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791.
New insights into the mechanism of Alzheimer amyloid-beta fibrillogenesis inhibition by N-methylated peptides 总被引:1,自引:0,他引:1
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Alzheimer's disease is a debilitating neurodegenerative disorder associated with the abnormal self-assembly of amyloid-beta (Abeta) peptides into fibrillar species. N-methylated peptides homologous to the central hydrophobic core of the Abeta peptide are potent inhibitors of this aggregation process. In this work, we use fully atomistic molecular dynamics simulations to study the interactions of the N-methylated peptide inhibitor Abeta16-20m (Ac-Lys(16)-(Me)Leu(17)-Val(18)-(Me)Phe(19)-Phe(20)-NH(2)) with a model protofilament consisting of Alzheimer Abeta16-22 peptides. Our simulations indicate that the inhibitor peptide can bind to the protofilament at four different sites: 1), at the edge of the protofilament; 2), on the exposed face of a protofilament layer; 3), between the protofilament layers; and 4), between the protofilament strands. The different binding scenarios suggest several mechanisms of fibrillogenesis inhibition: 1), fibril inhibition of longitudinal growth (in the direction of monomer deposition); 2), fibril inhibition of lateral growth (in the direction of protofilament assembly); and 3), fibril disassembly by strand removal and perturbation of the periodicity of the protofilament (disruption of fibril morphology). Our simulations suggest that the Abeta16-20m inhibitor can act on both prefibrillar species and mature fibers and that the specific mechanism of inhibition may depend on the structural nature of the Abeta aggregate. Disassembly of the fibril can be explained by a mechanism through which the inhibitor peptides bind to disaggregated or otherwise free Abeta16-22 peptides in solution, leading to a shift in the equilibrium from a fibrillar state to one dominated by inhibitor-bound Abeta16-22 peptides. 相似文献
792.
Pannier AK Ariazi EA Bellis AD Bengali Z Jordan VC Shea LD 《Biotechnology and bioengineering》2007,98(2):486-497
Transfected cell arrays (TCAs) represent a high-throughput technique to correlate gene expression with functional cell responses. Despite advances in TCAs, improvements are needed for the widespread application of this technology. We have developed a TCA that combines a two-plasmid system and dual-bioluminescence imaging to quantitatively normalize for variability in transfection and increase sensitivity. The two-plasmids consist of: (i) normalization plasmid present within each spot, and (ii) functional plasmid that varies between spots, responsible for the functional endpoint of the array. Bioluminescence imaging of dual-luciferase reporters (renilla, firefly luciferase) provides sensitive and quantitative detection of cellular response, with minimal post-transfection processing. The array was applied to quantify estrogen receptor alpha (ERalpha) activity in MCF-7 breast cancer cells. A plasmid containing an ERalpha-regulated promoter directing firefly luciferase expression was mixed with a normalization plasmid, complexed with cationic lipids and deposited into an array. ER induction mimicked results obtained through traditional assays methods, with estrogen inducing luciferase expression 10-fold over the antiestrogen fulvestrant or vehicle. Furthermore, the array captured a dose response to estrogen, demonstrating the sensitivity of bioluminescence quantification. This system provides a tool for basic science research, with potential application for the development of patient specific therapies. 相似文献
793.
Probing the structural hierarchy and energy landscape of an RNA T-loop hairpin 总被引:1,自引:0,他引:1
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The T-loop motif is an important recurrent RNA structural building block consisting of a U-turn sub-motif and a UA trans Watson–Crick/Hoogsteen base pair. In the presence of a hairpin stem, the UA non-canonical base pair becomes part of the UA-handle motif. To probe the hierarchical organization and energy landscape of the T-loop, we performed replica exchange molecular dynamics (REMD) simulations of the T-loop in isolation and as part of a hairpin. Our simulations reveal that the isolated T-loop adopts coil conformers stabilized by base stacking. The T-loop hairpin shows a highly rugged energy landscape featuring multiple local minima with a transition state for folding consisting of partially zipped states. The U-turn displays a high conformational flexibility both when the T-loop is in isolation and as part of a hairpin. On the other hand, the stability of the UA non-canonical base pair is enhanced in the presence of the UA-handle. This motif is apparently a key component for stabilizing the T-loop, while the U-turn is mostly involved in long-range interaction. Our results suggest that the stability and folding of small RNA motifs are highly dependent on local context. 相似文献
794.
