Direct Capture Technologies for Genomics-Guided Discovery of Natural Products

Microbes are important producers of natural products, which have played key roles in understanding biology and treating disease. However, the full potential of microbes to produce natural products has yet to be realized; the overwhelming majority of natural product gene clusters encoded in microbial genomes remain “cryptic”, and have not been expressed or characterized. In contrast to the fast-growing number of genomic sequences and bioinformatic tools, methods to connect these genes to natural product molecules are still limited, creating a bottleneck in genome-mining efforts to discover novel natural products. Here we review developing technologies that leverage the power of homologous recombination to directly capture natural product gene clusters and express them in model hosts for isolation and structural characterization. Although direct capture is still in its early stages of development, it has been successfully utilized in several different classes of natural products. These early successes will be reviewed, and the methods will be compared and contrasted with existing traditional technologies. Lastly, we will discuss the opportunities for the development of direct capture in other organisms, and possibilities to integrate direct capture with emerging genome-editing techniques to accelerate future study of natural products

Quasi-static characterisation and impact testing of auxetic foam for sports safety applications

This study compared low strain rate material properties and impact force attenuation of auxetic foam and the conventional open-cell polyurethane counterpart. This furthers our knowledge with regards to how best to apply these highly conformable and breathable auxetic foams to protective sports equipment. Cubes of auxetic foam measuring 150 x 150 x 150 mm were fabricated using a thermo-mechanical conversion process. Quasi-static compression confirmed the converted foam to be auxetic, prior to being sliced into 20 mm thick cuboid samples for further testing. Density, Poisson’s ratio and the stress-strain curve were all found to be dependent on the position of each cuboid from within the cube. Impact tests with a hemispherical drop hammer were performed for energies up to 6 J, on foams covered with a polypropylene sheet between 1 and 2 mm thick. Auxetic samples reduced peak force by ~10 times in comparison to the conventional foam. This work has shown further potential for auxetic foam to be applied to protective equipment, while identifying that improved fabrication methods are required

Course of FEV1 after Onset of Bronchiolitis Obliterans Syndrome in Lung Transplant Recipients

Rationale: Bronchiolitis obliterans syndrome (BOS), defined by loss of lung function, develops in the majority of lung transplant recipients. However, there is a paucity of information on the subsequent course of lung function in these patients. Objectives: To characterize the course of FEV1 over time after development of BOS and to determine the predictors that influence the rate of functional decline of FEV1. Methods: FEV1% predicted (FEV1%pred) trajectories were studied in 111 lung transplant recipients with BOS by multivariate, linear, mixed-effects statistical models. Measurements and Main Results: FEV1%pred varied over time after BOS onset, with the steepest decline typically seen in the first 6 months (12% decline; p < 0.0001). Bilateral lung transplant recipients had significantly higher FEV1%pred at BOS diagnosis (71 vs. 47%; p < 0.0001) and at 24 months after BOS onset (58 vs. 41%; p = 0.0001). Female gender and pretransplant diagnosis of idiopathic pulmonary fibrosis were associated with a steeper decline in FEV1%pred in the first 6 months after BOS diagnosis (p = 0.02 and 0.04, respectively). A fall in FEV1 greater than 20% in the 6 months preceding BOS (termed “rapid onset”) was associated with shorter time to BOS onset (p = 0.01), lower FEV1%pred at BOS onset (p < 0.0001), steeper decline in the first 6 months (p = 0.03), and lower FEV1%pred at 2 years after onset (p = 0.0002). Conclusions: Rapid onset of BOS, female gender, pretransplant diagnosis of idiopathic pulmonary fibrosis, and single-lung transplantation are associated with worse pulmonary function after BOS onset.Supported in part by National Institutes of Health grants K23 HL077719 (V.N.L.) and K24 HL04212 (F.J.M.), and by a grant from the American Society of Transplantation/ Chest Foundation (V.N.L.).Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91969/1/2007 AJRCCM Course of FEV1 after Onset of Bronchiolitis Obliterans Syndrome in Lung Transplant Recipients.pd

Microbiota-Produced N-Formyl Peptide fMLF Promotes Obesity-Induced Glucose Intolerance.

