Inositols in Insulin Signaling and Glucose Metabolism

In the past decades, both the importance of inositol for human health and the complex interaction between glucose and inositol have been the subject of increasing consideration. Glucose has been shown to interfere with cellular transmembrane transport of inositol, inhibiting, among others, its intestinal absorption. Moreover, intracellular glucose is required for de novo biosynthesis of inositol through the inositol-3-phosphate synthase 1 pathway, while a few glucose-related metabolites, like sorbitol, reduce intracellular levels of inositol. Furthermore, inositol, via its major isomers myo-inositol and D-chiro-inositol, and probably some of its phosphate intermediate metabolites and correlated enzymes (like inositol hexakisphosphate kinase) participate in both insulin signaling and glucose metabolism by influencing distinct pathways. Indeed, clinical data support the beneficial effects exerted by inositol by reducing glycaemia levels and hyperinsulinemia and buffering negative effects of sustained insulin stimulation upon the adipose tissue and the endocrine system. Due to these multiple effects, myoIns has become a reliable treatment option, as opposed to hormonal stimulation, for insulin-resistant PCOS patients

Does the catechol-O-methyltransferase (COMT) Val158Met human polymorphism in influence procrastination?

Genetic studies are enlightening how the expression of several genes influences neuronal activity and all facets of human normal and abnormal behaviour. Among these, a growing body of information shows that a few key genes regulating activity of central neurotransmitters have specific roles in cognitive and/or emotional processes, as ‘procrastination’. We investigated the association of the 5-HTTLPR and COMT Val158Met polymorphisms with students’ procrastination in an academic writing task. Results: showed no relationship between procrastination and the 5-HTT polymorphism but they revealed an association with the COMT Val158Met one. Particularly, the presence of the Met158 allele was found to be significantly associated with the tendency to initiate and complete the assigned task. We hypothesize that the role of central monoamines and of dopamine already identified in impulsive behaviour, extends to procrastination. Since the 158Met allele provides neurons with significantly higher basal dopamine levels when compared to the 158Val allele, our observation suggests that under normal conditions the 158Met allele provides carriers with increased inhibitory control, resulting in an increased tendency to adhere to a planned schedule and therefore reducing procrastination. On the other hand, the Val158 allele may result more effective in increasing carriers’ performances under stress conditions, namely when the schedule deadline is approaching, and dopamine release is increased. This would result in a higher tendency to procrastinate. This hypothesis can readily be tested by applying the experimental approach here employed to various samples of subjects belonging to different categories and extending the analysis to other putative neuron-expressed gene

Stage-Specific Regulation of Murine Hsp68 Gene Promoter in Preimplantation Mouse Embryos

AbstractIn early mouse embryos, the major inducible heat shock gene, hsp68, is spontaneously and transiently activated at the two-cell stage and becomes heat-inducible around blastocyst stage. We have probed mouse embryo's ability to activate the promoter of this gene during preimplantation development by expression analysis of DNA constructs containing a reporter lacZ gene driven by hsp68 (hsp70A1) 5′-regulatory sequences of various length: (i) a full-length promoter (construct phsplacZ); (ii) a heat shock element (HSE)-deleted promoter (pΔ1hsplacZ); and (iii) a minimal, proximal promoter (pΔ2hsplacZ). When analyzed in transfected L-cells, phsplacZ was heat-inducible, while neither pΔ1hsplacZ nor pΔ2hsplacZ was. Developmental activity of the full-length construct was first analyzed after genome integration in transgenic embryos and found to follow endogenous hsp68 expression in terms of spontaneous activation at the 2-cell stage, down-regulation at the 4-cell stage, and acquisition of heat inducibility at the 16/32-cell stage. In transient expression experiments, injected phsplacZ, pΔ1hsplacZ, and pΔ2hsplacZ were expressed at similar levels by 2-cell embryos, independently of construct topology and injection stage. At the 4-cell stage, however, phsplacZ and pΔ1hsplacZ were expressed at similar levels, while pΔ2hsplacZ was inactive. Only phsplacZ became heat-inducible in late morulas. We conclude that in early mouse embryos, developmental activity of episomic hsp68 promoter depends on proximal sequences at the 2-cell stage and on putative enhancer sequences at the 4-cell stage, while HSEs appear dispensable during early cleavage

