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The singular French PCSK9-p.Ser127Arg gain-of-function variant: A significant player in cholesterol levels from a 775-year-old common ancestor
No full textInternational audienceBackground and aims :PCSK9 is a key regulator of LDL-cholesterol levels. PCSK9 gain of function variants (GOFVs) cause autosomal dominant hypercholesterolemia (ADH). The first described PCSK9-GOFV, p.Ser127Arg, almost exclusively reported in France, represents 67 % of the PCSK9 French GOFVs due to a founder effect. Few other carriers are reported in South Africa and Norway. This study aims to estimate when the common ancestor lived and to describe a cohort of p.Ser127Arg carriers.Methods :Eight families and 14 p.Ser127Arg carriers were genotyped and phenotyped. Haplotypes were constructed using 11 microsatellites around PCSK9 and 6 intragenic single nucleotide polymorphisms (SNPs). To add to the biological analysis, eight additional p.Ser127Arg carriers, 12 carriers of other PCSK9-GOFVs, 93 LDLR loss of function variant (LOFV) carriers and 49 non-carriers subjects were phenotyped.Results :The most common ancestor of p.Ser127Arg was estimated to have lived 775 years ago [95 % CI: 575-1075]. French Protestants exiled after the revocation of the Edict of Nantes in 1685 AD likely brought the variant to South Africa and Norway. As expected for ADH subjects, carriers of LDLR-LOFV, the p.Ser127Arg, or other PCSK9-GOFVs showed significantly higher LDL-C levels than that of the non-carriers. Interestingly, LDL-C levels are higher for LDLR-LOFVs and for the reduced secreted p.Ser127Arg than for secreted PCSK9-GOFVs, suggesting a greater effect of the p.Ser127Arg. Conversely, HDL-C was significantly lower for LDLR-LOFV and p.Ser127Arg carriers.Conclusions :This first report from a large cohort of PCSK9-p.Ser127Arg carriers provides observations suggesting a stronger hypercholesterolemic potential of the mutated pro-PCSK9 compared with the secreted mature protein. This work also provides additional data to support the association between PCSK9 and HDL metabolism, and molecular evidence that this variant appeared in France around 1248 AD (Graphical Abstract = Fig. 1)
Fluid simulation of a CCRF dusty plasma using COMSOL®: First stage under dust-free conditions
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The peptidyl-prolyl isomerase Pin1 controls GM-CSF-induced priming of NADPH oxidase in human neutrophils and priming at inflammatory sites
No full textInternational audienceThe production of superoxide anions and other reactive oxygen species (ROS) by neutrophils is necessary for host defense against microbes. However, excessive ROS production can induce cell damage that participates in the inflammatory response. Superoxide anions are produced by the phagocyte NADPH oxidase, a multicomponent enzyme system consisting of two transmembrane proteins (gp91phox/NOX2 and p22phox) and four soluble cytosolic proteins (p40phox, p47phox, p67phox and the small G proteins Rac1/2). Stimulation of neutrophils by various agonists, such as the bacterial peptide formyl-Met-Leu-Phe (fMLF), induces NADPH oxidase activation and superoxide production, a process that is enhanced by the pro-inflammatory cytokines such as GM-CSF. The pathways involved in this GM-CSF-induced up-regulation or priming are not fully understood. Here we show that GM-CSF induces the activation of the prolyl cis/trans isomerase Pin1 in human neutrophils. Juglone and PiB, two selective Pin1 inhibitors, were able to block GM-CSF-induced priming of ROS production by human neutrophils. Interestingly, GM-CSF induced Pin1 binding to phosphorylated p47phox at Ser345. Neutrophils isolated from synovial fluid of patients with rheumatoid arthritis are known to be primed. Here we show that Pin1 activity was also increased in these neutrophils and that Pin1 inhibitors effectively inhibited ROS hyperproduction by the same cells. These results suggest that the prolyl cis/trans isomerase Pin1 may control GM-CSF-induced priming of ROS production by neutrophils and priming of neutrophils in synovial fluid of rheumatoid arthritis patients. Pharmacological targeting of Pin1 may be a valuable approach to the treatment of inflammation
Lithium inelastic cross-sections and their impact on micro and nano dosimetry of boron neutron capture
