Parallelizing an Index Generator for Desktop Search

International audienceExperience with the parallelization of an index generator for desktop search is presented. Several configurations of the index generator are compared on three different Intel platforms with 4, 8, and 32 cores. The optimal configurations for these platforms are not intuitive and are markedly different for the three platforms. For finding the optimal configuration, detailed measurements and experimentation were necessary. Several recommendations for parallel software design are derived from this study

Multi-omics assessment of dilated cardiomyopathy using non-negative matrix factorization

Dilated cardiomyopathy (DCM), a myocardial disease, is heterogeneous and often results in heart failure and sudden cardiac death. Unavailability of cardiac tissue has hindered the comprehensive exploration of gene regulatory networks and nodal players in DCM. In this study, we carried out integrated analysis of transcriptome and methylome data using nonnegative matrix factorization from a cohort of DCM patients to uncover underlying latent factors and covarying features between whole-transcriptome and epigenome omics datasets from tissue biopsies of living patients. DNA methylation data from Infinium HM450 and mRNA Illumina sequencing of n = 33 DCM and n = 24 control probands were filtered, analyzed and used as input for matrix factorization using R NMF package. Mann-Whitney U test showed 4 out of 5 latent factors are significantly different between DCM and control probands (P<0.05). Characterization of top 10% features driving each latent factor showed a significant enrichment of biological processes known to be involved in DCM pathogenesis, including immune response (P = 3.97E-21), nucleic acid binding (P = 1.42E-18), extracellular matrix (P = 9.23E-14) and myofibrillar structure (P = 8.46E-12). Correlation network analysis revealed interaction of important sarcomeric genes like Nebulin, Tropomyosin alpha-3 and ERC-protein 2 with CpG methylation of ATPase Phospholipid Transporting 11A0, Solute Carrier Family 12 Member 7 and Leucine Rich Repeat Containing 14B, all with significant P values associated with correlation coefficients >0.7. Using matrix factorization, multiomics data derived from human tissue samples can be integrated and novel interactions can be identified. Hypothesis generating nature of such analysis could help to better understand the pathophysiology of complex traits such as DCM

Ergodicity-breaking reveals time optimal decision making in humans

Ergodicity describes an equivalence between the expectation value and the time average of observables. Applied to human behaviour, ergodic theories of decision-making reveal how individuals should tolerate risk in different environments. To optimise wealth over time, agents should adapt their utility function according to the dynamical setting they face. Linear utility is optimal for additive dynamics, whereas logarithmic utility is optimal for multiplicative dynamics. Whether humans approximate time optimal behavior across different dynamics is unknown. Here we compare the effects of additive versus multiplicative gamble dynamics on risky choice. We show that utility functions are modulated by gamble dynamics in ways not explained by prevailing decision theory. Instead, as predicted by time optimality, risk aversion increases under multiplicative dynamics, distributing close to the values that maximise the time average growth of wealth. We suggest that our findings motivate a need for explicitly grounding theories of decision-making on ergodic considerations.Comment: 43 pages including supplementary methods & material

A job monitoring system for the LCG computing grid

hsnr.de physik.uni-wuppertal.de Experience with generating simulation data of high energy physics experiments has shown that a job moni-toring system (JMS) is essential to understand failures of jobs within the Grid. Such a system can give in-formation about the status of the user job as well as the worker node in parallel while a user job is run-ning. It should support the user directly by allowing the user to interact with the running job and should be able to make an automatic error correction. Further-more, such a system can be extended for an automatic classification of errors which can improve the stability and performance of the Grid environment. To increase the acceptance of the Grid, a graphical user interface (GUI) has been developed and integrated with the job monitoring system. Both components are currently in-tegrated in the computing environment for generating data for the DØ Experiment. In this paper we want to describe the basic components of the job monitoring software.

Tuning the Brake While Raising the Stake:Network Dynamics during Sequential Decision-Making

