120589 research outputs found
Sort by
La problématique du pastoralisme dans les alpes occidentales au Néolithique et les objectifs de la fouille des dépôts de bergerie de la Grande Rivoire
No full textQuestion foncière et transition agricole dans l’oblast de Iakoutie : les relégués socialistes face aux autorités impériales russes à la fin du xixe siècle
No full textL’article analyse le point de vue des acteurs étatiques (gouverneur-général, gouverneur de l’oblast de Iakoutie, Comité statistique) et de deux relégués politiques socialistes sur la question agraire dans l’oblast de Iakoutie entre 1885 et 1895. Il s’agit de comparer les solutions que les autorités publiques et les relégués politiques préconisent pour résoudre deux problèmes qui se posent concernant l’économie des campagnes iakoutes : régler les conflits fonciers entre paysans russes et exploitants iakoutes et encourager l’extension de l’agriculture dans une région traditionnellement exploitée par l’élevage extensif de type pastoral. Ces deux problèmes renvoient à la question de l’intervention étatique dans une région d’emprise impériale. Nous observons que les deux relégués politiques socialistes proposent des solutions qui, bien que favorisant la transformation du milieu iakoute au profit de l’ordre impérial, prennent le contre-pied des autorités par une analyse qualitative de l’exploitation des terres iakoutes et par une analyse environnementale du rôle de la forêt sibérienne
Sex-dependent role of Pannexin1 in the crosstalk between lymphatic function and atherosclerosis
No full textThis thesis investigates the role of Pannexin1 (Panx1) channels in lymphatic endothelial cells (LECs) and their impact on lymphatic function and atherosclerosis, with a focus on sex-dependent effects. Panx1 channels, which facilitate ion and molecule passage across cell membranes, show higher expression in male LECs. The study found that Panx1 deletion in male mice reduced lymphatic drainage, leading to fluid accumulation, while affecting lipid absorption in both sexes. In females, Panx1 deletion increased dendritic cell migration to lymph nodes. Additionally, Panx1 influenced atherosclerosis progression differently between sexes; male mice showed higher lipid levels, while females had more advanced atherosclerotic plaques. The findings suggest Panx1 channels play a crucial, sex-specific role in lymphatic function and atherosclerosis, highlighting their potential as therapeutic targets for personalized atherosclerosis treatment
[Review of:] Emotions and Surgery in Britain, 1793-1912 / Michael Brown. Cambridge University Press, 2022
No full text
Understanding and Targeting RNA Conformational Ensemble to Develop Therapeutic Approaches for Splicing-related Diseases: A Case Study of Hutchinson-Gilford Progeria Syndrome
No full textRNA splicing is a biological process that involves the transformation of pre-mRNA into a mature mRNA. During splicing, introns are excised and exons are fused. Exons have the potential to be constitutive or alternative. Alternative splicing leads to inclusion or exclusion of specific exons in the final mRNA. The human genome has alternative exons in over 90% of the protein-coding genes, enabling the creation of several protein isoforms from one gene. Diseases can also be caused by aberrant splicing isoforms; one such example is Hutchinson-Gilford progeria syndrome (HGPS), which results from a splicing modifying mutation in the LMNA gene. The molecular mechanism of HGPS is characterised by a C to T mutation in a specific location of the LMNA gene, leading to the formation and accumulation of the protein, called progerin. Presence of progerin contributes to accelerated-aging phenotype and characteristic features seen in HGPS. As of now, progeria has no known cure and only treatments for relieving symptoms have been used. In this point, understanding the molecular mechanisms of HGPS has paved the way for research into potential therapeutic approaches targeting progerin production and its effects on cellular function. The potential of small molecules targeting RNA structural elements that regulate exon usage in treating splicing-related diseases has been demonstrated by several groups in recent times. In particular, our group has identified compounds that target the TSL2 RNA structure and modify the splicing of SMN2 transcripts, involved in Spinal Muscular Atrophy. Taken the knowledge acquired from those studies, in this PhD thesis, it was firstly aimed at understanding RNA hairpin conformation in the absence or presence of progeria mutation and secondly targeting the progeria-mutated hairpin conformation by RNA-binding small molecules as splicing modifiers to reduce