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91.
Kara A. Bernstein Eleni P. Mimitou Michael J. Mihalevic Huan Chen Ivana Sunjaveric Lorraine S. Symington Rodney Rothstein 《Genetics》2013,195(4):1241-1251
The RecQ helicase family is critical during DNA damage repair, and mutations in these proteins are associated with Bloom, Werner, or Rothmund-Thompson syndromes in humans, leading to cancer predisposition and/or premature aging. In the budding yeast Saccharomyces cerevisiae, mutations in the RecQ homolog, SGS1, phenocopy many of the defects observed in the human syndromes. One challenge to studying RecQ helicases is that their disruption leads to a pleiotropic phenotype. Using yeast, we show that the separation-of-function allele of SGS1, sgs1-D664Δ, has impaired activity at DNA ends, resulting in a resection processivity defect. Compromising Sgs1 resection function in the absence of the Sae2 nuclease causes slow growth, which is alleviated by making the DNA ends accessible to Exo1 nuclease. Furthermore, fluorescent microscopy studies reveal that, when Sgs1 resection activity is compromised in sae2Δ cells, Mre11 repair foci persist. We suggest a model where the role of Sgs1 in end resection along with Sae2 is important for removing Mre11 from DNA ends during repair. 相似文献
92.
93.
Jirayu Tanprasertsuk Binxing Li Paul S. Bernstein Rohini Vishwanathan Mary Ann Johnson Leonard Poon Elizabeth J. Johnson 《PloS one》2016,11(5)
Lutein, a dietary carotenoid, selectively accumulates in human retina and brain. While many epidemiological studies show evidence of a relationship between lutein status and cognitive health, lutein’s selective uptake in human brain tissue and its potential function in early neural development and cognitive health have been poorly evaluated at a molecular level. The objective of this study was to evaluate the cross-sectional relationship between concentrations of brain lutein and StARD3 (identified as its binding protein in retinal tissue) among three age groups: infants (1–4 months, n = 10), older adults (55–86 years, n = 8), and centenarians (98–105 years, n = 10). Brain lutein concentrations were analyzed by high-performance liquid chromatography and StARD3 levels were analyzed by Western Blot analysis. The strong relationship in infant brains (r = 0.75, P < 0.001) suggests that lutein has a role in neural development. The relationship remained significant but weaker in older adults (r = 0.51, P < 0.05) and insignificant in centenarians (r = 0.08, P > 0.05), seven of whom had mild cognitive impairment (MCI) or dementia. These exploratory findings suggest an age-related decrease or abnormality of StARD3 activity in human brain. Given that StARD3 is also involved in cholesterol transportation, a process that is aberrant in neurodegenerative diseases, the potential protective function of lutein against these diseases remains to be explored. 相似文献
94.
Yan Guo Mary A. Johnson Zara Mehrabian Manoj K. Mishra Rangaramanujam Kannan Neil R. Miller Steven L. Bernstein 《PloS one》2016,11(4)
IntroductionPolyamidoamine dendrimer nanoparticles (~ 4 nanometers) are inert polymers that can be linked to biologically active compounds. These dendrimers selectively target and accumulate in inflammatory cells upon systemic administration. Dendrimer-linked compounds enable sustained release of therapeutic compounds directly at the site of damage. The purpose of this study was to determine if dendrimers can be used to target the optic nerve (ON) ischemic lesion in our rodent and nonhuman primate models of nonarteritic anterior ischemic optic neuropathy (NAION), a disease affecting >10,000 individuals in the US annually, and for which there currently is no effective treatment.MethodsNAION was induced in male Long-Evans rats (rNAION) and in one adult male rhesus monkey (pNAION) using previously described procedures. Dendrimers were covalently linked to near-infrared cyanine-5 fluorescent dye (D-Cy5) and injected both intravitreally and systemically (in the rats) or just systemically (in the monkey) to evaluate D-Cy5 tissue accumulation in the eye and optic nerve following induction of NAION.ResultsFollowing NAION induction, Cy-5 dendrimers selectively accumulated in astrocytes and circulating macrophages. Systemic dendrimer administration provided the best penetration of the ON lesion site when injected shortly after induction. Systemic administration 1 day post-induction in the pNAION model gave localization similar to that seen in the rats.ConclusionsDendrimers selectively target the ischemic ON lesion after induction of both rNAION and pNAION. Systemic nanoparticle-linked therapeutics thus may provide a powerful, targeted and safe approach to NAION treatment by providing sustained and focused treatment of the cells directly affected by ischemia. 相似文献
95.
Ilana Chefetz Edward Grimley Kun Yang Linda Hong Ekaterina V. Vinogradova Radu Suciu Ilya Kovalenko David Karnak Cynthia A. Morgan Mikhail Chtcherbinine Cameron Buchman Brandt Huddle Scott Barraza Meredith Morgan Kara A. Bernstein Euisik Yoon David B. Lombard Andrea Bild Ronald J. Buckanovich 《Cell reports》2019,26(11):3061-3075.e6
96.
Linda M. Delahanty Thomas A. Wadden Pamela J. Goodwin Catherine M. Alfano Cynthia A. Thomson Melinda L. Irwin Marian L. Neuhouser Tracy E. Crane Elizabeth Frank Patricia A. Spears Bonnie P. Gillis Dawn L. Hershman Electra D. Paskett Judith Hopkins Vanessa Bernstein Vered Stearns Julia White Clifford Hudis Eric P. Winer Lisa A. Carey Ann H. Partridge Jennifer A. Ligibel 《Obesity (Silver Spring, Md.)》2022,30(1):28-38
97.
