Insitu Remediation of Mercury Contaminated Sites

Source: ICHE Conference Archive - https://mdi-de.baw.de/icheArchiv

The role of Sirtuin1-PPARγ axis in placental development and function.

Placental development is important for proper in utero growth and development of the fetus, as well as maternal well-being during pregnancy. Abnormal differentiation of placental epithelial cells, called trophoblast, is at the root of multiple pregnancy complications, including miscarriage, the maternal hypertensive disorder preeclampsia and intrauterine growth restriction. The ligand-activated nuclear receptor, PPARγ, and nutrient sensor, Sirtuin-1, both play a role in numerous pathways important to cell survival and differentiation, metabolism and inflammation. However, each has also been identified as a key player in trophoblast differentiation and placental development. This review details these studies, and also describes how various stressors, including hypoxia and inflammation, alter the expression or activity of PPARγ and Sirtuin-1, thereby contributing to placenta-based pregnancy complications

xCT increases tuberculosis susceptibility by regulating antimicrobial function and inflammation

The physiological functions of macrophage, which plays a central role in the pathogenesis of tuberculosis, depend on its redox state. System xc-, a cystine-glutamate transporter, which consists of xCT and CD98, influences many ROS-dependent pathways by regulating the production of the antioxidant glutathione. xCT\u27s ability to alter this critical host redox balance by increasing the glutathione synthesis aspect of phagocyte physiology suggested that it might influence tuberculosis pathogenesis. In this study, we found that the xCT expression was increased in peripheral blood monocyte of active tuberculosis. xCT expression in macrophage was induced by Mycobacterium tuberculosis (Mtb) through TLR2/Akt- and p38-dependent signaling pathway. Importantly, xCT deficiency conferred protection against tuberculosis, as xCT knock out mice displayed increased Mtb load and reduced pulmonary pathology in lung compared to wild type mice. xCT disruption enhanced the mycobateriacidal activity of macrophage through increasing the mycothiol oxidation. Importantly, chemical inhibition of xCT with sulfasalazine, a specific xCT inhibitor that is already approved by the FDA for treatment of inflammatory bowel disease, produces similar protective effects in vivo and in vitro, indicating xCT might be a novel and useful target for host-directed TB treatment strategy

Falls and potential therapeutic interventions among elderly and older adult patients with cancer: a systematic review

Objectives: The aim of this study was to perform a systematic review for previous publications that have assessed the incidence, risk factors, and favorable procedures to prevent and manage falls among cancer survivors of elderly and older adults. Materials: This systematic review was undertook using PubMed, SCOPUS, Web of Science, Medline, and Cochrane Database of clinical studies and systematic reviews to determine the incidence, risk factors, favorable inpatient and outpatient management, and non-pharmacological interventions for falls among elderly and older adult patients with cancer from 2010 to October, 2020. Results: After the comprehensive screening, clinical studies, meta-analysis, systematic reviews, and established guidelines were included in this review. Only 5 clinical studies (3 randomized and 2 single-arm studies), 5 systematic reviews, and 6 established guidelines were considered eligible. The five systematic reviews provide risk factors of falls and the 6 guidelines provide assessment & prevention modalities of falls, however, the 6 clinical studies provide the non-pharmacological intervention for falling among cancer survivors. Many factors associated are demonstrated among wide range of elderly individuals.Earlier falls were reliably listed as an important risk factor of falls in the two inpatient and outpatient environments including both general older people and geriatric cancer populations. Conclusions: This review concludes that the assessment of falls among older individuals with cancer is the most important way for determining who could need additional observation and treatment program. Health professions involving physical therapy and occupational therapy have an important function for promoting health well-being in elderly and older adults with cancer. Keywords: Cancer; falls; elderly; older adults, risk factors, intervention

Mapping the scarcity of data on antibiotics in natural and engineered water environments across India

