Avoiding the pitfalls of gene set enrichment analysis with SetRank.

The purpose of gene set enrichment analysis (GSEA) is to find general trends in the huge lists of genes or proteins generated by many functional genomics techniques and bioinformatics analyses. Here we present SetRank, an advanced GSEA algorithm which is able to eliminate many false positive hits. The key principle of the algorithm is that it discards gene sets that have initially been flagged as significant, if their significance is only due to the overlap with another gene set. The algorithm is explained in detail and its performance is compared to that of other methods using objective benchmarking criteria. Furthermore, we explore how sample source bias can affect the results of a GSEA analysis. The benchmarking results show that SetRank is a highly specific tool for GSEA. Furthermore, we show that the reliability of results can be improved by taking sample source bias into account. SetRank is available as an R package and through an online web interface

Flaring Up All Over -- Radio Activity in Rapidly-Rotating Late-Type M and L Dwarfs

We present Very Large Array observations of twelve late M and L dwarfs in the Solar neighborhood. The observed sources were chosen to cover a wide range of physical characteristics - spectral type, rotation, age, binarity, and X-ray and H\alpha activity - to determine the role of these properties in the production of radio emission, and hence magnetic fields. Three of the twelve sources, TVLM513-46546, 2MASS J0036159+182110, and BRI0021-0214, were observed to flare and also exhibit persistent emission, indicating that magnetic activity is not quenched at the bottom of the main sequence. The radio emission extends to spectral type L3.5, and there is no apparent decrease in the ratio of flaring luminosities to bolometric luminosities between M8-L3.5. Moreover, contrary to the significant drop in persistent H\alpha activity beyond spectral type M7, the persistent radio activity appears to steadily increase between M3-L3.5. Similarly, the radio emission from BRI0021-0214 violates the phenomenological relations between the radio and X-ray luminosities of coronally active stars, hinting that radio and X-ray activity are also uncorrelated at the bottom of the main sequence. The radio active sources that have measured rotational velocities are rapid rotators, Vsin(i)>30 km/sec, while the upper limits on radio activity in slowly-rotating late M dwarfs (Vsin(i)<10 km/sec) are lower than these detections. These observations provide tantalizing evidence that rapidly-rotating late M and L dwarfs are more likely to be radio active. This possible correlation is puzzling given that the observed radio emission requires sustained magnetic fields of 10-1000 G and densities of 10^12 cm^-3, indicating that the active sources should have slowed down considerably due to magnetic braking.Comment: Accepted to ApJ; Two new figures; Minor text revision

Heterogeneity and incorporation of chromium isotopes in recent marine molluscs (Mytilus)

The mollusc genus Mytilus is abundant in various modern marine environments and is an important substrate for palaeo-proxy work. The redox-sensitive chromium (Cr) isotope system is emerging as a proxy for changes in the oxidation state of the Earth's atmosphere and oceans. However, potential isotopic offsets between ambient sea water and modern biogenic carbonates have yet to be constrained. We measured Cr concentrations ([Cr]) and isotope variations (δ53 Cr) in recent mollusc shells (Mytilus) from open and restricted marine environments and compared these to ambient sea water δ53 Cr values. We found a large range in mollusc [Cr] (12-309 ppb) and δ53 Cr values (-0.30 to +1.25‰) and in the offset between δ53 Cr values of mollusc shells and ambient sea water ( Δ53CrseawaterbulkMytilus , -0.17 to -0.91‰). Step digestions of cultivated Mytilus edulis specimens indicate that Cr is mainly concentrated in organic components of the shell (periostracum: 407 ppb, n = 2), whereas the mollusc carbonate minerals contain ≤3 ppb Cr. Analyses of individual Cr-hosting phases (i.e., carbonate minerals and organic matrix) did not reveal significant differences in δ53 Cr values, and thus, we suggest that Cr isotope fractionation may likely take place prior to rather than during biomineralisation of Mytilus shells. Heterogeneity of δ53 Cr values in mollusc shells depends on sea water chemistry (e.g., salinity, food availability, faeces). The main control for δ53 Cr values incorporated into shells, however, is likely vital effects (in particular shell valve closure time) since Cr can be partially or quantitatively reduced in sea water trapped between closed shell valves. The δ53 Cr values recorded in Mytilus shells may thus be de-coupled from the redox conditions of ambient sea water, introducing additional heterogeneity that needs to be better constrained before using δ53 Cr values in mollusc shells for palaeo-reconstructions.Sylvie Bruggmann, Robert M. Klaebe, Cora Paulukat, Robert Fre

