Endothelial LRP1 transports amyloid-β1-42 across the blood-brain barrier

According to the neurovascular hypothesis, impairment of low-density lipoprotein receptor-related protein-1 (LRP1) in brain capillaries of the blood-brain barrier (BBB) contributes to neurotoxic amyloid-beta (A beta) brain accumulation and drives Alzheimer's disease (AD) pathology. However, due to conflicting reports on the involvement of LRP1 in A beta transport and the expression of LRP1 in brain endothelium, the role of LRP1 at the BBB is uncertain. As global Lrp1 deletion in mice is lethal, appropriate models to study the function of LRP1 are lacking. Moreover, the relevance of systemic A beta clearance to AD pathology remains unclear, as no BBB-specific knockout models have been available. Here, we developed transgenic mouse strains that allow for tamoxifen-inducible deletion of Lrp1 specifically within brain endothelial cells (Slo1c1-CreER(Tz) Lrp1(fl/fl) mice) and used these mice to accurately evaluate LRP1-mediated A beta BBB clearance in vivo. Selective deletion of Lrp1 in the brain endothelium of C57BL/6 mice strongly reduced brain efflux of injected [I-125] A beta(1-42). Additionally, in the 5xFAD mouse model of AD, brain endothelial-specific Lrp1 deletion reduced plasma A beta levels and elevated soluble brain A beta, leading to aggravated spatial learning and memory deficits, thus emphasizing the importance of systemic AD elimination via the BBB. Together, our results suggest that receptor-mediated A beta BBB clearance may be a potential target for treatment and prevention of A beta brain accumulation in AD

Mouse nuclear myosin I knock-out shows interchangeability and redundancy of myosin isoforms in the cell nucleus.

Nuclear myosin I (NM1) is a nuclear isoform of the well-known "cytoplasmic" Myosin 1c protein (Myo1c). Located on the 11(th) chromosome in mice, NM1 results from an alternative start of transcription of the Myo1c gene adding an extra 16 amino acids at the N-terminus. Previous studies revealed its roles in RNA Polymerase I and RNA Polymerase II transcription, chromatin remodeling, and chromosomal movements. Its nuclear localization signal is localized in the middle of the molecule and therefore directs both Myosin 1c isoforms to the nucleus. In order to trace specific functions of the NM1 isoform, we generated mice lacking the NM1 start codon without affecting the cytoplasmic Myo1c protein. Mutant mice were analyzed in a comprehensive phenotypic screen in cooperation with the German Mouse Clinic. Strikingly, no obvious phenotype related to previously described functions has been observed. However, we found minor changes in bone mineral density and the number and size of red blood cells in knock-out mice, which are most probably not related to previously described functions of NM1 in the nucleus. In Myo1c/NM1 depleted U2OS cells, the level of Pol I transcription was restored by overexpression of shRNA-resistant mouse Myo1c. Moreover, we found Myo1c interacting with Pol II. The ratio between Myo1c and NM1 proteins were similar in the nucleus and deletion of NM1 did not cause any compensatory overexpression of Myo1c protein. We observed that Myo1c can replace NM1 in its nuclear functions. Amount of both proteins is nearly equal and NM1 knock-out does not cause any compensatory overexpression of Myo1c. We therefore suggest that both isoforms can substitute each other in nuclear processes

High-level IGF1R expression is required for leukemia-initiating cell activity in T-ALL and is supported by Notch signaling

Notch-driven expression of IGF1R promotes the growth, viability, and transplantability of T-ALL cells

Specific Nuclear Localizing Sequence Directs Two Myosin Isoforms to the Cell Nucleus in Calmodulin-Sensitive Manner

BACKGROUND: Nuclear myosin I (NM1) was the first molecular motor identified in the cell nucleus. Together with nuclear actin, they participate in crucial nuclear events such as transcription, chromatin movements, and chromatin remodeling. NM1 is an isoform of myosin 1c (Myo1c) that was identified earlier and is known to act in the cytoplasm. NM1 differs from the "cytoplasmic" myosin 1c only by additional 16 amino acids at the N-terminus of the molecule. This amino acid stretch was therefore suggested to direct NM1 into the nucleus. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the mechanism of nuclear import of NM1 in detail. Using over-expressed GFP chimeras encoding for truncated NM1 mutants, we identified a specific sequence that is necessary for its import to the nucleus. This novel nuclear localization sequence is placed within calmodulin-binding motif of NM1, thus it is present also in the Myo1c. We confirmed the presence of both isoforms in the nucleus by transfection of tagged NM1 and Myo1c constructs into cultured cells, and also by showing the presence of the endogenous Myo1c in purified nuclei of cells derived from knock-out mice lacking NM1. Using pull-down and co-immunoprecipitation assays we identified importin beta, importin 5 and importin 7 as nuclear transport receptors that bind NM1. Since the NLS sequence of NM1 lies within the region that also binds calmodulin we tested the influence of calmodulin on the localization of NM1. The presence of elevated levels of calmodulin interfered with nuclear localization of tagged NM1. CONCLUSIONS/SIGNIFICANCE: We have shown that the novel specific NLS brings to the cell nucleus not only the "nuclear" isoform of myosin I (NM1 protein) but also its "cytoplasmic" isoform (Myo1c protein). This opens a new field for exploring functions of this molecular motor in nuclear processes, and for exploring the signals between cytoplasm and the nucleus

