Screening of DUB activity and specificity by MALDI-TOF mass spectrometry

Deubiquitylases (DUBs) are key regulators of the ubiquitin system which cleave ubiquitin moieties from proteins and polyubiquitin chains. Several DUBs have been implicated in various diseases and are attractive drug targets. We have developed a sensitive and fast assay to quantify in vitro DUB enzyme activity using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. Unlike other current assays, this method uses unmodified substrates, such as diubiquitin topoisomers. By analyzing 42 human DUBs against all diubiquitin topoisomers we provide an extensive characterization of DUB activity and specificity. Our results confirm the high specificity of many members of the OTU and JAMM DUB families and highlight that all USPs tested display low linkage selectivity. We also demonstrate that this assay can be deployed to assess the potency and specificity of DUB inhibitors by profiling 11 compounds against a panel of 32 DUBs

A gene signature for post-infectious chronic fatigue syndrome

Background: At present, there are no clinically reliable disease markers for chronic fatigue syndrome. DNA chip microarray technology provides a method for examining the differential expression of mRNA from a large number of genes. Our hypothesis was that a gene expression signature, generated by microarray assays, could help identify genes which are dysregulated in patients with post-infectious CFS and so help identify biomarkers for the condition. Methods: Human genome-wide Affymetrix GeneChip arrays (39,000 transcripts derived from 33,000 gene sequences) were used to compare the levels of gene expression in the peripheral blood mononuclear cells of male patients with post-infectious chronic fatigue (n = 8) and male healthy control subjects (n = 7). Results: Patients and healthy subjects differed significantly in the level of expression of 366 genes. Analysis of the differentially expressed genes indicated functional implications in immune modulation, oxidative stress and apoptosis. Prototype biomarkers were identified on the basis of differential levels of gene expression and possible biological significance Conclusion: Differential expression of key genes identified in this study offer an insight into the possible mechanism of chronic fatigue following infection. The representative biomarkers identified in this research appear promising as potential biomarkers for diagnosis and treatment

Interleukin-6 gene (IL-6): a possible role in brain morphology in the healthy adult brain

Background: Cytokines such as interleukin 6 (IL-6) have been implicated in dual functions in neuropsychiatric disorders. Little is known about the genetic predisposition to neurodegenerative and neuroproliferative properties of cytokine genes. In this study the potential dual role of several IL-6 polymorphisms in brain morphology is investigated. Methodology: In a large sample of healthy individuals (N = 303), associations between genetic variants of IL-6 (rs1800795; rs1800796, rs2069833, rs2069840) and brain volume (gray matter volume) were analyzed using voxel-based morphometry (VBM). Selection of single nucleotide polymorphisms (SNPs) followed a tagging SNP approach (e.g., Stampa algorigthm), yielding a capture 97.08% of the variation in the IL-6 gene using four tagging SNPs. Principal findings/results: In a whole-brain analysis, the polymorphism rs1800795 (−174 C/G) showed a strong main effect of genotype (43 CC vs. 150 CG vs. 100 GG; x = 24, y = −10, z = −15; F(2,286) = 8.54, puncorrected = 0.0002; pAlphaSim-corrected = 0.002; cluster size k = 577) within the right hippocampus head. Homozygous carriers of the G-allele had significantly larger hippocampus gray matter volumes compared to heterozygous subjects. None of the other investigated SNPs showed a significant association with grey matter volume in whole-brain analyses. Conclusions/significance: These findings suggest a possible neuroprotective role of the G-allele of the SNP rs1800795 on hippocampal volumes. Studies on the role of this SNP in psychiatric populations and especially in those with an affected hippocampus (e.g., by maltreatment, stress) are warranted.Bernhard T Baune, Carsten Konrad, Dominik Grotegerd, Thomas Suslow, Eva Birosova, Patricia Ohrmann, Jochen Bauer, Volker Arolt, Walter Heindel, Katharina Domschke, Sonja Schöning, Astrid V Rauch, Christina Uhlmann, Harald Kugel and Udo Dannlowsk

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Characteristic of 24-Hour Blood Pressure Dipping Patterns in Hypertensive Stroke Patients

