Investigation of Indian Diospyros Species for Antiplasmodial Properties

Despite decades of intense research, malaria remains a deadly disease worldwide and new antimalarials are urgently needed due to increasing drug resistance of Plasmodium falciparum to existing drugs. This article reports the evaluation of four Indian Diospyros species viz., Diospyros melanoxylon, D. peregrina, D. sylvatica, D. tomentosa for antiplasmodial activities against chloroquine-sensitive (3D7) and chloroquine-resistant (K1) strains of P. falciparum. Six of eight methanolic extracts were found to have significant activity, (IC50 = 16.5–92.9 µg ml−1), against strain 3D7 and five of these showed similar activities against strain K1 (IC50 = 20.5–121.6 µg ml−1). Diospyros sylvatica was found to be the most active species (IC50 = 16.5–29.4 µg ml−1) and is worthy of further investigation

Fit for work? Health, employability and challenges for the UK welfare reform agenda

This article introduces a special issue of Policy Studies entitled “Fit for work? Health, employability and challenges for the UK welfare reform agenda”. Growing from a shared concern over the need to expand the evidence base around the processes that led to large numbers of people claiming disability benefits in the UK, it brings together contributions from leading labour market and social policy researchers providing evidence and commentary on major reforms to Incapacity Benefit (IB) in the UK. This special issue address three key questions: what are the main causes of the long-term rise in the number of people claiming IBs; what will reduce the number of claimants; and what is likely to deliver policy effectively and efficiently? This introduction first explains and examines the challenges to reforms to IB in the UK, and then, in conclusion, highlights the answers to the previous three questions – first, labour market restructuring and marginalisation have driven the rise in numbers claiming IBs. Second, economic regeneration in the Britain’s less prosperous areas coupled with intensive and sustained supply-side support measures will bring numbers down. Third, delivery need to be flexible and tailored to individual needs and needs to be able to access local and expert knowledge in a range of organisations, including Job Centre Plus, the NHS as well as the private and voluntary sectors

The distribution of carbon in C1 to C6 carbonaceous chondrites

The carbon content and δ^C of carbon in ten carbonaceous chondrites, spanning petrologic grades 1 to 6,have been determined. There is a gradual change in the nature of the major carbonaceous components from C1 to C6 chondrites : C1 and C2 samples contain carbon as organics, whereas in higher petrologic types, carbon is predominantly amorphous or graphitic. This transition is consistent with carbon in C3 and C4 samples being formed either by dehydrogenation of organic materials during metamorphism on the parent body, or nebular heating followed by accretion at higher temperatures than prevailed during formation of C1-2 meteorites. In addition to a major carbonaceous component, ^C-rich interstellar grains are found in C1 and C2 samples and, to a much lesser extent, CV3 meteorites. CO3 and C4-6 meteorites do not appear to contain ^C-rich materials, a distribution controlled by primary accretion processes and not a result of secondary effects on parent-bodies. However, among the C1 to C3 meteorites aqueous activity might have acted to re-distribute ^C-rich grains by either concentrating them into C1 meteorites, or alternatively by transporting them into the source region of CV3 samples

Ancient Chinese methods are remarkably effective for the preparation of artemisinin-rich extracts of Qing Hao with potent antimalarial activity.

yesAncient Chinese herbal texts as far back as the 4th Century Zhou hou bei ji fang describe methods for the use of Qing Hao (Artemisia annua) for the treatment of intermittent fevers. Today, the A. annua constituent artemisinin is an important antimalarial drug and the herb itself is being grown and used locally for malaria treatment although this practice is controversial. Here we show that the ancient Chinese methods that involved either soaking, (followed by wringing) or pounding, (followed by squeezing) the fresh herb are more effective in producing artemisinin-rich extracts than the usual current method of preparing herbal teas from the dried herb. The concentrations of artemisinin in the extracts was up to 20-fold higher than that in a herbal tea prepared from the dried herb, but the amount of total artemisinin extracted by the Chinese methods was much less than that removed in the herbal tea. While both extracts exhibited potent in vitro activities against Plasmodium falciparum, only the pounded juice contained sufficient artemisinin to suppress parasitaemia in P. berghei infected mice. The implications of these results are discussed in the context of malaria treatment using A. annua infusions

Cryptolepine-Induced Cell Death of Leishmania donovani Promastigotes Is Augmented by Inhibition of Autophagy