Involvement of Phospholipase C-gamma1 in Mouse Egg Activation Induced by a Truncated Form of the C-kit Tyrosine Kinase Present in Spermatozoa

Microinjection of a truncated form of the c-kit tyrosine kinase present in mouse spermatozoa (tr-kit) activates mouse eggs parthenogenetically, and tr-kit- induced egg activation is inhibited by preincubation with an inhibitor of phospholipase C (PLC) (Sette, C., A. Bevilacqua, A. Bianchini, F. Mangia, R. Geremia, and P. Rossi. 1997. Development [Camb.]. 124:2267-2274). Co-injection of glutathione-S-transferase (GST) fusion proteins containing the src-homology (SH) domains of the gamma1 isoform of PLC (PLCgamma1) competitively inhibits tr-kit- induced egg activation. A GST fusion protein containing the SH3 domain of PLCgamma1 inhibits egg activation as efficiently as the whole SH region, while a GST fusion protein containing the two SH2 domains is much less effective. A GST fusion protein containing the SH3 domain of the Grb2 adaptor protein does not inhibit tr-kit-induced egg activation, showing that the effect of the SH3 domain of PLCgamma1 is specific. Tr-kit-induced egg activation is also suppressed by co-injection of antibodies raised against the PLCgamma1 SH domains, but not against the PLCgamma1 COOH-terminal region. In transfected COS cells, coexpression of PLCgamma1 and tr-kit increases diacylglycerol and inositol phosphate production, and the phosphotyrosine content of PLCgamma1 with respect to cells expressing PLCgamma1 alone. These data indicate that tr-kit activates PLCgamma1, and that the SH3 domain of PLCgamma1 is essential for tr-kit-induced egg activation

Myo-Inositol Safety in Pregnancy: From Preimplantation Development to Newborn Animals

Myo-inositol (myo-Ins) has a physiological role in mammalian gametogenesis and embryonic development and a positive clinical impact on human medically assisted reproduction. We have previously shown that mouse embryo exposure to myo-Ins through preimplantation development in vitro increases proliferation activity and blastocyst production, representing an improvement in culture conditions. We have herein investigated biochemical mechanisms elicited by myo-Ins in preimplantation embryos and evaluated myo-Ins effects on postimplantation/postnatal development. To this end naturally fertilized embryos were cultured in vitro to blastocyst in the presence or absence of myo-Ins and analyzed for activation of the PKB/Akt pathway, known to modulate proliferation/survival cellular processes. In parallel, blastocyst-stage embryos were transferred into pseudopregnant females and allowed to develop to term and until weaning. Results obtained provide evidence that myo-Ins induces cellular pathways involving Akt and show that (a) exposure of preimplantation embryos to myo-Ins increases the number of blastocysts available for uterine transfer and of delivered animals and (b) the developmental patterns of mice obtained from embryos cultured in the presence or absence of myo-Ins, up to three weeks of age, overlap. These data further identify myo-Ins as a possibly important supplement for human preimplantation embryo culture in assisted reproduction technology

Prediction of functional outcome in young patients with a recent-onset psychiatric disorder: Beyond the traditional diagnostic classification system