Thirty years of HIV pregnancies in French Guiana: prevention successes and remaining obstetrical challenges

IntroductionIn a context of high HIV prevalence, poor pregnancy follow-up, frequent poverty, preeclampsia, and preterm delivery, we aimed to describe the characteristics and outcomes of pregnancies among women living with HIV in French Guiana.MethodsA retrospective cohort study was conducted on HIV-infected pregnancies enrolled between January 1st 1992 to 31st July 2022. Overall, there were 1,774 pregnancies in 881 women living with HIV.ResultsFor 75.1% of pregnancies, the HIV diagnosis was already known before pregnancy and in 67.6% of women, HIV follow-up predated pregnancy. Nearly half of women, 49.6%, only had one pregnancy since having been diagnosed with HIV. Although most women received antiretroviral therapy during pregnancy, for those with the available information we found only 48.5% had an undetectable viral load at delivery. Overall, 15.3% of pregnancies ended with an abortion. There were a total of 110 newborns infected with HIV representing an overall transmission rate of 6.2% (110/1,771). Between 1993 and 2002, the transmission rate was 34%, between 2003 and 2012 it was 1.3%, and between 2013 and 2022 it was 0.7%. Overall, in Cayenne, since 2008, 106 of 581 HIV–infected pregnancies (18.2%) with available information were premature before 37 weeks of pregnancy; of these, 33 (5.7%) were very preterm deliveries and 73 (13.3%) were late preterm deliveries. Over time, in Cayenne, preterm delivery declined significantly.ConclusionsThe present study emphasizes that, despite spectacular progress in reducing mother to child transmission, pregnancy outcomes among women living with HIV are still preoccupying with high incidence of preterm delivery and low birth weight. Teasing out what fraction is linked to HIV and what fraction is linked to social precariousness and poor follow-up was not possible in this study. Despite the high incidence of very preterm delivery recent progress suggests that coordination efforts to improve follow-up may also have improved obstetrical outcomes

Protein 4.1B Contributes to the Organization of Peripheral Myelinated Axons

Neurons are characterized by extremely long axons. This exceptional cell shape is likely to depend on multiple factors including interactions between the cytoskeleton and membrane proteins. In many cell types, members of the protein 4.1 family play an important role in tethering the cortical actin-spectrin cytoskeleton to the plasma membrane. Protein 4.1B is localized in myelinated axons, enriched in paranodal and juxtaparanodal regions, and also all along the internodes, but not at nodes of Ranvier where are localized the voltage-dependent sodium channels responsible for action potential propagation. To shed light on the role of protein 4.1B in the general organization of myelinated peripheral axons, we studied 4.1B knockout mice. These mice displayed a mildly impaired gait and motility. Whereas nodes were unaffected, the distribution of Caspr/paranodin, which anchors 4.1B to the membrane, was disorganized in paranodal regions and its levels were decreased. In juxtaparanodes, the enrichment of Caspr2, which also interacts with 4.1B, and of the associated TAG-1 and Kv1.1, was absent in mutant mice, whereas their levels were unaltered. Ultrastructural abnormalities were observed both at paranodes and juxtaparanodes. Axon calibers were slightly diminished in phrenic nerves and preterminal motor axons were dysmorphic in skeletal muscle. βII spectrin enrichment was decreased along the axolemma. Electrophysiological recordings at 3 post-natal weeks showed the occurrence of spontaneous and evoked repetitive activity indicating neuronal hyperexcitability, without change in conduction velocity. Thus, our results show that in myelinated axons 4.1B contributes to the stabilization of membrane proteins at paranodes, to the clustering of juxtaparanodal proteins, and to the regulation of the internodal axon caliber