Leishmania donovani are the causative agents of visceral leishmaniasis worldwide. Lack of vaccines and emergence of drug resistance warrants the need for improved drug therapy and newer therapeutic intervention strategies against leishmaniasis. In the present study, we have investigated the effect of the natural indoloquinoline alkaloid cryptolepine on L. donovani AG83 promastigotes. Our results show that cryptolepine induces cellular dysfunction in L. donovani promastigotes, which leads to the death of this unicellular parasite. Interestingly, our study suggest that cryptolepine-induced cell death of L. donovani is counteracted by initial autophagic features elicited by the cells. For the first time, we show that autophagy serves as a survival mechanism in response to cryptolepine treatment in L. donovani promastigotes and inhibition of autophagy causes an early increase in the amount of cell death. This study can be exploited for designing better drugs and better therapeutic strategies against leishmaniasis in future

Search for Nanosecond Near-infrared Transients around 1280 Celestial Objects

Stars and planetary system

Cross-species oncogenomics offers insight into human muscle-invasive bladder cancer

Background In humans, muscle-invasive bladder cancer (MIBC) is highly aggressive and associated with a poor prognosis. With a high mutation load and large number of altered genes, strategies to delineate key driver events are necessary. Dogs and cats develop urothelial carcinoma (UC) with histological and clinical similarities to human MIBC. Cattle that graze on bracken fern also develop UC, associated with exposure to the carcinogen ptaquiloside. These species may represent relevant animal models of spontaneous and carcinogen-induced UC that can provide insight into human MIBC. Results Whole-exome sequencing of domestic canine (n = 87) and feline (n = 23) UC, and comparative analysis with human MIBC reveals a lower mutation rate in animal cases and the absence of APOBEC mutational signatures. A convergence of driver genes (ARID1A, KDM6A, TP53, FAT1, and NRAS) is discovered, along with common focally amplified and deleted genes involved in regulation of the cell cycle and chromatin remodelling. We identify mismatch repair deficiency in a subset of canine and feline UCs with biallelic inactivation of MSH2. Bovine UC (n = 8) is distinctly different; we identify novel mutational signatures which are recapitulated in vitro in human urinary bladder UC cells treated with bracken fern extracts or purified ptaquiloside. Conclusion Canine and feline urinary bladder UC represent relevant models of MIBC in humans, and cross-species analysis can identify evolutionarily conserved driver genes. We characterize mutational signatures in bovine UC associated with bracken fern and ptaquiloside exposure, a human-linked cancer exposure. Our work demonstrates the relevance of cross-species comparative analysis in understanding both human and animal UC

A methanolic extract of Zanthoxylum bungeanum modulates secondary metabolism regulator genes in Aspergillus flavus and shuts down aflatoxin production

Aflatoxin B1 (AFB1) is a food-borne toxin produced by Aspergillus flavus and a few similar fungi. Natural anti-aflatoxigenic compounds are used as alternatives to chemical fungicides to prevent AFB1 accumulation. We found that a methanolic extract of the food additive Zanthoxylum bungeanum shuts down AFB1 production in A. flavus. A methanol sub-fraction (M20) showed the highest total phenolic/flavonoid content and the most potent antioxidant activity. Mass spectrometry analyses identified four flavonoids in M20: quercetin, epicatechin, kaempferol-3-O-rhamnoside, and hyperoside. The anti-aflatoxigenic potency of M20 (IC50: 2–4 µg/mL) was significantly higher than its anti-proliferation potency (IC50: 1800–1900 µg/mL). RNA-seq data indicated that M20 triggers significant transcriptional changes in 18 of 56 secondary metabolite pathways in A. flavus, including repression of the AFB1 biosynthesis pathway. Expression of aflR, the specific activator of the AFB1 pathway, was not changed by M20 treatment, suggesting that repression of the pathway is mediated by global regulators. Consistent with this, the Velvet complex, a prominent regulator of secondary metabolism and fungal development, was downregulated. Decreased expression of the conidial development regulators brlA and Medusa, genes that orchestrate redox responses, and GPCR/oxylipin-based signal transduction further suggests a broad cellular response to M20. Z. bungeanum extracts may facilitate the development of safe AFB1 control strategies. </p

Synthesis and antiprotozoal activity of oligomethylene- and p-phenylene-bis(methylene)-linked bis(+)-huprines

We have synthesized a series of dimers of (+)-(7R,11R)-huprine Y and evaluated their activity against Trypanosoma brucei, Plasmodium falciparum, rat myoblast L6 cells and human acetylcholinesterase (hAChE), and their brain permeability. Most dimers have more potent and selective trypanocidal activity than huprine Y and are brain permeable, but they are devoid of antimalarial activity and remain active against hAChE. Lead optimization will focus on identifying compounds with a more favourable trypanocidal/anticholinesterase activity ratio