Hypertensive disorders of pregnancy and risk of neurodevelopmental disorders in the offspring: a systematic review and meta-analysis protocol

Introduction Hypertensive disorders of pregnancy (HDPs), that is chronic hypertension, gestational hypertension, pre-eclampsia (de novo or superimposed on chronic hypertension) and white coat hypertension, affect approximately 5%–15% of pregnancies. HDP exposure has been linked to an increased risk of autism spectrum disorder, attention deficit/hyperactivity disorder and other neurodevelopmental disorders in children. However, findings are inconsistent, and a clear consensus on the impact of HDPs on the risk of neurodevelopmental disorders is needed. Therefore, we aim to synthesise the published literature on the relationship between HDPs and the risk of neurodevelopmental disorders in the form of a systematic review and meta-analysis. Methods and analysis We will include cohort, case– control and cross-sectional studies in which diagnosis of an HDP was reported, and neurodevelopmental disorders were the outcome of interest based on a preprepared protocol. A systematic search of PubMed, CINAHL, Embase, PsycINFO and Web of Science will be conducted in accordance with a detailed search strategy. Two authors will independently review the titles and abstracts of all studies, perform data extraction using a standardised data collection form and assess study quality using a bias classification tool. Meta-analyses will be performed to calculate overall pooled estimates using the generic inverse variance method. This systematic review will be reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses. Ethics and dissemination This proposed systematic review and meta-analysis is based on published data, therefore, does not require ethics approval. Findings will be presented at scientific conferences and disseminated through publication in a peer-reviewed journal. Registration CRD42017068258

Gene Co-expression Analysis Identifies Histone Deacetylase 5 and 9 Expression in Midbrain Dopamine Neurons and as Regulators of Neurite Growth via Bone Morphogenetic Protein Signaling

Parkinson’s disease is characterized by the intracellular accumulation of α-synuclein which has been linked to early dopaminergic axonal degeneration. Identifying druggable targets that can promote axonal growth in cells overexpressing α-synuclein is important in order to develop strategies for early intervention. Class-IIa histone deacetylases (HDACs) have previously emerged as druggable targets, however, it is not known which specific class-IIa HDACs should be targeted to promote neurite growth in dopaminergic neurons. To provide insight into this, we used gene co-expression analysis to identify which, if any, of the class-IIa HDACs had a positive correlation with markers of dopaminergic neurons in the human substantia nigra. This revealed that two histone deacetylases, HDAC5 and HDAC9, are co-expressed with TH, GIRK2 and ALDH1A1 in the human SN. We further found that HDAC5 and HDAC9 are expressed in dopaminergic neurons in the adult mouse substantia nigra. We show that siRNAs targeting HDAC5 or HDAC9 can promote neurite growth in SH-SY5Y cells, and that their pharmacological inhibition, using the drug MC1568, promoted neurite growth in cultured rat dopaminergic neurons. Moreover, MC1568 treatment upregulated the expression of the neurotrophic factor, BMP2, and its downstream transcription factor, SMAD1. In addition, MC1568 or siRNAs targeting HDAC5 or HDAC9 led to an increase in Smad-dependent GFP expression in a reporter assay. Furthermore, MC1568 treatment of cultured rat dopaminergic neurons increased cellular levels of phosphorylated Smad1, which was prevented by the BMP receptor inhibitor, dorsomorphin. Dorsomorphin treatment prevented the neurite growth-promoting effects of siRNAs targeting HDAC5, as did overexpression of dominant-negative Smad4 or of the inhibitory Smad7, demonstrating a functional link to BMP signaling. Supplementation with BMP2 prevented the neurite growth-inhibitory effects of nuclear-restricted HDAC5. Finally, we report that siRNAs targeting HDAC5 or HDAC9 promoted neurite growth in cells overexpressing wild-type or A53T-α-synuclein and that MC1568 protected cultured rat dopaminergic neurons against the neurotoxin, MPP+. These findings establish HDAC5 and HDAC9 as novel regulators of BMP-Smad signaling, that additionally may be therapeutic targets worthy of further exploration in iPSC-derived human DA neurons and in vivo models of Parkinson’s disease

The elastic constants of MgSiO3 perovskite at pressures and temperatures of the Earth's mantle

The temperature anomalies in the Earth's mantle associated with thermal convection1 can be inferred from seismic tomography, provided that the elastic properties of mantle minerals are known as a function of temperature at mantle pressures. At present, however, such information is difficult to obtain directly through laboratory experiments. We have therefore taken advantage of recent advances in computer technology, and have performed finite-temperature ab initio molecular dynamics simulations of the elastic properties of MgSiO3 perovskite, the major mineral of the lower mantle, at relevant thermodynamic conditions. When combined with the results from tomographic images of the mantle, our results indicate that the lower mantle is either significantly anelastic or compositionally heterogeneous on large scales. We found the temperature contrast between the coldest and hottest regions of the mantle, at a given depth, to be about 800K at 1000 km, 1500K at 2000 km, and possibly over 2000K at the core-mantle boundary.Comment: Published in: Nature 411, 934-937 (2001

