Manganese-Catalyzed Electrochemical Deconstructive Chlorination of Cycloalkanols via Alkoxy Radicals

A manganese-catalyzed electrochemical deconstructive chlorination of cycloalkanols has been developed. This electrochemical method provides access to alkoxy radicals from alcohols and exhibits a broad substrate scope, with various cyclopropanols and cyclobutanols converted into synthetically useful β- and γ-chlorinated ketones (40 examples). Furthermore, the combination of recirculating flow electrochemistry and continuous inline purification was employed to access products on a gram scale

Advancing precision public health using human genomics: examples from the field and future research opportunities

Precision public health is a relatively new field that integrates components of precision medicine, such as human genomics research, with public health concepts to help improve population health. Despite interest in advancing precision public health initiatives using human genomics research, current and future opportunities in this emerging field remain largely undescribed. To that end, we provide examples of promising opportunities and current applications of genomics research within precision public health and outline future directions within five major domains of public health: biostatistics, environmental health, epidemiology, health policy and health services, and social and behavioral science. To further extend applications of genomics within precision public health research, three key cross-cutting challenges will need to be addressed: developing policies that implement precision public health initiatives at multiple levels, improving data integration and developing more rigorous methodologies, and incorporating initiatives that address health equity. Realizing the potential to better integrate human genomics within precision public health will require transdisciplinary efforts that leverage the strengths of both precision medicine and public health

Functional analysis of altered Tenascin isoform expression in breast cancer

Background: Cellular interactions with the extracellular matrix (ECM) control many aspects of cell function. The complex ECM protein Tenascin-C (TN), which exists as multiple isoforms, is upregulated in breast cancer. We previously have identified a change in the TN isoform profile in breast cancer, with detection of two additional isoforms — TN16 and TN14/16 — not seen in normal breast [1]. The purpose of this study was to investigate directly the effects of these tumour-associated TNC isoforms on breast cancer cell behaviour

Screening families of patients with premature coronary heart disease to identify avoidable cardiovascular risk: a cross-sectional study of family members and a general population comparison group

<b>Background:</b> Primary prevention should be targeted at individuals with high global cardiovascular risk, but research is lacking on how best to identify such individuals in the general population. Family history is a good proxy measure of global risk and may provide an efficient mechanism for identifying high risk individuals. The aim was to test the feasibility of using patients with premature cardiovascular disease to recruit family members as a means of identifying and screening high-risk individuals. <b>Findings:</b> We recruited family members of 50 patients attending a cardiology clinic for premature coronary heart disease (CHD). We compared their cardiovascular risk with a general population control group, and determined their perception of their risk and current level of screening. 103 (36%) family members attended screening (27 siblings, 48 adult offspring and 28 partners). Five (5%) had prevalent CHD. A significantly higher percentage had an ASSIGN risk score >20% compared with the general population (13% versus 2%, p < 0.001). Only 37% of family members were aware they were at increased risk and only 50% had had their blood pressure and serum cholesterol level checked in the previous three years. <b>Conclusions:</b> Patients attending hospital for premature CHD provide a mechanism to contact family members and this can identify individuals with a high global risk who are not currently screened

Difficult at dusk? Illuminating the debate on cricket ball visibility

Objectives: Investigate the visibility of new and old red, white and pink cricket balls under lighting and background conditions experienced during a day–night cricket match. Design: We modelled the luminance contrast signals available for a typical observer for a ball against backgrounds in a professional cricket ground, at different times of day. Methods: Spectral reflectance (light reflected as a function of wavelength) was derived from laboratory measurements of new and old red, white and pink balls. We also gathered spectral measurements from backgrounds (pitch, grass, sightscreens, crowd, sky) and spectral illuminance during a day–night match (natural afternoon light, through dusk to night under floodlights) from Lord's Cricket Ground (London, UK). The luminance contrast of the ball relative to the background was calculated for each combination of ball, time of day, and background surface. Results: Old red and old pink balls may offer little or no contrast against the grass, pitch and crowd. New pink balls can also be of low contrast against the crowd at dusk, as can pink and white balls (of any age) against the sky at dusk. Conclusions: Reports of difficulties with visibility of the pink ball are supported by our data. However, our modelling also shows that difficulties with visibility may also be expected under certain circumstances for red and white balls. The variable conditions in a cricket ground and the changing colour of an ageing ball make maintaining good visibility of the ball a challenge when playing day–night matches

The Universal Plausibility Metric (UPM) & Principle (UPP)

<p>Abstract</p> <p>Background</p> <p>Mere possibility is not an adequate basis for asserting scientific plausibility. A precisely defined universal bound is needed beyond which the assertion of <it>plausibility</it>, particularly in life-origin models, can be considered operationally falsified. But can something so seemingly relative and subjective as plausibility ever be quantified? Amazingly, the answer is, "Yes." A method of objectively measuring the plausibility of any chance hypothesis (The Universal Plausibility Metric [UPM]) is presented. A numerical inequality is also provided whereby any chance hypothesis can be definitively falsified when its UPM metric of ξ is < 1 (The Universal Plausibility Principle [UPP]). Both UPM and UPP pre-exist and are independent of any experimental design and data set.</p> <p>Conclusion</p> <p>No low-probability hypothetical plausibility assertion should survive peer-review without subjection to the UPP inequality standard of formal falsification (ξ < 1).</p

Mitochondrial and nuclear genes suggest that stony corals are monophyletic but most families of stony corals are not (Order Scleractinia, Class Anthozoa, Phylum Cnidaria)