Linh Tran Pham,1 Si Dung Chu,2,3 Hien Van Hoang4 1Department of C5, Vietnam Heart Institute, Bach Mai Hospital, Hanoi, Vietnam; 2Training and Direction of Healthcare Activities Center, Bach Mai Hospital, Hanoi, Vietnam; 3Hospital of Vietnam National University (VNU), VNU, Hanoi, Vietnam; 4Master of Cardiology in the Course of 27st, Hanoi Medical University, Hanoi, VietnamCorrespondence: Si Dung Chu, Hospital of Vietnam National University, Vietnam National University, Hanoi, Vietnam, Tel +84 906086168, Email [email protected]; [email protected]: We conducted a study titled for Investigation on the characteristics of 24-hour blood pressure (BP) dipping patterns in hypertensive stroke patients.Methods: Descriptive research, analysis, and comparison, the research was conducted from July 2019 to September 2020 at the Vietnam Heart Institute - Bach Mai Hospital. There are 100 patients diagnosed with idiopathic hypertension who were divided into two groups (without stroke complications and another group with chronic stroke complications > 6 weeks), both groups were similar in age (45– 64 years old).Results: The daytime systolic BP (SBP) indices, 24-hour BP including SBP, diastolic BP (DBP), and mean arterial pressure (MAP), and particularly night-time BP indices were elevated in the stroke group compared with those without stroke complications (p < 0.05); there were no significant differences observed in daytime DBP and MAP between the two groups. SBP indices were higher in those with hemorrhage stroke compared with those with ischemic stroke, albeit without statistical significance. The prevalence of non-dipper was significantly higher in the stroke group compared with the non-stroke group (p < 0.001).Conclusion: The daytime SBP indices, 24-hour BP (SBP, DBP, MAP), and particularly night-time BP indices were elevated in the stroke group compared with those without stroke complications. The prevalence of non-dipper was significantly higher in the stroke group compared with the non-stroke group.Keywords: characteristic, dipper, hypertension, stroke complications, 24-hour B

Laser writing of coherent colour centres in diamond

Optically active point defects in crystals have gained widespread attention as photonic systems that can find use in quantum information technologies [1,2]. However challenges remain in the placing of individual defects at desired locations, an essential element of device fabrication. Here we report the controlled generation of single nitrogen-vacancy (NV) centres in diamond using laser writing [3]. The use of aberration correction in the writing optics allows precise positioning of vacancies within the diamond crystal, and subsequent annealing produces single NV centres with up to 45% success probability, within about 200 nm of the desired position. Selected NV centres fabricated by this method display stable, coherent optical transitions at cryogenic temperatures, a pre-requisite for the creation of distributed quantum networks of solid-state qubits. The results illustrate the potential of laser writing as a new tool for defect engineering in quantum technologies

An ensemble of eddy-permitting global ocean reanalyses from the MyOcean project

A set of four eddy-permitting global ocean reanalyses produced in the framework of the MyOcean project have been compared over the altimetry period 1993–2011. The main differences among the reanalyses used here come from the data assimilation scheme implemented to control the ocean state by inserting reprocessed observations of sea surface temperature (SST), in situ temperature and salinity profiles, sea level anomaly and sea-ice concentration. A first objective of this work includes assessing the interannual variability and trends for a series of parameters, usually considered in the community as essential ocean variables: SST, sea surface salinity, temperature and salinity averaged over meaningful layers of the water column, sea level, transports across pre-defined sections, and sea ice parameters. The eddy-permitting nature of the global reanalyses allows also to estimate eddy kinetic energy. The results show that in general there is a good consistency between the different reanalyses. An intercomparison against experiments without data assimilation was done during the MyOcean project and we conclude that data assimilation is crucial for correctly simulating some quantities such as regional trends of sea level as well as the eddy kinetic energy. A second objective is to show that the ensemble mean of reanalyses can be evaluated as one single system regarding its reliability in reproducing the climate signals, where both variability and uncertainties are assessed through the ensemble spread and signal-to-noise ratio. The main advantage of having access to several reanalyses differing in the way data assimilation is performed is that it becomes possible to assess part of the total uncertainty. Given the fact that we use very similar ocean models and atmospheric forcing, we can conclude that the spread of the ensemble of reanalyses is mainly representative of our ability to gauge uncertainty in the assimilation methods. This uncertainty changes a lot from one ocean parameter to another, especially in global indices. However, despite several caveats in the design of the multi-system ensemble, the main conclusion from this study is that an eddy-permitting multi-system ensemble approach has become mature and our results provide a first step towards a systematic comparison of eddy-permitting global ocean reanalyses aimed at providing robust conclusions on the recent evolution of the oceanic state