Ice XII in its second regime of metastability

We present neutron powder diffraction results which give unambiguous evidence for the formation of the recently identified new crystalline ice phase[Lobban et al.,Nature, 391, 268, (1998)], labeled ice XII, at completely different conditions. Ice XII is produced here by compressing hexagonal ice I_h at T = 77, 100, 140 and 160 K up to 1.8 GPa. It can be maintained at ambient pressure in the temperature range 1.5 < T < 135 K. High resolution diffraction is carried out at T = 1.5 K and ambient pressure on ice XII and accurate structural properties are obtained from Rietveld refinement. At T = 140 and 160 K additionally ice III/IX is formed. The increasing amount of ice III/IX with increasing temperature gives an upper limit of T ~ 150 K for the successful formation of ice XII with the presented procedure.Comment: 3 Pages of RevTeX, 3 tables, 3 figures (submitted to Physical Review Letters

Understanding the nature of "superhard graphite"

Numerous experiments showed that on cold compression graphite transforms into a new superhard and transparent allotrope. Several structures with different topologies have been proposed for this phase. While experimental data are consistent with these models, the only way to solve this puzzle is to find which structure is kinetically easiest to form. Using state-of-the-art molecular-dynamics transition path sampling simulations, we investigate kinetic pathways of the pressure-induced transformation of graphite to various superhard candidate structures. Unlike hitherto applied methods for elucidating nature of superhard graphite, transition path sampling realistically models nucleation events necessary for physically meaningful transformation kinetics. We demonstrate that nucleation mechanism and kinetics lead to $M$-carbon as the final product. $W$-carbon, initially competitor to $M$-carbon, is ruled out by phase growth. Bct-C$_4$ structure is not expected to be produced by cold compression due to less probable nucleation and higher barrier of formation

Low-Multiplicity Burst Search At The Sudbury Neutrino Observatory

Results are reported from a search for low-multiplicity neutrino bursts in the Sudbury Neutrino Observatory. Such bursts could indicate the detection of a nearby core-collapse supernova explosion. The data were taken from Phase I (1999 November-2001 May), when the detector was filled with heavy water, and Phase II (2001 July-2003 August), when NaCl was added to the target. The search was a blind analysis in which the potential backgrounds were estimated and analysis cuts were developed to eliminate such backgrounds with 90% confidence before the data were examined. The search maintained a greater than 50% detection probability for standard supernovae occurring at a distance of up to 60 kpc for Phase I and up to 70 kpc for Phase II. No low-multiplicity bursts were observed during the data-taking period.Natural Sciences and Engineering Research Council, CanadaIndustry Canada, CanadaNational Research Council, CanadaNorthern Ontario Heritage Fund, CanadaAtomic Energy of Canada, Ltd., CanadaOntario Power Generation, CanadaHigh Performance Computing Virtual Laboratory, CanadaCanada Foundation for Innovation, CanadaCanada Research Chairs, CanadaDepartment of Energy, USNational Energy Research Scientific Computing Center, USAlfred P. Sloan Foundation, USScience and Technology Facilities Council, UKFundacao para a Ciencia e a Technologia, PortugalAstronom

A Search for Neutrinos from the Solar hep Reaction and the Diffuse Supernova Neutrino Background with the Sudbury Neutrino Observatory

A search has been made for neutrinos from the hep reaction in the Sun and from the diffus

Searches For High-Frequency Variations In The B-8 Solar Neutrino Flux At The Sudbury Neutrino Observatory

We have performed three searches for high-frequency signals in the solar neutrino flux measured by the Sudbury Neutrino Observatory, motivated by the possibility that solar g-mode oscillations could affect the production or propagation of solar B-8 neutrinos. The first search looked for any significant peak in the frequency range 1-144 day(-1), with a sensitivity to sinusoidal signals with amplitudes of 12% or greater. The second search focused on regions in which g-mode signals have been claimed by experiments aboard the Solar and Heliospheric Observatory satellite, and was sensitive to signals with amplitudes of 10% or greater. The third search looked for extra power across the entire frequency band. No statistically significant signal was detected in any of the three searches.Natural Sciences and Engineering Research Council, CanadaIndustry Canada, CanadaNational Research Council, CanadaNorthern Ontario Heritage Fund, CanadaAtomic Energy of Canada, Ltd., CanadaOntario Power Generation, CanadaHigh Performance Computing Virtual Laboratory, CanadaCanada Foundation for InnovationDept. of Energy, USNational Energy Research Scientific Computing Center, USScience and Technologies Facilities Council, UKAstronom

Low Multiplicity Burst Search at the Sudbury Neutrino Observatory

Results are reported from a search for low-multiplicity neutrino bursts in the Sudbury Neutrino Observatory (SNO). Such bursts could indicate detection of a nearby core-collapse supernova explosion. The data were taken from Phase I (November 1999 - May 2001), when the detector was filled with heavy water, and Phase II (July 2001 - August 2003), when NaCl was added to the target. The search was a blind analysis in which the potential backgrounds were estimated and analysis cuts were developed to eliminate such backgrounds with 90% confidence before the data were examined. The search maintained a greater than 50% detection probability for standard supernovae occurring at a distance of up to 60 kpc for Phase I and up to 70 kpc for Phase II. No low-multiplicity bursts were observed during the data-taking period.Comment: 11 pages, 4 figures, submitted to Ap

Reticular synthesis and the design of new materials

The long-standing challenge of designing and constructing new crystalline solid-state materials from molecular building blocks is just beginning to be addressed with success. A conceptual approach that requires the use of secondary building units to direct the assembly of ordered frameworks epitomizes this process: we call this approach reticular synthesis. This chemistry has yielded materials designed to have predetermined structures, compositions and properties. In particular, highly porous frameworks held together by strong metal-oxygen-carbon bonds and with exceptionally large surface area and capacity for gas storage have been prepared and their pore metrics systematically varied and functionalized.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62718/1/nature01650.pd