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71.
Pseudomonas aeruginosa is an opportunistic pathogen and the leading cause of mortality among immunocompromised patients in clinical setups. The hallmarks of virulence in P. aeruginosa encompass six biologically competent attributes that cumulatively drive disease progression in a multistep manner. These multifaceted hallmarks lay the principal foundation for rationalizing the complexities of pseudomonal infections. They include factors for host colonization and bacterial motility, biofilm formation, production of destructive enzymes, toxic secondary metabolites, iron-chelating siderophores and toxins. This arsenal of virulence hallmarks is fostered and stringently regulated by the bacterial signalling system called quorum sensing (QS). The central regulatory functions of QS in controlling the timely expression of these virulence hallmarks for adaptation and survival drive the disease outcome. This review describes the intricate mechanisms of QS in P. aeruginosa and its role in shaping bacterial responses, boosting bacterial fitness. We summarize the virulence hallmarks of P. aeruginosa, relating them with the QS circuitry in clinical infections. We also examine the role of QS in the development of drug resistance and propose a novel antivirulence therapy to combat P. aeruginosa infections. This can prove to be a next-generation therapy that may eventually become refractory to the use of conventional antimicrobial treatments.  相似文献   
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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an emerging respiratory virus responsible for the ongoing coronavirus disease 19 (COVID-19) pandemic. More than a year into this pandemic, the COVID-19 fatigue is still escalating and takes hold of the entire world population. Driven by the ongoing geographical expansion and upcoming mutations, the COVID-19 pandemic has taken a new shape in the form of emerging SARS-CoV-2 variants. These mutations in the viral spike (S) protein enhance the virulence of SARS-CoV-2 variants by improving viral infectivity, transmissibility and immune evasion abilities. Such variants have resulted in cluster outbreaks and fresh infection waves in various parts of the world with increased disease severity and poor clinical outcomes. Hence, the variants of SARS-CoV-2 pose a threat to human health and public safety. This review enlists the most recent updates regarding the presently characterized variants of SARS-CoV-2 recognized by the global regulatory health authorities (WHO, CDC). Based on the slender literature on SARS-CoV-2 variants, we collate information on the biological implications of these mutations on virus pathology. We also shed light on the efficacy of therapeutics and COVID-19 vaccines against the emerging SARS-CoV-2 variants.  相似文献   
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Selection on running capacity has created rat phenotypes of high-capacity runners (HCRs) that have enhanced cardiac function and low-capacity runners (LCRs) that exhibit risk factors of metabolic syndrome. We analysed hearts of HCRs and LCRs from generation 22 of selection using DIGE and identified proteins from MS database searches. The running capacity of HCRs was six-fold greater than LCRs. DIGE resolved 957 spots and proteins were unambiguously identified in 369 spots. Protein expression profiling detected 67 statistically significant (p<0.05; false discovery rate <10%, calculated using q-values) differences between HCRs and LCRs. Hearts of HCR rats exhibited robust increases in the abundance of each enzyme of the β-oxidation pathway. In contrast, LCR hearts were characterised by the modulation of enzymes associated with ketone body or amino acid metabolism. LCRs also exhibited enhanced expression of antioxidant enzymes such as catalase and greater phosphorylation of α B-crystallin at serine 59, which is a common point of convergence in cardiac stress signalling. Thus, proteomic analysis revealed selection on low running capacity is associated with perturbations in cardiac energy metabolism and provided the first evidence that the LCR cardiac proteome is exposed to greater oxidative stress.  相似文献   
