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Sea urchin eggs are covered with layers of extracellular matrix, namely, the vitelline layer (VL) and jelly coat (JC). It has been shown that sea urchin eggs’ JC components serve as chemoattractants or ligands for the receptor on the fertilizing sperm to promote the acrosome reaction. Moreover, the egg’s VL provides receptors for conspecific sperm to bind, and, to date, at least two sperm receptors have been identified on the surface of sea urchin eggs. Interestingly, however, according to our previous work, denuded sea urchin eggs devoid of the JC and VL do not fail to become fertilized by sperm. Instead, they are bound and penetratedby multiple sperm, raising the possibility that an alternative pathway independent of the VL-residing sperm receptor may be at work. In this research, we studied the roles of the JC and VL using intact and denuded eggs and the synthetic polyamine BPA-C8. BPA-C8 is known to bind to the negatively charged macromolecular complexes in the cells, such as the JC, VL, and the plasma membrane of echinoderm eggs, as well as to the actin filaments in fibroblasts. Our results showed that, when added to seawater, BPA-C8 significantly repressed the Ca2+ wave in the intact P. lividus eggs at fertilization. In eggs deprived of the VL and JC, BPA-C8 binds to the plasma membrane and increases fibrous structures connecting microvilli, thereby allowing the denuded eggs to revert towards monospermy at fertilization. However, the reduced Ca2+ signal in denuded eggs was nullified compared to the intact eggs because removing the JC and VL already decreased the Ca2+ wave. BPA-C8 does not cross the VL and the cell membrane of unfertilized sea urchin eggs to diffuse into the cytoplasm at variance with the fibroblasts. Indeed, the jasplakinolide-induced polymerization of subplasmalemmal actin filaments was inhibited in the eggs microinjected with BPA-C8, but not in the ones bath-incubated with the same dose of BPA-C8.

The vitelline layer (VL) of a sea urchin egg is an intricate meshwork of glycoproteins that intimately ensheathes the plasma membrane. During fertilization, the VL plays important roles. Firstly, the receptors for sperm reside on the VL. Secondly, following cortical granule exocytosis, the VL is elevated and transformed into the fertilization envelope (FE), owing to the assembly and crosslinking of the extruded materials. As these two crucial stages involve the VL, its alteration was expected to affect the fertilization process. In the present study, we addressed this question by mildly treating the eggs with a reducing agent, dithiothreitol (DTT). A brief pretreatment with DTT resulted in partial disruption of the VL, as judged by electron microscopy and by a novel fluorescent polyamine probe that selectively labelled the VL. The DTT-pretreated eggs did not elevate the FE but were mostly monospermic at fertilization. These eggs also manifested certain anomalies at fertilization: (i) compromised Ca2+ signaling, (ii) blocked translocation of cortical actin filaments, and (iii) impaired cleavage. Some of these phenotypic changes were reversed by restoring the DTT-exposed eggs in normal seawater prior to fertilization. Our findings suggest that the FE is not the decisive factor preventing polyspermy and that the integrity of the VL is nonetheless crucial to the egg’s fertilization response.

The hypoxic microenvironment is crucial for tumour cell growth and invasiveness. Tumour tissue results from adaptation to reduced oxygen availability. Hypoxia first activates pro‐angiogenic signals for alleviation. Pathologic, tumour angiogenesis maintains hypoxia, impairing treatment outcomes. Vessel normalisation requires physioxia. Oxygen delivery by red blood cell (RBC) carrying haemoglobin (Hb) is enhanced by myo‐inositol trispyrophosphate (ITPP), an effector of oxygen transport by RBCs. Altering glycolytic activity, it lowers intracellular pH and increases oxygen release from Hb. 31P NMR tracking of 2,3‐diphosphoglycerate (2,3‐DPG), allosteric effector of Hb and non‐penetrating anion in RBCs, reports on erythrocytes internal environment. 31P resonances of 2,3‐DPG are pH‐sensitive, their positions indicate the oxygenation state of RBCs and interactions with effectors such as ITPP. Here we show in vitro and in vivo, that modifying Hb activity through band‐3 anion transporter, ITPP enhances oxygen release and controls RBC internal pH. Its blood availability validates applicability of ITPP‐based strategies.

