DNA Microspheres Coated with Bioavailable Polymer as an Efficient Gene Expression Agent in Yeasts

Gene delivery is one of the steps necessary for gene therapy and for genetic modification. However, delivering DNA into cells is challenging due to its negative charge that leads to repulsion by the negative cell membrane. In the current research, DNA spheres with a DNA encoding to a certain gene were coated with bioavailable polymers, polyethylene imine (PEI) and polycaprolactone (PCL), in a short, one-step sonochemical reaction. The polymers were used in order to neutralize the negative charge of the DNA. Our study shows that the DNA nanospheres not only managed to penetrate the cell without causing it any damage, but also expressed the desired gene inside it

Extracellular Vesicle Characteristics in β-thalassemia as Potential Biomarkers for Spleen Functional Status and Ineffective Erythropoiesis

β-thalassemia major (β-TM) is a therapeutically challenging chronic disease in which ineffective erythropoiesis is a main pathophysiological factor. Extracellular vesicles (EVs) are membrane-enclosed vesicles released by cells into biological fluids; they are involved in intercellular communication and in multiple physiological and pathological processes. The chaperone heat-shock protein 70 (HSP70), which is released from cells via EVs, aggravates ineffective erythropoiesis in β-TM. We propose that β-TM EVs may show specific signatures, reflecting disease mechanisms, stages and severity. Our study aims were to define EV profiles in β-TM patients, investigate the influence of hypersplenism and splenectomy on EV features, and explore the association of circulating EVs with ineffective erythropoiesis and iron-overload parameters. We characterized circulating EVs in 35 transfusion-dependent β-thalassemia patients and 35 controls using several techniques. Nanoparticle-tracking analysis revealed increased EV concentration in patients vs. controls (P = 0.0036), with smaller EV counts and sizes in patients with hypersplenism. Flow cytometry analysis showed lower levels of RBC and monocyte EVs in patients vs. controls. RBC-EV levels correlated with patient hematocrit, reflecting degree of anemia. The procoagulant potential of the EVs evaluated by flow cytometry revealed lower levels of endothelial protein C receptor-labeled EVs in patients vs. controls, and increased tissue factor-to-tissue factor pathway inhibitor-labeled EV ratio in splenectomized patients, suggesting a hypercoagulable state. Protein content, evaluated in EV pellets, showed increased levels of HSP70 in patients (P = 0.0018), inversely correlated with transfusion requirement and hemoglobin levels, and positively correlated with reticulocyte, erythropoietin and lactate dehydrogenase levels. This first description of EVs in patients with hypersplenism reveals the spleen’s importance in EV physiology and clearance. Circulating EV-HSP70 levels were associated with markers of ineffective erythropoiesis, hemolysis and hematological disease severity. EV analysis in β-TM—reflecting spleen status, hypercoagulability state and ineffective erythropoiesis—may serve as a biomarker of disease dynamics, supporting both anticipation of the risk of complications and optimizing treatment

p45 NF-E2 regulates syncytiotrophoblast differentiation by post-translational GCM1 modifications in human intrauterine growth restriction