A critical research goal is to identify modifiable risk factors leading to functional disabilities in young psychiatric patients. The authors developed a multidimensional trans-diagnostic predictive model of functional outcome in patients with the recent-onset of a psychiatric illness. Baseline clinical, psychosis-risk status, cognitive, neurological-soft-signs measures, and dopamine-related-gene polymorphisms (DRD1-rs4532, COMT-rs165599, and DRD4-rs1300955) were collected in 133 young non-psychotic outpatients. 116 individuals underwent follow-up (mean = 22 years, SD = 0.9) examination, A binary logistic model was used to predict low-functioning status at follow-up as defined by a score lower than 65 in the social occupational functioning assessment scale. A total of 54% of patients experiences low functioning at follow-up. Attention, Avolition, and Motor-Coordination subscale were significant predictors of low-functioning with an accuracy of 79.7%. A non-significant trend was found for a dopamine-related-gene polymorphism (DRD1-rs4532). The model was independent of psychotic risk status, DSM-diagnosis, and psychotic conversion. A trans-diagnostic approach taking into account specific neurocognitive, clinical, and neurological information has the potential to identify those individuals with low-functioning independent of DSM diagnosis or the level of psychosis-risk. Specific early interventions targeting modifiable risk factors and emphasize functional recovery in young psychiatric samples, independent of DSM-diagnosis and psychosis-risk, are essential. (C) 2016 Elsevier B.V. All rights reserved

Examining legitimatisation of additive manufacturing in the interplay between innovation, lean manufacturing and sustainability

In response to hypercompetition, globalisation and increasing consumer expectations, many manufacturing firms have embraced lean manufacturing (LM). The primary goal of LM is to reduce/eliminate waste (muda). There is broad consensus as to what constitutes waste, but not on LM implementation. Implementation is not prescriptive with each firm relying on a different combination of administrative, process and routine change/innovation. Lean manufacturing brings about incremental change relying on administrative, process and routine levers. It best fits mass production where process variability is low and demand is high and stable. Lean manufacturing can significantly reduce waste but not eliminate waste, and the attained benefits have not always lived up to expectations. Additive manufacturing (AM) promises to revolutionise manufacturing beyond recognition by eliminating or drastically removing the waste thereby achieving sustainability. But AM is at its formative stage – the space between the concept and growth - where many promising breakthrough technologies fail. To reach its full potential, it needs to achieve high-scale adoption. In this paper, we examine how AM can significantly reduce/eliminate waste and how it can deliver triple bottom line on an unprecedented scale. We contend that AM, if adopted deeply and widely, will take LM to its final frontier, but there are a number of impediments to this end. We identify legitimation as critical to its wide diffusion and develop a number of propositions expediting AM's legitimation. Legitimation of AM will ensure its deep and broad diffusion and should this happen, waste will be a thing of the past an important stride towards sustainable future

The limits of association studies in behavioral genetics: a revenge of sexual reproduction?

Genetic testing is showing its limits in assessing the hereditary risk for complex diseases as well as for psychic/psychiatric normal and pathological conditions. Genetic associations studies have revealed unable to produce consistent data on major disorders and more recent genome-wide association studies (GWAS) have provided more promising results identifying several genetic markers for individual risk of genetic diseases, but these generally consist of common variants that explain a small fraction of the overall genetic contribution to such risk. Even the mapping of copy number variations (CNVs) has so far produced inconsistent results. The future is thus to investigate how the alleles carried by our cells are expressed, and this is being pursued by two approaches: the study of our non-coding DNA, which is known to have an important role in the regulation of gene expression, and that of epigenetic mechanisms that represent the interface of gene x environment interactions and may allow us to better understand how neuronal populations direct behavior. As of now, the complex, multifactorial nature of our behavior and the continuous genotypic variation of human populations appear to represent the premise for such limits. Since sexual reproduction is the source of allelic assortment that makes our genetic variation continuous, it represents a strong restraint for geneticists

The mother of mothers

When developmental biology was born, in the 1850s, everyone was far from imagining what the new disci- pline would give rise to in a little more than the one and a half century to come. Etymologically, development means “getting out of an envelope”, i.e. coming out of a shapeless state and acquiring an organized form. In its most restricted biological meaning, the term refers to embryonic de- velopment, through which the zygote produces a new organism. As such, biology of development comes di- rectly from embryology, particularly from the ancient interest in the process of embryonic development de- scribed for many centuries through the anatomic stu- dy of variously staged embryos. Aristotle himself was known to observe embryos analytically and get clues about a general theory to explain the making up of such natural entities (2006; 2008)