progerin level in order to overcome the negative effects of the disease. Structure of Lamin A mRNA has not been well understood, and there has been insufficient research on HGPS. In the literature, effects of progeria mutation was hypothesised as a conformational change and loosening the hairpin structure. However, there is a lack of certain information concerning loop or stem interactions in hairpin structures with or without progeria mutation. Therefore, it was aimed to understand mutation effects on the conformational ensemble of cryptic splicing site, where progeria mutation occurs. Experimental outcomes showed a strong correlation and substantially supporting our hypothesis on conformation ensemble in several ways. In the second experimental part, it was successfully established binding and splicing abilities of small molecules and their effects on cellular characteristics. Intriguingly, compound 18 had been observed to ameliorate outcomes of patient-derived progeria cells as in healthy ones with no toxic effects. Besides, in vitro and in silico binding interactions with progeria mutated hairpin showed promising results. There are several of pharmaceutical treatments for progeria, but none have yielded complete recovery from the disease’s symptoms. Taken the knowledge of previous studies of HGPS and this project, where promising small molecules targeting RNA conformation are characterised, could open a new avenue for the most effective treatments as well as could instil hope for other rare diseases linked to splicing issues
Hormonal changes in professional printers exposed to phthalates suggesting potential disturbances of the hypothalamic–pituitary–gonadal axis
No full textBackground: Phthalate exposures might alter male reproductive health, but human evidence remains limited and inconsistent. Occupational settings often have consistently high exposures from known sources, providing a basis for developing risk reduction strategies and interventions.
Objectives: Evaluate dose-response relationships between phthalate exposures in professional printers (urinary metabolites) and male reproductive hormones, which were examined twice in one working week for workweek value (mean) and change within-week (ratio) responses.
Methods: Occupational biomonitoring of 59 male printers was used to assess exposures to 18 phthalates by measuring 35 urinary phthalate metabolites. Blood samples collected on the first and last day of the workweek were analyzed for total testosterone, calculated free testosterone (cFT), bioavailable testosterone (BioT), measured free testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone, follicle-stimulating hormone, prolactin, estradiol (E2), and inhibin B (INHB). Multiple linear covariate-adjusted regressions were used to evaluate the dose-response relationship.
Results: cFT hormonal workweek response was negatively associated with di-n-butyl phthalate (DnBP) metabolites while SHBG was positively associated with di-ethyl-hexyl phthalate (DEHP) metabolites. BioT and E2 withinweek responses were negatively associated with the DiBP metabolite mono-2-hydroxy-isobutyl phthalate (2OH-MiBP). Overall, ten low-molecular-weight phthalate metabolite concentrations were positively associated with INHB, while eight high-molecular-weight phthalates metabolite concentrations were negatively associated with FSH. Occupational exposure to these phthalates was elevated, as median concentrations of their metabolites were between 2- to 7-fold higher than general population levels.
Conclusions: Occupational exposures to certain phthalates in professional printers were associated with hormonal patterns, indicative of antiandrogenic reproductive disturbance and potential alteration of the HPG-axis.</p
Not all anti-parietal cell antibody tests are equal for diagnosing pernicious anemia
No full textObjectives: Pernicious anemia (PA) is a common cause of vitamin B12 deficiency and requires a robust diagnosis to guide lifelong treatment. Anti-parietal cell antibodies (APCA) are frequently used as a diagnostic marker, but their poor specificity raises concerns about overdiagnosis, particularly in patients lacking the more specific but less sensitive anti-intrinsic factor antibodies (IFA). We compared the diagnostic performance of two APCA detection methods: indirect immunofluorescence (IIF) and immunodot assay.
Methods: We prospectively enrolled patients with B12 deficiency and APCA positivity without IFA. PA diagnosis was adjudicated by blinded expert based on histology and response to oral B12. Patients were classified as true PA (APCA-PA), false positive (APCA-FP), or undetermined. Only APCA-PA and APCA-FP cases were analyzed.