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The human cysteine dioxygenase 1 (CDO1) gene is a non-heme structured, iron-containing metalloenzyme involved in the conversion of cysteine to cysteine sulfinate, and plays a key role in taurine biosynthesis. In our search for novel methylated gene promoters, we have analyzed differential RNA expression profiles of colorectal cancer (CRC) cell lines with or without treatment of 5-aza-2′-deoxycytidine. Among the genes identified, the CDO1 promoter was found to be differentially methylated in primary CRC tissues with high frequency compared to normal colon tissues. In addition, a statistically significant difference in the frequency of CDO1 promoter methylation was observed between primary normal and tumor tissues derived from breast, esophagus, lung, bladder and stomach. Downregulation of CDO1 mRNA and protein levels were observed in cancer cell lines and tumors derived from these tissue types. Expression of CDO1 was tightly controlled by promoter methylation, suggesting that promoter methylation and silencing of CDO1 may be a common event in human carcinogenesis. Moreover, forced expression of full-length CDO1 in human cancer cells markedly decreased the tumor cell growth in an in vitro cell culture and/or an in vivo mouse model, whereas knockdown of CDO1 increased cell growth in culture. Our data implicate CDO1 as a novel tumor suppressor gene and a potentially valuable molecular marker for human cancer.  相似文献   
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It has been suggested that Mycobacterium avium subspecies paratuberculosis has a role in Crohn''s disease. The organism may be acquired but is difficult to culture from the environment. We describe a quantitative PCR (qPCR) method to detect M. avium subsp. paratuberculosis in drinking water and the results of its application to drinking water and faucet biofilm samples collected in the United States.Mycobacterium avium subspecies paratuberculosis is a member of the Mycobacterium avium complex. M. avium subsp. paratuberculosis causes Johne''s disease in bovine and ovine animals and has been hypothetically linked to Crohn''s disease in humans. Several review articles have been written describing the association between M. avium subsp. paratuberculosis and Crohn''s disease (1, 2, 10, 11, 16, 23). Most mycobacterial infections are acquired from the environment; however, M. avium subsp. paratuberculosis can elude laboratory culture from environmental samples (28). M. avium subsp. paratuberculosis has been cultured only once from drinking water in the United States; therefore, its occurrence in drinking water is unknown (17). There are several reasons one could expect to find M. avium subsp. paratuberculosis in drinking water. The bacterium has been isolated from surface water used as a source of drinking water (19, 20, 24, 26). It is resistant to chlorine disinfection (25). Also, other subspecies of M. avium have been detected in biofilms obtained from drinking water pipes in the United States (8, 22, 27).Due to the potential for waterborne transmission of mycobacteria and the association of M. avium subsp. paratuberculosis with human illness, the focus of this study was to estimate the organism''s occurrence in drinking water in the United States using quantitative PCR (qPCR) (15). A comprehensive method was developed for detection of M. avium subsp. paratuberculosis in drinking water and biofilms that includes the concentration of microorganisms from samples using membrane filtration, total DNA extraction and purification, and detection of two targets unique to this bacterium: IS900 and target 251. IS900 is a common target used to identify M. avium subsp. paratuberculosis, and the average number of copies per genome is 14 to 18 (13). Target 251 qPCR analysis, which corresponds to the M. avium subsp. paratuberculosis gene 2765c (David Alexander, personal communication), was developed by Rajeev et al. (21). Samples positive for both targets are considered positive for M. avium subsp. paratuberculosis. TaqMan primer and probe sequences and qPCR assay characteristics are described in Table Table1.1. The complete method is described in Fig. S1 in the supplemental material.

TABLE 1.