Multimodal stimulus coding by a gustatory sensory neuron in Drosophila larvae.

Accurate perception of taste information is crucial for animal survival. In adult Drosophila, gustatory receptor neurons (GRNs) perceive chemical stimuli of one specific gustatory modality associated with a stereotyped behavioural response, such as aversion or attraction. We show that GRNs of Drosophila larvae employ a surprisingly different mode of gustatory information coding. Using a novel method for calcium imaging in the larval gustatory system, we identify a multimodal GRN that responds to chemicals of different taste modalities with opposing valence, such as sweet sucrose and bitter denatonium, reliant on different sensory receptors. This multimodal neuron is essential for bitter compound avoidance, and its artificial activation is sufficient to mediate aversion. However, the neuron is also essential for the integration of taste blends. Our findings support a model for taste coding in larvae, in which distinct receptor proteins mediate different responses within the same, multimodal GRN

A systematic look at chromium isotopes in modern shells – implications for paleo-environmental reconstructions

The chromium isotope system (53Cr&thinsp;∕&thinsp;52Cr, expressed as δ53Cr relative to NIST SRM 979) in marine biogenic and non-biogenic carbonates is currently being evaluated as a proxy for the redox state of the ocean. Previous work has concentrated on using corals and foraminifera for this purpose, but investigations focusing on the behavior of Cr in bivalves as potential archives are lacking. Due to their often good preservation, fossil marine biogenic carbonates have the potential to serve as useful archives for the reconstruction of past ocean redox fluctuations and eventually link those to climatic changes throughout Earth's history. Here, we present an evaluation of the Cr isotope system in shells of some modern bivalves. Shell species from Lucidinadae, Cardiidae, Glycimerididae and Pectenidae, collected systematically from one Mediterranean location (Playa Poniente, Benidorm, Spain) over a 3-year period reveal δ53Cr values ranging from 0.15&thinsp;‰ to 0.65&thinsp;‰, values that are systematically below the local seawater δ53Cr value of 0.83±0.05&thinsp;‰. This attests to a significant reduction of dissolved seawater chromium in the process leading to calcification and thus for control of Cr isotope fractionation during biological routes. A similar, constant offset in δ53Cr values relative to surface seawater is observed in shells from Mytilius edulis from an arctic location (Godhavn, Disko Bay, Greenland). Chromium concentrations in the studied shells are significantly controlled by organic matter and typically range from 0.020 to 0.100&thinsp;ppm, with some higher concentrations of up to 0.163&thinsp;ppm recorded in Pectenidae. We also observe subtle, species-dependent differences in average Cr isotope signatures in the samples from Playa Poniente, particularly of Lucidinadae and Cardiidae, with considerably depressed and elevated δ53Cr values, respectively, relative to the other species investigated. Intra-species heterogeneities, both in Cr concentrations and δ53Cr values, are favorably seen to result from vital effects during shell calcification rather than from heterogeneous seawater composition. This is because we observe that the surface seawater composition in the particular Playa Poniente location remained constant during the month of July of the 3 years we collected bivalve samples. Intra-shell heterogeneities – associated with growth zones reflecting one to several years of growth, both in δ53Cr and Cr concentrations – are observed in a sample of Placuna placenta and Mimachlamys townsendi. We suspect that these variations are, at least partially, related to seasonal changes in δ53Cr of surface seawaters. Recognizing the importance of organic substances in the bivalve shells, we propose a model whereby reduction of Cr(VI) originally contained in the seawater as chromate ion and transported to the calcifying space, to Cr(III), is effectively adsorbed onto organic macromolecules which eventually get included in the growing shell carbonates. This study, with its definition of statistically sound offsets in δ53Cr values of certain bivalve species from ambient seawater, forms a base for future investigations aimed at using fossil shells as archives for the reconstruction of paleo-seawater redox fluctuations.</p

Chronic Hepatitis C Treatment in Patients with Drug Injection History: Findings of the INTEGRATE Prospective, Observational Study.