AbstractPlacental insufficiency jeopardizes prenatal development, potentially leading to intrauterine growth restriction (IUGR) and stillbirth. Surviving fetuses are at an increased risk for chronic diseases later in life. IUGR is closely linked with altered trophoblast and placental differentiation. However, due to a paucity of mechanistic insights, suitable biomarkers and specific therapies for IUGR are lacking. The transcription factor p45 NF-E2 (nuclear factor erythroid derived 2) has been recently found to regulate trophoblast differentiation in mice. The absence of p45 NF-E2 in trophoblast cells causes IUGR and placental insufficiency in mice, but mechanistic insights are incomplete and the relevance of p45 NF-E2 for human syncytiotrophoblast differentiation remains unknown. Here we show that p45 NF-E2 negatively regulates human syncytiotrophoblast differentiation and is associated with IUGR in humans. Expression of p45 NF-E2 is reduced in human placentae complicated with IUGR compared with healthy controls. Reduced p45 NF-E2 expression is associated with increased syncytiotrophoblast differentiation, enhanced glial cells missing-1 (GCM1) acetylation and GCM1 desumoylation in IUGR placentae. Induction of syncytiotrophoblast differentiation in BeWo and primary villous trophoblast cells with 8-bromo-adenosine 3′,5′-cyclic monophosphate (8-Br-cAMP) reduces p45 NF-E2 expression. Of note, p45 NF-E2 knockdown is sufficient to increase syncytiotrophoblast differentiation and GCM1 expression. Loss of p45 NF-E2 using either approach resulted in CBP-mediated GCM1 acetylation and SENP-mediated GCM1 desumoylation, demonstrating that p45 NF-E2 regulates post-translational modifications of GCM1. Functionally, reduced p45 NF-E2 expression is associated with increased cell death and caspase-3 activation in vitro and in placental tissues samples. Overexpression of p45 NF-E2 is sufficient to repress GCM1 expression, acetylation and desumoylation, even in 8-Br-cAMP exposed BeWo cells. These results suggest that p45 NF-E2 negatively regulates differentiation and apoptosis activation of human syncytiotrophoblast by modulating GCM1 acetylation and sumoylation. These studies identify a new pathomechanism related to IUGR in humans and thus provide new impetus for future studies aiming to identify new biomarkers and/or therapies of IUGR.</jats:p

Parents&rsquo; Adherence to Childhood Screening Tests and Referrals: A Retrospective Cohort Study with Randomized Sampling

Routine timely examinations of well-child health are important for achieving children&rsquo;s good health outcomes. Nevertheless, there is evidence of low compliance with well-child visit recommendations. The aim of the study was to examine potential factors associated with parents&rsquo; nonadherence to routine childhood screening tests and their acting on further referrals following unusual findings. A retrospective cohort study was conducted among 14,348 children born in 2016&ndash;2017 and registered at mother&ndash;child health clinics in a large city in Israel. A sample of 844 children was randomly selected. Screening tests at the age of two months and nine months were examined. A multiple logistic regression examined potential factors associated with nonadherence to screening tests and to further referral for evaluation. Lower adherence to screening tests was found among parents of nine-month-old children, but adherence was higher for nurses&rsquo; screening tests than for those of physicians. Children born in a complex delivery process, older mothers with a higher number of children, and Israeli citizens were at risk of not undergoing screening tests. Fewer children in the family and initial physician&rsquo;s findings were the only explanation for acting to referrals. In order to promote children&rsquo;s health outcomes and public health, health policymakers should conduct campaigns to convince parents of the importance of screening tests and of adherence to referrals with the aim of ensuring their children&rsquo;s wellbeing throughout the life cycle

International telecommunications as international movement : The case of Israel, 1951-88

International telecommunications involve the transmission of economic, social, institutional and produced information, all of which have demand, flow, interaction and exchange aspects. International telecommunications is assumed to depend on other international movements, namely commoities, people and capital. The case of Israel is examined inlight of this assumption. Annual growth in Israeli international telecommunications is best explained by two-year lagged exports for 1975-87. Exports have also been found to be the leading variable for the 1980s, when annual examinations were performed for the most frequently called/calling countries every year. Most of Israel's international messages are exchanged with North America and Europe, with the USA leading. Separate trend analyses for nine leading countries did not produce decisive results in terms of the levels of explanation or the leading variables.

Coagulation and placenta-mediated complications

Pregnancy is a physiological hypercoagulable state, preparing the mother for the hemostatic challenge of delivery. However, this is associated with an increased risk of venous thrombosis and placenta-mediated complications, which present major challenges for mother and fetus. Although these conditions are heterogeneous in their pathophysiology, hereditary and acquired thrombophilia has been associated with recurrent pregnancy loss and gestational vascular complications, such as early-onset pre-eclampsia and placental abruption. Prevention of such placenta-mediated complications, which collectively complicate up to 15% of pregnancies, is a major issue for women’s health. Prospective interventional studies stratified by current knowledge of pathophysiological mechanisms related to placental and systemic hemostatic alterations will impact on the management of pregnancies at risk of these complications