Les facteurs de risque de la naissance prématurée en Guyane Française

Context and objective: French Guiana, an overseas department and region, has nearly 8,000 births per year.Since 1992, the proportion of premature births, although stable, has remained high at around 13.5%, almost double that of France (7%) (data from the Pregnancy Outcome Register and national perinatal survey). While in most countries we see an increase in prematurity, we could, wrongly, be satisfied with a non-increase in the prematurity rate that would reflect progress. However, deaths from perinatal causes remain one of the main causes of premature mortality in French Guiana and partly explain the gap with France in terms of life expectancy at birth.Given this lack of improvement in the prematurity rate, it seems important to better understand the factors that make prematurity so frequent and so difficult to control in French Guiana. The thesis focused on identifying the predictive factors of prematurity with the ultimate aim of contributing to improving the care of pregnant women and curbing the curve of the prematurity rate. Methodology: This research work is divided into 4 areas of investigation:- A descriptive retrospective study, based on data from the RIGI (Register of Computerized Pregnancy Outcomes) 2013-2014 of 12,983 viable births in the department,- The development of a predictive prematurity score from the 2013-2014 RIGI, compared to the 2015 RIGI data of 6,914 viable births,- A case-control etiological study of extreme prematurity, monocentric, from February 2016 to January 2017 in the only type III health-care institution in the French Guiana Region,- Analysis of the average term at birth and morbidity and mortality from the RIG (Register of Pregnancy Outcomes) 2002-2007 of 35,648 viable births and the RIGI 2013-2014.Results:Over the study period, the proportion of preterm births was 13.5% (1,755/12,983). The proportion of spontaneous prematurity was 51.3% , compared to 48.7% of induced prematurity. More than half (57.2% or 7 421/12 983) of the study population had social security, but 9.3% had no social security coverage. The lack of social security coverage was a risk factor for prematurity with an adjusted OR of 1.9 CI at 95% [1.6-2.3] p=0.0001. Similarly, with regard to pregnancy management, the absence of prenatal care as well as that of birth preparation would double the risk of premature birth. For pathologies associated with pregnancy, pre-eclampsia syndrome was the main dysgravidia associated with the risk of prematurity (OR adjusted by 6.7[95% CI =5.6-8.1] p=0.0001). Finally, the fairly common hypothesis that part of the high prematurity rate is related to the fact that black babies are more mature and black mothers give birth physiologically a little earlier did not emerge in our analyses. Indeed, there was no statistically significant difference in morbidity and mortality for infants born to Afro-Caribbean mothers and Caucasian women. Conclusion: The work carried out has identified many factors associated with prematurity, factors already described elsewhere. Although at the individual level it was impossible to predict who would give birth prematurely, the weight of social factors and poor follow-up suggested that a population-based approach might be appropriate. Thus, the most vulnerable women often reside in well-identified areas that could be the subject of targeted actions to improve follow-up and identify complications. This problem of social inequalities in health goes well beyond prematurity and is found for almost all pathologies, suggesting that there are synergies to be sought and that the population scale is undoubtedly strategic. The weight of preeclampsia as a risk factor for induced prematurity in French Guiana raises questions: indeed, it seems much more important than elsewhere for reasons