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Bergman MR Teerlink JR Mahimkar R Li L Zhu BQ Nguyen A Dahi S Karliner JS Lovett DH 《American journal of physiology. Heart and circulatory physiology》2007,292(4):H1847-H1860
Although enhanced cardiac matrix metalloproteinase (MMP)-2 synthesis has been associated with ventricular remodeling and failure, whether MMP-2 expression is a direct mediator of this process is unknown. We generated transgenic mice expressing active MMP-2 driven by the alpha-myosin heavy chain promoter. At 4 mo MMP-2 transgenic hearts demonstrated expression of the MMP-2 transgene, myocyte hypertrophy, breakdown of Z-band registration, lysis of myofilaments, disruption of sarcomere and mitochondrial architecture, and cardiac fibroblast proliferation. Hearts from 8-mo-old transgenic mice displayed extensive myocyte disorganization and dropout with replacement fibrosis and perivascular fibrosis. Older transgenic mice also exhibited a massive increase in cardiac MMP-2 expression, representing recruitment of endogenous MMP-2 synthesis, with associated expression of MMP-9 and membrane type 1 MMP. Increases in diastolic [control (C) 33 +/- 3 vs. MMP 51 +/- 12 microl; P = 0.003] and systolic (C 7 +/- 2 vs. MMP 28 +/- 14 microl; P = 0.003) left ventricular (LV) volumes and relatively preserved stroke volume (C 26 +/- 4 vs. MMP 23 +/- 3 microl; P = 0.16) resulted in markedly decreased LV ejection fraction (C 78 +/- 7% vs. MMP 48 +/- 16%; P = 0.0006). Markedly impaired systolic function in the MMP transgenic mice was demonstrated in the reduced preload-adjusted maximal power (C 240 +/- 84 vs. MMP 78 +/- 49 mW/microl(2); P = 0.0003) and decreased end-systolic pressure-volume relation (C 7.5 +/- 1.5 vs. MMP 4.7 +/- 2.0; P = 0.016). Expression of active MMP-2 is sufficient to induce severe ventricular remodeling and systolic dysfunction in the absence of superimposed injury. 相似文献
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Glial Fibrillary Acidic Protein (GFAP) is an intermediate-filament (IF) protein that maintains the astrocytes of the Central Nervous
System in Human. This is differentially expressed during serological studies in inflamed condition such as Rheumatoid Arthritis
(RA). Therefore, it is of interest to glean molecular insight using a model of GFAP (49.88 kDa) due to its crystallographic nonavailability.
The present study has been taken into consideration to construct computational protein model using Modeller 9.11.
The structural relevance of the protein was verified using Gromacs 4.5 followed by validation through PROCHECK, Verify 3D,
WHAT-IF, ERRAT and PROVE for reliability. The constructed three dimensional (3D) model of GFAP protein had been scrutinized
to reveal the associated functions by identifying ligand binding sites and active sites. Molecular level interaction study revealed
five possible surface cavities as active sites. The model finds application in further computational analysis towards drug discovery
in order to minimize the effect of inflammation. 相似文献
56.
Janez Jenko Gregor Gorjanc Matthew A Cleveland Rajeev K Varshney C. Bruce A Whitelaw John A Woolliams John M Hickey 《遗传、选种与进化》2015,47(1)
Background
Genome editing (GE) is a method that enables specific nucleotides in the genome of an individual to be changed. To date, use of GE in livestock has focussed on simple traits that are controlled by a few quantitative trait nucleotides (QTN) with large effects. The aim of this study was to evaluate the potential of GE to improve quantitative traits that are controlled by many QTN, referred to here as promotion of alleles by genome editing (PAGE).Methods
Multiple scenarios were simulated to test alternative PAGE strategies for a quantitative trait. They differed in (i) the number of edits per sire (0 to 100), (ii) the number of edits per generation (0 to 500), and (iii) the extent of use of PAGE (i.e. editing all sires or only a proportion of them). The base line scenario involved selecting individuals on true breeding values (i.e., genomic selection only (GS only)-genomic selection with perfect accuracy) for several generations. Alternative scenarios complemented this base line scenario with PAGE (GS + PAGE). The effect of different PAGE strategies was quantified by comparing response to selection, changes in allele frequencies, the number of distinct QTN edited, the sum of absolute effects of the edited QTN per generation, and inbreeding.Results
Response to selection after 20 generations was between 1.08 and 4.12 times higher with GS + PAGE than with GS only. Increases in response to selection were larger with more edits per sire and more sires edited. When the total resources for PAGE were limited, editing a few sires for many QTN resulted in greater response to selection and inbreeding compared to editing many sires for a few QTN. Between the scenarios GS only and GS + PAGE, there was little difference in the average change in QTN allele frequencies, but there was a major difference for the QTN with the largest effects. The sum of the effects of the edited QTN decreased across generations.Conclusions
This study showed that PAGE has great potential for application in livestock breeding programs, but inbreeding needs to be managed.Electronic supplementary material
The online version of this article (doi:10.1186/s12711-015-0135-3) contains supplementary material, which is available to authorized users. 相似文献57.
