Evaluating PCR-Based Detection of Salmonella Typhi and Paratyphi A in the Environment as an Enteric Fever Surveillance Tool.

With prequalification of a typhoid conjugate vaccine by the World Health Organization, countries are deciding whether and at what geographic scale to provide the vaccine. Optimal local data to clarify typhoid risk are expensive and often unavailable. To determine whether quantitative polymerase chain reaction (qPCR) can be used as a tool to detect typhoidal Salmonella DNA in the environment and approximate the burden of enteric fever, we tested water samples from urban Dhaka, where enteric fever burden is high, and rural Mirzapur, where enteric fever burden is low and sporadic. Sixty-six percent (38/59) of the water sources of Dhaka were contaminated with typhoidal Salmonella DNA, in contrast to none of 33 samples of Mirzapur. If these results can be replicated in larger scale in Bangladesh and other enteric fever endemic areas, drinking water testing could become a low-cost approach to determine the presence of typhoidal Salmonella in the environment that can, in turn, guide informed-design of blood culture-based surveillance and thus assist policy decisions on investing to control typhoid

Integrating facility-based surveillance with healthcare utilization surveys to estimate enteric fever incidence: Methods and challenges

Cohort studies and facility-based sentinel surveillance are common approaches to characterizing infectious disease burden, but present trade-offs; cohort studies are resource-intensive and may alter disease natural history, while sentinel surveillance underestimates incidence in the population. Hybrid surveillance, whereby facility-based surveillance is paired with a community-based healthcare utilization assessment, represents an alternative approach to generating population-based disease incidence estimates with moderate resource investments. Here, we discuss this method in the context of the Surveillance for Enteric Fever in Asia Project (SEAP) study. We describe how data are collected and utilized to adjust enteric fever incidence for blood culture sensitivity, facility-based enrollment, and healthcare seeking, incorporating uncertainty in these parameters in the uncertainty around incidence estimates. We illustrate how selection of surveillance sites and their coverage may influence precision and bias, and we identify approaches in the study design and analysis to minimize and control for these biases. Rigorously designed hybrid surveillance systems can be an efficient approach to generating population-based incidence estimates for infectious diseases

Environmental surveillance as a tool for identifying high-risk settings for typhoid transmission

Enteric fever remains a major cause of morbidity in developing countries with poor sanitation conditions that enable fecal contamination of water distribution systems. Historical evidence has shown that contamination of water systems used for household consumption or agriculture are key transmission routes for Salmonella Typhi and Salmonella Paratyphi A. The World Health Organization now recommends that typhoid conjugate vaccines (TCV) be used in settings with high typhoid incidence; consequently, governments face a challenge regarding how to prioritize typhoid against other emerging diseases. A key issue is the lack of typhoid burden data in many low- and middle-income countries where TCV could be deployed. Here we present an argument for utilizing environmental sampling for the surveillance of enteric fever organisms to provide data on community-level typhoid risk. Such an approach could complement traditional blood culture-based surveillance or even replace it in settings where population-based clinical surveillance is not feasible. We review historical studies characterizing the transmission of enteric fever organisms through sewage and water, discuss recent advances in the molecular detection of typhoidal Salmonella in the environment, and outline challenges and knowledge gaps that need to be addressed to establish environmental sampling as a tool for generating actionable data that can inform public health responses to enteric fever

Observation of ultrafast internal conversion in fullerene anions in solution

The ultrafast decay rates of photoexcited View the MathML source ions have been measured in the condensed phase. The mechanism for decay is internal conversion, and the decay rate is a strong function of the charge on the ion. A bottleneck in the ground state recovery has also been detected, and its interpretation is discussed

Functional Analysis of the Aspergillus nidulans Kinome

The filamentous fungi are an ecologically important group of organisms which also have important industrial applications but devastating effects as pathogens and agents of food spoilage. Protein kinases have been implicated in the regulation of virtually all biological processes but how they regulate filamentous fungal specific processes is not understood. The filamentous fungus Aspergillus nidulans has long been utilized as a powerful molecular genetic system and recent technical advances have made systematic approaches to study large gene sets possible. To enhance A. nidulans functional genomics we have created gene deletion constructs for 9851 genes representing 93.3% of the encoding genome. To illustrate the utility of these constructs, and advance the understanding of fungal kinases, we have systematically generated deletion strains for 128 A. nidulans kinases including expanded groups of 15 histidine kinases, 7 SRPK (serine-arginine protein kinases) kinases and an interesting group of 11 filamentous fungal specific kinases. We defined the terminal phenotype of 23 of the 25 essential kinases by heterokaryon rescue and identified phenotypes for 43 of the 103 non-essential kinases. Uncovered phenotypes ranged from almost no growth for a small number of essential kinases implicated in processes such as ribosomal biosynthesis, to conditional defects in response to cellular stresses. The data provide experimental evidence that previously uncharacterized kinases function in the septation initiation network, the cell wall integrity and the morphogenesis Orb6 kinase signaling pathways, as well as in pathways regulating vesicular trafficking, sexual development and secondary metabolism. Finally, we identify ChkC as a third effector kinase functioning in the cellular response to genotoxic stress. The identification of many previously unknown functions for kinases through the functional analysis of the A. nidulans kinome illustrates the utility of the A. nidulans gene deletion constructs

Systematic Investigation of the Permeability of Androgen Receptor PROTACs.