that remain to be clarified.Contexte et objectif : La Guyane Française, département-région d’outre-mer, compte près de 8 000 naissances par année.Depuis 1992, la proportion de naissances prématurées y est importante aux alentours de 13,5% ; soit presque le double de celle de la France (7%). Contrairement à la plupart des pays où une augmentation de la prématurité est observée, en Guyane, son taux est stable. Certes, on pourrait se satisfaire de cette non-augmentation, cependant, les décès liés à la périnatalité restent l’une des principales causes de mortalité prématurée dans ce département. Si en Guyane, le taux de prématurité n’augmente pas, il ne régresse pas non plus. Devant cette absence de régression, il semble important de comprendre les facteurs qui font qu’en Guyane, la prématurité reste si fréquente et si difficile à endiguer. Méthodologie : Ce travail de recherche se décline en quatre axes d'investigations : Une étude rétrospective descriptive, à partir des données du RIGI (Registre d’Issue de Grossesses Informatisé) 2013-2014 de 12 983 naissances viables du département. L’élaboration d’un score prédictif de prématurité à partir du RIGI 2013-2014, confronté aux données du RIGI 2015 de 6 914 naissances viables. Une étude étiologique cas-témoins de la grande prématurité, monocentrique, de Février 2016 à Janvier 2017 dans l’unique établissement de santé de type III de la Région. Enfin, l’analyse du terme moyen à la naissance et de la morbi-mortalité à partir du RIG (Registre d’Issue de Grossesses) 2002-2007 de 35 648 naissances viables et du RIGI 2013-2014. Résultats :Sur la période d’étude, la proportion de naissances prématurées était de 13,5% (1 755/12 983). La proportion de prématurité spontanée et induite était respectivement de 51,3% et 48,7% selon le RIGI 2013-2014.Plus de la moitié (57,2%) de la population d’étude bénéficiait de la sécurité sociale, néanmoins 9,3% (1 211/12 983) n’avait aucune couverture sociale. L’absence de couverture sociale représentait un facteur de risque de prématurité avec un OR ajusté de 1,9 IC à 95% [1,6-2,3] p=0,0001. De même, l’absence d’entretien prénatal tout comme celui de préparation à la naissance multiplieraient par deux le risque de naissance prématurée. D’autre part, le syndrome pré-éclamptique était la principale dysgravidie associée au risque de prématurité (OR ajusté de 6,7 [IC 95% =5,6-8,1] p=0,001). Enfin, l’hypothèse assez répandue, suggérant qu’une partie du taux de prématurité élevée serait liée du fait que les bébés « noirs » seraient plus matures et que les mères « noires » d’ascendance afro-caraibéenne accoucheraient physiologiquement plus tôt, ne ressortait pas dans nos analyses. En effet, il n’y avait pas de différence statistiquement significative de morbi-mortalité pour les nouveau-nés de mères d’origine afro-caribéennes et ceux de femmes caucasiennes.Conclusion : Les travaux réalisés ont retrouvé nombre de facteurs associés à la prématurité, pour certains déjà décrits par ailleurs. Bien qu’à l’échelle individuelle, il était impossible de prédire qui accoucherait prématurément, le poids des facteurs sociaux et du mauvais suivi de grossesse, suggéraient qu’une approche populationnelle pourrait être pertinente. Ainsi les femmes les plus vulnérables résidaient souvent dans des zones bien identifiées qui pourraient faire l’objet d’actions ciblées pour améliorer le suivi et dépister les complications. Cette problématique d’inégalités sociales de santé va bien au-delà de la prématurité et se retrouve pour presque toutes les pathologies, ce qui suggère qu’il y a des synergies à rechercher et que l’échelle populationnelle est sans doute stratégique. Le poids du syndrome pré-éclamptique comme facteur de risque de prématurité induite en Guyane pose question, il semble nettement plus important qu’ailleurs pour des raisons qui restent à élucider

