Untangling the Most Probable Role for Vitamin D\u3csub\u3e3\u3c/sub\u3e in Autism

Recent studies indicate an important role for vitamin D3 in autism spectrum disorder (ASD), although its mechanism is not completely understood. The most puzzling aspect of ASD is that identical twins, who share identical DNA, do not have 100% concordance rates (∼88% for identical and ∼31% for fraternal twins). These findings provide major clues into the etiology: ASD must involve an environmental factor present in the prenatal milieu that both identical twins are not always exposed to because they do not always share it (i.e., placentas). Combined with the exponential increasing rates of ASD around the world, these observations suggest a contagious disease is probably transferred to the fetus via the placenta becoming infected by a cervical virus. Vitamin D3 boosts immune responses clearing viral infections and increases serotonin and estrogen brain levels. Here we review the different roles and untangle the most probable one vitamin D3 plays in ASD

Testing of Two Novel Semi-Implicit Particle-In-Cell Techniques

PIC (Particle-in-cell) modeling is a computational technique which functions by advancing computer particles through a spatial grid consisting of cells, on which can be placed electric and magnetic fields. This method has proven useful for simulating a wide range of plasmas and excels at yielding accurate and detailed results such as particle number densities, particle energies, particle currents, and electric potentials. However, the detailed results of a PIC simulation come at a substantial cost of computational requirement and the algorithm can be susceptible to numerical instabilities. As processors become faster and contain more cores, the computational expense of PIC simulations is somewhat addressed, but this is not enough. Improvements must be made in the numerical algorithms as well. Unfortunately, a physical limit exists for how fast a silicon processor can operate, and increasing the number of processing cores increases the overhead of passing information between processors. Essentially, the solution for decreasing the computational time required by a PIC simulation is improving the solution algorithms and not through increasing the hardware capacity of the machine performing the simulation. In order to decrease the computational time and increase the stability of a PIC algorithm, it must be altered to circumvent the current limitations. The goal of the work presented in this thesis is twofold. The first objective is to develop a three-dimensional PIC simulation code that can be used to study different numerical algorithms. This computer code focuses on the solution of the equation of motion for charged particles moving in an electromagnetic field (Newton-Lorentz equation), the solution of the electric potentials caused by boundary conditions and charged particles (Poisson\u27s Equation), and the coupling of these two equations. The numerical solution of these two equations, their coupling, which is the primary cause of instabilities, and the severe computational requirements for PIC codes make writing this code a difficult task. Solving the Newton-Lorentz equation for large numbers of charged particles and Poisson\u27s equation is complex. This is the focus of this newly developed computer code. The second objective of the work presented in this thesis is to use the developed computer code to study two ideas for improving the numerical algorithm used in PIC codes. The two techniques investigated are: 1) implementing a fourth order electric field approximation in the equation of motion and 2) solving for the electric field, i.e. solving Poisson\u27s equation, multiple times within a single time step. The first of these methods uses the electric fields of many cells that a charged particle may pass through in one time step. This is opposed to using only the cell of origin electric field for the particle\u27s entire path during one time step. The idea here is to allow PIC codes to use larger time steps while remaining stable and avoiding numerical heating; thus reducing the overall computer time required. The second technique studied is utilizing multiple Poisson equation solves during a single time step. Typically, an explicit PIC model will solve the electric field only once during a time step; however, solving the field multiple times during the particle push allows particles to distribute themselves in a more electrically neutral manner within a single time step. The idea here is to allow larger time steps to be used without obtaining unrealistic electric potentials due to an artificial degree of charge separation. This eliminates instabilities and numerical heating. Explicit PIC codes have limits on how large the numerical time step can be before the electric potentials blow up. This work has shown that neither of these techniques, in their current state, are practical options to increase the time step of the PIC algorithm while ..

