Search for AL amyloidosis risk factors using Mendelian randomization

In amyloid light chain (AL) amyloidosis, amyloid fibrils derived from immunoglobulin light chain are deposited in many organs, interfering with their function. The etiology of AL amyloidosis is poorly understood. Summary data from genome-wide association studies (GWASs) of multiple phenotypes can be exploited by Mendelian randomization (MR) methodology to search for factors influencing AL amyloidosis risk. We performed a 2-sample MR analyzing 72 phenotypes, proxied by 3461 genetic variants, and summary genetic data from a GWAS of 1129 AL amyloidosis cases and 7589 controls. Associations with a Bonferroni-defined significance level were observed for genetically predicted increased monocyte counts (P = 3.8 × 10−4) and the tumor necrosis factor receptor superfamily member 17 (TNFRSF17) gene (P = 3.4 × 10−5). Two other associations with the TNFRSF (members 6 and 19L) reached a nominal significance level. The association between genetically predicted decreased fibrinogen levels may be related to roles of fibrinogen other than blood clotting. be related to its nonhemostatic role. It is plausible that a causal relationship with monocyte concentration could be explained by selection of a light chain–producing clone during progression of monoclonal gammopathy of unknown significance toward AL amyloidosis. Because TNFRSF proteins have key functions in lymphocyte biology, it is entirely plausible that they offer a potential link to AL amyloidosis pathophysiology. Our study provides insight into AL amyloidosis etiology, suggesting high circulating levels of monocytes and TNFRSF proteins as risk factors

Identification and Localization of Proteins Associated with Biomineralization in the Iron Deposition Vesicles of Honeybees (Apis mellifera)

Honeybees (Apis mellifera) form superparamagnetic magnetite to act as a magnetoreceptor for magnetoreception. Biomineralization of superparamagnetic magnetite occurs in the iron deposition vesicles of trophocytes. Even though magnetite has been demonstrated, the mechanism of magnetite biomineralization is unknown. In this study, proteins in the iron granules and iron deposition vesicles of trophocytes were purified and identified by mass spectrometry. Antibodies against such proteins were produced. The major proteins include actin, myosin, ferritin 2, and ATP synthase. Immunolabeling and co-immunoprecipitation studies suggest that iron is stored in ferritin 2 for the purpose of forming 7.5-nm diameter iron particles and that actin-myosin-ferritin 2 may serve as a transporter system. This system, along with calcium and ATP, conveys the iron particles (ferritin) to the center of iron deposition vesicles for iron granules formation. These proteins and reactants are included in iron deposition vesicles during the formation of iron deposition vesicles from the fusion of smooth endoplasmic reticulum. A hypothetical model for magnetite biomineralization in iron deposition vesicles is proposed for honeybees

A novel class of sulphonamides potently block malaria transmission by targeting a Plasmodium vacuole membrane protein

Phenotypic cell-based screens are critical tools for discovering candidate drugs for development, yet identification of the cellular target and mode of action of a candidate drug is often lacking. Using an imaging-based screen, we recently discovered an N-[(4-hydroxychroman-4-yl)methyl]-sulphonamide (N-4HCS) compound, DDD01035881, that blocks male gamete formation in the malaria parasite life cycle and subsequent transmission of the parasite to the mosquito with nanomolar activity. To identify the target(s) of DDD01035881, and of the N-4HCS class of compounds more broadly, we synthesised a photoactivatable derivative, probe 2. Photoaffinity labelling of probe 2 coupled with mass spectrometry identified the 16 kDa Plasmodium falciparum parasitophorous vacuole membrane protein Pfs16 as a potential parasite target. Complementary methods including cellular thermal shift assays confirmed that the parent molecule DDD01035881 stabilised Pfs16 in lysates from activated mature gametocytes. Combined with high-resolution, fluorescence and electron microscopy data, which demonstrated that parasites inhibited with N-4HCS compounds phenocopy the targeted deletion of Pfs16 in gametocytes, these data implicate Pfs16 as a likely target of DDD01035881. This finding establishes N-4HCS compounds as being flexible and effective starting candidates from which transmission-blocking antimalarials can be developed in the future

Deletion of transketolase triggers a stringent metabolic response in promastigotes and loss of virulence in amastigotes of Leishmania mexicana

