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991.
992.
Christian L. Klein Giorgio Rovelli† Wolfdieter Springer Christoph Schall‡ Thomas Gasser Philipp J. Kahle 《Journal of neurochemistry》2009,111(3):703-715
Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are the most common cause of autosomal-dominant familial and late-onset sporadic Parkinson's disease (PD). LRRK2 is a large multi-domain protein featuring a GTP-binding C-terminal of Ras of complex proteins (ROC) (ROCO) domain combination unique for the ROCO protein family, directly followed by a kinase domain. Dimerization is a well-established phenomenon among protein kinases. Here, we confirm LRRK2 self-interaction, and provide evidence for general homo- and heterodimerization potential among the ROCO kinase family (LRRK2, LRRK1, and death-associated protein kinase 1). The ROCO domain was critically, though not exclusively involved in dimerization, as a LRRK2 deletion mutant lacking the ROCO domain retained dimeric properties. GTP binding did not appear to influence ROCOLRRK2 self-interaction. Interestingly, ROCOLRRK2 fragments exerted an inhibitory effect on both wild-type and the elevated G2019S LRRK2 autophosphorylation activity. Insertion of PD mutations into ROCOLRRK2 reduced self-interaction and led to a reduction of LRRK2 kinase inhibition. Collectively, these results suggest a functional link between ROCO interactions and kinase activity of wild-type and mutant LRRK2. Importantly, our finding of ROCOLRRK2 fragment-mediated LRRK2 kinase inhibition offers a novel lead for drug design and thus might have important implications for new therapeutic avenues in PD. 相似文献
993.
Fibrils of Prostatic Acid Phosphatase Fragments Boost Infections with XMRV (Xenotropic Murine Leukemia Virus-Related Virus), a Human Retrovirus Associated with Prostate Cancer 下载免费PDF全文
Seunghee Hong Eric A. Klein Jaydip Das Gupta Kirsten Hanke Christopher J. Weight Carvell Nguyen Christina Gaughan Kyeong-Ae Kim Norbert Bannert Frank Kirchhoff Jan Munch Robert H. Silverman 《Journal of virology》2009,83(14):6995-7003
The xenotropic murine leukemia virus-related virus (XMRV) has recently been detected in prostate cancer tissues and may play a role in tumorigenesis. It is currently unclear how this virus is transmitted and which factors promote its spread in the prostate. We show that amyloidogenic fragments known as semen-derived enhancer of virus infection (SEVI) originating from prostatic acid phosphatase greatly increase XMRV infections of primary prostatic epithelial and stromal cells. Hybrid simian/human immunodeficiency chimeric virus particles pseudotyped with XMRV envelope protein were used to demonstrate that the enhancing effect of SEVI, or of human semen itself, was at the level of viral attachment and entry. SEVI enhanced XMRV infectivity but did not bypass the requirement for the xenotropic and polytropic retrovirus receptor 1. Furthermore, XMRV RNA was detected in prostatic secretions of some men with prostate cancer. The fact that the precursor of SEVI is produced in abundance by the prostate indicates that XMRV replication occurs in an environment that provides a natural enhancer of viral infection, and this may play a role in the spread of this virus in the human population.Viruses are etiologic agents of various human cancers, including cervical carcinoma (caused by human papillomavirus), Kaposi''s sarcoma (caused by human herpesvirus 8), hepatocellular carcinoma (caused by hepatitis B virus and hepatitis C virus), and adult T-cell leukemia (caused by human T-cell leukemia virus type 1) (6). Genetic and epidemiologic evidence suggests that prostate cancer may also have an infectious etiology, although a causative agent has not been identified (4, 12). The gammaretrovirus xenotropic murine leukemia virus-related virus (XMRV) is a candidate human tumor virus based on its association in human prostate tumors with a reduced-activity variant of the antiviral gene, RNASEL (also known as the hereditary prostate cancer 1 gene or HPC1) (17) and because it is a member of a viral family known to cause leukemias and lymphomas in different mammalian species (8). Interferon, through its effector RNase L, potently inhibits XMRV replication (5). XMRV integration sites in human prostate cancer tissues were mapped to cancer breakpoints, common fragile sites, micro-RNA genes, and cancer-related genes (11). Many of these genes are implicated directly or indirectly in prostate cancer and metabolic pathways that affect prostate cancer, including androgen signaling. XMRV has also been observed in prostate tissue from a nonfamilial prostate cancer patient and in an individual without prostate cancer (7). The possible role of XMRV in prostatic cancer raises questions about its ability to infect the prostate and the route of viral transmission.Recently, it has been shown that fragments of prostatic acid phosphatase (PAP), an abundant nonspecific protein phosphatase produced by the prostate (18) and secreted in semen in large quantities (about 2 mg/ml) (16), form amyloid fibrils that drastically enhance human immunodeficiency virus type 1 (HIV-1) infection (14). The fibrils of PAP248-286, termed semen-derived enhancer of virus infection (SEVI), enhanced the infectious virus titer by several orders of magnitude by capturing HIV-1 virions and promoting their attachment to target cells. The ability of SEVI to promote the interaction between virions and the cell surface is independent of the viral glycoprotein and hence is not restricted to HIV-1, although subsequent fusion between the viral and cellular membranes still required gp120, CD4, and an appropriate coreceptor (14). A recent study indicates that the positive charges on SEVI (pI = 10.21) promote infectivity by neutralizing negative-charge repulsion between HIV particles and the cell surface (15).Because SEVI originates from the prostate (the organ from which XMRV infection was discovered [17]) and promotes viral attachment in a relatively nonspecific manner, we sought to determine its effect on XMRV infection. Here we demonstrate that XMRV infectivity is greatly enhanced by SEVI or human semen and that XMRV RNA is detectable in expressed prostatic secretions (EPS) from human tumor-bearing prostates. 相似文献
994.
