Sulphated Polysaccharides and the Differentiation of the Cellular Slime Mould Dictyostelium Discoideum

SUMMARYCell surface and endocellular polysaccharides of growing and differentiated Dictyostelium discoideum have been isolated and characterized with electrophoretic and chromatographyc procedures.The mould exhibit a very eterogeneous family of sulphated polysaccharides which are externalized during the differentiation.The possible role of cell surface polysaccharides in the differentiation process is discussed

Epigenetic approaches and methods in developmental toxicology : role of HDAC inhibition in teratogenic events

The relevance of histone acetylation/deacetylation in regulating decompaction/compaction of chromatin and, consequently, in regulating gene expression, has been described for many physiological and pathological biological processes, including normal and altered embryo development. Similarly to other biological systems, also in embryo cells the acetylation status is controlled by the antagonist activity of histone acetyl transferases (HATs) and histone deacetylases (HDACs) and is influenced by other factors acting on chromatin structure (i.e., every epigenetic modification of chromatin). The relevance of acetylation during development has been demonstrated in all developmental phases, from gametogenesis to zygote formation and during early and late embryonic stages. Moreover, the increase number of xenobiotic showing HDAC inhibitory activity recently focused the attention of teratologists on the possible role of HDAC inhibition as a novel teratogenic mechanism. This hypothesis has been demonstrated at least in embryos at somitogenic stages (for mouse embryos from stage E8 till stage E15): HDAC inhibition, histone hyperacetylation, increased cell death (apoptosis) has been suggested as the main event cascade involved in axial skeletal defects induced in rodent by a number of HDAC inhibitors, including the antiepileptic drug valproic acid

Boric acid inhibits embryonic histone deacetylases: a suggested mechanism to explain boric acid-related teratogenicity

Histone deacetylases (HDAC) control gene expression by changing histonic as well as non histonic protein conformation. HDAC inhibitors (HDACi) are considered to be among the most promising drugs for epigenetic treatment for cancer. Recently a strict relationship between histone hyperacetylation in specific tissues of mouse embryos exposed to two HDACi (valproic acid and trichostatin A) and specific axial skeleton malformations has been demonstrated. The aim of this study is to verify if boric acid (BA), that induces in rodents malformations similar to those valproic acid and trichostatinA-related, acts through similar mechanisms: HDAC inhibition and histone hyperacetylation. Pregnant mice were treated intraperitoneally with a teratogenic dose of BA (1000 mg/kg, day 8 of gestation). Western blot analysis and immunostaining were performed with anti hyperacetylated histone 4 (H4) antibody on embryos explanted 1, 3 or 4 hours after treatment and revealed H4 hyperacetylation at the level of somites. HDAC enzyme assay was performed on embryonic nuclear extracts. A significant HDAC inhibition activity (compatible with a mixed type partial inhibition mechanism) was evident with BA. Kinetic analyses indicate that BA modifies substrate affinity by a factor \uf061=0.51 and maximum velocity by a factor \uf062 = 0.70. This work provides the first evidence for HDAC inhibition by BA and suggests such a molecular mechanism for the induction of BA-related malformations

The inhibition of embryonic histone deacetylases as the possible mechanism accounting for axial skeletal malformations induced by Sodium Salicylate

In spite of the large use of salicylates, introduced into clinical practice more than 100 years ago, their anti-inflammatory and cancer preventive mechanisms are still under study. Teratogenic effects of salicylates have been reported in experimental animals since 1959 but the pathogenic pathways and the mechanisms of action were never described until now. The aim of this work is to verify if the inhibition of embryonic histone deacetylase (HDAC) enzymes and the consequent tissue hyperacetylation could be the mechanism responsible for axial skeletal defects described after the exposure of pregnant rodents to sodium salicylate (SAL). E8 pregnant CD-1 mice were intraperitoneally treated with SAL 0-150-300-450 mg/kg and sacrificed at 1, 3, 5 hrs after treatment or at term of gestation (E18). E8 embryos were processed for Western blotting and immunostaining analyses, while skeletons of E18 fetuses were double stained for bone and cartilage. A group of control E8 embryos were used to prepare embryonic nuclear extract for the HDAC enzyme assay. A significant SAL dose-related HDAC inhibition activity, compatible with a mixed type partial inhibition mechanism, was detected. A clear dose-related hyperacetylation of histones was observed in embryos exposed in utero to SAL, with a peak at 3 hrs after treatment of dams. The most hyperacetylated organs were somites and the heart. Histone hyperacetylation is suggested to be the mechanism accounting for SAL-related axial skeletal and cardiovascular defects and is proposed as the mechanism responsible for other biological effects of salicylates

Sulphated Polysaccharides and the Differentiation of the Cellular Slime Mould Dictyostelium Discoideum