Modern hard corals (Class Hexacorallia; Order Scleractinia) are widely studied because of their fundamental role in reef building and their superb fossil record extending back to the Triassic. Nevertheless, interpretations of their evolutionary relationships have been in flux for over a decade. Recent analyses undermine the legitimacy of traditional suborders, families and genera, and suggest that a non-skeletal sister clade (Order Corallimorpharia) might be imbedded within the stony corals. However, these studies either sampled a relatively limited array of taxa or assembled trees from heterogeneous data sets. Here we provide a more comprehensive analysis of Scleractinia (127 species, 75 genera, 17 families) and various outgroups, based on two mitochondrial genes (cytochrome oxidase I, cytochrome b), with analyses of nuclear genes (ßtubulin, ribosomal DNA) of a subset of taxa to test unexpected relationships. Eleven of 16 families were found to be polyphyletic. Strikingly, over one third of all families as conventionally defined contain representatives from the highly divergent "robust" and "complex" clades. However, the recent suggestion that corallimorpharians are true corals that have lost their skeletons was not upheld. Relationships were supported not only by mitochondrial and nuclear genes, but also often by morphological characters which had been ignored or never noted previously. The concordance of molecular characters and more carefully examined morphological characters suggests a future of greater taxonomic stability, as well as the potential to trace the evolutionary history of this ecologically important group using fossils

Deletion of parasite immune modulatory sequences combined with immune activating signals enhances vaccine mediated protection against filarial nematodes

&lt;p&gt;Background: Filarial nematodes are tissue-dwelling parasites that can be killed by Th2-driven immune effectors, but that have evolved to withstand immune attack and establish chronic infections by suppressing host immunity. As a consequence, the efficacy of a vaccine against filariasis may depend on its capacity to counter parasite-driven immunomodulation.&lt;/p&gt; &lt;p&gt;Methodology and Principal Findings: We immunised mice with DNA plasmids expressing functionally-inactivated forms of two immunomodulatory molecules expressed by the filarial parasite Litomosoides sigmodontis: the abundant larval transcript-1 (LsALT) and cysteine protease inhibitor-2 (LsCPI). The mutant proteins enhanced antibody and cytokine responses to live parasite challenge, and led to more leukocyte recruitment to the site of infection than their native forms. The immune response was further enhanced when the antigens were targeted to dendritic cells using a single chain Fv-αDEC205 antibody and co-administered with plasmids that enhance T helper 2 immunity (IL-4) and antigen-presenting cell recruitment (Flt3L, MIP-1α). Mice immunised simultaneously against the mutated forms of LsALT and LsCPI eliminated adult parasites faster and consistently reduced peripheral microfilaraemia. A multifactorial analysis of the immune response revealed that protection was strongly correlated with the production of parasite-specific IgG1 and with the numbers of leukocytes present at the site of infection.&lt;/p&gt; &lt;p&gt;Conclusions: We have developed a successful strategy for DNA vaccination against a nematode infection that specifically targets parasite-driven immunosuppression while simultaneously enhancing Th2 immune responses and parasite antigen presentation by dendritic cells.&lt;/p&gt

Down-regulation of miR-27a might inhibit proliferation and drug resistance of gastric cancer cells

<p>Abstract</p> <p>Aims</p> <p>Here we aimed to firstly investigate the role of miR-27a in proliferation and multidrug resistance of gastric cancer cells.</p> <p>Methods</p> <p>The role of miR-27a in gastric cancer cells was detected using MTT assay, soft agar assay, flow cytometry assay, nude mice assay, real-time PCR, western blot and reporter gene assay, etc.</p> <p>Results</p> <p>Down-regulation of miR-27a could inhibit porliferation of gastric cancer cells in vitro and in vivo. Down-regulation of miR-27a could also confer sensitivity of drugs on gastric cancer cells, and might increase accumulation and decrease releasing amount of adriamycin in gastric cancer cells. Down-regulation of miR-27a could significantly decrease the expression of P-glycoprotein and the transcriptional activity of cyclin D1, and up-regulate the expression of p21.</p> <p>Conclusions</p> <p>MiR-27a might play important roles in porliferation and drug resistance of gastric cancer. MiR-27a might be considered as a useful target for cancer therapy.</p

A four-helix bundle stores copper for methane oxidation

Methane-oxidising bacteria (methanotrophs) require large quantities of copper for the membrane-bound (particulate) methane monooxygenase (pMMO). Certain methanotrophs are also able to switch to using the iron-containing soluble MMO (sMMO) to catalyse methane oxidation, with this switchover regulated by copper. MMOs are Nature’s primary biological mechanism for suppressing atmospheric levels of methane, a potent greenhouse gas. Furthermore, methanotrophs and MMOs have enormous potential in bioremediation and for biotransformations producing bulk and fine chemicals, and in bioenergy, particularly considering increased methane availability from renewable sources and hydraulic fracturing of shale rock. We have discovered and characterised a novel copper storage protein (Csp1) from the methanotroph Methylosinus trichosporium OB3b that is exported from the cytosol, and stores copper for pMMO. Csp1 is a tetramer of 4-helix bundles with each monomer binding up to 13 Cu(I) ions in a previously unseen manner via mainly Cys residues that point into the core of the bundle. Csp1 is the first example of a protein that stores a metal within an established protein-folding motif. This work provides a detailed insight into how methanotrophs accumulate copper for the oxidation of methane. Understanding this process is essential if the wide-ranging biotechnological applications of methanotrophs are to be realised. Cytosolic homologues of Csp1 are present in diverse bacteria thus challenging the dogma that such organisms do not use copper in this location