Enhancing lysosome biogenesis attenuates BNIP3-induced cardiomyocyte death

Hypoxia-inducible pro-death protein BNIP3 (BCL-2/adenovirus E1B 19-kDa interacting protein 3), provokes mitochondrial permeabilization causing cardiomyocyte death in ischemia-reperfusion injury. Inhibition of autophagy accelerates BNIP3-induced cell death, by preventing removal of damaged mitochondria. We tested the hypothesis that stimulating autophagy will attenuate BNIP3-induced cardiomyocyte death. Neonatal rat cardiac myocytes (NRCMs) were adenovirally transduced with BNIP3 (or LacZ as control; at multiplicity of infection = 100); and autophagy was stimulated with rapamycin (100 nM). Cell death was assessed at 48 h. BNIP3 expression increased autophagosome abundance 8-fold and caused a 3.6-fold increase in cardiomyocyte death as compared with control. Rapamycin treatment of BNIP3-expressing cells led to further increase in autophagosome number without affecting cell death. BNIP3 expression led to accumulation of autophagosome-bound LC3-II and p62, and an increase in autophagosomes, but not autolysosomes (assessed with dual fluorescent mCherry-GFP-LC3 expression). BNIP3, but not the transmembrane deletion variant, interacted with LC3 and colocalized with mitochondria and lysosomes. However, BNIP3 did not target to lysosomes by subcellular fractionation, provoke lysosome permeabilization or alter lysosome pH. Rather, BNIP3-induced autophagy caused a decline in lysosome numbers with decreased expression of the lysosomal protein LAMP-1, indicating lysosome consumption and consequent autophagosome accumulation. Forced expression of transcription factor EB (TFEB) in BNIP3-expressing cells increased lysosome numbers, decreased autophagosomes and increased autolysosomes, prevented p62 accumulation, removed depolarized mitochondria and attenuated BNIP3-induced death. We conclude that BNIP3 expression induced autophagosome accumulation with lysosome consumption in cardiomyocytes. Forced expression of TFEB, a lysosomal biogenesis factor, restored autophagosome processing and attenuated BNIP3-induced cell death

Exponentially Increasing Incidences of Cutaneous Malignant Melanoma in Europe Correlate with Low Personal Annual UV Doses and Suggests 2 Major Risk Factors

For several decades the incidence of cutaneous malignant melanoma (CMM) steadily increased in fair-skinned, indoor-working people around the world. Scientists think poor tanning ability resulting in sunburns initiate CMM, but they do not understand why the incidence continues to increase despite the increased use of sunscreens and formulations offering more protection. This paradox, along with lower incidences of CMM in outdoor workers, although they have significantly higher annual UV doses than indoor workers have, perplexes scientists. We found a temporal exponential increase in the CMM incidence indicating second-order reaction kinetics revealing the existence of 2 major risk factors. From epidemiology studies, we know one major risk factor for getting CMM is poor tanning ability and we now propose the other major risk factor may be the Human Papilloma Virus (HPV) because clinicians find β HPVs in over half the biopsies. Moreover, we uncovered yet another paradox; the increasing CMM incidences significantly correlate with decreasing personal annual UV dose, a proxy for low vitamin D3 levels. We also discovered the incidence of CMM significantly increased with decreasing personal annual UV dose from 1960, when it was almost insignificant, to 2000. UV and other DNA-damaging agents can activate viruses, and UV-induced cytokines can hide HPV from immune surveillance, which may explain why CMM also occurs in anatomical locations where the sun does not shine. Thus, we propose the 2 major risk factors for getting CMM are intermittent UV exposures that result in low cutaneous levels of vitamin D3 and possibly viral infection

Animal models of tic disorders: A translational perspective

Tics are repetitive, sudden movements and/or vocalizations, typically enacted as maladaptive responses to intrusive premonitory urges. The most severe tic disorder, Tourette syndrome (TS), is a childhood-onset condition featuring multiple motor and at least one phonic tic for a duration longer than 1 year. The pharmacological treatment of TS is mainly based on antipsychotic agents; while these drugs are often effective in reducing tic severity and frequency, their therapeutic compliance is limited by serious motor and cognitive side effects. The identification of novel therapeutic targets and development of better treatments for tic disorders is conditional on the development of animal models with high translational validity. In addition, these experimental tools can prove extremely useful to test hypotheses on the etiology and neurobiological bases of TS and related conditions. In recent years, the translational value of these animal models has been enhanced, thanks to a significant re-organization of our conceptual framework of neuropsychiatric disorders, with a greater focus on endophenotypes and quantitative indices, rather than qualitative descriptors. Given the complex and multifactorial nature of TS and other tic disorders, the selection of animal models that can appropriately capture specific symptomatic aspects of these conditions can pose significant theoretical and methodological challenges. In this article, we will review the state of the art on the available animal models of tic disorders, based on genetic mutations, environmental interventions as well as pharmacological manipulations. Furthermore, we will outline emerging lines of translational research showing how some of these experimental preparations have led to significant progress in the identification of novel therapeutic targets for tic disorders