Results: Among 56 included patients, 19 were classified as APCA-PA and compared to 24 APCA-FP. APCA immunodot assay was positive in 19/19 APCA-PA vs. 23/24 APCA-FP (p>0.99), while APCA IIF was positive in 13/19 APCA-PA vs. 2/24 APCA-FP (p<0.001), with higher IIF titers among APCA-PA (p<0.001). Only IIF positivity was significantly associated with PA (68.4 % vs. 8.3 %, p<0.001), with 92 % specificity. This association was confirmed in multivariate analysis (OR 37.1 [95 % CI: 6.1-439.4]). APCA IIF titer was also associated with PA diagnosis (AUC 0.82 [95 % CI: 0.68-0.96]), and titer ≥1:80 further improved specificity to 96 %.
Conclusions: IIF is more specific than immunodot for PA diagnosis, and its result should prevail over immunodot when deciding whether to perform EGD, when EGD is not feasible, and when establishing the diagnosis if biopsies are inconclusive.</p
Fetal and maternal outcome in the pregnancies of patients with systemic sclerosis and very early diagnosis of systemic sclerosis in France : a prospective study
No full text Background: Prospective data on pregnancies in systemic sclerosis are scarce. We aimed to examine the frequency of adverse pregnancy outcomes and maternal disease progression in systemic sclerosis, as well as the factors that predict these events.
Methods: In this analysis, we studied pregnant women with systemic sclerosis (American College of Rheumatology-European League Against Rheumatism 2013 classification) or with Very Early Diagnosis of Systemic Sclerosis (VEDOSS criteria) included in the GR2 French prospective study. Frequency of composite adverse pregnancy outcomes (preterm birth at 34 weeks or less, placental insufficiency complications, small for gestational age, or fetal or neonatal death) and maternal disease course were the primary objectives. The secondary objectives were to assess other complications related to pregnancy (including delivery outcomes and postpartum complications) and compare these results with outcomes for age-matched controls from the French perinatal survey (ENP) 2016 (ie, general population), and to identify predictive factors associated with composite adverse pregnancy outcomes and maternal disease course using univariate analysis.
Findings: Between May 1, 2014, and Dec 27, 2020, we included 58 pregnancies (in 52 women), with 53 (91·4%) resulting in livebirths. Of the 53 ongoing pregnancies beyond 22 weeks of gestation, 14 (26·4%) had a composite adverse pregnancy outcome, including two (3·8%) preterm deliveries at 34 weeks of gestation or less, 12 (22·6%) placental insufficiency complications (pre-eclampsia or fetal growth restriction), and six (11·3%) small for gestational age. Among the 53 pregnancies, six (11·3%) severe postpartum haemorrhage events occurred. When compared with the 2016 ENP survey results, pre-eclampsia (seven [13·2%] of 53 vs 16 [3·0%] of 530, p=0·0010, preterm birth before 37 weeks of gestation (seven [13·2%] of 53 vs 31 [5·8%] of 530, p=0·047), birthweight of less than 2500 g (11 [21·1%] of 52 vs 23 [4·3%] of 530, p<0·0001), and severe postpartum haemorrhage (six [11·3%] of 53 vs seven [1·4%] of 516, p=0·0001) were more frequent than in the general population. No factors were significantly associated with the composite adverse pregnancy outcome in univariate analysis. Systemic sclerosis or VEDOSS worsened in 23 (39·7%) of 58 pregnancies, mainly during the postpartum period. In the univariate analysis, diffuse cutaneous systemic sclerosis (odds ratio 3·7 [95% CI 1·1-12·4]) and previous cutaneous vascular involvement (3·7 [1·2-11·5]) were associated with maternal disease progression, whereas the presence of anticentromere antibodies was inversely associated with stable disease (0·2 [0·1-0·8]).
Interpretation: Despite 53 (91·4%) of 58 livebirths, systemic sclerosis pregnancies were associated with higher rates of adverse pregnancy outcomes and severe postpartum haemorrhage. Disease worsened in 23 (39·7%) of 58 pregnancies, particularly during the postpartum period, especially in women with diffuse cutaneous systemic sclerosis, previous cutaneous vascular involvement, and antibodies other than anticentromere.</p