SUMMARYCell surface and endocellular polysaccharides of growing and differentiated Dictyostelium discoideum have been isolated and characterized with electrophoretic and chromatographyc procedures.The mould exhibit a very eterogeneous family of sulphated polysaccharides which are externalized during the differentiation.The possible role of cell surface polysaccharides in the differentiation process is discussed

Symptoms of anxiety and depression and family's quality of life in children and adolescents with epilepsy

Introduction We studied children and adolescents with epilepsy (CAWE) and their families to evaluate symptoms of anxiety and depression, quality of life (QoL), and their correlations with epilepsy characteristics. Material and methods The study included 326 (52.5% females) 8 to 18 years old CAWE. Anxiety and depression were assessed with the â\u80\u9cSelf-administered psychiatric scales for children and adolescentsâ\u80\u9d (SAFA), and family's QoL with the parentsâ\u80\u99 report â\u80\u9cImpact of Epilepsy on QoLâ\u80\u9d (IEQoL). Results The CAWE exhibiting abnormal (T â\u89¥ 70) scores were 8.0% in the anxiety scale, 9.2% in the depression scale, and 4.6% in both scales. Social anxiety was the predominant anxiety symptom, while irritable mood and desperation were the most frequent symptoms of depression. Depressive symptoms were associated with parentsâ\u80\u99 complaint of higher worries about the child's condition and future and lower well-being of the family. Severity and duration of the epilepsy and polypharmacy were independent from abnormal scores of anxiety and depression, but were associated with parentsâ\u80\u99 worries about the child's condition and family's well-being. Conclusions Anxiety and depression in CAWE are independent from the characteristics of the disease but are correlated to the lower well-being of the family. A search of these emotional problems is recommended for better care of the patients and their families

A next-generation GMMA-based vaccine candidate to fight shigellosis

Abstract Shigellosis is a leading cause of diarrheal disease in low-middle-income countries (LMICs). Effective vaccines will help to reduce the disease burden, exacerbated by increasing antibiotic resistance, in the most susceptible population represented by young children. A challenge for a broadly protective vaccine against shigellosis is to cover the most epidemiologically relevant serotypes among >50 Shigella serotypes circulating worldwide. The GMMA platform has been proposed as an innovative delivery system for Shigella O-antigens, and we have developed a 4-component vaccine against S. sonnei, S. flexneri 1b, 2a and 3a identified among the most prevalent Shigella serotypes in LMICs. Driven by the immunogenicity results obtained in clinic with a first-generation mono-component vaccine, a new S. sonnei GMMA construct was generated and combined with three S. flexneri GMMA in a 4-component Alhydrogel formulation (altSonflex1-2-3). This formulation was highly immunogenic, with no evidence of negative antigenic interference in mice and rabbits. The vaccine induced bactericidal antibodies also against heterologous Shigella strains carrying O-antigens different from those included in the vaccine. The Monocyte Activation Test used to evaluate the potential reactogenicity of the vaccine formulation revealed no differences compared to the S. sonnei mono-component vaccine, shown to be safe in several clinical trials in adults. A GLP toxicology study in rabbits confirmed that the vaccine was well tolerated. The preclinical study results support the clinical evaluation of altSonflex1-2-3 in healthy populations, and a phase 1–2 clinical trial is currently ongoing

Multicenter prospective longitudinal study in 34 patients with Dravet syndrome: Neuropsychological development in the first six years of life

The objective of this study was to identify developmental trajectories of developmental/behavioral phenotypes and possibly their relationship to epilepsy and genotype by analyzing developmental and behavioral features collected prospectively and longitudinally in a cohort of patients with Dravet syndrome (DS).Thirty-four patients from seven Italian tertiary pediatric neurology centers were enrolled in the study. All patients were examined for the SCN1A gene mutation and prospectively assessed from the first years of life with repeated full clinical observations including neurological and developmental examinations. Subjects were found to follow three neurodevelopmental trajectories. In the first group (16 patients), an initial and usually mild decline was observed between the second and the third year of life, specifically concerning visuomotor abilities, later progressing towards global involvement of all abilities. The second group (12 patients) showed an earlier onset of global developmental impairment, progressing towards a generally worse outcome. The third group of only two patients ended up with a normal neurodevelopmental quotient, but with behavioral and linguistic problems. The remaining four patients were not classifiable due to a lack of critical assessments just before developmental decline.The neurodevelopmental trajectories described in this study suggest a differential contribution of neurobiological and genetic factors. The profile of the first group, which included the largest fraction of patients, suggests that in the initial phase of the disease, visuomotor defects might play a major role in determining developmental decline.Early diagnosis of milder cases with initial visuomotor impairment may therefore provide new tools for a more accurate habilitation strategy. (c) 2020 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved