Comprehensive comparison of in silico MS/MS fragmentation tools of the CASMI contest: database boosting is needed to achieve 93% accuracy.

In mass spectrometry-based untargeted metabolomics, rarely more than 30% of the compounds are identified. Without the true identity of these molecules it is impossible to draw conclusions about the biological mechanisms, pathway relationships and provenance of compounds. The only way at present to address this discrepancy is to use in silico fragmentation software to identify unknown compounds by comparing and ranking theoretical MS/MS fragmentations from target structures to experimental tandem mass spectra (MS/MS). We compared the performance of four publicly available in silico fragmentation algorithms (MetFragCL, CFM-ID, MAGMa+ and MS-FINDER) that participated in the 2016 CASMI challenge. We found that optimizing the use of metadata, weighting factors and the manner of combining different tools eventually defined the ultimate outcomes of each method. We comprehensively analysed how outcomes of different tools could be combined and reached a final success rate of 93% for the training data, and 87% for the challenge data, using a combination of MAGMa+, CFM-ID and compound importance information along with MS/MS matching. Matching MS/MS spectra against the MS/MS libraries without using any in silico tool yielded 60% correct hits, showing that the use of in silico methods is still important

Transfer as a reciprocal process: How to foster receptivity to results of transdisciplinary research

Transdisciplinary research (TDR) seeks to address real-world problems and aims to be socially transformative. This normative objective extends beyond particular TDR projects, as real-world problems are embedded in concrete contexts but, at the same time, are also related to wider societal challenges that are not restricted to one context. Therefore, TDR generally entails transfer of knowledge and results to other contexts. However, the TDR discourse has mainly treated transfer efforts from the perspective of scientific generalization, translation and packaging of knowledge. Within this understanding of transfer, little attention has been paid to interplay between contexts and the role of new contexts themselves. This article is based on qualitative explorative research on four TDR projects. Its results were iteratively derived through project analysis, reflection on insights from the literature and discussions with TDR experts. We propose that transfer is a complex reciprocal process in which different types of knowledge are provided and transferred to other contexts, where knowledge is adapted, enriched and modified. In addition to project researchers, actors in other (pick-up) contexts also play an important role for successful transfer and appropriation of TDR results. Generating transfer potential within the duration of a project depends on being aware of potential pick-up contexts. To address the interdependent aspects of transfer (results, mediation, and appropriation in other contexts), we present a comprehensive model outlining TDR transfer processes. To support projects seeking to raise their transfer potential in a more conscious manner, we also formulate three overarching recommendations: 1) process results for transfer adequately, 2) identify and support intermediaries and, 3) increase awareness of and address other contexts. Considering these recommendations while also being aware of their interdependence may increase potential for transfer of knowledge and results to other contexts. Our conceptual understanding acknowledges the complexity and non-linearity of endeavors to take advantage of case-specifically gained knowledge and results in other contexts or at other scales

An artificial Rb atom in a semiconductor with lifetime-limited linewidth

We report results important for the creation of a best-of-both-worlds quantum hybrid system consisting of a solid-state source of single photons and an atomic ensemble as quantum memory. We generate single photons from a GaAs quantum dot (QD) frequency-matched to the Rb D2-transitions and then use the Rb transitions to analyze spectrally the quantum dot photons. We demonstrate lifetime-limited QD linewidths (1.48 GHz) with both resonant and non-resonant excitation. The QD resonance fluorescence in the low power regime is dominated by Rayleigh scattering, a route to match quantum dot and Rb atom linewidths and to shape the temporal wave packet of the QD photons. Noise in the solid-state environment is relatively benign: there is a blinking of the resonance fluorescence at MHz rates but negligible upper state dephasing of the QD transition. We therefore establish a close-to-ideal solid-state source of single photons at a key wavelength for quantum technologies

Prokaryotic Heme Biosynthesis: Multiple Pathways to a Common Essential Product

The advent of heme during evolution allowed organisms possessing this compound to safely and efficiently carry out a variety of chemical reactions that otherwise were difficult or impossible. While it was long assumed that a single heme biosynthetic pathway existed in nature, over the past decade, it has become clear that there are three distinct pathways among prokaryotes, although all three pathways utilize a common initial core of three enzymes to produce the intermediate uroporphyrinogen III. The most ancient pathway and the only one found in the Archaea converts siroheme to protoheme via an oxygen-independent four-enzyme-step process. Bacteria utilize the initial core pathway but then add one additional common step to produce coproporphyrinogen III. Following this step, Gram-positive organisms oxidize coproporphyrinogen III to coproporphyrin III, insert iron to make coproheme, and finally decarboxylate coproheme to protoheme, whereas Gram-negative bacteria first decarboxylate coproporphyrinogen III to protoporphyrinogen IX and then oxidize this to protoporphyrin IX prior to metal insertion to make protoheme. In order to adapt to oxygen-deficient conditions, two steps in the bacterial pathways have multiple forms to accommodate oxidative reactions in an anaerobic environment. The regulation of these pathways reflects the diversity of bacterial metabolism. This diversity, along with the late recognition that three pathways exist, has significantly slowed advances in this field such that no single organism's heme synthesis pathway regulation is currently completely characterized

To Biopsy or Not to Biopsy: Evaluation of a Large German Cohort of Patients with Abnormal Liver Tests of Unknown Etiology

Background and Aims: Despite increasingly sensitive and accurate blood tests to detect liver disease, liver biopsy remains very useful in patients with atypical clinical features and abnormal liver tests of unknown etiology. The aim was to determine those elevated laboratory liver parameters that cause the clinician to order a biopsy, and whether laboratory tests are associated with pathological findings on histology. Methods: 504 patients with unclear hepatopathy, admitted to the outpatient clinic of a university hospital between 2007 and 2010, were analyzed with respect to laboratory results, clinical data, and the results of liver biopsies. Results: Aspartate aminotransferase (AST) and glutamate dehydrogenase (GLDH) levels above the normal range significantly increased the likelihood of recommending a liver biopsy by 81% [OR with 95% CI 1.81 (1.21-2.71), p = 0.004] and 159% [OR with 95% CI 2.59 (1.70-3.93), p < 0.001], respectively. AST values above normal were associated with fibrosis (63 vs. 40% for normal AST, p = 0.010). Elevated ferritin levels pointed to a higher incidence of steatosis (48 vs. 10% for normal ferritin, p < 0.001) and inflammation (87 vs. 62% for normal ferritin, p = 0.004). Conclusions: Our results indicate that elevated AST and GLDH were associated with a greater likelihood of recommending liver biopsy. Elevated AST and ferritin levels were associated with steatosis, inflammation and fibrosis on liver biopsies. Thus, AST and ferritin may be useful non-invasive predictors of liver pathology in patients with unclear hepatopathy

Association of Leptin Gene DNA Methylation With Diagnosis and Treatment Outcome of Anorexia Nervosa

Epigenetic alterations are increasingly implicated in the pathophysiology of anorexia nervosa (AN) but are as yet poorly understood. We investigated possible associations between the leptin gene (LEP) and the leptin receptor gene (LEPR) DNA promoter methylation and (1) a diagnosis of AN and (2) outcome after a 10 months psychotherapeutic outpatient treatment. 129 (LEPR: n = 135) patients with AN were investigated during the large scale psychotherapeutic Anorexia Nervosa Treatment Outpatient Study (ANTOP) trial, compared to 117 (LEPR: n = 119) age and height matched, normal-weight healthy controls. Blood samples were taken at baseline, the end of therapy (40 weeks) and the 12-months follow-up and compared to controls. Methylation was measured in whole blood via bisulfite sequencing. Within the promoter region 32 (LEP) and 39 CpG sites (LEPR) were analyzed. Two key findings were observed. First, LEP and LEPR methylation at baseline were lower in patients compared to controls (LEP: [%] AN: 30.94 ± 13.2 vs. controls: 34.53 ± 14.6); LEPR ([%] AN: 3.73 ± 5.4 vs. controls: 5.22 ± 8.3, mixed linear models: both P &lt; 0.001). Second, lower DNA methylation of the LEP promoter, with a dynamic upregulation during treatment, was associated with a full recovery in AN patients (% change from baseline to follow-up in full recovery patients: +35.13% (SD: 47.56); mixed linear model: P &lt; 0.0001). To test for potential predictive properties of mean LEP DNA methylation a LEP DNA methylation cut-off (31.25% DNA methylation) was calculated, which significantly discriminated full recovery vs. full syndrome AN patients. This cut-off was then tested in a group of previously unclassified patients (missing follow-up data of the Structured Interview for Anorexic and Bulimic disorders; n = 33). Patients below the cut-off (31.25% LEP DNA methylation) showed an increase in BMI over time, while those above the cut-off had a decrease in BMI (ANOVA at the 12-months follow-up: P = 0.0142). To our knowledge, this is the first study investigating epigenetic alterations in AN over time. Our findings indicate that LEP DNA methylation might be involved in the disease course of AN

Increased d-amino acid oxidase expression in the bilateral hippocampal CA4 of schizophrenic patients: a post-mortem study

An important risk gene in schizophrenia is d-amino acid oxidase (DAAO). To establish if expression of DAAO is altered in cortical, hippocampal or thalamic regions of schizophrenia patients, we measured gene expression of DAAO in a post-mortem study of elderly patients with schizophrenia and non-affected controls in both hemispheres differentiating between gray and white matter. We compared cerebral post-mortem samples (granular frontal cortex BA9, middle frontal cortex BA46, superior temporal cortex BA22, entorhinal cortex BA28, sensoric cortex BA1–3, hippocampus (CA4), mediodorsal nucleus of the thalamus) from 10 schizophrenia patients to 13 normal subjects investigating gene expression of DAAO in the gray and white matter of both hemispheres of the above-mentioned brain regions by in situ-hybridization. We found increased expression of DAAO-mRNA in the hippocampal CA4 of schizophrenic patients. Compared to the control group, both hemispheres of the hippocampus of schizophrenic patients showed an increased expression of 46% (right, P = 0.013) and 54% (left, P = 0.019), respectively. None of the other regions examined showed statistically significant differences in DAAO expression. This post-mortem study demonstrated increased gene expression of DAAO in the left and right hippocampus of schizophrenia patients. This increased expression could be responsible for a decrease in local d-serine levels leading to a NMDA-receptor hypofunction that is hypothesized to play a major role in the pathophysiology of schizophrenia. However, our study group was small and results should be verified using larger samples