Bifunctional molecules known as PROTACs simultaneously bind an E3 ligase and a protein of interest to direct ubiquitination and clearance of that protein, and they have emerged in the past decade as an exciting new paradigm in drug discovery. In order to investigate the permeability and properties of these large molecules, we synthesized two panels of PROTAC molecules, constructed from a range of protein-target ligands, linkers, and E3 ligase ligands. The androgen receptor, which is a well-studied protein in the PROTAC field was used as a model system. The physicochemical properties and permeability of PROTACs are discussed.This work was funded by Alzheimer’s Research UK (grant: ARUK-2015DDI-CAM), with support from the ALBORADA Trust. The ALBORADA Drug Discovery Institute is core funded by Alzheimer’s Research UK (registered charity No. 1077089 and SC042474)

Zip4 (Slc39a4) Expression is Activated in Hepatocellular Carcinomas and Functions to Repress Apoptosis, Enhance Cell Cycle and Increase Migration

Background: The zinc transporter ZIP4 (Slc39a4) is important for proper mammalian development and is an essential gene in mice. Recent studies suggest that this gene may also play a role in pancreatic cancer. Methods/Principal Findings: Herein, we present evidence that this essential zinc transporter is expressed in hepatocellular carcinomas. Zip4 mRNA and protein were dramatically elevated in hepatocytes in the majority of human hepatocellular carcinomas relative to noncancerous surrounding tissues, as well as in hepatocytes in hepatocellular carcinomas occurring in farnesoid X receptor-knockout mice. Interestingly, meta-analysis of microarray data in the Geo and Oncomine databases suggests that Zip4 mRNA may also be elevated in many types of cancer. Potential mechanisms of action of ZIP4 were examined in cultured cell lines. RNAi knockdown of Zip4 in mouse Hepa cells significantly increased apoptosis and modestly slowed progression from G0/G1 to S phase when cells were released from hydroxyurea block into zinc-deficient medium. Cell migration assays revealed that RNAi knockdown of Zip4 in Hepa cells depressed in vitro migration whereas forced over-expression in Hepa cells and MCF-7 cells enhanced in vitro migration. Conclusions: ZIP4 may play a role in the acquisition of zinc by hepatocellular carcinomas, and potentially many different cancerous cell-types, leading to repressed apoptosis, enhanced growth rate and enhanced invasive behavior

Measurements of extragalactic background light from the far UV to the far IR from deep ground- and space-based galaxy counts

Funding: Australian Research Council via Discovery Project DP130103505 (SPD).We combine wide and deep galaxy number-count data from the Galaxy And Mass Assembly, COSMOS/G10, Hubble Space Telescope (HST) Early Release Science, HST UVUDF, and various near-, mid-, and far-IR data sets from ESO, Spitzer, and Herschel. The combined data range from the far UV (0.15 μm) to far-IR (500 μm), and in all cases the contribution to the integrated galaxy light (IGL) of successively fainter galaxies converges. Using a simple spline fit, we derive the IGL and the extrapolated IGL in all bands. We argue that undetected low-surface-brightness galaxies and intracluster/group light are modest, and that our extrapolated-IGL measurements are an accurate representation of the extragalactic background light (EBL). Our data agree with most earlier IGL estimates and with direct measurements in the far IR, but disagree strongly with direct estimates in the optical. Close agreement between our results and recent very high-energy experiments (H.E.S.S. and MAGIC) suggests that there may be an additional foreground affecting the direct estimates. The most likely culprit could be the adopted model of zodiacal light. Finally we use a modified version of the two-component model to integrate the EBL and obtain measurements of the cosmic optical background (COB) and cosmic infrared background of 24+4-4 nW m−2sr−1 and 26+5-5 nW m−2sr−1 respectively (48%:52%). Over the next decade, upcoming space missions such as Euclid and the Wide Field Infrared Space Telescope will have the capacity to reduce the COB error to <1%, at which point comparisons to the very high-energy data could have the potential to provide a direct detection and measurement of the reionization field.Publisher PDFPeer reviewe