Repositioning of Verrucosidin, a purported inhibitor of chaperone protein GRP78, as an inhibitor of mitochondrial electron transport chain complex I.

Verrucosidin (VCD) belongs to a group of fungal metabolites that were identified in screening programs to detect molecules that preferentially kill cancer cells under glucose-deprived conditions. Its mode of action was proposed to involve inhibition of increased GRP78 (glucose regulated protein 78) expression during hypoglycemia. Because GRP78 plays an important role in tumorigenesis, inhibitors such as VCD might harbor cancer therapeutic potential. We therefore sought to characterize VCD's anticancer activity in vitro. Triple-negative breast cancer cell lines MDA-MB-231 and MDA-MB-468 were treated with VCD under different conditions known to trigger increased expression of GRP78, and a variety of cellular processes were analyzed. We show that VCD was highly cytotoxic only under hypoglycemic conditions, but not in the presence of normal glucose levels, and VCD blocked GRP78 expression only when glycolysis was impaired (due to hypoglycemia or the presence of the glycolysis inhibitor 2-deoxyglucose), but not when GRP78 was induced by other means (hypoxia, thapsigargin, tunicamycin). However, VCD's strictly hypoglycemia-specific toxicity was not due to the inhibition of GRP78. Rather, VCD blocked mitochondrial energy production via inhibition of complex I of the electron transport chain. As a result, cellular ATP levels were quickly depleted under hypoglycemic conditions, and common cellular functions, including general protein synthesis, deteriorated and resulted in cell death. Altogether, our study identifies mitochondria as the primary target of VCD. The possibility that other purported GRP78 inhibitors (arctigenin, biguanides, deoxyverrucosidin, efrapeptin, JBIR, piericidin, prunustatin, pyrvinium, rottlerin, valinomycin, versipelostatin) might act in a similar GRP78-independent fashion will be discussed

National Center for Biomedical Ontology: Advancing biomedicine through structured organization of scientific knowledge

The National Center for Biomedical Ontology is a consortium that comprises leading informaticians, biologists, clinicians, and ontologists, funded by the National Institutes of Health (NIH) Roadmap, to develop innovative technology and methods that allow scientists to record, manage, and disseminate biomedical information and knowledge in machine-processable form. The goals of the Center are (1) to help unify the divergent and isolated efforts in ontology development by promoting high quality open-source, standards-based tools to create, manage, and use ontologies, (2) to create new software tools so that scientists can use ontologies to annotate and analyze biomedical data, (3) to provide a national resource for the ongoing evaluation, integration, and evolution of biomedical ontologies and associated tools and theories in the context of driving biomedical projects (DBPs), and (4) to disseminate the tools and resources of the Center and to identify, evaluate, and communicate best practices of ontology development to the biomedical community. Through the research activities within the Center, collaborations with the DBPs, and interactions with the biomedical community, our goal is to help scientists to work more effectively in the e-science paradigm, enhancing experiment design, experiment execution, data analysis, information synthesis, hypothesis generation and testing, and understand human disease

A Propensity for n-omega-Amino Acids in Thermally-Altered Antarctic Meteorites

Carbonaceous meteorites are known to contain a wealth of indigenous organic molecules, including amino acids, which suggests that these meteorites could have been an important source of prebiotic organic material during the origins of life on Earth and possibly elsewhere. We report the detection of extraterrestrial amino acids in thermally-altered type 3 CV and CO carbonaceous chondrites and ureilites recovered from Antarctica. The amino acid concentrations of the thirteen Antarctic meteorites were generally less abundant than in more amino acid-rich CI, CM, and CR carbonaceous chondrites that experienced much lower temperature aqueous alteration on their parent bodies. In contrast to low-temperature aqueously-altered meteorites that show complete structural diversity in amino acids formed predominantly by Strecker-cyanohydrin synthesis, the thermally-altered meteorites studied here are dominated by small, straight-chain, amine terminal (n-omega-amino) amino acids that are not consistent with Strecker formation. The carbon isotopic ratios of two extraterrestrial n-omega-amino acids measured in one of the CV chondrites are consistent with C-13-depletions observed previously in hydrocarbons produced by Fischer-Tropsch type reactions. The predominance of n-omega-amino acid isomers in thermally-altered meteorites hints at cosmochemical mechanisms for the preferential formation and preservation of a small subset of the possible amino acids

Feasibility Study of an Electrodialysis System for In-Home Water Desalination and Purification in Urban India

Desalination of high salinity water is an effective way of improving the aesthetic quality of drinking water and has been demonstrated to be a characteristic valued by consumers. Across India, 60% of the groundwater, the primary water source for millions, is brackish or contains a high salt content with total dissolved solids (TDS) ranging from 500 parts per million (ppm) to 3,000ppm. The government does not provide sufficient desalination treatment before the water reaches the tap of a consumer. Therefore consumers have turned to in-home desalination. However, current products are either expensive or have low recovery, product water output per untreated feed water, (∼30%) wasting water resources. Electrodialysis (ED) is a promising technology that desalinates water while maintaining higher recovery (up to 95%) compared to existing consumer reverse osmosis (RO) products. This paper first explores the in-home desalination market to determine critical design requirements for an in-home ED system. A model was then used to evaluate and optimize the performance of an ED stack at this scale and designated salinity range. Additionally, testing was conducted in order to validate the model and demonstrate feasibility. Finally, cost estimates of the proposed in-home ED system and product design concept are presented. The results of this work identified a system design that provides consumers with up to 80% recovery of feed water with cost and size competitive to currently available in-home RO products