BLOC-1 and BLOC-3 regulate VAMP7 cycling to and from melanosomes via distinct tubular transport carriers.

Endomembrane organelle maturation requires cargo delivery via fusion with membrane transport intermediates and recycling of fusion factors to their sites of origin. Melanosomes and other lysosome-related organelles obtain cargoes from early endosomes, but the fusion machinery involved and its recycling pathway are unknown. Here, we show that the v-SNARE VAMP7 mediates fusion of melanosomes with tubular transport carriers that also carry the cargo protein TYRP1 and that require BLOC-1 for their formation. Using live-cell imaging, we identify a pathway for VAMP7 recycling from melanosomes that employs distinct tubular carriers. The recycling carriers also harbor the VAMP7-binding scaffold protein VARP and the tissue-restricted Rab GTPase RAB38. Recycling carrier formation is dependent on the RAB38 exchange factor BLOC-3. Our data suggest that VAMP7 mediates fusion of BLOC-1-dependent transport carriers with melanosomes, illuminate SNARE recycling from melanosomes as a critical BLOC-3-dependent step, and likely explain the distinct hypopigmentation phenotypes associated with BLOC-1 and BLOC-3 deficiency in Hermansky-Pudlak syndrome variants.This work was supported by grants from the National Institutes of Health, National Eye Institute (R01 EY015625, to M.S. Marks and G.  Raposo), National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01 AR048155, to M.S. Marks, and F32 AR062476, to M.K. Dennis), National Institute of General Medical Sciences (R01 GM108807, to M.S. Marks); Fondation pour la Recherche Médicale (to T.  Galli); the UK Medical Research Council (G0900113, to J.P. Luzio); and the Wellcome Trust (108429, to E.V. Sviderskaya and D.C. Bennett). This work was also supported by a Canadian Institutes of Health Research Fellowship (to G.G.  Hesketh) and a Fondation pour la Recherche Médicale grant from Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Institut Curie, and Fondation pour la Recherche Médicale (DEQ20140329491 Team label, to G. Raposo).This is the final version of the article. It first appeared from Rockefeller University Press via http://dx.doi.org/10.1083/jcb.20160509

A Systematic Review of Social Factors and Suicidal Behavior in Older Adulthood

Suicide in later life is a global public health problem. The aim of this review was to conduct a systematic analysis of studies with comparison groups that examined the associations between social factors and suicidal behavior (including ideation, non-fatal suicidal behavior, or deaths) among individuals aged 65 and older. Our search identified only 16 articles (across 14 independent samples) that met inclusion criteria. The limited number of studies points to the need for further research. Included studies were conducted in Canada (n = 2), Germany (n = 1), Hong Kong (n = 1), Japan (n = 1), Singapore (n = 1), Sweden (n = 2), Taiwan (n = 1), the U.K. (n = 2), and the U.S. (n = 3). The majority of the social factors examined in this review can be conceptualized as indices of positive social connectedness—the degree of positive involvement with family, friends, and social groups. Findings indicated that at least in industrialized countries, limited social connectedness is associated with suicidal ideation, non-fatal suicidal behavior, and suicide in later life. Primary prevention programs designed to enhance social connections as well as a sense of community could potentially decrease suicide risk, especially among men

Consideration of the bioavailability of metal/metalloid species in freshwaters: experiences regarding the implementation of biotic ligand model-based approaches in risk assessment frameworks

After the scientific development of Biotic Ligand Models (BLMs) in recent decades these models are now considered suitable for implementation in regulatory risk assessment of metals in freshwater bodies. The approach has been developed over several years and has been described in many peer-reviewed publications. The original complex BLMs have been applied in prospective risk assessment reports for metals and metal compounds and are also recommended as suitable concepts for the evaluation of monitoring data in the context of the European Water Framework Directive. Currently, several user-friendly BLM-based bioavailability software tools are available for assessing the aquatic toxicity of a limited number of metals (mainly copper, nickel, and zinc). These tools need only a basic set of water parameters as input (e.g., pH, hardness, dissolved organic matter and dissolved metal concentration). Such tools seem appropriate to foster the implementation in routine water quality assessments. This work aims to review the existing bioavailability-based regulatory approaches and the application of available BLM-based bioavailability tools for this purpose. Advantages and possible drawbacks of these tools (e.g., feasibility, boundaries of validity) are discussed, and recommendations for further implementation are given