Hereditary sensory neuropathy type 1-associated deoxysphingolipids cause neurotoxicity, acute calcium handling abnormalities and mitochondrial dysfunction in vitro

Hereditary sensory neuropathy type 1 (HSN-1) is a peripheral neuropathy most frequently caused by mutations in the SPTLC1 or SPTLC2 genes, which code for two subunits of the enzyme serine palmitoyltransferase (SPT). SPT catalyzes the first step of de novo sphingolipid synthesis. Mutations in SPT result in a change in enzyme substrate specificity, which causes the production of atypical deoxysphinganine and deoxymethylsphinganine, rather than the normal enzyme product, sphinganine. Levels of these abnormal compounds are elevated in blood of HSN-1 patients and this is thought to cause the peripheral motor and sensory nerve damage that is characteristic of the disease, by a largely unresolved mechanism. In this study, we show that exogenous application of these deoxysphingoid bases causes dose- and time-dependent neurotoxicity in primary mammalian neurons, as determined by analysis of cell survival and neurite length. Acutely, deoxysphingoid base neurotoxicity manifests in abnormal Ca2+ handling by the endoplasmic reticulum (ER) and mitochondria as well as dysregulation of cell membrane store-operated Ca2+ channels. The changes in intracellular Ca2+ handling are accompanied by an early loss of mitochondrial membrane potential in deoxysphingoid base-treated motor and sensory neurons. Thus, these results suggest that exogenous deoxysphingoid base application causes neuronal mitochondrial dysfunction and Ca2+ handling deficits, which may play a critical role in the pathogenesis of HSN-1

Diagnostic Yield of Genetic Testing in Young Athletes with T-wave Inversion.

Background -T-wave inversion (TWI) is common in patients with cardiomyopathy. However, up to 25% of athletes of African/Afro-Caribbean descent (black athletes) and 5% of white athletes also have TWI of unclear clinical significance despite comprehensive clinical evaluation and long-term follow-up. The aim of this study was to determine the diagnostic yield from genetic testing, beyond clinical evaluation, when investigating athletes with TWI. Methods -We investigated 50 consecutive asymptomatic black and 50 white athletes aged 14-35-years-old with TWI and a normal echocardiogram who were referred to a UK tertiary center for cardiomyopathy and sports cardiology. Subjects underwent exercise testing, 24-hour ECG, signal-averaged ECG, cardiac magnetic resonance imaging, and a blood-based analysis of a comprehensive 311 gene panel for cardiomyopathies including hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, left ventricular non-compaction, and ion channel disorders such as long QT syndrome and Brugada syndrome. Results -In total, 21 athletes (21%) were diagnosed with cardiac disease on the basis of comprehensive clinical investigations. Of these, 8 (38.1%) were gene positive (MYPBC3, MYH7, GLA, and ACTC1 genes) and 13 (61.9%) were gene negative. Of the remaining 79 athletes (79%), 2 (2.5%) were gene positive (TTR and SCN5A genes) in the absence of a clinical phenotype. The prevalence of newly diagnosed cardiomyopathy was higher in white athletes compared with black athletes (30.0% vs. 12%, P=0.027). Hypertrophic cardiomyopathy accounted for 90.5% of all clinical diagnoses. All black athletes and 93.3% of white athletes with a clinical diagnosis of cardiomyopathy or a genetic mutation capable of causing cardiomyopathy exhibited lateral TWI as opposed to isolated anterior or inferior TWI; the genetic yield of diagnoses from lateral TWI was 14.0%. Conclusions -Up to 10% of athletes with TWI revealed mutations capable of causing cardiac disease. Despite the substantial cost, the positive diagnostic yield from genetic testing was one-half of that from clinical evaluation (10% vs. 21%) and contributed to additional diagnoses in only 2.5% of athletes with TWI in the absence of a clear clinical phenotype, making it of negligible use in routine clinical practice

Twitter mood predicts the stock market

Behavioral economics tells us that emotions can profoundly affect individual behavior and decision-making. Does this also apply to societies at large, i.e., can societies experience mood states that affect their collective decision making? By extension is the public mood correlated or even predictive of economic indicators? Here we investigate whether measurements of collective mood states derived from large-scale Twitter feeds are correlated to the value of the Dow Jones Industrial Average (DJIA) over time. We analyze the text content of daily Twitter feeds by two mood tracking tools, namely OpinionFinder that measures positive vs. negative mood and Google-Profile of Mood States (GPOMS) that measures mood in terms of 6 dimensions (Calm, Alert, Sure, Vital, Kind, and Happy). We cross-validate the resulting mood time series by comparing their ability to detect the public's response to the presidential election and Thanksgiving day in 2008. A Granger causality analysis and a Self-Organizing Fuzzy Neural Network are then used to investigate the hypothesis that public mood states, as measured by the OpinionFinder and GPOMS mood time series, are predictive of changes in DJIA closing values. Our results indicate that the accuracy of DJIA predictions can be significantly improved by the inclusion of specific public mood dimensions but not others. We find an accuracy of 87.6% in predicting the daily up and down changes in the closing values of the DJIA and a reduction of the Mean Average Percentage Error by more than 6%