No full textInternational audienceObjective: To present a new set of lithium-ion cross-sections for (i) ionization and excitation processes down to 700 eV, and (ii) charge-exchange processes down to 1 keV u −1 . To evaluate the impact of the use of these cross-sections on micro a nano dosimetric quantities in the context of boron neutron capture (BNC) applications/techniques.Approach: The Classical Trajectory Monte Carlo method was used to calculate Li ion charge-exchange cross sections in the energy range of 1 keV u −1 to 10 MeV u −1 . Partial Li ion charge states ionization and excitation cross-sections were calculated using a detailed charge screening factor. The cross-sections were implemented in Geant4-DNA v10.07 and simulations and verified using TOPAS-nBio by calculating stopping power and continuous slowing down approximation (CSDA) range against data from ICRU and SRIM. Further microdosimetric and nanodosimetric calculations were performed to quantify differences against other simulation approaches for low energy Li ions. These calculations were: lineal energy spectra ( yf ( y ) and yd ( y )), frequency mean lineal energy , dose mean lineal energy and ionization cluster size distribution analysis. Microdosimetric calculations were compared against a previous MC study that neglected charge-exchange and excitation processes. Nanodosimetric results were compared against pure ionization scaled cross-sections calculations.Main results: Calculated stopping power differences between ICRU and Geant4-DNA decreased from 33.78% to 6.9%. The CSDA range difference decreased from 621% to 34% when compared against SRIM calculations. Geant4-DNA/TOPAS calculated dose mean lineal energy differed by 128% from the previous Monte Carlo. Ionization cluster size frequency distributions for Li ions differed by 76%–344.11% for 21 keV and 2 MeV respectively. With a decrease in the N 1 within 9% at 10 keV and agreeing after the 100 keV. With the new set of cross-sections being able to better simulate low energy behaviors of Li ions.Significance: This work shows an increase in detail gained from the use of a more complete set of low energy cross-sections which include charge exchange processes. Significant differences to previous simulation results were found at the microdosimetric and nanodosimetric scales that suggest that Li ions cause less ionizations per path length traveled but with more energy deposits. Microdosimetry results suggest that the BNC’s contribution to cellular death may be mainly due to alpha particle production when boron-based drugs are distributed in the cellular membrane and beyond and by Li when it is at the cell cytoplasm regions
Current practices in clinical gait analysis in Europe: A comprehensive survey-based study from the European society for movement analysis in adults and children (ESMAC) standard initiative
No full textInternational audienceBackground: Clinical gait analysis (CGA) is a systematic approach to comprehensively evaluate gait patterns, quantify impairments, plan targeted interventions, and evaluate the impact of interventions. However, international standards for CGA are currently lacking, resulting in various national initiatives. Standards are important to ensure safe and effective healthcare practices and to enable evidence-based clinical decision-making, facilitating interoperability, and reimbursement under national healthcare policies. Collaborative clinical and research work between European countries would benefit from common standards.Research objective: This study aimed to review the current laboratory practices for CGA in Europe.Methods: A comprehensive survey was conducted by the European Society for Movement Analysis in Adults and Children (ESMAC), in close collaboration with the European national societies. The survey involved 97 gait laboratories across 16 countries. The survey assessed several aspects related to CGA, including equipment used, data collection, processing, and reporting methods.Results: There was a consensus between laboratories concerning the data collected during CGA. The Conventional Gait Model (CGM) was the most used biomechanical model for calculating kinematics and kinetics. Respondents also reported the use of video recording, 3D motion capture systems, force plates, and surface electromyography. While there was a consensus on the reporting of CGA data, variations were reported in training, documentation, data preprocessing and equipment maintenance practices.Significance: The findings of this study will serve as a foundation for the development of standardized guidelines for CGA in Europe
Bioproduction of 2-Phenylethanol by Yarrowia lipolytica on Sugar Beet Molasses as a Low-Cost Substrate
No full textInternational audience2-phenylethanol (2-PE) is a valuable aromatic alcohol with diverse applications in cosmetics, food, beverages, and pharmaceutical industries. Currently, 2-PE is produced either through chemical synthesis or by extraction from plant materials. However, both conventional production methods have their own limitations. Therefore, there is a need for more eco-friendly and cost-effective approaches to produce natural 2-PE. Biotechnological routes, particularly microbial fermentations, hold promise for natural 2-PE production, especially when using low-cost substrates. In this study, 2-PE was produced by de novo synthesis via the shikimate pathway, using the yeast Yarrowia lipolytica in a medium composed of sugar beet molasses (SBM) and yeast extract (YE) as carbon and nitrogen sources, respectively. A genetically engineered strain was generated, in which the SUC2 gene was transformed, expressing the invertase enzyme, enabling Y. lipolytica to efficiently utilize SBM as a cost-effective substrate. A central composite design allowed for the optimization of the concentrations of the carbon and nitrogen sources, resulting in approximately 0.71 g(2-PE)/L(culture medium). The results obtained highlight the potential of utilizing SBM as a low-cost substrate for 2-PE production, advancing biotechnological approaches in fragrance synthesis