Autophagy is impaired in cardiac ischemia-reperfusion injury

Accumulating evidence attests to a prosurvival role for autophagy under stress, by facilitating removal of damaged proteins and organelles and recycling basic building blocks, which can be utilized for energy generation and targeted macromolecular synthesis to shore up cellular defenses. These observations are difficult to reconcile with the dichotomous prosurvival and death-inducing roles ascribed to macroautophagy in cardiac ischemia and reperfusion injury, respectively. A careful reexamination of ‘flux’ through the macroautophagy pathway reveals that autophagosome clearance is markedly impaired with reperfusion (reoxygenation) in cardiomyocytes following an ischemic (hypoxic) insult, resulting from reactive oxygen species (ROS)-mediated decline in LAMP2 and increase in BECN1 abundance. This results in impaired autophagy that is ‘ineffective’ in protecting against cell death with ischemia-reperfusion injury. Restoration of autophagosome clearance and by inference, ‘adequate’ autophagy, attenuates reoxygenation-induced cell death

The implication of neuroactive steroids in Tourette syndrome pathogenesis: a role for 5α-reductase?

This is the peer reviewed version of the following article: Bortolato, M., Frau, R., Godar, S. C., Mosher, L. J., Paba, S., Marrosu, F. and Devoto, P. (2013), The Implication of Neuroactive Steroids in Tourette's Syndrome Pathogenesis: A Role for 5α-Reductase?. J Neuroendocrinol, 25: 1196–1208. doi:10.1111/jne.12066, which has been published in final form at http://doi.org/10.1111/jne.12066. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.Tourette syndrome (TS) is a neurodevelopmental disorder characterized by recurring motor and phonic tics. The pathogenesis of TS is thought to reflect dysregulations in the signaling of dopamine (DA) and other neurotransmitters, which lead to excitation/inhibition imbalances in cortico-striato-thalamocortical circuits. The causes of these deficits may reflect complex gene × environment × sex (G×E×S) interactions; indeed, the disorder is markedly predominant in males, with a male-to-female prevalence ratio of ~4:1. Converging lines of evidence point to neuroactive steroids as likely molecular candidates to account for GxExS interactions in TS. Building on these premises, our group has begun examining the possibility that alterations in the steroid biosynthetic process may be directly implicated in TS pathophysiology; in particular, our research has focused on 5α-reductase (5αR), the enzyme catalyzing the key rate-limiting step in the synthesis of pregnane and androstane neurosteroids. In clinical and preclinical studies, we found that 5αR inhibitors exerted marked anti-DAergic and tic-suppressing properties, suggesting a central role for this enzyme in TS pathogenesis. Based on these data, we hypothesize that enhancements in 5αR activity in early developmental stages may lead to an inappropriate activation of the “backdoor” pathway for androgen synthesis from adrenarche until the end of puberty. We predict that the ensuing imbalances in steroid homeostasis may impair the signaling of DA and other neurotransmitters, ultimately resulting in the facilitation of tics and other behavioral abnormalities in TS

A produçao familiar como alternativa de um desenvolvimento sustentável para a Amazônia; Liçoes aprendidas de iniciativas de uso florestal por produtores familiares na Amazônia boliviana, brasileira, equatoriana e peruana