Geographical Distribution and Relative Abundance of Vectors of Scrub Typhus in the Republic of Korea
In Yong Lee Heung Chul Kim Young-Sun Lee Jang Hoon Seo Jae Won Lim Tae Soon Yong Terry A. Klein Won Ja Lee 《The Korean journal of parasitology》2009,47(4):381-386
A survey to determine the geographical distribution and relative abundance of potential vectors of scrub typhus was conducted from October to November 2006 at 13 localities throughout the Republic of Korea. Apodemus agrarius accounted for 97.6% (80/82) of all rodents, while only 2 Myodes regulus (2/82) were collected. A total of 10,860 chiggers were collected from A. agrarius belonging to 4 genera and 8 species, while only Walchia fragilis (40) was collected from Myodes regulus. Leptotrombidium pallidum (8,137; 74.9%), a vector of scrub typhus, was the predominant species collected from A. agrarius followed by Leptotrombidium scutellare (2,057, 18.9%), Leptotrombidium palpale (279; 2.7%), Leptotrombidium orientale (232; 2.1%), and Leptotrombidium zetum (79; 0.7%), Neotrombicula tamiyai (58; 0.5%), Euschoengastica koreaensis (16; 0.1%), and Cheladonta ikaoensis (2; < 0.1%). L. pallidum was the predominant chigger collected at collection sites in Gangwon (100%), Gyeonggi (87.2%), Chungnam (100%), Chungbuk (100%), Jeonbuk (73.9%), Jeonnam (77.0%), and Gyeongbuk (66.1%) provinces, whereas L. scutellare was the predominant chigger collected in Gyeongnam province (77.9%) and Jeju Island (62.3%). Data suggest a correlation between chigger population abundance and human cases of scrub typhus in Korea. 相似文献
995.
Human NADPH : cytochrome P450 oxidoreductase (POR) is encoded by a single gene on chromosome 7q11.2. This flavoprotein donates electrons derived from NADPH to a variety of acceptor proteins, including squalene monooxygenase, heme oxygenase, cytochrome b5, and many microsomal cytochromes P450 (CYPs), which are involved in oxidative drug metabolism, steroidogenesis, and other functions. Numerous aspects related to cellular POR expression have not been systematically investigated. Interestingly, POR expression is lower compared to CYPs and may thus be limiting for monooxygenase activities, but conversely, POR knock‐out in mice resulted in compensatory upregulation of CYPs. POR may also influence intracellular cholesterol and lipid homeostasis. To systematically investigate such effects, we developed specific POR gene silencing in cell lines and primary human hepatocytes by RNA interference using small interfering RNAs (siRNAs). In HepG2 cells, POR mRNA could be reduced by 95% over 4 days accompanied by reduced protein content and activity. In primary human hepatocytes, POR mRNA knock‐down was less effective and more variable. Analysis of CYPs indicated induction of CYP3A4 but not CYP1A2 or CYP2D6. These results demonstrate that POR can be efficiently and almost completely silenced in HepG2 cells and, at least partially, in primary human hepatocytes. This will allow systematic studies of various consequences of POR variability in human cells. 相似文献
996.
997.
