curth U Sixma TK Friedhoff P 《The Journal of biological chemistry》2011,286(19):17326-17337
The ternary complex comprising MutS, MutL, and DNA is a key intermediate in DNA mismatch repair. We used chemical cross-linking and fluorescence resonance energy transfer (FRET) to study the interaction between MutS and MutL and to shed light onto the structure of this complex. Via chemical cross-linking, we could stabilize this dynamic complex and identify the structural features of key events in DNA mismatch repair. We could show that in the complex between MutS and MutL the mismatch-binding and connector domains of MutS are in proximity to the N-terminal ATPase domain of MutL. The DNA- and nucleotide-dependent complex formation could be monitored by FRET using single cysteine variants labeled in the connector domain of MutS and the transducer domain of MutL, respectively. In addition, we could trap MutS after an ATP-induced conformational change by an intramolecular cross-link between Cys-93 of the mismatch-binding domain and Cys-239 of the connector domain. 相似文献
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Julius Mulindwa Joyce Namulondo Anna Kitibwa Jacent Nassuuna Oscar Asanya Nyangiri Magambo Phillip Kimuda Alex Boobo Barbara Nerima Fred Busingye Rowel Candia Annet Namukuta Ronald Ssenyonga Noah Ukumu Paul Ajal Moses Adriko Harry Noyes Claudia J. de Dood Paul L. A. M. Corstjens Govert J. van Dam Alison M. Elliott Enock Matovu TrypanoGEN+ Research group 《PLoS neglected tropical diseases》2022,16(7)
BackgroundKnowing the prevalence of schistosomiasis is key to informing programmes to control and eliminate the disease as a public health problem. It is also important to understand the impact of infection on child growth and development in order to allocate appropriate resources and effort to the control of the disease.MethodsWe conducted a survey to estimate the prevalence of schistosomiasis among school aged children in villages along the Albert-Nile shore line in the district of Pakwach, North Western Uganda. A total of 914 children aged between 10–15 years were screened for Schistosoma mansoni using the POC-CCA and Kato Katz (KK) techniques. The infection intensities were assessed by POC-CCA and KK as well as CAA tests. The KK intensities were also correlated with POC-CCA and with CAA intensity. Anthropometric measurements were also taken and multivariate analysis was carried out to investigate their association with infection status.ResultsThe prevalence of schistosomiasis using the POC-CCA diagnostic test was estimated at 85% (95% CI: 83–87), being highest amongst children living closer to the Albert-Nile shoreline. Visual scoring of the POC-CCA results was more sensitive than the Kato Katz test and was positively correlated with the quantified infection intensities by the CAA test. The majority of the children were underweight (BMI<18.5), and most notably, boys had significantly lower height for age (stunting) than girls in the same age range (p < 0.0001), but this was not directly associated with S. mansoni infection.ConclusionHigh prevalence of S. mansoni infection in the region calls for more frequent mass drug administration with praziquantel. We observed high levels of stunting which was not associated with schistosomiasis. There is a need for improved nutrition among the children in the area. 相似文献
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Long-term effects of polyacrylamide hydrogel on human breast tissue 总被引:23,自引:0,他引:23
Christensen LH Breiting VB Aasted A Jørgensen A Kebuladze I 《Plastic and reconstructive surgery》2003,111(6):1883-1890
Polyacrylamide hydrogel is an atoxic, stable, nonresorbable sterile watery gel consisting of approximately 2.5% cross-linked polyacrylamide and nonpyrogenic water. Polyacrylamide hydrogel is widely used in ophthalmic operations, drug treatment, food packaging products, and water purification. In the former Soviet Union, polyacrylamide hydrogel has been used in plastic and aesthetic surgery for more than 10 years, and Kiev City Hospital treats approximately 300 women a year for breast augmentation using the polyacrylamide hydrogel Interfall (Contura SA, Montreux, Switzerland). Capsule shrinkage following these injections has never been observed. The authors examined breast tissue samples from a total of 27 women who had polyacrylamide hydrogel injected at Kiev City Hospital up to 8 years and 10 months earlier. Age at operation, duration of polyacrylamide hydrogel implantation, history of possible side effects to the gel injection, other intercurrent diseases, the reason for present open breast operation, and breast palpation findings before operation were in each case compared with the histological findings on samples taken from breast tissue bordering the gel. The gel presented itself as a dark violet, homogenous mass with a rounded or ragged outline in large or medium-size deposits and as elongated strands, which mimicked the extracellular matrix, in small deposits. Histological findings of the breast tissue bordering the gel showed three different patterns: large collections of gel gave rise to a thick, soft-looking cellular membrane of macrophages and foreign-body giant cells; medium-size deposits were surrounded by just a thin layer of macrophages; and small deposits were not associated with any reaction in the surrounding tissue. Projections of the cellular soft membrane, known as granulomas, were seen in six patients. The granulomas were composed of macrophages, foreign-body giant cells, lymphocytes, and blood cells. A thin layer of fibrous connective tissue was occasionally present around the foreign-body membrane, but the thick fibrous capsule, which has been described in connection with silicone implants, was completely absent. The gel changes could be correlated to neither time since gel injection nor a history of recent injury or inflammation. It is concluded that the polyacrylamide hydrogel Interfall, which has been used in the former Soviet Union, is stable over time, nondegradable, confined to the breast, and diffusion and migration resistant. When the hydrogel is injected in medium-size or large quantities a cellular foreign-body reaction occurs, but in small amounts it is capable of splitting up individual connective tissue fibers and fat cells, substituting for the extracellular connective tissue matrix without eliciting any foreign-body reaction. As far as these data are concerned, polyacrylamide hydrogel is well tolerated by the breast and does not give rise to severe fibrosis, pain, or capsule shrinkage. However, to determine safety with more certainty, a larger sample size would be necessary. 相似文献