Rb regulates interactions between hematopoietic stem cells and their bone marrow microenvironment 总被引:5,自引:0,他引:5
Hematopoiesis is maintained by stem cells (HSCs) that undergo fate decisions by integrating intrinsic and extrinsic signals, with the latter derived from the bone marrow (BM) microenvironment. Cell-cycle regulation can modulate stem cell fate, but it is unknown whether this represents an intrinsic or extrinsic effector of fate decisions. We have investigated the role of the retinoblastoma protein (RB), a central regulator of the cell cycle, in hematopoiesis. Widespread inactivation of RB in the murine hematopoietic system resulted in profound myeloproliferation. HSCs were lost from the BM due to mobilization to extramedullary sites and differentiation. This phenotype was not intrinsic to HSCs, but, rather, was the consequence of an RB-dependent interaction between myeloid-derived cells and the microenvironment. These findings demonstrate that myeloproliferation may result from perturbed interactions between hematopoietic cells and the niche. Therefore, RB extrinsically regulates HSCs by maintaining the capacity of the BM to support normal hematopoiesis and HSCs. 相似文献
795.
Jos F Muoz Rory M Welsh Terrance Shea Dhwani Batra Lalitha Gade Dakota Howard Lori A Rowe Jacques F Meis Anastasia P Litvintseva Christina A Cuomo 《Genetics》2021,218(1)
Candida auris is an emerging fungal pathogen of rising concern due to global spread, the ability to cause healthcare-associated outbreaks, and antifungal resistance. Genomic analyses revealed that early contemporaneously detected cases of C. auris were geographically stratified into four major clades. While Clades I, III, and IV are responsible for ongoing outbreaks of invasive and multidrug-resistant infections, Clade II, also termed the East Asian clade, consists primarily of cases of ear infection, is often susceptible to all antifungal drugs, and has not been associated with outbreaks. Here, we generate chromosome-level assemblies of twelve isolates representing the phylogenetic breadth of these four clades and the only isolate described to date from Clade V. This Clade V genome is highly syntenic with those of Clades I, III, and IV, although the sequence is highly divergent from the other clades. Clade II genomes appear highly rearranged, with translocations occurring near GC-poor regions, and large subtelomeric deletions in most chromosomes, resulting in a substantially different karyotype. Rearrangements and deletion lengths vary across Clade II isolates, including two from a single patient, supporting ongoing genome instability. Deleted subtelomeric regions are enriched in Hyr/Iff-like cell-surface proteins, novel candidate cell wall proteins, and an ALS-like adhesin. Cell wall proteins from these families and other drug-related genes show clade-specific signatures of selection in Clades I, III, and IV. Subtelomeric dynamics and the conservation of cell surface proteins in the clades responsible for global outbreaks causing invasive infections suggest an explanation for the different phenotypes observed between clades. 相似文献
796.
Diane E. Bild Robyn McClelland Joel D. Kaufman Roger Blumenthal Gregory L. Burke J. Jeffrey Carr Wendy S. Post Thomas C. Register Steven Shea Moyses Szklo 《PloS one》2014,9(4)
Background
Coronary heart disease (CHD) incidence has declined significantly in the US, as have levels of major coronary risk factors, including LDL-cholesterol, hypertension and smoking, but whether trends in subclinical atherosclerosis mirror these trends is not known.Methods and Findings
To describe recent secular trends in subclinical atherosclerosis as measured by serial evaluations of coronary artery calcification (CAC) prevalence in a population over 10 years, we measured CAC using computed tomography (CT) and CHD risk factors in five serial cross-sectional samples of men and women from four race/ethnic groups, aged 55–84 and without clinical cardiovascular disease, who were members of Multi-Ethnic Study of Atherosclerosis (MESA) cohort from 2000 to 2012. Sample sizes ranged from 1062 to 4837. After adjusting for age, gender, and CT scanner, the prevalence of CAC increased across exams among African Americans, whose prevalence of CAC was 52.4% in 2000–02, 50.4% in 2003–04, 60.0% is 2005–06, 57.4% in 2007–08, and 61.3% in 2010–12 (p for trend <0.001). The trend was strongest among African Americans aged 55–64 [prevalence ratio for 2010–12 vs. 2000–02, 1.59 (95% confidence interval 1.06, 2.39); p = 0.005 for trend across exams]. There were no consistent trends in any other ethnic group. Risk factors generally improved in the cohort, and adjustment for risk factors did not change trends in CAC prevalence.Conclusions
There was a significant secular trend towards increased prevalence of CAC over 10 years among African Americans and no change in three other ethnic groups. Trends did not reflect concurrent general improvement in risk factors. The trend towards a higher prevalence of CAC in African Americans suggests that CHD risk in this population is not improving relative to other groups. 相似文献797.
Dynamic transcription factor activity profiles reveal key regulatory interactions during megakaryocytic and erythroid differentiation
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798.
Vicente Ramírez Sjoerd Van der Ent Javier García-Andrade Alberto Coego Corné MJ Pieterse Pablo Vera 《BMC plant biology》2010,10(1):199
Background
Upon appropriate stimulation, plants increase their level of resistance against future pathogen attack. This phenomenon, known as induced resistance, presents an adaptive advantage due to its reduced fitness costs and its systemic and broad-spectrum nature. In Arabidopsis, different types of induced resistance have been defined based on the signaling pathways involved, particularly those dependent on salicylic acid (SA) and/or jasmonic acid (JA). 相似文献799.
Anna E van der Windt Esther Haak Ruud HJ Das Nicole Kops Tim JM Welting Marjolein MJ Caron Niek P van Til Jan AN Verhaar Harrie Weinans Holger Jahr 《Arthritis research & therapy》2010,12(3):R100
Introduction
Chondrocytes experience a hypertonic environment compared with plasma (280 mOsm) due to the high fixed negative charge density of cartilage. Standard isolation of chondrocytes removes their hypertonic matrix, exposing them to nonphysiological conditions. During in vitro expansion, chondrocytes quickly lose their specialized phenotype, making them inappropriate for cell-based regenerative strategies. We aimed to elucidate the effects of tonicity during isolation and in vitro expansion on chondrocyte phenotype. 相似文献800.
FSD-1, a designed small ultrafast folder with a ββα fold, has been actively studied in the last few years as a model system for studying protein folding mechanisms and for testing of the accuracy of computational models. The suitability of this protein to describe the folding of naturally occurring α/β proteins has recently been challenged based on the observation that the melting transition is very broad, with ill-resolved baselines. Using molecular dynamics simulations with the AMBER protein force field (ff96) coupled with the implicit solvent model (IGB = 5), we shed new light into the nature of this transition and resolve the experimental controversies. We show that the melting transition corresponds to the melting of the protein as a whole, and not solely to the helix-coil transition. The breadth of the folding transition arises from the spread in the melting temperatures (from ∼325 K to ∼302 K) of the individual transitions: formation of the hydrophobic core, β-hairpin and tertiary fold, with the helix formed earlier. Our simulations initiated from an extended chain accurately predict the native structure, provide a reasonable estimate of the transition barrier height, and explicitly demonstrate the existence of multiple pathways and multiple transition states for folding. Our exhaustive sampling enables us to assess the quality of the Amber ff96/igb5 combination and reveals that while this force field can predict the correct native fold, it nonetheless overstabilizes the α-helix portion of the protein (Tm = ∼387K) as well as the denatured structures. 相似文献