Núñez NP Carpenter CL Perkins SN Berrigan D Jaque SV Ingles SA Bernstein L Forman MR Barrett JC Hursting SD 《Obesity (Silver Spring, Md.)》2007,15(8):1980-1987
Objective: To evaluate the effects of body adiposity on bone mineral density in the presence and absence of ovarian hormones in female mice and postmenopausal women. Research Methods and Procedures: We assessed percentage body fat, serum leptin levels, and bone mineral density in ovariectomized and non‐ovariectomized C57BL/6 female mice that had been fed various calorically dense diets to induce body weight profiles ranging from lean to very obese. Additionally, we assessed percentage body fat and whole body bone mineral density in 37 overweight and extremely obese postmenopausal women from the Women's Contraceptive and Reproductive Experiences study. Results: In mice, higher levels of body adiposity (>40% body fat) were associated with lower bone mineral density in ovariectomized C57BL/6 female mice. A similar trend was observed in a small sample of postmenopausal women. Discussion: The complementary studies in mice and women suggest that extreme obesity in postmenopausal women may be associated with reduced bone mineral density. Thus, extreme obesity (BMI > 40 kg/m2) may increase the risk for osteopenia and osteoporosis. Given the obesity epidemic in the U.S. and in many other countries, and, in particular, the rising number of extremely obese adult women, increased attention should be drawn to the significant and interrelated public health issues of obesity and osteoporosis. 相似文献
98.
Physiological basis for conservation of the signal recognition particle targeting pathway in Escherichia coli 总被引:2,自引:0,他引:2
The Escherichia coli signal recognition particle (SRP) is a ribonucleoprotein complex that targets nascent inner membrane proteins (IMPs) to transport sites in the inner membrane (IM). Since SRP depletion only partially inhibits IMP insertion under some growth conditions, however, it is not clear why the particle is absolutely essential for viability. Insights into this question emerged from experiments in which we analyzed the physiological consequences of reducing the intracellular concentration of SRP below the wild-type level. We found that even moderate SRP deficiencies that have little effect on cell growth led to the induction of a heat shock response. Genetic manipulations that suppress the heat shock response were lethal in SRP-deficient cells, indicating that the elevated synthesis of heat shock proteins plays an important role in maintaining cell viability. Although it is conceivable that the heat shock response serves to increase the capacity of cells to target IMPs via chaperone-based mechanisms, SRP-deficient cells did not show an increased dependence on either GroEL or DnaK. By contrast, the heat shock-regulated proteases Lon and ClpQ became essential for viability when SRP levels were reduced. These results suggest that the heat shock response protects SRP-deficient cells by increasing their capacity to degrade mislocalized IMPs. Consistent with this notion, a model IMP that was mislocalized in the cytoplasm as the result of SRP depletion appeared to be more stable in a Deltalon DeltaclpQ strain than in control cells. Taken together, the data provide direct evidence that SRP is essential in E. coli and possibly conserved throughout prokaryotic evolution as well partly because efficient IMP targeting prevents a toxic accumulation of aggregated proteins in the cytoplasm. 相似文献
99.
The angiotensin II type 1 (AT(1)) receptor signals via heterotrimeric G-proteins and intracellular tyrosine kinases. Here, we investigate a modified AT(1) receptor, termed M5, where the last five tyrosines (residues 292, 302, 312, 319, and 339) within the intracellular carboxyl tail have been mutated to phenylalanine. This receptor did not elevate cytosolic free calcium or inositol phosphate production in response to angiotensin II, suggesting an uncoupling of the receptor from G-protein activation. Despite this, the M5 receptor still activated tyrosine kinases, induced STAT1 tyrosine phosphorylation, and stimulated cell proliferation. We also studied another AT(1) mutant receptor, D74E, stably expressed in Chinese hamster ovarian cells and a fibroblast cell line from mice with a genetic inactivation of Galpha(q/11). Both cell lines have a deficit in calcium signaling and in G-protein activation, and yet in both cell lines, angiotensin II induced the time-dependent tyrosine phosphorylation of STAT1. These studies are the first to show the ability of a seven-transmembrane receptor to activate intracellular tyrosine kinase pathways in the absence of a G-protein-coupled rise in intracellular calcium. 相似文献
100.
The JB6 cell culture model is used to identify molecular determinants of susceptibility to the promotion of neoplastic transformation. Clonal variants susceptible to transformation ('P+' cells) form numerous anchorage-independent colonies in soft agar upon treatment with the phorbol ester tumor promoter TPA, whereas resistant variants ('P-' cells) do not. We now report that there is significantly less binding of activator protein-1 (AP-1) to its DNA binding site in P- cells than in P+ cells. Gel supershift assays were performed to detect association of all seven AP-1 family members with their DNA binding site in TPA-treated and -untreated P+ and P- cells. Significantly lower DNA binding and protein expression of JunD were detected in P- cells than in P+ cells. c-Jun was detected in P+, but not P-, AP-1-DNA complexes, and c-Fos was detected in P-, but not P+, AP-1-DNA complexes. These and other phenotype-specific differences in abundance and composition of AP-1-DNA complexes may play a role in the resistance of P- cells to tumor promoter-induced transformation. 相似文献