La collection Martin-Charpenel, amateur éclairé ayant fait de nombreuses prospections archéologiques dans la région de Manosque, Alpes-de-Haute-Provence, conserve deux intailles inédites. La première ...intaille en agate blanche, d’époque romaine, représente le héros Énée, fuyant la ville de Troie portant son père Anchise et tenant son fils Ascagne par la main. Ce motif est pour la première fois identifié en Gaule Narbonnaise. La deuxième intaille en jaspe noir représente Athéna ou Roma. Il pourrait s’agir, d’après H. Guiraud, de la copie d’un original romain datant de l’époque médiévale ou moderne.
We performed whole-exome and whole-genome sequencing in 927 late-onset Alzheimer disease (LOAD) cases, 852 early-onset AD (EOAD) cases, and 1273 controls from France. We assessed the evidence for ...gene-based association of rare variants with AD in 6 genes for which an association with such variants was previously claimed. When aggregating protein-truncating and missense-predicted damaging variants, we found exome-wide significant association between EOAD risk and rare variants in SORL1, TREM2, and ABCA7. No exome-wide significant signal was obtained in the LOAD sample, and significance of the order of 10−6 was observed in the whole AD group for TREM2. Our study confirms previous gene-level results for TREM2, SORL1, and ABCA7 and provides a clearer insight into the classes of rare variants involved. Despite different effect sizes and varying cumulative minor allele frequencies, the rare protein-truncating and missense-predicted damaging variants in TREM2, SORL1, and ABCA7 contribute similarly to the heritability of EOAD and explain between 1.1% and 1.5% of EOAD heritability each, compared with 9.12% for APOE ε4.
From the very first organizational theories, boredom at work has been closely linked to the issue of time. However, studies on boredom have often considered the phenomenon as a mere behavioral ...outcome of organizational processes or practices and have built on an instrumental approach, neglecting its deeper manifestations. Following recent calls to tackle boredom as a fundamental issue in organization studies, we build on Heidegger’s framework to delve into superficial, retrospective, and profound boredom. This phenomenological approach enables us to go beyond the instrumental view of boredom, revealing the close links between boredom at work, time, and authenticity. To this end, we adopt a genuine empirical tool, immersed in the eight novels of the famous French writer, Michel Houellebecq, a unique observer of contemporary workers. Our findings help us to highlight two contributions. First, we argue that in trying to divert their employees from boredom by creating and developing “passing the time” activities, organizations only reinforce boredom at work, leading them to an unauthentic relationship with time and being. Second, we delve into the meanders of profound boredom at work and suggest that by listening to its call, individuals may unveil what truly matters to them and find a way to reach authenticity at work.
The cytidine analogues azacytidine and 5-aza-2'-deoxycytidine (decitabine) are commonly used to treat myelodysplastic syndromes, with or without a myeloproliferative component. It remains unclear ...whether the response to these hypomethylating agents results from a cytotoxic or an epigenetic effect. In this study, we address this question in chronic myelomonocytic leukaemia. We describe a comprehensive analysis of the mutational landscape of these tumours, combining whole-exome and whole-genome sequencing. We identify an average of 14±5 somatic mutations in coding sequences of sorted monocyte DNA and the signatures of three mutational processes. Serial sequencing demonstrates that the response to hypomethylating agents is associated with changes in DNA methylation and gene expression, without any decrease in the mutation allele burden, nor prevention of new genetic alteration occurence. Our findings indicate that cytosine analogues restore a balanced haematopoiesis without decreasing the size of the mutated clone, arguing for a predominantly epigenetic effect.
Malignant pleural mesothelioma (MPM) is an aggressive cancer with rising incidence and challenging clinical management. Through a large series of whole-genome sequencing data, integrated with ...transcriptomic and epigenomic data using multiomics factor analysis, we demonstrate that the current World Health Organization classification only accounts for up to 10% of interpatient molecular differences. Instead, the MESOMICS project paves the way for a morphomolecular classification of MPM based on four dimensions: ploidy, tumor cell morphology, adaptive immune response and CpG island methylator profile. We show that these four dimensions are complementary, capture major interpatient molecular differences and are delimited by extreme phenotypes that-in the case of the interdependent tumor cell morphology and adapted immune response-reflect tumor specialization. These findings unearth the interplay between MPM functional biology and its genomic history, and provide insights into the variations observed in the clinical behavior of patients with MPM.
As hearing rehabilitation research evolves to include both retrospective and momentary assessment outcome measures, it is important to understand how in-the-moment contextual factors influence ...subjective ratings. We aimed to determine, over a 4-week period of participants responding to ecological momentary assessments (EMAs) in their own environments, whether: (1) participants will complete surveys in speech-in-noise listening situations; (2) ratings of speech in noise change in a predictable manner as the acoustic conditions change; and (3) EMAs provide patient insights beyond those provided from retrospective ratings.