Risk factors for premature birth in French Guiana

Contexte et objectif : La Guyane Française, département-région d’outre-mer, compte près de 8 000 naissances par année.Depuis 1992, la proportion de naissances prématurées y est importante aux alentours de 13,5% ; soit presque le double de celle de la France (7%). Contrairement à la plupart des pays où une augmentation de la prématurité est observée, en Guyane, son taux est stable. Certes, on pourrait se satisfaire de cette non-augmentation, cependant, les décès liés à la périnatalité restent l’une des principales causes de mortalité prématurée dans ce département. Si en Guyane, le taux de prématurité n’augmente pas, il ne régresse pas non plus. Devant cette absence de régression, il semble important de comprendre les facteurs qui font qu’en Guyane, la prématurité reste si fréquente et si difficile à endiguer. Méthodologie : Ce travail de recherche se décline en quatre axes d'investigations : Une étude rétrospective descriptive, à partir des données du RIGI (Registre d’Issue de Grossesses Informatisé) 2013-2014 de 12 983 naissances viables du département. L’élaboration d’un score prédictif de prématurité à partir du RIGI 2013-2014, confronté aux données du RIGI 2015 de 6 914 naissances viables. Une étude étiologique cas-témoins de la grande prématurité, monocentrique, de Février 2016 à Janvier 2017 dans l’unique établissement de santé de type III de la Région. Enfin, l’analyse du terme moyen à la naissance et de la morbi-mortalité à partir du RIG (Registre d’Issue de Grossesses) 2002-2007 de 35 648 naissances viables et du RIGI 2013-2014. Résultats :Sur la période d’étude, la proportion de naissances prématurées était de 13,5% (1 755/12 983). La proportion de prématurité spontanée et induite était respectivement de 51,3% et 48,7% selon le RIGI 2013-2014.Plus de la moitié (57,2%) de la population d’étude bénéficiait de la sécurité sociale, néanmoins 9,3% (1 211/12 983) n’avait aucune couverture sociale. L’absence de couverture sociale représentait un facteur de risque de prématurité avec un OR ajusté de 1,9 IC à 95% [1,6-2,3] p=0,0001. De même, l’absence d’entretien prénatal tout comme celui de préparation à la naissance multiplieraient par deux le risque de naissance prématurée. D’autre part, le syndrome pré-éclamptique était la principale dysgravidie associée au risque de prématurité (OR ajusté de 6,7 [IC 95% =5,6-8,1] p=0,001). Enfin, l’hypothèse assez répandue, suggérant qu’une partie du taux de prématurité élevée serait liée du fait que les bébés « noirs » seraient plus matures et que les mères « noires » d’ascendance afro-caraibéenne accoucheraient physiologiquement plus tôt, ne ressortait pas dans nos analyses. En effet, il n’y avait pas de différence statistiquement significative de morbi-mortalité pour les nouveau-nés de mères d’origine afro-caribéennes et ceux de femmes caucasiennes.Conclusion : Les travaux réalisés ont retrouvé nombre de facteurs associés à la prématurité, pour certains déjà décrits par ailleurs. Bien qu’à l’échelle individuelle, il était impossible de prédire qui accoucherait prématurément, le poids des facteurs sociaux et du mauvais suivi de grossesse, suggéraient qu’une approche populationnelle pourrait être pertinente. Ainsi les femmes les plus vulnérables résidaient souvent dans des zones bien identifiées qui pourraient faire l’objet d’actions ciblées pour améliorer le suivi et dépister les complications. Cette problématique d’inégalités sociales de santé va bien au-delà de la prématurité et se retrouve pour presque toutes les pathologies, ce qui suggère qu’il y a des synergies à rechercher et que l’échelle populationnelle est sans doute stratégique. Le poids du syndrome pré-éclamptique comme facteur de risque de prématurité induite en Guyane pose question, il semble nettement plus important qu’ailleurs pour des raisons qui restent à élucider.Context and objective: French Guiana, an overseas department and region, has nearly 8,000 births per year.Since 1992, the proportion of premature births, although stable, has remained high at around 13.5%, almost double that of France (7%) (data from the Pregnancy Outcome Register and national perinatal survey). While in most countries we see an increase in prematurity, we could, wrongly, be satisfied with a non-increase in the prematurity rate that would reflect progress. However, deaths from perinatal causes remain one of the main causes of premature mortality in French Guiana and partly explain the gap with France in terms of life expectancy at birth.Given this lack of improvement in the prematurity rate, it seems important to better understand the factors that make prematurity so frequent and so difficult to control in French Guiana. The thesis focused on identifying the predictive factors of prematurity with the ultimate aim of contributing to improving the care of pregnant women and curbing the curve of the prematurity rate. Methodology: This research work is divided into 4 areas of investigation:- A descriptive retrospective study, based on data from the RIGI (Register of Computerized Pregnancy Outcomes) 2013-2014 of 12,983 viable births in the department,- The development of a predictive prematurity score from the 2013-2014 RIGI, compared to the 2015 RIGI data of 6,914 viable births,- A case-control etiological study of extreme prematurity, monocentric, from February 2016 to January 2017 in the only type III health-care institution in the French Guiana Region,- Analysis of the average term at birth and morbidity and mortality from the RIG (Register of Pregnancy Outcomes) 2002-2007 of 35,648 viable births and the RIGI 2013-2014.Results:Over the study period, the proportion of preterm births was 13.5% (1,755/12,983). The proportion of spontaneous prematurity was 51.3% , compared to 48.7% of induced prematurity. More than half (57.2% or 7 421/12 983) of the study population had social security, but 9.3% had no social security coverage. The lack of social security coverage was a risk factor for prematurity with an adjusted OR of 1.9 CI at 95% [1.6-2.3] p=0.0001. Similarly, with regard to pregnancy management, the absence of prenatal care as well as that of birth preparation would double the risk of premature birth. For pathologies associated with pregnancy, pre-eclampsia syndrome was the main dysgravidia associated with the risk of prematurity (OR adjusted by 6.7[95% CI =5.6-8.1] p=0.0001). Finally, the fairly common hypothesis that part of the high prematurity rate is related to the fact that black babies are more mature and black mothers give birth physiologically a little earlier did not emerge in our analyses. Indeed, there was no statistically significant difference in morbidity and mortality for infants born to Afro-Caribbean mothers and Caucasian women. Conclusion: The work carried out has identified many factors associated with prematurity, factors already described elsewhere. Although at the individual level it was impossible to predict who would give birth prematurely, the weight of social factors and poor follow-up suggested that a population-based approach might be appropriate. Thus, the most vulnerable women often reside in well-identified areas that could be the subject of targeted actions to improve follow-up and identify complications. This problem of social inequalities in health goes well beyond prematurity and is found for almost all pathologies, suggesting that there are synergies to be sought and that the population scale is undoubtedly strategic. The weight of preeclampsia as a risk factor for induced prematurity in French Guiana raises questions: indeed, it seems much more important than elsewhere for reasons that remain to be clarified