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Halohydrin dehalogenase (HheC) from Agrobacterium radiobacter AD1 is a homotetrameric protein containing four tryptophan residues per subunit. The fluorescence properties of the enzyme are strongly influenced by halide binding. To examine the role of the tryptophans (W139, W192, W238, and W249) in halide binding and catalysis, they were individually mutated to a phenylalanine. All mutations, except for W238F, influenced the enzymatic properties. Mutating W192 to phenylalanine inactivated the enzyme and led to dissociation into dimers and monomers. In the structure of HheC, residue W139 and residue W249 from the opposite subunit are close to the active site of the enzyme. Substitution of W139 mainly affected K(m) values with all tested substrates and reduced the enantiopreference for p-nitro-2-bromo-1-phenylethanol. Replacing W249 increased both k(cat) and K(m) values with all tested substrates except for the (S)-enantiomer of p-nitro-2-bromo-1-phenylethanol, for which k(cat) was 3-fold decreased, resulting in a 6-fold increase of the enantioselectivity. Fluorescence measurements revealed that in the ligand-free state the intrinsic protein fluorescence of mutant W139F is higher than that of the wild-type enzyme, while the fluorescence intensity of mutants W238F and W249F was lower. The fluorescence intensities of the W238F and W249F enzymes were increased when they were unfolded or when bromide was added, whereas the fluorescence of mutant W139F was not increased by unfolding or addition of bromide. These results demonstrate that the fluorescence of residues W238 and W249 is partially quenched in the folded ligand-free state, and that W139 is completely quenched and acts as an energy acceptor for the other tryptophan residues as well. Changes of the maximum fluorescence emission wavelength of the HheC variants and the results of acrylamide quenching experiments confirmed that bromide binding induces a local conformational change around the active site, resulting in residue W139 and the quencher group being separated. 相似文献
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Annet Nanvubya Julius Ssempiira Juliet Mpendo Ali Ssetaala Annet Nalutaaya Mathias Wambuzi Paul Kitandwe Bernard S. Bagaya Sabrina Welsh Stephen Asiimwe Leslie Nielsen Fredrick Makumbi Noah Kiwanuka 《PloS one》2015,10(10)
Introduction
Fishing communities (FCs) in Uganda have high HIV infection rates but poor access to health services including family planning (FP). Although FP is a cost-effective public health intervention, there is a paucity of data on knowledge and use of modern FP in FCs. This study determined knowledge and use of modern FP methods in FCs of Uganda.Methods
Data were accrued from a 12-month follow up of 1,688 HIV-uninfected individuals, 18–49 years from 8 FCs along Lake Victoria, between September 2011 and March 2013. Data on knowledge and use of modern FP were collected through a semi-structured questionnaire. Prevalence Risk Ratios with corresponding 95% CIs were used to determine factors associated with Modern FP knowledge and use.Results
The mean age was 31.4 years, with nearly half (48.8%) being females while more than half (58.6%) had attained up to primary education level. Knowledge of modern FP was high, 87.5% (1477/1688); significantly higher among females [adj. PRR = 4.84 (95% CI; 3.08, 7.61)], among older respondents (25–29 years) [adj. PRR = 1.83 (95% CI; 1.12, 2.99)] compared to younger ones (18–24 years) and among those conducting business [adj. PRR = 2.42(95% CI; 1.02, 5.74)] relative to those primarily in fishing. Just over a third (35.2%, 595/1688) reported use of at least one modern FP method. Use of modern FP methods was significantly higher among females [adj. PRR = 2.04 (95% CI; 1.56, 2.65, and among those reporting multiple sexual partnerships [adj. PRR = 2.12, 95% CI; 1.63, 2.76)]. Nonuse of modern methods was mostly due to desire for more children (30.6%), fear of side effects (12.2%) and partner refusal (5.2%).Conclusion
Despite their high knowledge of FP, FCs have low use of modern FP methods. Key barriers to use of modern FP methods were high fertility desires, fear of perceived side effects and partner refusal of methods. 相似文献19.
Jessica L. Prodger Aloysious Ssemaganda Ali Ssetaala Paul K. Kitandwe Enoch Muyanja Juliet Mpendo Annet Nanvubya Mathias Wambuzi Leslie Nielsen Noah Kiwanuka Rupert Kaul 《PLoS neglected tropical diseases》2015,9(9)
Background
Schistosoma mansoni infection has been associated with an increased HIV prevalence in humans and SHIV incidence in primate models. We hypothesized that immune activation from this gastrointestinal mucosa infection would increase highly HIV-susceptible CD4 T cell subsets in the blood and the foreskin through common mucosal homing.Conclusions/Significance
S. mansoni infection was associated with an increased frequency of highly HIV-susceptible Th1, Th17 and Th22 cell subsets in the blood, but these T cell immune differences did not extend to the foreskin. S. mansoni induced changes in T cell immunology mediated through the common mucosal immune system are not likely to increase HIV susceptibility in the foreskin. 相似文献
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Juliet Mpendo Gaudensia Mutua Julien Nyombayire Rosine Ingabire Annet Nanvubya Omu Anzala Etienne Karita Peter Hayes Jakub Kopycinski Len Dally Drew Hannaman Michael A. Egan John H. Eldridge Kristen Syvertsen Jennifer Lehrman Beth Rasmussen Jill Gilmour Josephine H. Cox Patricia E. Fast Claudia Schmidt 《PloS one》2015,10(8)