Abstract: Between 2005 and 2009, the EU-financed project ForLive set out to analyse promising local forest management initiatives in the Amazon Basin in four countries: Ecuador, Bolivia, Brazil, and Peru. Researchers aimed to identify locally viable practices that benefit livelihoods and ecological stabilisation of landscapes, as well as to define ways to promote these practices as a basis for sound rural development. This book presents lessons learnt from more than 100 studies by researchersfrom Latin America, from practitioners and from local families themselves. The findings suggest that the focus of current development strategies designed to support smallholders in adopting management and organization, which are usually externally defined systems made from expert-driven policy and research, mayrequire a review of fundamental assumptions and methods. Most of these initiatives widely ignored the immense potential of Amazonian smallholders—settlers, traditional communities and indigenous groups—to contribute to sound rural development with their own ideas and knowledge. Strong evidence was found that the socio-productive systems of Amazonian smallholders could serve as a reference for new methods that support a more equitable and environmentallysustainable development of the region

Regulation of the transcription factor EB-PGC1α axis by beclin-1 controls mitochondrial quality and cardiomyocyte death under stress

In cardiac ischemia-reperfusion injury, reactive oxygen species (ROS) generation and upregulation of the hypoxia-inducible protein BNIP3 result in mitochondrial permeabilization, but impairment in autophagic removal of damaged mitochondria provokes programmed cardiomyocyte death. BNIP3 expression and ROS generation result in upregulation of beclin-1, a protein associated with transcriptional suppression of autophagy-lysosome proteins and reduced activation of transcription factor EB (TFEB), a master regulator of the autophagy-lysosome machinery. Partial beclin-1 knockdown transcriptionally stimulates lysosome biogenesis and autophagy via mTOR inhibition and activation of TFEB, enhancing removal of depolarized mitochondria. TFEB activation concomitantly stimulates mitochondrial biogenesis via PGC1α induction to restore normally polarized mitochondria and attenuate BNIP3- and hypoxia-reoxygenation-induced cell death. Conversely, overexpression of beclin-1 activates mTOR to inhibit TFEB, resulting in declines in lysosome numbers and suppression of PGC1α transcription. Importantly, knockdown of endogenous TFEB or PGC1α results in a complete or partial loss, respectively, of the cytoprotective effects of partial beclin-1 knockdown, indicating a critical role for both mitochondrial autophagy and biogenesis in ensuring cellular viability. These studies uncover a transcriptional feedback loop for beclin-1-mediated regulation of TFEB activation and implicate a central role for TFEB in coordinating mitochondrial autophagy with biogenesis to restore normally polarized mitochondria and prevent ischemia-reperfusion-induced cardiomyocyte death

A spatially explicit data-driven approach to calculating commodity-specific shipping emissions per vessel

Oceangoing ships carry approximately 80% of the world's traded goods by volume, which translates into more than 10 billion tonnes in shipped traded volumes per year (UNCTAD, 2017). Despite its importance, the maritime shipping sector has been traditionally overlooked in climate mitigation discussions, since this sector was largely neglected in the 1997 Kyoto Protocol. Key barriers for successful implementation of CO2 abatement measures in the sector include the lack of reliable emissions data and the inherent difficulty of attributing responsibility for international shipping emissions to the involved countries, companies and commodities, as well as the threat to global trade interests. We argue that the data paucity on maritime emissions from international trade can be addressed by linking and integrating a large wealth of data, previously used in isolation. By linking per vessel cargo composition data, individual vessel journeys from the Automatic Identification System and a bottom-up methodology to estimate emissions, using vessel specifications and details on their movements and operations, this paper describes and demonstrates this new approach for the case of Brazil's shipping manifests in 2014. We find that the maritime transportation associated with these trades is responsible for 25.99 million tonnes of CO2, an addition of 5% to Brazil's total CO2 emissions of 2014 (reported by the World Bank, currently excluding international shipping and aviation). We discuss the contribution of all traded commodities, as well as the role of the first destination ports and countries. The voyage- and commodity-specificity of this method allows us to showcase those commodities and trading routes which contribute the most towards this emissions account, in relation to those that are most valuable to Brazil's economy. We go on to discuss the implications of scaling up this methodology for global greenhouse gas abatement efforts and demand-side footprint calculations, as well as to improve accountability mechanisms for the maritime sector as a whole