Fourteen adults aged 26 to 86 years with at least 6 months of hearing aid experience were recruited for an 8-week crossover field trial (4 weeks wearing hearing aids with no EMA; 4 weeks wearing hearing aids with EMA). Participants were fitted with hearing aids and provided with a streamer and a smartphone with an app that analyzed the acoustic signal from the hearing aids and alerted the participant to respond to a survey when predetermined acoustic conditions were detected. Participants were prompted to complete brief surveys up to 9 times/day that contained establishing questions, quality ratings, and items assessing perceived benefit, residual activity limitation, and satisfaction. Participants also completed retrospective questionnaires at intake and after each 4-week field trial.
Participants completed an average of 4.4 surveys per day. The quality ratings changed as the acoustics changed: Ratings of intelligibility were lower for 10 dB signal-to-noise ratio (SNR) than 20 dB SNR (p = 0.006); ratings of noisiness were higher for 10 dB SNR than 20 dB SNR (p = 0.001) and higher for 65 dB SPL than 50 dB SPL (p < 0.001); ratings of effort were higher for 65 dB SPL than 50 dB SPL (p = 0.004); ratings of loudness were higher for 65 dB SPL than 50 dB SPL (p = 0.001). Descriptive analysis of satisfaction, benefit, and residual activity limitation responses showed that the momentary surveys provided more detail about individual variability across acoustic conditions than the retrospective questions.
Participants completed more than 99% of the triggered surveys, demonstrating high compliance. Because the quality ratings generally changed in the hypothesized direction, it is concluded that the participants provided valid responses. The greater variability in responses with EMA than retrospective questionnaires demonstrates its potential utility as a clinical tool for exploring hearing aid outcomes in real-world environments.
Via whole-exome sequencing, we identified rare autosomal-recessive variants in UBA5 in five children from four unrelated families affected with a similar pattern of severe intellectual deficiency, ...microcephaly, movement disorders, and/or early-onset intractable epilepsy. UBA5 encodes the E1-activating enzyme of ubiquitin-fold modifier 1 (UFM1), a recently identified ubiquitin-like protein. Biochemical studies of mutant UBA5 proteins and studies in fibroblasts from affected individuals revealed that UBA5 mutations impair the process of ufmylation, resulting in an abnormal endoplasmic reticulum structure. In Caenorhabditis elegans, knockout of uba-5 and of human orthologous genes in the UFM1 cascade alter cholinergic, but not glutamatergic, neurotransmission. In addition, uba5 silencing in zebrafish decreased motility while inducing abnormal movements suggestive of seizures. These clinical, biochemical, and experimental findings support our finding of UBA5 mutations as a pathophysiological cause for early-onset encephalopathies due to abnormal protein ufmylation.
•Advanced Gibbs free energy minimization applied for modeling physical and chemical processes in various industrial rotary kilns.•A combined model of thermochemistry and kinetics for rotary ...kilns.•KilnSimu application to an industrial case in cement clinker manufacturing.
Advanced Gibbs free energy minimization was applied for modeling physical and chemical processes in various industrial rotary kilns. The method is the core of a generic computer program (KilnSimu), used to simulate kiln operations with different multiphase chemistries. KilnSimu combines iterative solution of the balance equations coupled with the Gibbs energy calculation of the kiln thermochemistry, thus providing a detailed quantitative analysis of the chemical and phase transformations as well as of mass and heat flows inside the kiln. Adding reaction rate constraints into the Gibbs energy procedure allows for the necessary reaction kinetics in the simulation. The calculation results are typically given as 1-dimensional steady state axial profiles in the longitudinal direction of the kiln.
The presented model was applied to an industrial problem in cement clinker manufacturing. The impact of pure oxygen addition at the main burner on the specific heat consumption of the full process was evaluated.
Molecular diagnosis of neurodevelopmental disorders (NDDs) is mainly based on exome sequencing (ES), with a diagnostic yield of 31% for isolated and 53% for syndromic NDD. As sequencing costs ...decrease, genome sequencing (GS) is gradually replacing ES for genome-wide molecular testing. As many variants detected by GS only are in deep intronic or non-coding regions, the interpretation of their impact may be difficult. Here, we showed that integrating RNA-Seq into the GS workflow can enhance the analysis of the molecular causes of NDD, especially structural variants (SVs), by providing valuable complementary information such as aberrant splicing, aberrant expression and monoallelic expression.
We performed trio-GS on a cohort of 33 individuals with NDD for whom ES was inconclusive. RNA-Seq on skin fibroblasts was then performed in nine individuals for whom GS was inconclusive and optical genome mapping (OGM) was performed in two individuals with an SV of unknown significance.
We identified pathogenic or likely pathogenic variants in 16 individuals (48%) and six variants of uncertain significance. RNA-Seq contributed to the interpretation in three individuals, and OGM helped to characterise two SVs.
Our study confirmed that GS significantly improves the diagnostic performance of NDDs. However, most variants detectable by GS alone are structural or located in non-coding regions, which can pose challenges for interpretation. Integration of RNA-Seq data overcame this limitation by confirming the impact of variants at the transcriptional or regulatory level. This result paves the way for new routinely applicable diagnostic protocols.
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