The hypoxic microenvironment is crucial for tumour cell growth and invasiveness. Tumour tissue results from adaptation to reduced oxygen availability. Hypoxia first activates pro‐angiogenic signals for alleviation. Pathologic, tumour angiogenesis maintains hypoxia, impairing treatment outcomes. Vessel normalisation requires physioxia. Oxygen delivery by red blood cell (RBC) carrying haemoglobin (Hb) is enhanced by myo ‐inositol trispyrophosphate (ITPP), an effector of oxygen transport by RBCs. Altering glycolytic activity, it lowers intracellular pH and increases oxygen release from Hb. 31 P NMR tracking of 2,3‐diphosphoglycerate (2,3‐DPG), allosteric effector of Hb and non‐penetrating anion in RBCs, reports on erythrocytes internal environment. 31 P resonances of 2,3‐DPG are pH‐sensitive, their positions indicate the oxygenation state of RBCs and interactions with effectors such as ITPP. Here we show in vitro and in vivo, that modifying Hb activity through band‐3 anion transporter, ITPP enhances oxygen release and controls RBC internal pH. Its blood availability validates applicability of ITPP‐based strategies.

In starfish, the addition of the hormone 1-methyladenine (1-MA) to immature oocytes (germinal vesicle, GV-stage) arrested at the prophase of the first meiotic division induces meiosis resumption (maturation), which makes the mature eggs able to respond to the sperm with a normal fertilization response. The optimal fertilizability achieved during the maturation process results from the exquisite structural reorganization of the actin cytoskeleton in the cortex and cytoplasm induced by the maturing hormone. In this report, we have investigated the influence of acidic and alkaline seawater on the structure of the cortical F-actin network of immature oocytes of the starfish (Astropecten aranciacus) and its dynamic changes upon insemination. The results have shown that the altered seawater pH strongly affected the sperm-induced Ca[sup.2+] response and the polyspermy rate. When immature starfish oocytes were stimulated with 1-MA in acidic or alkaline seawater, the maturation process displayed a strong dependency on pH in terms of the dynamic structural changes of the cortical F-actin. The resulting alteration of the actin cytoskeleton, in turn, affected the pattern of Ca[sup.2+] signals at fertilization and sperm penetration.

In starfish, the addition of the hormone 1-methyladenine (1-MA) to immature oocytes (germinal vesicle, GV-stage) arrested at the prophase of the first meiotic division induces meiosis resumption (maturation), which makes the mature eggs able to respond to the sperm with a normal fertilization response. The optimal fertilizability achieved during the maturation process results from the exquisite structural reorganization of the actin cytoskeleton in the cortex and cytoplasm induced by the maturing hormone. In this report, we have investigated the influence of acidic and alkaline seawater on the structure of the cortical F-actin network of immature oocytes of the starfish (Astropecten aranciacus) and its dynamic changes upon insemination. The results have shown that the altered seawater pH strongly affected the sperm-induced Ca2+ response and the polyspermy rate. When immature starfish oocytes were stimulated with 1-MA in acidic or alkaline seawater, the maturation process displayed a strong dependency on pH in terms of the dynamic structural changes of the cortical F-actin. The resulting alteration of the actin cytoskeleton, in turn, affected the pattern of Ca2+ signals at fertilization and sperm penetration.

In starfish, the addition of the hormone 1-methyladenine (1-MA) to immature oocytes (germinal vesicle, GV-stage) arrested at the prophase of the first meiotic division induces meiosis resumption (maturation), which makes the mature eggs able to respond to the sperm with a normal fertilization response. The optimal fertilizability achieved during the maturation process results from the exquisite structural reorganization of the actin cytoskeleton in the cortex and cytoplasm induced by the maturing hormone. In this report, we have investigated the influence of acidic and alkaline seawater on the structure of the cortical F-actin network of immature oocytes of the starfish ( ) and its dynamic changes upon insemination. The results have shown that the altered seawater pH strongly affected the sperm-induced Ca response and the polyspermy rate. When immature starfish oocytes were stimulated with 1-MA in acidic or alkaline seawater, the maturation process displayed a strong dependency on pH in terms of the dynamic structural changes of the cortical F-actin. The resulting alteration of the actin cytoskeleton, in turn, affected the pattern of Ca signals at fertilization and sperm penetration.

