A neuronal enhancer network upstream of MEF2C is compromised in patients with Rett-like characteristics

Mutations in myocyte enhancer factor 2C (MEF2C), an important transcription factor in neurodevelopment, are associated with a Rett-like syndrome. Structural variants (SVs) upstream of MEF2C, which do not disrupt the gene itself, have also been found in patients with a similar phenotype, suggesting that disruption of MEF2C regulatory elements can also cause a Rett-like phenotype. To characterize those elements that regulate MEF2C during neural development and that are affected by these SVs, we used genomic tools coupled with both in vitro and in vivo functional assays. Through circularized chromosome conformation capture sequencing (4C-seq) and the assay for transposase-accessible chromatin using sequencing (ATAC-seq), we revealed a complex interaction network in which the MEF2C promoter physically contacts several distal enhancers that are deleted or translocated by disease-associated SVs. A total of 16 selected candidate regulatory sequences were tested for enhancer activity in vitro, with 14 found to be functional enhancers. Further analyses of their in vivo activity in zebrafish showed that each of these enhancers has a distinct activity pattern during development, with eight enhancers displaying neuronal activity. In summary, our results disentangle a complex regulatory network governing neuronal MEF2C expression that involves multiple distal enhancers. In addition, the characterized neuronal enhancers pose as novel candidates to screen for mutations in neurodevelopmental disorders, such as Rett-like syndrome

Perinatal Outcomes of Small for Gestational Age Neonates Born With an Isolated Single Umbilical Artery

Objective: To investigate pregnancy outcomes of small for gestational age (SGA) neonates born with isolated single umbilical artery (iSUA) compared to SGA neonates without iSUA.Study Design: This was a population-based retrospective cohort analysis. The study group was defined as a singleton SGA neonate born with iSUA, while an SGA neonate without iSUA comprised the comparison group. We evaluated adverse perinatal outcomes in all SGA neonates born at the Soroka University Medical Center between the years 1998–2013. Multiple gestations, fetuses with known congenital malformations or chromosomal abnormalities and patients with lack of prenatal care were excluded from the study. Multivariate logistic regression models were constructed to identify independent factors associated with adverse perinatal outcomes.Results: Of 12,915 SGA deliveries, 1.2% (162) were complicated with iSUA. Women in the study group were older with a significantly lower gestational age at delivery compared with the comparison group. Rates of women who conceived after infertility treatments were higher in the study group. Additionally, patients in the study group had significantly higher rates of preterm deliveries, placental abruption, cord prolapse, non-reassuring fetal heart rates and cesarean delivery were noted in the study group. These neonates had a significantly lower birth weight (1988.0 ± 697 vs. 2388.3 ± 481 p < 0.001) and higher rates of low APGAR scores at the first and fifth minutes after birth compared with controls. Perinatal mortality was also found to be significantly higher among SGA neonates complicated with iSUA. Preterm delivery as well as perinatal mortality were found independently associated with iSUA among SGA neonates (aOR 4.01, 95% CI 2.88–5.59, aOR 2.24, 95% CI 1.25–4.01, respectively).Conclusion: SGA pregnancies complicated with iSUA are at higher risk for adverse pregnancy and perinatal outcomes as compared to SGA pregnancies without iSUA

ВЛИЯНИЕ КОНСТРУКТИВНО-ТЕХНОЛОГИЧЕСКИХ ДЕФЕКТОВ НА ПРОЧНОСТЬ АРМАТУРНЫХ СТЕРЖНЕЙ

The paper contains calculation on durability of a reinforcement bars with a constructive and technological defect. The factors determining constructive and technological durability of reinforcing bars have been investigated in the paper. The paper demonstrates classification of reinforcement bar parts in accordance with danger of constructive and technological influences.  Выполнен расчет на прочность арматурного стержня с конструктивно-технологическим дефектом. Рассмотрены факторы, определяющие конструктивно-технологическую прочность арматурного проката. Приведена классификация участков арматурного стержня по опасности конструктивно-технологических воздействий

A Differential Effect of E. coli Toxin-Antitoxin Systems on Cell Death in Liquid Media and Biofilm Formation

Toxin-antitoxin (TA) modules are gene pairs specifying for a toxin and its antitoxin and are found on the chromosomes of many bacteria including pathogens. Here we report how each of five such TA systems in E. coli affect bacterial cell death differently in liquid media and during biofilm formation. Of all these systems, only the TA system mazEF mediated cell death both in liquid media and during biofilm formation. At the other extreme, as our results have revealed here, the TA system dinJ-YafQ is unique in that it is involved only in the death process during biofilm formation. Cell death governed by mazEF and dinJ-YafQ seems to participate in biofilm formation through a novel mechanism

Surface state atoms and their contribution to the surface tension of quantum liquids

We investigate the new type of excitations on the surface of liquid helium. These excitations, called surfons, appear because helium atoms have discrete energy level at the liquid surface, being attracted to the surface by the van der Waals force and repulsed at a hard-core interatomic distance. The concentration of the surfons increases with temperature. The surfons propagate along the surface and form a two-dimensional gas. Basing on the simple model of the surfon microscopic structure, we estimate the surfon activation energy and effective mass for both helium isotopes. We also calculate the contribution of the surfons to the temperature dependence of the surface tension. This contribution explains the great and long-standing discrepancy between theory and experiment on this temperature dependence in both helium isotopes. The achieved agreement between our theory and experiment is extremely high. The comparison with experiment allows to extract the surfon activation energy and effective mass. The values of these surfon microscopic parameters are in a reasonable agreement with the calculated from the proposed simple model of surfon structure.Comment: 10 pages, 6 figure

