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961.
Chau DM Crump CJ Villa JC Scheinberg DA Li YM 《The Journal of biological chemistry》2012,287(21):17288-17296
Presenilin-1 (PS1) is the catalytic subunit of γ-secretase, and mutations in this protein cause familial Alzheimer Disease (FAD). However, little is known about how these mutations affect the active site of γ-secretase. Here, we show that PS1 mutations alter the S2 subsite within the active site of γ-secretase using a multiple photoaffinity probe approach called "photophore walking." Moreover, we developed a unique in vitro assay with a biotinylated recombinant Notch1 substrate and demonstrated that PS1 FAD mutations directly and significantly reduced γ-secretase activity for Notch1 cleavage. Substitution of the Notch Cys-1752 residue, which interacts with the S2 subsite, with Val, Met, or Ile has little effect on wild-type PS1 but leads to more efficient substrates for mutant PS1s. This study indicates that alteration of this S2 subsite plays an important role in determining the activity and specificity of γ-secretase for APP and Notch1 processing, which provides structural basis and insights on how certain PS1 FAD mutations lead to AD pathogenesis. 相似文献
962.
Sethna Lienne R. Royer Todd V. Speir Shannon L. Trentman Matt T. Mahl Ursula H. Hagemeier Leah P. Tank Jennifer L. 《Biogeochemistry》2022,159(2):265-282
Biogeochemistry - Agriculture alters the biogeochemical cycling of nutrients such as nitrogen (N), phosphorus (P), and silicon (Si) which contributes to the stoichiometric imbalance among these... 相似文献
963.
The overexpression of a Saccharomyces cerevisiae centromeric histone H3 variant mutant protein leads to a defect in kinetochore biorientation 下载免费PDF全文
Chromosomes segregate using their kinetochores, the specialized protein structures that are assembled on centromeric DNA and mediate attachment to the mitotic spindle. Because centromeric sequences are not conserved, centromere identity is propagated by an epigenetic mechanism. All eukaryotes contain an essential histone H3 variant (CenH3) that localizes exclusively to centromeres. Because CenH3 is required for kinetochore assembly and is likely to be the epigenetic mark that specifies centromere identity, it is critical to elucidate the mechanisms that assemble and maintain CenH3 exclusively at centromeres. To learn more about the functions and regulation of CenH3, we isolated mutants in the budding yeast CenH3 that are lethal when overexpressed. These CenH3 mutants fall into three unique classes: (I) those that localize to euchromatin but do not alter kinetochore function, (II) those that localize to the centromere and disrupt kinetochore function, and (III) those that no longer target to the centromere but still disrupt chromosome segregation. We found that a class III mutant is specifically defective in the ability of sister kinetochores to biorient and attach to microtubules from opposite spindle poles, indicating that CenH3 mutants defective in kinetochore biorientation can be obtained. 相似文献
964.
Anders Svenningsson Eva Falk Elisabeth G. Celius Siegrid Fuchs Karen Schreiber Sara Berk? Jennifer Sun Iris-Katharina Penner for the TYNERGY trial investigators 《PloS one》2013,8(3)
Fatigue is a significant symptom in multiple sclerosis (MS) patients. First-generation disease modifying therapies (DMTs) are at best moderately effective to improve fatigue. Observations from small cohorts have indicated that natalizumab, an antibody targeting VLA-4, may reduce MS-related fatigue. The TYNERGY study aimed to further evaluate the effects of natalizumab treatment on MS-related fatigue. In this one-armed clinical trial including 195 MS patients, natalizumab was prescribed in a real-life setting, and a validated questionnaire, the Fatigue Scale for Motor and Cognitive functions (FSMC), was used both before and after 12 months of treatment to evaluate a possible change in the fatigue experienced by the patients. In the treated cohort all measured variables, that is, fatigue score, quality of life, sleepiness, depression, cognition, and disability progression were improved from baseline (all p values<0.0001). Walking speed as measured by the six-minute walk-test also increased at month 12 (p = 0.0016). All patients were aware of the nature of the treatment agent, and of the study outcomes.
Conclusion
Natalizumab, as used in a real-life setting, might improve MS-related fatigue based on the results from this one-armed un-controlled stud. Also other parameters related to patients'' quality of life seemed to improve with natalizumab treatment.Trial Registration
ClinicalTrials.gov NCT00884481相似文献965.