Antimicrobial resistance is a growing public health concern, increasingly recognized as a silent pandemic across the globe. Therefore, it is important to monitor all factors that could contribute to the emergence, maintenance and spread of antimicrobial resistance. Environmental antibiotic pollution is thought to be one of the contributing factors. India is one of the world’s largest consumers and producers of antibiotics. Hence, antibiotics have been detected in different environments across India, sometimes at very high concentrations due to their extensive use in humans and agriculture or due to manufacturing. We summarize the current state of knowledge on the occurrence and transport pathways of antibiotics in Indian water environments, including sewage or wastewater and treatment plants, surface waters such as rivers, lakes, and reservoirs as well as groundwater and drinking water. The factors influencing the distribution of antibiotics in the water environment, such as rainfall, population density and variations in sewage treatment are discussed, followed by existing regulations and policies aimed at the mitigation of environmental antimicrobial resistance in India, which will have global benefits. Then, we recommend directions for future research, development of standardized methods for monitoring antibiotics in water, ecological risk assessment, and exploration of strategies to prevent antibiotics from entering the environment. Finally, we provide an evaluation of how scarce the data is, and how a systematic understanding of the occurrence and concentrations of antibiotics in the water environment in India could be achieved. Overall, we highlight the urgent need for sustainable solutions to monitor and mitigate the impact of antibiotics on environmental, animal, and public health

Statistical analysis of genetic interactions in Tn-Seq data

Tn-Seq is an experimental method for probing the functions of genes through construction of complex random transposon insertion libraries and quantification of each mutant\u27s abundance using next-generation sequencing. An important emerging application of Tn-Seq is for identifying genetic interactions, which involves comparing Tn mutant libraries generated in different genetic backgrounds (e.g. wild-type strain versus knockout strain). Several analytical methods have been proposed for analyzing Tn-Seq data to identify genetic interactions, including estimating relative fitness ratios and fitting a generalized linear model. However, these have limitations which necessitate an improved approach. We present a hierarchical Bayesian method for identifying genetic interactions through quantifying the statistical significance of changes in enrichment. The analysis involves a four-way comparison of insertion counts across datasets to identify transposon mutants that differentially affect bacterial fitness depending on genetic background. Our approach was applied to Tn-Seq libraries made in isogenic strains of Mycobacterium tuberculosis lacking three different genes of unknown function previously shown to be necessary for optimal fitness during infection. By analyzing the libraries subjected to selection in mice, we were able to distinguish several distinct classes of genetic interactions for each target gene that shed light on their functions and roles during infection

Cardiovascular Disease Prevention: Training Opportunities, the Challenges, and Future Directions

Purpose: Cardiovascular diseases (CVDs) are a leading cause of morbidity and mortality worldwide, necessitating major efforts in prevention. This review summarizes the currently available training opportunities in CVD prevention for fellows-in-training (FITs) and residents. We also highlight the challenges and future directions for CVD prevention as a field and propose a structure for an inclusive CVD prevention training program. Recent Findings: At present, there is a lack of centralized training resources for FITs and residents interested in pursuing a career in CVD prevention. Training in CVD prevention is not an accredited subspecialty fellowship by the American Council of Graduate Medical Education (ACGME). Although there are several independent training programs under the broad umbrella of CVD prevention focusing on different aspects of prevention, there is no unified curriculum or training. More collaborative efforts are needed to identify CVD prevention as an ACGME-accredited subspecialty fellowship. Providing more resources can encourage and produce more leaders in this essential field

ORBIT: a new paradigm for genetic engineering of mycobacterial chromosomes [preprint]

Current methods for genome engineering in mycobacteria rely on relatively inefficient recombination systems that require the laborious construction of a long double-stranded DNA substrate for each desired modification. We combined two efficient recombination systems to produce a versatile method for high-throughput chromosomal engineering that obviates the need for the preparation of double-stranded DNA recombination substrates. A synthetic targeting oligonucleotide is incorporated into the chromosome via homologous recombination mediated by the phage Che9c RecT annelase. This oligo contains a site-specific recombination site for the directional Bxb1 integrase (Int), which allows the simultaneous integration of a payload plasmid that contains a cognate recombination site and selectable marker. The targeting oligo and payload plasmid are co-transformed into a RecT- and Int- expressing strain, and drug-resistant homologous recombinants are selected in a single step. A library of reusable target-independent payload plasmids is available to generate knockouts and promoter replacements, or to fuse the C-terminal-encoding regions of target genes with tags of various functionalities. This new system is called ORBIT (Oligo-mediated Recombineering followed by Bxb1 Integrase Targeting) and is ideally suited for the creation of libraries consisting of large numbers of deletions, insertions or fusions in a target bacterium. We demonstrate the utility of ORBIT by the construction of insertions or deletions in over 100 genes in M. tuberculosis and M. smegmatis. The report describes the first genetic engineering technique for making selectable chromosomal fusions and deletions that does not require the construction of target- or modification-specific double-stranded DNA recombination substrates