When gathering valued goods, risk and reward are often coupled and escalate over time, for instance, during foraging, trading, or gambling. This escalating frame requires agents to continuously balance expectations of reward against those of risk. To address how the human brain dynamically computes these tradeoffs, we performed whole-brain fMRI while healthy young individuals engaged in a sequential gambling task. Participants were repeatedly confronted with the option to continue with throwing a die to accumulate monetary reward under escalating risk, or the alternative option to stop to bank the current balance. Within each gambling round, the accumulation of gains gradually increased reaction times for “continue” choices, indicating growing uncertainty in the decision to continue. Neural activity evoked by “continue” choices was associated with growing activity and connectivity of a cortico-subcortical “braking” network that positively scaled with the accumulated gains, including pre-supplementary motor area (pre-SMA), inferior frontal gyrus, caudate, and subthalamic nucleus (STN). The influence of the STN on continue-evoked activity in the pre-SMA was predicted by interindividual differences in risk-aversion attitudes expressed during the gambling task. Furthermore, activity in dorsal anterior cingulate cortex (ACC) reflected individual choice tendencies by showing increased activation when subjects made nondefault “continue” choices despite an increasing tendency to stop, but ACC activity did not change in proportion with subjective choice uncertainty. Together, the results implicate a key role of dorsal ACC, pre-SMA, inferior frontal gyrus, and STN in computing the trade-off between escalating reward and risk in sequential decision-making. SIGNIFICANCE STATEMENT Using a paradigm where subjects experienced increasing potential rewards coupled with increasing risk, this study addressed two unresolved questions in the field of decision-making: First, we investigated an “inhibitory” network of regions that has so far been investigated with externally cued action inhibition. In this study, we show that the dynamics in this network under increasingly risky decisions are predictive of subjects' risk attitudes. Second, we contribute to a currently ongoing debate about the anterior cingulate cortex's role in sequential foraging decisions by showing that its activity is related to making nondefault choices rather than to choice uncertainty

Epigenetic Regulation of Alternative mRNA Splicing in Dilated Cardiomyopathy

In recent years, the genetic architecture of dilated cardiomyopathy (DCM) has been more thoroughly elucidated. However, there is still insufficient knowledge on the modifiers and regulatory principles that lead to the failure of myocardial function. The current study investigates the association of epigenome-wide DNA methylation and alternative splicing, both of which are important regulatory principles in DCM. We analyzed screening and replication cohorts of cases and controls and identified distinct transcriptomic patterns in the myocardium that differ significantly, and we identified a strong association of intronic DNA methylation and flanking exons usage (p < 2 × 10−16). By combining differential exon usage (DEU) and differential methylation regions (DMR), we found a significant change of regulation in important sarcomeric and other DCM-associated pathways. Interestingly, inverse regulation of Titin antisense non-coding RNA transcript splicing and DNA methylation of a locus reciprocal to TTN substantiate these findings and indicate an additional role for non-protein-coding transcripts. In summary, this study highlights for the first time the close interrelationship between genetic imprinting by DNA methylation and the transport of this epigenetic information towards the dynamic mRNA splicing landscape. This expands our knowledge of the genome–environment interaction in DCM besides simple gene expression regulation

Marathon-Induced Cardiac Strain as Model for the Evaluation of Diagnostic microRNAs for Acute Myocardial Infarction

Background: The current gold standard biomarker for myocardial infarction (MI), cardiac troponin (cTn), is recognized for its high sensitivity and organ specificity; however, it lacks diagnostic specificity. Numerous studies have introduced circulating microRNAs as potential biomarkers for MI. This study investigates the MI-specificity of these serum microRNAs by investigating myocardial stress/injury due to strenuous exercise. Methods: MicroRNA biomarkers were retrieved by comprehensive review of 109 publications on diagnostic serum microRNAs for MI. MicroRNA levels were first measured by next-generation sequencing in pooled sera from runners (n = 46) before and after conducting a full competitive marathon. Hereafter, reverse transcription quantitative real-time PCR (qPCR) of 10 selected serum microRNAs in 210 marathon runners was performed (>10,000 qPCR measurements). Results: 27 potential diagnostic microRNA for MI were retrieved by the literature review. Eight microRNAs (miR-1-3p, miR-21-5p, miR-26a-5p, miR-122-5p, miR-133a-3p, miR-142-5p, miR-191-5p, miR-486-3p) showed positive correlations with cTnT in marathon runners, whereas two miRNAs (miR-134-5p and miR-499a-5p) showed no correlations. Upregulation of miR-133a-3p (p = 0.03) and miR-142-5p (p = 0.01) went along with elevated cTnT after marathon. Conclusion: Some MI-associated microRNAs (e.g., miR-133a-3p and miR-142-5p) have similar kinetics under strenuous exercise and MI as compared to cTnT, which suggests that their diagnostic specificity could be limited. In contrast, several MI-associated microRNAs (miR-26a-5p, miR-134-5p, miR-191-5p) showed different release behavior; hence, combining cTnT with these microRNAs within a multi-marker strategy may add diagnostic accuracy in MI

Marathon-Induced Cardiac Strain as Model for the Evaluation of Diagnostic microRNAs for Acute Myocardial Infarction