The Gene Ontology project (http://www.geneontology.org/) produces structured, controlled vocabularies and gene product annotations. Gene products are classified according to the cellular locations and biological process in which they act, and the molecular functions that they carry out. We annotate gene products from a broad range of model species and provide support for those groups that wish to contribute annotation of further model species. The Gene Ontology facilitates the exchange of information between groups of scientists studying similar processes in different model organisms, and so provides a broad range of opportunities for plant scientists. 相似文献
966.
We examined the effects of endogenous basic proteins rich in the amino acidL-arginine on neuronal NO synthase activity by monitoring cyclic GMP formation in intact neuron-like neuroblastoma N1E-115 cells. Histone, protamine and myelin basic protein significantly stimulated cyclic GMP formation, both in a time- and concentration-dependent manner. These effects were blocked by hemoglobin and NO synthase inhibitors. Removal of the extracellular/intracellular Ca2+ gradient by a Ca2+ chelator completely abolished the cyclic GMP responses elicited by histone and protamine, suggesting that influex of extracellular Ca2+ might be involved in their activation of NO synthase. The effects of myelin basic protein on cyclic GMP formation, however, appeared to be due to Ca2+ release from intracellular stores. In cytosolic preparations of rat cerebellum, these basic proteins inhibited the metabolism ofL-arginine intoL-citrulline by NO synthase. We conclude from our findings that endogenous basic proteins might be involved in the regulation of neuronal NO synthase activity. Their effects on the enzyme could be either stimulatory or inhibitory, depending on whether the basic proteins exert their effects extracellularly or intracellularly, respectively. 相似文献
967.
Every two months, diel depth profiles were made of dissolved oxygen, pH, temperature and conductivity at two stations in Lake Kissimmee, Florida, from July 1974 through June 1975. Results suggest that stratification does not occur in the large (137 km2), shallow (mean depth 2.5 m) lake, though steep vertical gradients in these parameters may develop. The data also suggest that when these gradients do occur, they rapidly degenerate at night or under slight wind stress. Since many Florida lakes are relatively shallow (mean depth < 5 m) and topography offers little obstruction to wind action, it is believed that the holomictic condition observed in Lake Kissimmee may be typical of the state's lakes, particularly those in the central portion of the peninsula. 相似文献
968.
969.
Environmental RNA interference 总被引:5,自引:0,他引:5
The discovery of RNA interference (RNAi), the process of sequence-specific gene silencing initiated by double-stranded RNA (dsRNA), has broadened our understanding of gene regulation and has revolutionized methods for genetic analysis. A remarkable property of RNAi in the nematode Caenorhabditis elegans and in some other multicellular organisms is its systemic nature: silencing signals can cross cellular boundaries and spread between cells and tissues. Furthermore, C. elegans and some other organisms can also perform environmental RNAi: sequence-specific gene silencing in response to environmentally encountered dsRNA. This phenomenon has facilitated significant technological advances in diverse fields including functional genomics and agricultural pest control. Here, we describe the characterization and current understanding of environmental RNAi and discuss its potential applications. 相似文献
970.
Silva C Wood JR Salvador L Zhang Z Kostetskii I Williams CJ Strauss JF 《Molecular reproduction and development》2009,76(1):11-21
Cells that morphologically and functionally resemble male germ cells can be spontaneously derived from ES cells. However, this process is inefficient and unpredictable suggesting that the expression pattern of male germ cell associated genes during spontaneous ES cell differentiation does not mimic the in vivo profiles of the genes. Thus, in the present study, the temporal profile of genes expressed at different stages of male germ cell development was examined in differentiating ES cells. The effect of all-trans retinoic acid (RA) which is a known inducer of primordial germ cell (PGC) proliferation/survival in vitro and testosterone which is required for spermatogenesis in vivo on the expression of these genes was also determined. Each of the 12 genes analyzed exhibited one of four temporal expression patterns in untreated differentiating ES cells: progressively decreased (Dppa3, Sycp3, Msy2), initially low and then increased (Stra8, Sycp1, Dazl, Act, Prm1), initially decreased and then increased (Piwil2, Tex14), or relatively unchanged (Akap3, Odf2). RA-treated cells exhibited increased expression of Stra8, Dazl, Act, and Prm1 and suppressed expression of Dppa3 compared to untreated controls. Furthermore, testosterone increased expression of Stra8 while the combination of RA and testosterone synergistically increased expression of Act. Our findings establish a comprehensive profile of male germ cell gene expression during spontaneous differentiation of murine ES cells and describe the capacity of RA and testosterone to modulate the expression of these genes. Furthermore, these data represent an important first step in designing a plausible directed differentiation protocol for male germ cells. 相似文献