Examining the impact of humane entrepreneurship on overall firm performance: An empirical investigation of SMEs
No full textInternational audienceThis article explores the practical impact of humane entrepreneurship on small and medium-sized enterprises (SMEs), demonstrating how adopting a humane entrepreneurial orientation (HEO) can significantly enhance financial performance, employee engagement, and environmental sustainability. It provides valuable insights for business leaders and policy makers by showcasing how integrating humancentric approaches into business strategies not only drives profitability but also strengthens organizational commitment and social responsibility. The article emphasizes the practical benefits of HEO for SMEs, while calling for further research to assess its broader applicability across different industries and regions
Sex-dependent evolution of whole-body postural alignment with age
No full textInternational audiencePurposeThe goal of this study was to explore sex-related variations of global alignment parameters and their distinct evolution patterns across age groups.MethodsThis multicentric retrospective study included healthy volunteers with full-body biplanar radiographs in free-standing position. All radiographic data were collected from 3D reconstructions: global and lower limb parameters, pelvic incidence (PI) and sacral slope (SS). Lumbar lordosis (LL), thoracic kyphosis (TK) and cervical lordosis (CL) were also assessed as well as the lumbar and thoracic apex, and thoracolumbar inflexion point. The population was divided into five 5 age groups: Children, Adolescents, Young, Middle-Aged and Seniors.ResultsThis study included 861 subjects (53% females) with a mean age of 34 ± 17 years. Mean PI was 49.6 ± 11.1 and mean LL was − 57.1 ± 11.6°. Females demonstrated a PI increase between Young and Middle-Aged groups (49 ± 11° vs. 55 ± 12°, p < 0.001) while it remained stable in males. SS and LL increased with age in females while remaining constant in males between Children and Middle-aged and then significantly decreased for both sexes between Middle-Aged and Seniors. On average, lumbar apex, inflexion point, and thoracic apex were located one vertebra higher in females (p < 0.001). After skeletal maturity, males had greater TK than females (64 ± 11° vs. 60 ± 12°, p = 0.04), with significantly larger CL (-13 ± 10° vs. -8 ± 10°, p = 0.03). All global spinal parameters indicated more anterior alignment in males.ConclusionMales present more anteriorly tilted spine with age mainly explained by a PI increase in females between Young and Middle-Aged, which may be attributed to childbirth. Consequently, SS and LL increased before decreasing at senior age
Assessment of malalignment at early stage in adolescent idiopathic scoliosis: a longitudinal cohort study
No full textInternational audienceIntroductionOur objective was to assess abnormalities of the odontoid-hip axis (OD-HA) angle in a mild scoliotic population to determine whether screening for malalignment would help predict the distinction between progressive and stable adolescent idiopathic scoliosis (AIS) at early stage.Materials and methodsAll patients (non-scoliotic and AIS) underwent a biplanar X-ray between 2013 and 2020. In AIS, inclusion criteria were Cobb angle between 10° and 25°; Risser sign lower than 3; age higher than 10 years; and no previous treatment. A 3D spine reconstruction was performed, and the OD-HA was computed automatically. A reference corridor for OD-HA values in non-scoliotic subjects was calculated as the range [5th–95th percentiles]. A severity index, helping to distinguish stable and progressive AIS, was calculated and weighted according to the OD-HA value.ResultsEighty-three non-scoliotic and 205 AIS were included. The mean coronal and sagittal OD-HA angles in the non-scoliotic group were 0.2° and −2.5°, whereas in AIS values were 0.3° and −0.8°, respectively. For coronal and sagittal OD-HA, 27.5% and 26.8% of AIS were outside the reference corridor compared with 10.8% in non-scoliotic (OR = 3.1 and 3). Adding to the severity index a weighting factor based on coronal OD-HA, for thoracic scoliosis, improved the positive predictive value by 9% and the specificity by 13%.ConclusionAnalysis of OD-HA suggests that AIS patients are almost three times more likely to have malalignment compared with a non-scoliotic population. Furthermore, analysis of coronal OD-HA is promising to help the clinician distinguish between stable and progressive thoracic scoliosis