INTRODUCTION: People who inject drugs represent an under-treated chronic hepatitis C virus (HCV)-infected patient population. METHODS: INTEGRATE was a prospective, observational study investigating the effectiveness, safety, and adherence in routine clinical practice to telaprevir in combination with peg-interferon and ribavirin (Peg-IFN/RBV) in patients with history of injecting drug use chronically infected with genotype 1 HCV. RESULTS: A total of 46 patients were enrolled and included in the intent-to-treat (ITT) population. Among heroin and/or cocaine users (n = 37; 80%), 22% reported use in the past month; 74% (34/46) of patients were on opioid substitution therapy in the pre-treatment phase, and 43% (20/46) discontinued HCV treatment prematurely. Sustained virologic response rate was 54% (25/46) in the ITT population and 74% (25/34) in the per protocol (evaluable-for-effectiveness) population. The main reason for failure in the ITT analysis was loss to follow-up (n = 8; 17%). Adverse events occurred in 91% (42/46) of patients. Mean patient-reported adherence to study drugs was >89% at Week 4, Week 12 and end of treatment. CONCLUSION: Despite a high rate of treatment discontinuation (including loss to follow-up), self-reported adherence to treatment was good and virologic cure rates were similar to those reported in large real-world cohorts. Our findings suggest that people with a history of injecting drug use should be considered for treatment of chronic HCV infection, and highlight the need for improvements in patient support to boost retention in care and, in turn, help to prevent reinfection and transmission. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifier, NCT01980290. FUNDING: Janssen Pharmaceuticals

Hepatitis C virus dynamics among intravenous drug users suggest that an annual treatment uptake above 10% would eliminate the disease by 2030.

In Switzerland, the prevalence of hepatitis C virus (HCV) among people who inject drugs (PWID) has been decreasing owing to active harm reduction efforts and an aging population. Recent advances in HCV therapeutics may provide an opportunity to direct treatment to high-risk populations, with a goal of reducing HCV prevalence and preventing new infections. In order to guide these efforts, the current project was undertaken with the following aims: (1) to develop a simple model to estimate the number of new HCV infections using available data on PWID; (2) to examine the impact of intervention strategies (prevention and treatment) on new and total HCV infections among PWID. A dynamic HCV transmission model was used to track HCV incidence and prevalence among active PWID according to their harm reduction status. The relative impact of treating 1, 5, 10 or 15% of HCV+ PWID with new oral direct acting antivirals was considered. In 2015, there were an estimated 10 160 active PWID in Switzerland, more than 85% of whom were engaged in harm reduction programmes. Approximately 42% of active PWID were HCV-RNA+, with 55 new viraemic infections occurring annually. By 2030, a 60% reduction in the HCV+ PWID population would be expected. In the absence of behavioural changes, the number of secondary infections would increase under all treatment scenarios. With high level treatment, the number of secondary infections would peak and then drop, corresponding to depletion of the viral pool. In Switzerland, 5% treatment of the 2015 HCV+ PWID population per year would result in a 95% reduction in total cases by 2030, whereas ≥10% treatment would result in a &gt;99% reduction. Timely treatment of hepatitis C virus among people who inject drugs is necessary to reduce the prevalence and prevent new infections in Switzerland

Erratum: Author Correction: System immunology-based identification of blood transcriptional modules correlating to antibody responses in sheep.

[This corrects the article DOI: 10.1038/s41541-018-0078-0.]