Fine-tuning of Substrate Affinity Leads to Alternative Roles of Mycobacterium tuberculosis Fe2+-ATPases

Little is known about iron efflux transporters within bacterial systems. Recently, the participation of Bacillus subtilis PfeT, a P1B4-ATPase, in cytoplasmic Fe(2+) efflux has been proposed. We report here the distinct roles of mycobacterial P1B4-ATPases in the homeostasis of Co(2+) and Fe(2+) Mutation of Mycobacterium smegmatis ctpJ affects the homeostasis of both ions. Alternatively, an M. tuberculosis ctpJ mutant is more sensitive to Co(2+) than Fe(2+), whereas mutation of the homologous M. tuberculosis ctpD leads to Fe(2+) sensitivity but no alterations in Co(2+) homeostasis. In vitro, the three enzymes are activated by both Fe(2+) and Co(2+) and bind 1 eq of either ion at their transport site. However, equilibrium binding affinities and activity kinetics show that M. tuberculosis CtpD has higher affinity for Fe(2+) and twice the Fe(2+)-stimulated activity than the CtpJs. These parameters are paralleled by a lower activation and affinity for Co(2+) Analysis of Fe(2+) and Co(2+) binding to CtpD by x-ray absorption spectroscopy shows that both ions are five- to six-coordinate, constrained within oxygen/nitrogen environments with similar geometries. Mutagenesis studies suggest the involvement of invariant Ser, His, and Glu residues in metal coordination. Interestingly, replacement of the conserved Cys at the metal binding pocket leads to a large reduction in Fe(2+) but not Co(2+) binding affinity. We propose that CtpJ ATPases participate in the control of steady state Fe(2+) levels. CtpD, required for M. tuberculosis virulence, is a high affinity Fe(2+) transporter involved in the rapid response to iron dyshomeostasis generated upon redox stress

Bone mineral density among children living with HIV failing first-line anti-retroviral therapy in Uganda: A sub-study of the CHAPAS-4 trial

BACKGROUND: Children living with perinatally acquired HIV (CLWH) survive into adulthood on antiretroviral therapy (ART). HIV, ART, and malnutrition can all lead to low bone mineral density (BMD). Few studies have described bone health among CLWH in Sub-Saharan Africa. We determined the prevalence and factors associated with low BMD among CLWH switching to second-line ART in the CHAPAS-4 trial (ISRCTN22964075) in Uganda. METHODS: BMD was determined using dual-energy X-ray Absorptiometry (DXA). BMD Z-scores were adjusted for age, sex, height and race. Demographic characteristics were summarized using median interquartile range (IQR) for continuous variables and proportions for categorical variables. Logistic regression was used to determine the associations between each variable and low BMD. RESULTS: A total of 159 children were enrolled (50% male) with median age (IQR) 10 (7-12) years, median duration of first -line ART 5.2(3.3-6.8) years; CD4 count 774 (528-1083) cells/mm3, weight-for-age Z-score -1.36 (-2.19, -0.65) and body mass index Z-score (BMIZ) -1.31 (-2.06, -0.6). Low (Z-score≤ -2) total body less head (TBLH) BMD was observed in 28 (18%) children, 21(13%) had low lumbar spine (LS) BMD, and15 (9%) had both. Low TBLH BMD was associated with increasing age (adjusted odds ratio [aOR] 1.37; 95% CI: 1.13-1.65, p = 0.001), female sex (aOR: 3.8; 95% CL: 1.31-10.81, p = 0.014), low BMI (aOR 0.36:95% CI: 0.21-0.61, p<0.001), and first-line zidovudine exposure (aOR: 3.68; 95% CI: 1.25-10.8, p = 0.018). CD4 count, viral load and first- line ART duration were not associated with TBLH BMD. Low LS BMD was associated with increasing age (aOR 1.42; 95% CI: 1.16-1.74, p = 0.001) and female sex: (aOR 3.41; 95% CI: 1.18-9.8, p = 0.023). CONCLUSION: Nearly 20% CLWH failing first-line ART had low BMD which was associated with female sex, older age, first-line ZDV exposure, and low BMI. Prevention, monitoring, and implications following transition to adult care should be prioritized to identify poor bone health in HIV+adolescents entering adulthood