qPCR assay primers, probes, DNA targets, and assay characteristicsa
DNA targetPrimer or probe (sequence, 5′→3′)Product (bp)
Reference
LODbLOQc
IS900IS900F (CCGCTAATTGAGAGATGCGATTGG)2301.81.813
IS900R (ATTCAACTCCAGCAGCGCGGCCTC)
IS900P (6-FAM-TCCACGCCCGCCCAGACAGG-TAMRA)
Target 251251F (GCAAGACGTTCATGGGAACT)200NDND21
251R (GCGTAACTCAGCGAACAACA)
251P (6-FAM-CTGACTTCACGATGCGGTTCTTC-TAMRA)
Open in a separate windowaFAM, 6-carboxyfluorescein; TAMRA, 6-carboxytetramethylrhodamine; ND, not determined.bThe limit of detection (LOD) of the IS900 qPCR assay was defined as the lowest copy number resulting in a CT of <40, determined from six independent dilution series.cThe limit of quantification (LOQ) was defined as the lowest copy number per assay yielding a coefficient of variation (CV) of less than 25% (33).A master standard curve was generated from six series of 10-fold dilutions of genomic DNA from M. avium subsp. paratuberculosis strain 49164 for quantification of IS900 target copies (see Fig. S2A in the supplemental material). Each dilution series contained eight standards run in triplicate for a total of 18 threshold cycle (CT) measurements per standard. A linear regression was performed on CT versus log IS900 copy number and R2 was 0.997. The standard error of y was used to create two equations to estimate the upper and lower concentration, or range, of M. avium subsp. paratuberculosis IS900 copy number.The specificities of the IS900 and target 251 primer/probe sets were evaluated by Rajeev et al. (21) on 211 M. avium subsp. paratuberculosis and 38 non-M. avium subsp. paratuberculosis isolates, and each assay was 100% specific for M. avium subsp. paratuberculosis. We further evaluated specificity using 22 M. avium subsp. paratuberculosis isolates from animals and 10 non-M. avium subsp. paratuberculosis ATCC reference strains (see Table S1 in the supplemental material) (18). Target 251 was 100% specific; however, one M. avium subsp. paratuberculosis isolate (3063) repeatedly produced a negative result by IS900 qPCR. Results suggest that a small subset of M. avium subsp. paratuberculosis isolates may not contain the IS900 element or may have a sequence that differs from that of the IS900 primer/probe set.The sensitivity of the method for detection of M. avium subsp. paratuberculosis in different drinking water matrices was evaluated by spiking serial dilutions of strain 1112 cells, ranging from 104 cells to no addition of cells, into 1-liter tap water samples obtained from five locations in the United States. The number of M. avium subsp. paratuberculosis cell equivalents was estimated by dividing the IS900 copy number obtained from the master standard curve by 18 (mean, 18 IS900 copies/M. avium subsp. paratuberculosis genome). The method provided consistent detection (5/5 samples) in a spiked sample of 100 cells/liter. In a spiked sample of 10 cells/liter, the IS900 target was detected 40% (2/5 samples) of the time, and at 1 cell/liter we did not detect the target in any spiked sample. Percent recovery was variable and decreased as the number of spiked cells decreased (Fig. (Fig.1).1). At a spike level of 1 × 104 cells/liter, the average percent recovery was 64%; this decreased to 9.2% at 1 × 102 cells/liter. Cell surface hydrophobicity, a property of mycobacteria, may have influenced clumping of the spiked sample or partitioning of M. avium subsp. paratuberculosis onto the sample bottle or filtration unit, affecting recovery of the bacterium (3).Open in a separate windowFIG. 1.Average percent recovery of M. avium subsp. paratuberculosis spiked into drinking water collected from five sites in the United States. Error bars denote standard deviation. MAP, M. avium subsp. paratuberculosis.  相似文献   
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Aerobic glycolysis and mitochondrial dysfunction are common features of aggressive cancer growth. We observed promoter methylation and loss of expression in neurofilament heavy polypeptide (NEFH) in a significant proportion of primary esophageal squamous cell carcinoma (ESCC) samples that were of a high tumor grade and advanced stage. RNA interference-mediated knockdown of NEFH accelerated ESCC cell growth in culture and increased tumorigenicity in vivo, whereas forced expression of NEFH significantly inhibited cell growth and colony formation. Loss of NEFH caused up-regulation of pyruvate kinase-M2 type and down-regulation of pyruvate dehydrogenase, via activation of the Akt/β-catenin pathway, resulting in enhanced aerobic glycolysis and mitochondrial dysfunction. The acceleration of glycolysis and mitochondrial dysfunction in NEFH-knockdown cells was suppressed in the absence of β-catenin expression, and was decreased by the treatment of 2-Deoxyglucose, a glycolytic inhibitor, or API-2, an Akt inhibitor. Loss of NEFH activates the Akt/β-catenin pathway and increases glycolysis and mitochondrial dysfunction. Cancer cells with methylated NEFH can be targeted for destruction with specific inhibitors of deregulated downstream pathways.  相似文献   
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