Nanomechanics of single keratin fibres: A Raman study of the alpha helix -> beta sheet transition and water effect

The use of micro-Raman spectroscopy, through chemical bond nano-scale probes, allows the changes in conformations (alpha helix -> beta sheet), chain orientation, disconnection of disulfide bonds (-20%) and the increase of intra and inter-chain distances during the strain to be distinguished. The combination of micro-Raman spectroscopy and a allows a quantitative measure of the extension of chemical bonds in the peptidic chain during loading. The nano-structural transformations of keratin during the strain of human hair in a dry environment (40-60 % relative humidity) and saturated with water have been studied. The water permits the sliding of the chains and decreases the bond energy hair. Spectral analyses and 2D correlation are two coherent and independent methods to follow change the Raman probes which are sensitive to structural . The between nano-mechanical (Raman) and micro-mechanical (strain/stress) analyses confirms the validity of the experimental results, tools and principles used, as well as the agreement with the structural model of keratin fibres described by Chapman & Hearle

Characterisation of the spatio-temporal localisation of a pan-Mucorales specific antigen during germination and immunohistochemistry

This is the author accepted manuscript. The final version is available on open access from Oxford University Press via the DOI in this recordBACKGROUND: Mucormycosis is an aggressive, invasive fungal infection caused by moulds in the order Mucorales. Early diagnosis is key to improving patient prognosis, yet relies on insensitive culture or non-specific histopathology. A pan-Mucorales specific monoclonal antibody (mAb), TG11, was recently developed. Here, we investigate the spatio-temporal localisation of the antigen and specificity of the mAb for immunohistochemistry. METHODS: We use immunofluorescence (IF) microscopy to assess antigen localisation in eleven Mucorales species of clinical importance and live imaging of Rhizopus arrhizus germination. Immunogold transmission electron microscopy (immunoTEM) reveals the sub-cellular location of mAb TG11 binding. Finally, we perform immunohistochemistry of R. arrhizus in an ex vivo murine lung infection model alongside lung infection by Aspergillus fumigatus. RESULTS: IF revealed TG11 antigen production at the emerging hyphal tip and along the length of growing hyphae in all Mucorales except Sakasenea. Timelapse imaging revealed early antigen exposure during spore germination and along the growing hypha. ImmunoTEM confirmed mAb TG11 binding to the hyphal cell wall only. The TG11 mAb specifically stained Mucorales but not Aspergillus hyphae in infected murine lung tissue. CONCLUSIONS: TG11 detects early hyphal growth and has valuable potential for diagnosing mucormycosis by enhancing discriminatory detection of Mucorales in tissue.Noah’s Pink Balloon Leukaemia FundBiotechnology and Biological Sciences Research Council (BBSRC)National Science Foundation (NSF)Wellcome TrustRoyal SocietyLister InstituteMedical Research Council (MRC

Migrations and habitat use of the smooth hammerhead shark (Sphyrna zygaena) in the Atlantic Ocean

The smooth hammerhead shark, Sphyrna zygaena, is a cosmopolitan semipelagic shark captured as bycatch in pelagic oceanic fisheries, especially pelagic longlines targeting swordfish and/or tunas. From 2012 to 2016, eight smooth hammerheads were tagged with Pop-up Satellite Archival Tags in the inter-tropical region of the Northeast Atlantic Ocean, with successful transmissions received from seven tags (total of 319 tracking days). Results confirmed the smooth hammerhead is a highly mobile species, as the longest migration ever documented for this species (> 6600 km) was recorded. An absence of a diel vertical movement behavior was noted, with the sharks spending most of their time at surface waters (0-50 m) above 23 degrees C. The operating depth of the pelagic long-line gear was measured with Minilog Temperature and Depth Recorders, and the overlap with the species vertical distribution was calculated. The overlap is taking place mainly during the night and is higher for juveniles (similar to 40% of overlap time). The novel information presented can now be used to contribute to the provision of sustainable management tools and serve as input for Ecological Risk Assessments for smooth hammerheads caught in Atlantic pelagic longline fisheries.Oceanario de Lisboa through Project "SHARK-TAG: Migrations and habitat use of the smooth hammerhead shark in the Atlantic Ocean"; Investigador-FCT from the Portuguese Foundation for Science and Technology (FCT, Fundacao para a Ciencia e Tecnologia) [Ref: IF/00253/2014]; EU European Social Fund; Programa Operacional Potencial Human