Microwave observations of spinning dust emission in NGC6946

We report new cm-wave measurements at five frequencies between 15 and 18GHz of the continuum emission from the reportedly anomalous "region 4" of the nearby galaxy NGC6946. We find that the emission in this frequency range is significantly in excess of that measured at 8.5GHz, but has a spectrum from 15-18GHz consistent with optically thin free-free emission from a compact HII region. In combination with previously published data we fit four emission models containing different continuum components using the Bayesian spectrum analysis package radiospec. These fits show that, in combination with data at other frequencies, a model with a spinning dust component is slightly preferred to those that possess better-established emission mechanisms.Comment: submitted MNRA

High resolution AMI Large Array imaging of spinning dust sources: spatially correlated 8 micron emission and evidence of a stellar wind in L675

We present 25 arcsecond resolution radio images of five Lynds Dark Nebulae (L675, L944, L1103, L1111 & L1246) at 16 GHz made with the Arcminute Microkelvin Imager (AMI) Large Array. These objects were previously observed with the AMI Small Array to have an excess of emission at microwave frequencies relative to lower frequency radio data. In L675 we find a flat spectrum compact radio counterpart to the 850 micron emission seen with SCUBA and suggest that it is cm-wave emission from a previously unknown deeply embedded young protostar. In the case of L1246 the cm-wave emission is spatially correlated with 8 micron emission seen with Spitzer. Since the MIR emission is present only in Spitzer band 4 we suggest that it arises from a population of PAH molecules, which also give rise to the cm-wave emission through spinning dust emission.Comment: accepted MNRA

Incarceration history and risk of HIV and hepatitis C virus acquisition among people who inject drugs: a systematic review and meta-analysis

Background People who inject drugs (PWID) experience a high prevalence of incarceration and might be at high risk of HIV and hepatitis C virus (HCV) infection during or after incarceration. We aimed to assess whether incarceration history elevates HIV or HCV acquisition risk among PWID. Methods In this systematic review and meta-analysis, we searched MEDLINE, Embase, and PsycINFO databases for studies in any language published from Jan 1, 2000 until June 13, 2017 assessing HIV or HCV incidence among PWID. We included studies that measured HIV or HCV incidence among community-recruited PWID. We included only studies reporting original results and excluded studies that evaluated incident infections by self-report. We contacted authors of cohort studies that met the inclusion or exclusion criteria, but that did not report on the outcomes of interest, to request data. We extracted and pooled data from the included studies using random-effects meta-analyses to quantify the associations between recent (past 3, 6, or 12 months or since last follow-up) or past incarceration and HIV or HCV acquisition (primary infection or reinfection) risk among PWID. We assessed the risk of bias of included studies using the Newcastle-Ottawa Scale. Between-study heterogeneity was evaluated using the I2 statistic and the P-value for heterogeneity. Findings We included published results from 20 studies and unpublished results from 21 studies. These studies originated from Australasia, western and eastern Europe, North and Latin America, and east and southeast Asia. Recent incarceration was associated with an 81% (relative risk [RR] 1·81, 95% CI 1·40–2·34) increase in HIV acquisition risk, with moderate heterogeneity between studies (I2=63·5%; p=0·001), and a 62% (RR 1·62, 95% CI 1·28–2·05) increase in HCV acquisition risk, also with moderate heterogeneity between studies (I2=57·3%; p=0·002). Past incarceration was associated with a 25% increase in HIV (RR 1·25, 95% CI 0·94–1·65) and a 21% increase in HCV (1·21, 1·02–1·43) acquisition risk. Interpretation Incarceration is associated with substantial short-term increases in HIV and HCV acquisition risk among PWID and could be a significant driver of HCV and HIV transmission among PWID. These findings support the need for developing novel interventions to minimise the risk of HCV and HIV acquisition, including addressing structural risks associated with drug laws and excessive incarceration of PWID

AMI observations of unmatched Planck ERCSC LFI sources at 15.75 GHz

The Planck Early Release Compact Source Catalogue includes 26 sources with no obvious matches in other radio catalogues (of primarily extragalactic sources). Here we present observations made with the Arcminute Microkelvin Imager Small Array (AMI SA) at 15.75 GHz of the eight of the unmatched sources at declination > +10 degrees. Of the eight, four are detected and are associated with known objects. The other four are not detected with the AMI SA, and are thought to be spurious.Comment: 6 pages, 5 figures, 4 table

Follow-up observations at 16 and 33 GHz of extragalactic sources from WMAP 3-year data: I - Spectral properties

We present follow-up observations of 97 point sources from the Wilkinson Microwave Anisotropy Probe (WMAP) 3-year data, contained within the New Extragalactic WMAP Point Source (NEWPS) catalogue between declinations of -4 and +60 degrees; the sources form a flux-density-limited sample complete to 1.1 Jy (approximately 5 sigma) at 33 GHz. Our observations were made at 16 GHz using the Arcminute Microkelvin Imager (AMI) and at 33 GHz with the Very Small Array (VSA). 94 of the sources have reliable, simultaneous -- typically a few minutes apart -- observations with both telescopes. The spectra between 13.9 and 33.75 GHz are very different from those of bright sources at low frequency: 44 per cent have rising spectra (alpha < 0.0), where flux density is proportional to frequency^-alpha, and 93 per cent have spectra with alpha < 0.5; the median spectral index is 0.04. For the brighter sources, the agreement between VSA and WMAP 33-GHz flux densities averaged over sources is very good. However, for the fainter sources, the VSA tends to measure lower values for the flux densities than WMAP. We suggest that the main cause of this effect is Eddington bias arising from variability.Comment: 12 pages, 13 figures, submitted to MNRA