Pandrea I Gaufin T Gautam R Kristoff J Mandell D Montefiori D Keele BF Ribeiro RM Veazey RS Apetrei C 《PLoS pathogens》2011,7(8):e1002170
Understanding the mechanism of infection control in elite controllers (EC) may shed light on the correlates of control of disease progression in HIV infection. However, limitations have prevented a clear understanding of the mechanisms of elite controlled infection, as these studies can only be performed at randomly selected late time points in infection, after control is achieved, and the access to tissues is limited. We report that SIVagm infection is elite-controlled in rhesus macaques (RMs) and therefore can be used as an animal model for EC HIV infection. A robust acute infection, with high levels of viral replication and dramatic mucosal CD4(+) T cell depletion, similar to pathogenic HIV-1/SIV infections of humans and RMs, was followed by complete and durable control of SIVagm replication, defined as: undetectable VLs in blood and tissues beginning 72 to 90 days postinoculation (pi) and continuing at least 4 years; seroreversion; progressive recovery of mucosal CD4(+) T cells, with complete recovery by 4 years pi; normal levels of T cell immune activation, proliferation, and apoptosis; and no disease progression. This "functional cure" of SIVagm infection in RMs could be reverted after 4 years of control of infection by depleting CD8 cells, which resulted in transient rebounds of VLs, thus suggesting that control may be at least in part immune mediated. Viral control was independent of MHC, partial APOBEC restriction was not involved in SIVagm control in RMs and Trim5 genotypes did not impact viral replication. This new animal model of EC lentiviral infection, in which complete control can be predicted in all cases, permits research on the early events of infection in blood and tissues, before the defining characteristics of EC are evident and when host factors are actively driving the infection towards the EC status. 相似文献
58.
Agricultural biotechnology for crop improvement in a variable climate: hope or hype? 总被引:2,自引:0,他引:2
Developing crops that are better adapted to abiotic stresses is important for food production in many parts of the world today. Anticipated changes in climate and its variability, particularly extreme temperatures and changes in rainfall, are expected to make crop improvement even more crucial for food production. Here, we review two key biotechnology approaches, molecular breeding and genetic engineering, and their integration with conventional breeding to develop crops that are more tolerant of abiotic stresses. In addition to a multidisciplinary approach, we also examine some constraints that need to be overcome to realize the full potential of agricultural biotechnology for sustainable crop production to meet the demands of a projected world population of nine billion in 2050. 相似文献
59.
Chowdhury F Rahman MA Begum YA Khan AI Faruque AS Saha NC Baby NI Malek MA Kumar AR Svennerholm AM Pietroni M Cravioto A Qadri F 《PLoS neglected tropical diseases》2011,5(4):e999
Background
In Bangladesh, increases in cholera epidemics are being documented with a greater incidence and severity. The aim of this prospective study was to identify the prevalence and importance of V. cholerae O1 and enterotoxigenic Escherichia coli (ETEC) as causal agents of severe diarrhea in a high diarrhea prone urban area in Dhaka city.Methodology
Systematic surveillance was carried out on all diarrheal patients admitted from Mirpur between March 2008 to February 2010 at the ICDDR, B hospital. Stool or rectal swabs were collected from every third diarrheal patient for microbiological evaluation.Principal Findings
Of diarrheal patients attending the hospital from Mirpur, 41% suffered from severe dehydration with 39% requiring intravenous rehydration therapy. More diarrheal patients were above five years of age (64%) than those below five years of age (36%). About 60% of the patients above five years of age had severe dehydration compared with only 9% of patients under five years of age. The most prevalent pathogen isolated was Vibrio cholerae O1 (23%) followed by ETEC (11%). About 8% of cholera infection was seen in infants with the youngest children being one month of age while in the case of ETEC the rate was 11%. Of the isolated ETEC strains, the enterotoxin type were almost equally distributed; ST accounted for 31% of strains; LT/ST for 38% and LT for 31%.Conclusion
V. cholerae O1 is the major bacterial pathogen and a cause of severe cholera disease in 23% of patients from Mirpur. This represents a socioeconomic group that best reflects the major areas of high cholera burden in the country. Vaccines that can target such high risk groups in the country and the region will hopefully be able to reduce the disease morbidity and the transmission of pathogens that impact the life and health of people. 相似文献60.