Transketolase (TKT) is part of the non-oxidative branch of the pentose phosphate pathway (PPP). Here we describe the impact of removing this enzyme from the pathogenic protozoan Leishmania mexicana. Whereas the deletion had no obvious effect on cultured promastigote forms of the parasite, the Δtkt cells were not infective to mice. Δtkt promastigotes were more susceptible to oxidative stress and various leishmanicidal drugs than wild-type, and metabolomics analysis revealed profound changes to metabolism in these cells. In addition to changes consistent with those directly related to the role of TKT in the PPP, central carbon metabolism was substantially decreased, the cells consumed significantly less glucose, flux through glycolysis diminished, and production of the main end products of metabolism was decreased. Only minor changes in RNA abundance from genes encoding enzymes in central carbon metabolism, however, were detected although fructose-1,6-bisphosphate aldolase activity was decreased two-fold in the knock-out cell line. We also showed that the dual localisation of TKT between cytosol and glycosomes is determined by the C-terminus of the enzyme and by engineering different variants of the enzyme we could alter its sub-cellular localisation. However, no effect on the overall flux of glucose was noted irrespective of whether the enzyme was found uniquely in either compartment, or in both

The compensatory potential of increased immigration following intensive American mink population control is diluted by male-biased dispersal

Attempts to mitigate the impact of invasive species on native ecosystems increasingly target large land masses where control, rather than eradication, is the management objective. Depressing numbers of invasive species to a level where their impact on native biodiversity is tolerable requires overcoming the impact of compensatory immigration from non-controlled portions of the landscape. Because of the expected scale-dependency of dispersal, the overall size of invasive species management areas relative to the dispersal ability of the controlled species will determine the size of any effectively conserved core area unaffected by immigration from surrounding areas. However, when dispersal is male-biased, as in many mammalian invasive carnivores, males may be overrepresented amongst immigrants, reducing the potential growth rate of invasive species populations in re-invaded areas. Using data collected from a project that gradually imposed spatially comprehensive control on invasive American mink (Neovison vison) over a 10,000 km2 area of NE Scotland, we show that mink captures were reduced to almost zero in 3 years, whilst there was a threefold increase in the proportion of male immigrants. Dispersal was often long distance and linking adjacent river catchments, asymptoting at 38 and 31 km for males and females respectively. Breeding and dispersal were spatially heterogeneous, with 40 % of river sections accounting for most captures of juvenile (85 %), adult female (65 %) and immigrant (57 %) mink. Concentrating control effort on such areas, so as to turn them into “attractive dispersal sinks” could make a disproportionate contribution to the management of recurrent re-invasion of mainland invasive species management areas

Lack of association between modifiable exposures and glioma risk: a Mendelian randomization analysis.

Background The etiological basis of glioma is poorly understood. We have used genetic markers in a Mendelian randomization (MR) framework to examine if lifestyle, cardiometabolic, and inflammatory factors influence the risk of glioma. This methodology reduces bias from confounding and is not affected by reverse causation.Methods We identified genetic instruments for 37 potentially modifiable risk factors and evaluated their association with glioma risk using data from a genome-wide association study of 12 488 glioma patients and 18 169 controls. We used the estimated odds ratio of glioma associated with each of the genetically defined traits to infer evidence for a causal relationship with the following exposures:Lifestyle and dietary factors-height, plasma insulin-like growth factor 1, blood carnitine, blood methionine, blood selenium, blood zinc, circulating adiponectin, circulating carotenoids, iron status, serum calcium, vitamins (A1, B12, B6, E, and 25-hydroxyvitamin D), fatty acid levels (monounsaturated, omega-3, and omega-6) and circulating fetuin-A;Cardiometabolic factors-birth weight, high density lipoprotein cholesterol, low density lipoprotein cholesterol, total cholesterol, total triglycerides, basal metabolic rate, body fat percentage, body mass index, fasting glucose, fasting proinsulin, glycated hemoglobin levels, diastolic and systolic blood pressure, waist circumference, waist-to-hip ratio; andInflammatory factors- C-reactive protein, plasma interleukin-6 receptor subunit alpha and serum immunoglobulin E.Results After correction for the testing of multiple potential risk factors and excluding associations driven by one single nucleotide polymorphism, no significant association with glioma risk was observed (ie, PCorrected > 0.05).Conclusions This study did not provide evidence supporting any of the 37 factors examined as having a significant influence on glioma risk