Krupa Shah Abby Stufflebam Tiffany N. Hilton David R. Sinacore Samuel Klein Dennis T. Villareal 《Obesity (Silver Spring, Md.)》2009,17(12):2162-2168
Both obesity and aging increase intrahepatic fat (IHF) content, which leads to nonalcoholic fatty liver disease (NAFLD) and metabolic abnormalities such as insulin resistance. We evaluated the effects of diet and diet in conjunction with exercise on IHF content and associated metabolic abnormalities in obese older adults. Eighteen obese (BMI ≥30 kg/m2) older (≥65 years old) adults completed a 6‐month clinical trial. Participants were randomized to diet (D group; n = 9) or diet + exercise (D+E group; n = 9). Primary outcome was IHF quantified by magnetic resonance spectroscopy (MRS). Secondary outcomes included insulin sensitivity (assessed by oral glucose tolerance), body composition (assessed by dual‐energy X‐ray absorptiometry), physical function (VO2peak and strength), glucose, lipids, and blood pressure (BP). Body weight (D: ?9 ± 1%, D+E: ?10 ± 2%, both P < 0.05) and fat mass (D: ?13 ± 3%, D+E ?16 ± 3%, both P < 0.05) decreased in both groups but there was no difference between groups. IHF decreased to a similar extent in both groups (D: ?46 ± 11%, D+E: ?45 ± 8%, both P < 0.05), which was accompanied by comparable improvements in insulin sensitivity (D: 66 ± 25%, D+E: 68 ± 28%, both P < 0.05). The relative decreases in IHF correlated directly with relative increases in insulin sensitivity index (ISI) (r = ?0.52; P < 0.05). Improvements in VO2peak, strength, plasma triglyceride (TG), and low‐density lipoprotein–cholesterol concentration, and diastolic BP occurred in the D+E group (all P < 0.05) but not in the D group. Diet with or without exercise results in significant decreases in IHF content accompanied by considerable improvements in insulin sensitivity in obese older adults. The addition of exercise to diet therapy improves physical function and other obesity‐ and aging‐related metabolic abnormalities. 相似文献
998.
Peter Chi Youngho Kwon Dana N. Moses Changhyun Seong Michael G. Sehorn Akhilesh K. Singh Hideo Tsubouchi Eric C. Greene Hannah L. Klein Patrick Sung 《DNA Repair》2009,8(2):279-284
Genetic studies in budding and fission yeasts have provided evidence that Rdh54, a Swi2/Snf2-like factor, synergizes with the Dmc1 recombinase to mediate inter-homologue recombination during meiosis. Rdh54 associates with Dmc1 in the yeast two-hybrid assay, but whether the Rdh54–Dmc1 interaction is direct and the manner in which these two recombination factors may functionally co-operate to accomplish their biological task have not yet been defined. Here, using purified Schizosaccharomyces pombe proteins, we demonstrate complex formation between Rdh54 and Dmc1 and enhancement of the recombinase activity of Dmc1 by Rdh54. Consistent with published cytological and chromatin immunoprecipitation data that implicate Rdh54 in preventing the non-specific association of Dmc1 with chromatin, we show here that Rdh54 mediates the efficient removal of Dmc1 from dsDNA. These functional attributes of Rdh54 are reliant on its ATPase function. The results presented herein provide valuable information concerning the Rdh54–Dmc1 protein pair that is germane for understanding their role in meiotic recombination. The biochemical systems established in this study should be useful for the continuing dissection of the action mechanism of Rdh54 and Dmc1. 相似文献
999.
Tomomi Kiyota Masaru Yamamoto Huangui Xiong Mary P. Lambert William L. Klein Howard E. Gendelman Richard M. Ransohoff Tsuneya Ikezu 《PloS one》2009,4(7)
Background
The linkages between neuroinflammation and Alzheimer''s disease (AD) pathogenesis are well established. What is not, however, is how specific immune pathways and proteins affect the disease. To this end, we previously demonstrated that transgenic over-expression of CCL2 enhanced microgliosis and induced diffuse amyloid plaque deposition in Tg2576 mice. This rodent model of AD expresses a Swedish β-amyloid (Aβ) precursor protein mutant.Methodology/Principal Findings
We now report that CCL2 transgene expression accelerates deficits in spatial and working memory and hippocampal synaptic transmission in β-amyloid precursor protein (APP) mice as early as 2–3 months of age. This is followed by increased numbers of microglia that are seen surrounding Aβ oligomers. CCL2 does not suppress Aβ degradation. Rather, CCL2 and tumor necrosis factor-α directly facilitated Aβ uptake, intracellular Aβ oligomerization, and protein secretion.Conclusions/Significance
We posit that CCL2 facilitates Aβ oligomer formation in microglia and propose that such events accelerate memory dysfunction by affecting Aβ seeding in the brain. 相似文献1000.
Gregory E. Glass Lynne C. Gardner-Santana Robert D. Holt Jessica Chen Timothy M. Shields Manojit Roy Stephen Schachterle Sabra L. Klein 《PloS one》2009,4(6)