The composition of the gastrointestinal microbiota and associated metabolites changes dramatically with diet and the development of obesity. Although many correlations have been described, specific mechanistic links between these changes and glucose homeostasis remain to be defined. Here we show that blood and intestinal levels of the microbiota-produced N-formyl peptide, formyl-methionyl-leucyl-phenylalanine, are elevated in high-fat diet-induced obese mice. Genetic or pharmacological inhibition of the N-formyl peptide receptor Fpr1 leads to increased insulin levels and improved glucose tolerance, dependent upon glucagon-like peptide 1. Obese Fpr1 knockout mice also display an altered microbiome, exemplifying the dynamic relationship between host metabolism and microbiota. Overall, we describe a new mechanism by which the gut microbiota can modulate glucose metabolism, providing a potential approach for the treatment of metabolic disease

Role for dithiolopyrrolones in disrupting bacterial metal homeostasis

Antibiotic resistance is a rising health threat worldwide, against which novel strategies are urgently needed. We have taken a systems approach to examine a potent and underexplored class of broad-spectrum antibiotics, the dithiolopyrrolones (DTPs). Our results indicate that DTPs disrupt cellular processes by high-affinity chelation of essential metal ions and inhibition of a subset of metalloenzymes. This mode of action is unique amongst antibiotics and may be further explored for treatment of multidrug-resistant infections. Our study also highlights chemical genomics as a powerful approach for the identification of antimicrobial mechanisms of action

A systematic review of current knowledge of HIV epidemiology and of sexual behaviour in Nepal

OBJECTIVE: To systematically review information on HIV epidemiology and on sexual behaviour in Nepal with a view to identifying gaps in current knowledge. METHODS: Systematic review covering electronic databases, web-based information, personal contact with experts and hand searching of key journals. RESULTS: HIV-1 seroprevalence has been rising rapidly in association with high-risk behaviours, with current levels of 40% amongst the nation's injecting drug users and approaching 20% amongst Kathmandu's female commercial sex workers (FCSWs). HIV seroprevalence remains low in the general population (0.29% of 15–49 year olds). There are significant methodological limitations in many of the seroprevalence studies identified, and these estimates need to be treated with caution. There are extensive migration patterns both within the country and internationally which provide the potential for considerable sexual networking. However, studies of sexual behaviour have focused on FCSWs and the extent of sexual networks within the general population is largely unknown. CONCLUSIONS: Whilst some of the ingredients are present for an explosive HIV epidemic in Nepal, crucial knowledge on sexual behaviour in the general population is missing. Research on sexual networking is urgently required to guide HIV control in Nepal. There is also a need for further good-quality epidemiological studies of HIV seroprevalence

Systematic review estimating the burden of dementia in the WHO Southeast Asia Region using Bayesian and frequentist approaches

Background: Rapid increase in life expectancy in low- and middle-income countries including the World Health Organization's Southeast Asia Region (SEAR) has resulted in an increase in the global burden of dementia, which is expected to become a leading cause of morbidity. Accurate burden estimates are key for informing policy and planning. Given the paucity of data, estimates were developed using both a Bayesian methodology and as well as a traditional frequentist approach to gain better insights into methodological approaches for disease burden estimates. Methods: Seven databases were searched for studies published between 2010-2018 regarding dementia prevalence in SEAR, generating 8 relevant articles. A random-effects model (REM) and a Bayesian normal-normal hierarchical model (NNHM) were used to obtain the pooled prevalence estimate of dementia for people aged 60 and above in SEAR. The latter model was also developed to estimate age-specific dementia prevalence. Using UN population estimates for SEAR, total and age-specific projections of the burden of dementia in 2015, 2020 and 2030 were calculated. Results: The prevalence of dementia in SEAR was found to be 3% (95% confidence interval (CI) = 2-6%) in those above age 60 based on REM, and 3.1% (95% credible interval = 1.5-5.0%) based on the NNHM. The estimated prevalence varies with age, increasing from 1.6% (95% credible interval = 0.8-2.5%) in people aged 60-69 to 12.4% (95% credible interval = 5.6-20%) in people above the age of 80. The risk of developing dementia increased exponentially with age. The number of people living with dementia in SEAR in 2015 was estimated at 5.51 million (95% credible interval = 2.66-8.82), with projections of 6.66 million (95% credible interval = 3.21-10.7) in 2020 and 9.6 million (95% credible interval = 4.62-15.36) in 2030. Conclusion: The burden of dementia in SEAR is substantial and will continue to increase rapidly by 2030. The lack of research focusing on dementia in SEAR points to a significant under-recognition of this disease. The projected rise in dementia cases in the future should prompt urgent governmental response to address this growing public health issue. We also argue that given the overall paucity of data for the region, the Bayesian approach offers a promising methodology for improved estimates of disease prevalence and burden and should continue to be explored