Avpr1a variant associated with preschoolers' lower altruistic behavior

10.1371/journal.pone.0025274PLoS ONE69

‘Multi-Epitope-Targeted’ Immune-Specific Therapy for a Multiple Sclerosis-Like Disease via Engineered Multi-Epitope Protein Is Superior to Peptides

Antigen-induced peripheral tolerance is potentially one of the most efficient and specific therapeutic approaches for autoimmune diseases. Although highly effective in animal models, antigen-based strategies have not yet been translated into practicable human therapy, and several clinical trials using a single antigen or peptidic-epitope in multiple sclerosis (MS) yielded disappointing results. In these clinical trials, however, the apparent complexity and dynamics of the pathogenic autoimmunity associated with MS, which result from the multiplicity of potential target antigens and “epitope spread”, have not been sufficiently considered. Thus, targeting pathogenic T-cells reactive against a single antigen/epitope is unlikely to be sufficient; to be effective, immunospecific therapy to MS should logically neutralize concomitantly T-cells reactive against as many major target antigens/epitopes as possible. We investigated such “multi-epitope-targeting” approach in murine experimental autoimmune encephalomyelitis (EAE) associated with a single (“classical”) or multiple (“complex”) anti-myelin autoreactivities, using cocktail of different encephalitogenic peptides vis-a-vis artificial multi-epitope-protein (designated Y-MSPc) encompassing rationally selected MS-relevant epitopes of five major myelin antigens, as “multi-epitope-targeting” agents. Y-MSPc was superior to peptide(s) in concomitantly downregulating pathogenic T-cells reactive against multiple myelin antigens/epitopes, via inducing more effective, longer lasting peripheral regulatory mechanisms (cytokine shift, anergy, and Foxp3+ CTLA4+ regulatory T-cells). Y-MSPc was also consistently more effective than the disease-inducing single peptide or peptide cocktail, not only in suppressing the development of “classical” or “complex EAE” or ameliorating ongoing disease, but most importantly, in reversing chronic EAE. Overall, our data emphasize that a “multi-epitope-targeting” strategy is required for effective immune-specific therapy of organ-specific autoimmune diseases associated with complex and dynamic pathogenic autoimmunity, such as MS; our data further demonstrate that the “multi-epitope-targeting” approach to therapy is optimized through specifically designed multi-epitope-proteins, rather than myelin peptide cocktails, as “multi-epitope-targeting” agents. Such artificial multi-epitope proteins can be tailored to other organ-specific autoimmune diseases

Flower palate ultrastructure of the carnivorous plant Genlisea hispidula Stapf with remarks on the structure and function of the palate in the subgenus Genlisea (Lentibulariaceae)

In the genus Genlisea as well as in its sister genus Utricularia, the palate probably plays a key role in providing the colour, mechanical and olfactory stimuli to attract insect pollinators and to guide them to the generative structures and the nectary spur. However, information about the micro-morphology of the palate of Genlisea is scarce. This study aims to examine the structure of the palate in Genlisea hispidula in detail as well as the palate from other five species from the subgenus Genlisea. In particular, its aim is to ascertain whether these palates function as an area for the osmophores in the flower or whether they produce nectar. We showed that the palate in all of the species that were examined was the glandular type and that it had capitate, glandular trichomes, which had a similar general architecture across the species that were examined. No nectar secretion was observed on the palates. The ultrastructure of the palate trichomes showed that the palate glandular trichomes most probably function as scent glands that produce an olfactory stimulus for flower pollinators

Genetic Variants For Head Size Share Genes and Pathways With Cancer

The size of the human head is highly heritable, but genetic drivers of its variation within the general population remain unmapped. We perform a genome-wide association study on head size (N = 80,890) and identify 67 genetic loci, of which 50 are novel. Neuroimaging studies show that 17 variants affect specific brain areas, but most have widespread effects. Gene set enrichment is observed for various cancers and the p53, Wnt, and ErbB signaling pathways. Genes harboring lead variants are enriched for macrocephaly syndrome genes (37-fold) and high-fidelity cancer genes (9-fold), which is not seen for human height variants. Head size variants are also near genes preferentially expressed in intermediate progenitor cells, neural cells linked to evolutionary brain expansion. Our results indicate that genes regulating early brain and cranial growth incline to neoplasia later in life, irrespective of height. This warrants investigation of clinical implications of the link between head size and cancer

Physiological Correlates of Volunteering

We review research on physiological correlates of volunteering, a neglected but promising research field. Some of these correlates seem to be causal factors influencing volunteering. Volunteers tend to have better physical health, both self-reported and expert-assessed, better mental health, and perform better on cognitive tasks. Research thus far has rarely examined neurological, neurochemical, hormonal, and genetic correlates of volunteering to any significant extent, especially controlling for other factors as potential confounds. Evolutionary theory and behavioral genetic research suggest the importance of such physiological factors in humans. Basically, many aspects of social relationships and social activities have effects on health (e.g., Newman and Roberts 2013; Uchino 2004), as the widely used biopsychosocial (BPS) model suggests (Institute of Medicine 2001). Studies of formal volunteering (FV), charitable giving, and altruistic behavior suggest that physiological characteristics are related to volunteering, including specific genes (such as oxytocin receptor [OXTR] genes, Arginine vasopressin receptor [AVPR] genes, dopamine D4 receptor [DRD4] genes, and 5-HTTLPR). We recommend that future research on physiological factors be extended to non-Western populations, focusing specifically on volunteering, and differentiating between different forms and types of volunteering and civic participation