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991.
Jayaraman R 《Journal of genetics》2011,90(2):383-391
Hypermutability is a phenotype characterized by a moderate to high elevation of spontaneous mutation rates and could result
from DNA replication errors, defects in error correction mechanisms and many other causes. The elevated mutation rates are
helpful to organisms to adapt to sudden and unforeseen threats to survival. At the same time hypermutability also leads to
the generation of many deleterious mutations which offset its adaptive value and therefore disadvantageous. Nevertheless,
it is very common in nature, especially among clinical isolates of pathogens. Hypermutability is inherited by indirect (second
order) selection along with the beneficial mutations generated. At large population sizes and high mutation rates many cells
in the population could concurrently acquire beneficial mutations of varying adaptive (fitness) values. These lineages compete
with the ancestral cells and also among themselves for fixation. The one with the ‘fittest’ mutation gets fixed ultimately
while the others are lost. This has been called ‘clonal interference’ which puts a speed limit on adaptation. The original
clonal interference hypothesis has been modified recently. Nonheritable (transient) hypermtability conferring significant
adaptive benefits also occur during stress response although its molecular basis remains controversial. The adaptive benefits
of heritable hypermutability are discussed with emphasis on host–pathogen interactions. 相似文献
992.
Belser JA Jayaraman A Raman R Pappas C Zeng H Cox NJ Katz JM Sasisekharan R Tumpey TM 《PloS one》2011,6(9):e25091
Influenza viruses isolated during the 2009 H1N1 pandemic generally lack known molecular determinants of virulence associated with previous pandemic and highly pathogenic avian influenza viruses. The frequency of the amino acid substitution D222G in the hemagglutinin (HA) of 2009 H1N1 viruses isolated from severe but not mild human cases represents the first molecular marker associated with enhanced disease. To assess the relative contribution of this substitution in virus pathogenesis, transmission, and tropism, we introduced D222G by reverse genetics in the wild-type HA of the 2009 H1N1 virus, A/California/04/09 (CA/04). A dose-dependent glycan array analysis with the D222G virus showed a modest reduction in the binding avidity to human-like (α2-6 sialylated glycan) receptors and an increase in the binding to avian-like (α2-3 sialylated glycan) receptors in comparison with wild-type virus. In the ferret pathogenesis model, the D222G mutant virus was found to be similar to wild-type CA/04 virus with respect to lethargy, weight loss and replication efficiency in the upper and lower respiratory tract. Moreover, based on viral detection, the respiratory droplet transmission properties of these two viruses were found to be similar. The D222G virus failed to productively infect mice inoculated by the ocular route, but exhibited greater viral replication and weight loss than wild-type CA/04 virus in mice inoculated by the intranasal route. In a more relevant human cell model, D222G virus replicated with delayed kinetics compared with wild-type virus but to higher titer in human bronchial epithelial cells. These findings suggest that although the D222G mutation does not influence virus transmission, it may be considered a molecular marker for enhanced replication in certain cell types. 相似文献
993.
Bacterial lipoproteins have many important functions owing to their essential nature and roles in pathogenesis and represent a class of possible vaccine candidates. The prediction of bacterial lipoproteins from sequence is thus an important task for computational vaccinology. A Support Vector Machines (SVM) based module for predicting bacterial lipoproteins, LIPOPREDICT, has been developed. The best performing sequence model were generated using selected dipeptide composition, which gave 97% accuracy of prediction. The results obtained were compared very well with those of previously developed methods. 相似文献
994.
Zhou Z Li KL Rieck D Ouyang Y Chandra M Dong WJ 《The Journal of biological chemistry》2012,287(10):7661-7674
The regulatory function of cardiac troponin I (cTnI) involves three important contiguous regions within its C-domain: the inhibitory region (IR), the regulatory region (RR), and the mobile domain (MD). Within these regions, the dynamics of regional structure and kinetics of transitions in dynamic state are believed to facilitate regulatory signaling. This study was designed to use fluorescence anisotropy techniques to acquire steady-state and kinetic information on the dynamic state of the C-domain of cTnI in the reconstituted thin filament. A series of single cysteine cTnI mutants was generated, labeled with the fluorophore tetramethylrhodamine, and subjected to various anisotropy experiments at the thin filament level. The structure of the IR was found to be less dynamic than that of the RR and the MD, and Ca(2+) binding induced minimal changes in IR dynamics: the flexibility of the RR decreased, whereas the MD became more flexible. Anisotropy stopped-flow experiments showed that the kinetics describing the transition of the MD and RR from the Ca(2+)-bound to the Ca(2+)-free dynamic states were significantly faster (53.2-116.8 s(-1)) than that of the IR (14.1 s(-1)). Our results support the fly casting mechanism, implying that an unstructured MD with rapid dynamics and kinetics plays a critical role to initiate relaxation upon Ca(2+) dissociation by rapidly interacting with actin to promote the dissociation of the RR from the N-domain of cTnC. In contrast, the IR responds to Ca(2+) signals with slow structural dynamics and transition kinetics. The collective findings suggested a fourth state of activation. 相似文献
995.
Mahesh Bachu Swarupa Yalla Mangaiarkarasi Asokan Anjali Verma Ujjwal Neogi Shilpee Sharma Rajesh V. Murali Anil Babu Mukthey Raghavendra Bhatt Snehajyoti Chatterjee Roshan Elizabeth Rajan Narayana Cheedarla Venkat S. Yadavalli Anita Mahadevan Susarla K. Shankar Nirmala Rajagopalan Anita Shet Shanmugam Saravanan Pachamuthu Balakrishnan Suniti Solomon Madhu Vajpayee Kadappa Shivappa Satish Tapas K. Kundu Kuan-Teh Jeang Udaykumar Ranga 《The Journal of biological chemistry》2012,287(53):44714-44735
996.
Structure of Sad1-UNC84 homology (SUN) domain defines features of molecular bridge in nuclear envelope 总被引:1,自引:0,他引:1
Zhou Z Du X Cai Z Song X Zhang H Mizuno T Suzuki E Yee MR Berezov A Murali R Wu SL Karger BL Greene MI Wang Q 《The Journal of biological chemistry》2012,287(8):5317-5326
The SUN (Sad1-UNC-84 homology) domain is conserved in a number of nuclear envelope proteins involved in nuclear migration, meiotic telomere tethering, and antiviral responses. The LINC (linker of nucleoskeleton and cytoskeleton) complex, formed by the SUN and the nesprin proteins at the nuclear envelope, serves as a mechanical linkage across the nuclear envelope. Here we report the crystal structure of the SUN2 protein SUN domain, which reveals a homotrimer. The SUN domain is sufficient to mediate binding to the KASH (Klarsicht, ANC-1, and Syne homology) domain of nesprin 2, and the regions involved in the interaction have been identified. Binding of the SUN domain to the KASH domain is abolished by deletion of a region important for trimerization or by point mutations associated with nuclear migration failure. We propose a model of the LINC complex, where the SUN and the KASH domains form a higher ordered oligomeric network in the nuclear envelope. These findings provide the structural basis for understanding the function and the regulation of the LINC complex. 相似文献
997.
Keita Saito Shingo Matsumoto Hironobu Yasui Nallathamby Devasahayam Sankaran Subramanian Jeeva P. Munasinghe Vyomesh Patel J. Silvio Gutkind James B. Mitchell Murali C. Krishna 《PloS one》2012,7(11)
Rapamycin is an allosteric inhibitor of mammalian target of rapamycin, and inhibits tumor growth and angiogenesis. Recent studies suggested a possibility that rapamycin renormalizes aberrant tumor vasculature and improves tumor oxygenation. The longitudinal effects of rapamycin on angiogenesis and tumor oxygenation were evaluated in murine squamous cell carcinoma (SCCVII) by electron paramagnetic resonance imaging (EPRI) and magnetic resonance imaging (MRI) to identify an optimal time after rapamycin treatment for enhanced tumor radioresponse. Rapamycin treatment was initiated on SCCVII solid tumors 8 days after implantation (500–750 mm3) and measurements of tumor pO2 and blood volume were conducted from day 8 to 14 by EPRI/MRI. Microvessel density was evaluated over the same time period by immunohistochemical analysis. Tumor blood volume as measured by MRI significantly decreased 2 days after rapamycin treatment. Tumor pO2 levels modestly but significantly increased 2 days after rapamycin treatment; whereas, it decreased in non-treated control tumors. Furthermore, the fraction of hypoxic area (pixels with pO2<10 mm Hg) in the tumor region decreased 2 days after rapamycin treatments. Immunohistochemical analysis of tumor microvessel density and pericyte coverage revealed that microvessel density decreased 2 days after rapamycin treatment, but pericyte coverage did not change, similar to what was seen with anti-angiogenic agents such as sunitinib which cause vascular renormalization. Collectively, EPRI/MRI co-imaging can provide non-invasive evidence of rapamycin-induced vascular renormalization and resultant transient increase in tumor oxygenation. Improved oxygenation by rapamycin treatment provides a temporal window for anti-cancer therapies to realize enhanced response to radiotherapy. 相似文献
998.