Electricity market crisis in Europe and cross border price effects: A quantile return connectedness analysis

As the interconnection of the European electricity markets and integration of renewables progresses, there is little known about interconnectedness across them at times of market turbulence. The electricity crisis of 2021 and 2023 were significant events that can also provide lessons in the behaviour of integrated markets with high renewables under stress. Despite the impacts of the COVID-19 pandemic and the Russia-Ukraine war on the European energy market, little is known about their effects on the transmission of risks between the electricity markets. We employ the quantile connectedness approach to quantify the return connectedness between eleven key European markets, as well as the natural gas and carbon markets. We then examine the effect of the two crises on the interconnectedness. We find significant return interconnectedness, driven by spillover effects, among the markets. Analysis of connectedness across quantiles shows that the spillover effects are much stronger at tail ends of conditional distribution. Moreover, our results reveal opposite effects from crises on market interconnectedness. While the COVID-19 pandemic reduced the interconnectedness, the Russia-Ukraine war intensified the return shock transmission. Finally, we find that the natural gas and carbon markets are net recipients of return shocks across the quantiles.fals

Does the U.S. export inflation? Evidence from the dynamic inflation spillover between the U.S. and EAGLEs

Given the crucial role of inflation as a key economic barometer, our paper investigates the dynamic inflation spillover between the U.S. and the nine emerging and growth-leading economies (EAGLEs) between 1991M1 and 2020M2. Employing the recently developed time-varying parameter vector autoregressions (TVP-VAR)-based connectedness approach, we find evidence of a moderate inflation spillover across the sample countries at normal condition. We further point out that inflation spillover effects with the U.S. are more pronounced for the emerging markets with higher openness, the net oil-importing emerging markets, and the emerging markets following free-float exchange rate regimes. More importantly, the inflation spillover index among the system rises dramatically to over 70% under extremely inflationary conditions, implying that the transmission of spiral inflation is very high. Additionally, the time-varying analysis shows that the role of the U.S. in the inflation shock transmission with emerging countries varies between being a net inflation-exporter and inflation-importer over times. Finally, an investigation of the drivers of the inflation spillovers reveals that the U.S. dollar, emerging markets' economic policy uncertainty, and bilateral trade are key determinants of the inflation shock transmission among the system. Our findings justify central banks’ actions in decreasing U.S. dollar reserves to safeguard their domestic currencies.fals

As Far as the Eye Can See: Relationship between Psychopathic Traits and Pupil Response to Affective Stimuli

Psychopathic individuals show a range of affective processing deficits, typically associated with the interpersonal/affective component of psychopathy. However, previous research has been inconsistent as to whether psychopathy, within both offender and community populations, is associated with deficient autonomic responses to the simple presentation of affective stimuli. Changes in pupil diameter occur in response to emotionally arousing stimuli and can be used as an objective indicator of physiological reactivity to emotion. This study used pupillometry to explore whether psychopathic traits within a community sample were associated with hypo-responsivity to the affective content of stimuli. Pupil activity was recorded for 102 adult (52 female) community participants in response to affective (both negative and positive affect) and affectively neutral stimuli, that included images of scenes, static facial expressions, dynamic facial expressions and sound-clips. Psychopathic traits were measured using the Triarchic Psychopathy Measure. Pupil diameter was larger in response to negative stimuli, but comparable pupil size was demonstrated across pleasant and neutral stimuli. A linear relationship between subjective arousal and pupil diameter was found in response to sound-clips, but was not evident in response to scenes. Contrary to predictions, psychopathy was unrelated to emotional modulation of pupil diameter across all stimuli. The findings were the same when participant gender was considered. This suggests that psychopathy within a community sample is not associated with autonomic hypo-responsivity to affective stimuli, and this effect is discussed in relation to later defensive/appetitive mobilisation deficits