Epigenetic diseases can be produced by a stable alteration, called an epimutation, in DNA methylation, in which epigenome alterations are directly involved in the underlying molecular mechanisms of the disease. This review focuses on the epigenetics of two inherited metabolic diseases, epi-cblC, an inherited metabolic disorder of cobalamin (vitamin B12) metabolism, and alpha-thalassemia type α-ZF, an inherited disorder of α2-globin synthesis, with a particular interest in the role of aberrant antisense transcription of flanking genes in the generation of epimutations in CpG islands of gene promoters. In both disorders, the epimutation is triggered by an aberrant antisense transcription through the promoter, which produces an H3K36me3 histone mark involved in the recruitment of DNA methyltransferases. It results from diverse genetic alterations. In alpha-thalassemia type α-ZF, a deletion removes HBA1 and HBQ1 genes and juxtaposes the antisense LUC7L gene to the HBA2 gene. In epi-cblC, the epimutation in the MMACHC promoter is produced by mutations in the antisense flanking gene PRDX1, which induces a prolonged antisense transcription through the MMACHC promoter. The presence of the epimutation in sperm, its transgenerational inheritance via the mutated PRDX1, and the high expression of PRDX1 in spermatogonia but its nearly undetectable transcription in spermatids and spermatocytes, suggest that the epimutation could be maintained during germline reprogramming and despite removal of aberrant transcription. The epivariation seen in the MMACHC promoter (0.95 × 10–3) is highly frequent compared to epivariations affecting other genes of the Online Catalog of Human Genes and Genetic Disorders in an epigenome-wide dataset of 23,116 individuals. This and the comparison of epigrams of two monozygotic twins suggest that the aberrant transcription could also be influenced by post-zygotic environmental exposures.

BackgroundSubthalamic nucleus deep brain stimulation (STN-DBS) improves motor symptoms of Parkinson's disease, leading to improvement in health-related quality of life (HRQoL). However, an excessive decrease in dopaminergic medication can lead to a withdrawal syndrome with apathy as the predominant feature. The present study aims to assess the impact of postoperative apathy on HRQoL.MethodsA cohort of 88 patients who underwent STN-DBS was divided into two groups, those who were apathetic at 1 year and those who were not, as measured by the Starkstein scale. HRQoL was assessed using the Parkinson's disease questionnaire 39 (PDQ-39) and was compared between the two groups. We also compared activities of daily living, motor improvement and motor complications (Unified Parkinson's Disease Rating Scale, UPDRS), depression and anxiety, as well as cognition and drug dosages. Baseline characteristics and postoperative complications were recorded.ResultsOne year after surgery, 27.1% of patients suffered from apathy. While motor improvement was significant and equivalent in both the apathy (−40.4% of UPDRS motor score) and non-apathy groups (−48.6%), the PDQ-39 score did not improve in the apathy group (−5.5%; p=0.464), whereas it improved significantly (−36.7%; p≤0.001) in the non-apathy group. Change in apathy scores correlated significantly with change in HRQoL scores (r=0.278, p=0.009). Depression and anxiety scores remained unchanged from baseline in the apathy group (p=0.409, p=0.075), while they improved significantly in patients without apathy (p=0.006, p≤0.001). A significant correlation was found between changes in apathy and depression (r=0.594, p≤0.001).ConclusionsThe development of apathy after STN-DBS can cancel out the benefits of motor improvement in terms of HRQoL. Systematic evaluation and management of apathy occurring after subthalamic stimulation appears mandatory.

Patients and methods In order to investigate the effects of exposure to buprenorphine compared with methadone during pregnancy, a prospective multicenter study was conducted in collaboration with maternity hospitals, maintenance therapy centers, and general practitioners involved in addiction care. Ninety pregnant women exposed to buprenorphine and 45 to metadone were selected for the study. Results During pregnancy, some women were exposed to illicit agents: cannabis (42% in the buprenorphine group vs. 58% in the methadone-treated group), heroin (17% vs. 44%), or cocaine (3% vs. 11%). Pregnancies ended in 85 vs. 40 live births, one vs. two stillbirths, two vs. one spontaneous abortion, two vs. one voluntary termination, and one vs. one medical termination in the buprenorphine and the methadone groups, respectively. Newborns had a birth weight of 2,892 ± 506 g (buprenorphine) vs. 2,731 ± 634 g (methadone) and a body length of 47.6 ± 2.5 cm vs. 47.1 ± 3 cm. 18.8% vs. 10% of newborns were delivered before 37 weeks of amenorrhea. Neonatal withdrawal syndrome occurred more frequently in the methadone group (62.5% vs. 41.2, p  = 0.03). After adjustment for heroin exposure in late pregnancy, rates of neonatal withdrawal were no longer different between the methadone and buprenorphine groups. Twenty-one babies (84%) in the methadone group and 20 (57%) in the buprenorphine group ( p  = 0.03) required opiate treatment. Conclusions We did not observe more frequent malformations or cases of withdrawal syndrome in the buprenorphine group than in the methadone-treated group. Buprenorphine appears to be as safe as the currently approved substitute methadone considered to date as the reference treatment for pregnant opioid-dependent women.