999.
Murali G Milne GL Webb CD Stewart AB McMillan RP Lyle BC Hulver MW Saraswathi V 《Journal of lipid research》2012,53(10):2186-2197
Fish oil (FO) is a potent anti-inflammatory and lipid-lowering agent. Because inflammation can modulate lipid metabolism and vice versa, we hypothesized that combining FO with cyclooxygenase inhibitors (COXIBs), well-known anti-inflammatory drugs, can enhance the anti-inflammatory and lipid-lowering effect of FO. LDLR (-/-) mice were fed a high-fat diet supplemented with 6% olive oil or FO for 12 wk in the presence or absence of indomethacin (Indo, 6 mg/l drinking water). FO reduced plasma total cholesterol by 30% but, in combination with Indo, exerted a greater decrease (44%). The reduction of liver cholesterol ester (CE) and triglycerides (TG) by FO (63% and 41%, respectively) was enhanced by Indo (80% in CE and 64% in TG). FO + Indo greatly increased the expression of genes modulating lipid metabolism and reduced the expression of inflammatory genes compared with control. The mRNA and/or protein expression of pregnane X receptor (PXR) and cytochrome P450 isoforms that alter inflammation and/or lipid metabolism are increased to a greater extent in mice that received FO + Indo. Moroever, the nuclear level of PXR is significantly increased in FO + Indo group. Combining FO with COXIBs may exert their beneficial effects on inflammation and lipid metabolism via PXR and cytochrome P450. 相似文献
1000.
Mishra R Jayaraman M Roland BP Landrum E Fullam T Kodali R Thakur AK Arduini I Wetzel R 《Journal of molecular biology》2012,415(5):900-917
Although oligomeric intermediates are transiently formed in almost all known amyloid assembly reactions, their mechanistic roles are poorly understood. Recently, we demonstrated a critical role for the 17-amino-acid N-terminus (htt(NT) segment) of huntingtin (htt) in the oligomer-mediated amyloid assembly of htt N-terminal fragments. In this mechanism, the htt(NT) segment forms the α-helix-rich core of the oligomers, leaving much of the polyglutamine (polyQ) segment disordered and solvent-exposed. Nucleation of amyloid structure occurs within this local high concentration of disordered polyQ. Here we demonstrate the kinetic importance of htt(NT) self-assembly by describing inhibitory htt(NT)-containing peptides that appear to work by targeting nucleation within the oligomer fraction. These molecules inhibit amyloid nucleation by forming mixed oligomers with the htt(NT) domains of polyQ-containing htt N-terminal fragments. In one class of inhibitors, nucleation is passively suppressed due to the reduced local concentration of polyQ within the mixed oligomer. In the other class, nucleation is actively suppressed by a proline-rich polyQ segment covalently attached to htt(NT). Studies with D-amino acid and scrambled sequence versions of htt(NT) suggest that inhibition activity is strongly linked to the propensity of inhibitory peptides to make amphipathic α-helices. Htt(NT) derivatives with C-terminal cell-penetrating peptide segments also exhibit excellent inhibitory activity. The htt(NT)-based peptides described here, especially those with protease-resistant d-amino acids and/or with cell-penetrating sequences, may prove useful as lead therapeutics for inhibiting the nucleation of amyloid formation in Huntington's disease. 相似文献