Background: The current gold standard biomarker for myocardial infarction (MI), cardiac troponin (cTn), is recognized for its high sensitivity and organ specificity; however, it lacks diagnostic specificity. Numerous studies have introduced circulating microRNAs as potential biomarkers for MI. This study investigates the MI-specificity of these serum microRNAs by investigating myocardial stress/injury due to strenuous exercise. Methods: MicroRNA biomarkers were retrieved by compre hensive review of 109 publications on diagnostic serum microRNAs for MI. MicroRNA levels were first measured by next-generation sequencing in pooled sera from runners (n = 46) before and after conducting a full competitive marathon. Hereafter, reverse transcription quantitative real-time PCR (qPCR) of 10 selected serum microRNAs in 210 marathon runners was performed (>10,000 qPCR measurements). Results: 27 potential diagnostic microRNA for MI were retrieved by the literature review. Eight microRNAs (miR-1-3p, miR-21-5p, miR-26a-5p, miR-122-5p, miR-133a-3p, miR-142-5p, miR-191-5p, miR-486-3p) showed positive correlations with cTnT in marathon runners, whereas two miRNAs (miR-134-5p and miR-499a-5p) showed no correlations. Upregulation of miR-133a-3p (p = 0.03) and miR-142-5p (p = 0.01) went along with elevated cTnT after marathon. Conclusion: Some MI-associated microRNAs (e.g., miR-133a-3p and miR-142-5p) have similar kinetics under strenuous exercise and MI as compared to cTnT, which suggests that their diagnostic specificity could be lim ited. In contrast, several MI-associated microRNAs (miR-26a-5p, miR-134-5p, miR-191-5p) showed different release behavior; hence, combining cTnT with these microRNAs within a multi-marker strategy may add diagnostic accuracy in MI

Pontos-chave patológicos e ecocardiográficos da displasia da válvula atrioventricular direita