Evaluation of a 'virtual' approach to commissioning health research

BACKGROUND: The objective of this study was to evaluate the implementation of a 'virtual' (computer-mediated) approach to health research commissioning. This had been introduced experimentally in a DOH programme – the 'Health of Londoners Programme' – in order to assess whether is could enhance the accessibility, transparency and effectiveness of commissioning health research. The study described here was commissioned to evaluate this novel approach, addressing these key questions. METHODS: A naturalistic-experimental approach was combined with principles of action research. The different commissioning groups within the programme were randomly allocated to either the traditional face-to-face mode or the novel 'virtual' mode. Mainly qualitative data were gathered including observation of all (virtual and face-to-face) commissioning meetings; semi-structured interviews with a purposive sample of participants (n = 32/66); structured questionnaires and interviews with lead researchers of early commissioned projects. All members of the commissioning groups were invited to participate in collaborative enquiry groups which participated actively in the analysis process. RESULTS: The virtual process functioned as intended, reaching timely and relatively transparent decisions that participants had confidence in. Despite the potential for greater access using a virtual approach, few differences were found in practice. Key advantages included physical access, a more flexible and extended time period for discussion, reflection and information gathering and a more transparent decision-making process. Key challenges were the reduction of social cues available in a computer-mediated medium that require novel ways of ensuring appropriate dialogue, feedback and interaction. However, in both modes, the process was influenced by a range of factors and was not technology driven. CONCLUSION: There is potential for using computer-mediated communication within the research commissioning process. This may enhance access, effectiveness and transparency of decision-making but further development is needed for this to be fully realised, including attention to process as well as the computer-mediated medium

Loess plateau storage of northeastern Tibetan plateau-derived Yellow River sediment

Marine accumulations of terrigenous sediment are widely assumed to accurately record climatic- and tectonic-controlled mountain denudation and play an important role in understanding late Cenozoic mountain uplift and global cooling. Underpinning this is the assumption that the majority of sediment eroded from hinterland orogenic belts is transported to and ultimately stored in marine basins with little lag between erosion and deposition. Here we use a detailed and multi-technique sedimentary provenance dataset from the Yellow River to show that substantial amounts of sediment eroded from Northeast Tibet and carried by the river’s upper reach are stored in the Chinese Loess Plateau and the western Mu Us desert. This finding revises our understanding of the origin of the Chinese Loess Plateau and provides a potential solution for mismatches between late Cenozoic terrestrial sedimentation and marine geochemistry records, as well as between global CO2 and erosion records

Packages of Care for Alcohol Use Disorders in Low- And Middle-Income Countries

In the fourth in a series of six articles on packages of care for mental disorders in low- and middle-income countries, Vivek Benegal and colleagues discuss the treatment of alcohol use disorders

Untargeted Metabolomics Reveals a Lack Of Synergy between Nifurtimox and Eflornithine against Trypanosoma brucei

A non-targeted metabolomics-based approach is presented that enables the study of pathways in response to drug action with the aim of defining the mode of action of trypanocides. Eflornithine, a polyamine pathway inhibitor, and nifurtimox, whose mode of action involves its metabolic activation, are currently used in combination as first line treatment against stage 2, CNS-involved, human African trypanosomiasis (HAT). Drug action was assessed using an LC-MS based non-targeted metabolomics approach. Eflornithine revealed the expected changes to the polyamine pathway as well as several unexpected changes that point to pathways and metabolites not previously described in bloodstream form trypanosomes, including a lack of arginase activity and N-acetylated ornithine and putrescine. Nifurtimox was shown to be converted to a trinitrile metabolite indicative of metabolic activation, as well as inducing changes in levels of metabolites involved in carbohydrate and nucleotide metabolism. However, eflornithine and nifurtimox failed to synergise anti-trypanosomal activity in vitro, and the metabolomic changes associated with the combination are the sum of those found in each monotherapy with no indication of additional effects. The study reveals how untargeted metabolomics can yield rapid information on drug targets that could be adapted to any pharmacological situation