Congenital insufficiency of the right atrioventricular valve is defined as tricuspid dysplasia. The alteration occurs in septal and mural valve leaflets, in chordae tendineae or in papillary muscles. The malformation causes tricuspid regurgitation and presentation of clinical signs associated with congestive right heart failure. Macroscopic lesions include localized or diffuse nodulation or thickening of valves leaflets, short or elongated chordae tendineae, with incomplete development and partial fusion or union, papillary muscles with abnormal attachment or incomplete separation to the right ventricular wall, or absence of one or more muscles. The aim of this work is to provide information and casuistry for diagnostic purposes of a pathology of low prevalence in companion animals. Between 2011 and 2021, 24 canines with a definitive diagnosis of tricuspid dysplasia were treated. The pathology was more frequent in dogs of small to medium size, Poodle (4), Dachshund (3), French Bulldog (3), Yorkshire terrier (2), Bull terrier (1), Boxer (1) and 10 mongrels, 3 under 12 kg and 7 between 12 and 30 kg in weight, medium to large size. The findings are different, race and size, to those observed by other authors. Nodular thickening associated with short chordae tendineae was the most common valve malformation. Tricuspid dysplasia was associated with half (13 of 24) of the cases with pulmonary stenosis. Other congenital anomalies, interventricular and atrial septal defect, were also related. The precise diagnosis of the congenital abnormality of the tricuspid valve apparatus can only be made by echocardiography. Valve alterations, septal leaflet, characterized by nodulation, thickening and union to theinterventricular septum, were the most common. The continuous spectral Doppler exploration allowed determining severity, pressures in the atrial and right ventricular chambers and establishing hemodynamic effects of the process and its implication in the prognosis and treatment of the patient.La insuficiencia congénita de la válvula auriculoventricular derecha se define como displasia tricuspídea. La alteración se presenta en hojuelas valvares septal y mural, en cuerdas tendinosas o en músculos papilares. La malformación provoca regurgitación tricuspídea y presentación de signos clínicos asociados a insuficiencia cardíaca derecha congestiva. Las lesiones macroscópicas incluyen nodulación o engrosamiento localizado o difuso de hojuelas valvares, cuerdas tendinosas cortas o alargadas, con desarrollo incompleto y fusión o unión parcial, músculos papilares con inserción anormal o separación incompleta a la pared ventricular derecha o ausencia de uno o más músculos. El objetivo del presente trabajo es aportar información y casuística con fines diagnósticos de una patología de baja prevalencia en animales de compañía. Entre 2011 y 2021 se atendieron 24 caninos con diagnóstico definitivo de displasia tricuspídea. La patología fue más frecuente en perros de talla pequeña a mediana, Caniche (4), Dachshund (3), Bulldog francés (3), Yorkshire terrier (2), Bull terrier (1), Bóxer (1) y 10 mestizos, 3 menores a 12 kg y 7 entre 12 y 30 kg de peso, de talla mediana a grande. Los hallazgos son distintos, raza y talla, a los observados por otros autores. El engrosamiento nodular asociado a cuerdas tendinosas cortas fue la malformación valvar más común. La displasia tricuspídea se asoció con la mitad (13 de 24) de los casos con estenosis pulmonar. Otras anomalías congénitas, comunicación interventricular e interauricular, también se presentaron relacionadas. El diagnóstico preciso de la anormalidad congénita sobre el aparato valvular tricuspídeo sólo puede ser realizado por ecocardiografía. Las alteraciones valvares, hojuela septal, caracterizados por nodulación, engrosamiento y unión al septum interventricular, fueron las más habituales. La exploración doppler espectral continuo permitió determinar gravedad, presiones en cámaras atrial y ventricular derecha y establecer efectos hemodinámicos del proceso y su implicancia en el pronóstico y tratamiento del paciente.A regurgitação congênita da valva atrioventricular direita é definida como displasia tricúspide. A alteração ocorre nos folhetos valvares septais e murais, nas cordas tendíneas ou nos músculos papilares. A malformação causa regurgitação tricúspide e apresentação de sinais clínicos associados à insuficiência cardíaca direita congestiva. As lesões macroscópicas incluem nodulação localizada ou difusa ou espessamento dos folhetos valvares, cordas tendíneas curtas ou alongadas, com desenvolvimento incompleto e fusão ou união parcial, músculos papilares com inserção anormal ou separação incompleta da parede do ventrículo direito ou ausência de um ou mais músculos. O objetivo deste trabalho é fornecer informações e casuística para fins de diagnóstico de uma patologia de baixa prevalência em animais de companhia. Entre 2011 e 2021, foram tratados 24 cães com diagnóstico definitivo de displasia tricúspide. A patologia foi mais frequente em cães de pequeno a médio porte, Poodle (4), Dachshund (3), Bulldog Francês (3), Yorkshire Terrier (2), Bull Terrier (1), Boxer (1) e 10 mestiços , 3 com menos de 12 kg e 7 entre 12 e 30 kg de peso, de tamanho médio a grande. Os achados são diferentes, raça e estatura, aos observados por outros autores. Espessamento nodular associado a cordoalhas tendíneas curtas foi a malformação valvar mais comum. A displasia tricúspide esteve associada a metade (13 de 24) dos casos com estenose pulmonar. Outras anomalias congênitas, defeitos do septo interventricular e interatrial, também foram relatadas. O diagnóstico preciso da anormalidade congênita no aparelho da valva tricúspide só pode ser feito pela ecocardiografia. As alterações valvares, do folheto septal, caracterizadas por nodulação, espessamento e união ao septo interventricular, foram as mais comuns. A exploração contínua com Doppler espectral permitiu determinar a gravidade, as pressões nas câmaras atriais e ventriculares direitas e estabelecer os efeitos hemodinâmicos do processo e suas implicações no prognóstico e tratamento do paciente.patologia de baixa prevalência em animais de companhia. Entr

Locus coeruleus imaging as a biomarker for noradrenergic dysfunction in neurodegenerative diseases.

Pathological alterations to the locus coeruleus, the major source of noradrenaline in the brain, are histologically evident in early stages of neurodegenerative diseases. Novel MRI approaches now provide an opportunity to quantify structural features of the locus coeruleus in vivo during disease progression. In combination with neuropathological biomarkers, in vivo locus coeruleus imaging could help to understand the contribution of locus coeruleus neurodegeneration to clinical and pathological manifestations in Alzheimer's disease, atypical neurodegenerative dementias and Parkinson's disease. Moreover, as the functional sensitivity of the noradrenergic system is likely to change with disease progression, in vivo measures of locus coeruleus integrity could provide new pathophysiological insights into cognitive and behavioural symptoms. Locus coeruleus imaging also holds the promise to stratify patients into clinical trials according to noradrenergic dysfunction. In this article, we present a consensus on how non-invasive in vivo assessment of locus coeruleus integrity can be used for clinical research in neurodegenerative diseases. We outline the next steps for in vivo, post-mortem and clinical studies that can lay the groundwork to evaluate the potential of locus coeruleus imaging as a biomarker for neurodegenerative diseases.Includes MRC, NIHR, Wellcome Trust, H2020 and FP7