Neural tube defects: recent advances, unsolved questions, and controversies

Neural tube defects are severe congenital malformations affecting around one in every 1000 pregnancies. An innovation in clinical management has come from the finding that closure of open spina bifida lesions in utero can diminish neurological dysfunction in children. Primary prevention with folic acid has been enhanced through introduction of mandatory food fortification in some countries, although not yet in the UK. Genetic predisposition accounts for most of the risk of neural tube defects, and genes that regulate folate one-carbon metabolism and planar cell polarity have been strongly implicated. The sequence of human neural tube closure events remains controversial, but studies of mouse models of neural tube defects show that anencephaly, open spina bifida, and craniorachischisis result from failure of primary neurulation, whereas skin-covered spinal dysraphism results from defective secondary neurulation. Other malformations, such as encephalocele, are likely to be postneurulation disorders

Two-fluid and magnetohydrodynamic modelling of magnetic reconnection in the MAST spherical tokamak and the solar corona

Twisted magnetic flux ropes are ubiquitous in space and laboratory plasmas, and the merging of such flux ropes through magnetic reconnection is an important mechanism for restructuring magnetic fields and releasing free magnetic energy. The merging-compression scenario is one possible start up scheme for spherical tokamaks, which has been used on the Mega Amp Spherical Tokamak MAST. Two current-carrying plasma rings, or flux ropes, approach each other through the mutual attraction of their like currents, and merge, through magnetic reconnection, into a single plasma torus, with substantial plasma heating. 2D resistive MHD and Hall MHD simulations of this process are reported, and new results for the temperature distribution of ions and electrons are presented. A model of the based on relaxation theory is also described, which is now extended to tight aspect ratio geometry. This model allows prediction of the final merged state and the heating. The implications of the relaxation model for heating of the solar corona are also discussed, and a model of the merger of two or more twisted coronal flux ropes is presented, allowing for different senses of twist

Mouse Models of Syndromic Craniosynostosis

Craniosynostosis is a common craniofacial birth defect. This review focusses on the advances that have been achieved through studying the pathogenesis of craniosynostosis using mouse models. Classic methods of gene targeting which generate individual gene knockout models have successfully identified numerous genes required for normal development of the skull bones and sutures. However, the study of syndromic craniosynostosis has largely benefited from the production of knockin models that precisely mimic human mutations. These have allowed the detailed investigation of downstream events at the cellular and molecular level following otherwise unpredictable gain-of-function effects. This has greatly enhanced our understanding of the pathogenesis of this disease and has the potential to translate into improvement of the clinical management of this condition in the future

Vangl2-environment interaction causes severe neural tube defects, without abnormal neuroepithelial convergent extension

Planar cell polarity (PCP) signalling is vital for initiation of mouse neurulation, with diminished convergent extension (CE) cell movements leading to craniorachischisis, a severe neural tube defect (NTD). Some humans with NTDs also have PCP gene mutations but these are heterozygous, not homozygous as in mice. Other genetic or environmental factors may interact with partial loss of PCP function in human NTDs. We found that reduced sulfation of glycosaminoglycans interacts with heterozygosity for the Lp allele of Vangl2 (a core PCP gene), to cause craniorachischisis in cultured mouse embryos, with rescue by exogenous sulphate. We hypothesised this glycosaminoglycan-PCP interaction may regulate CE but, surprisingly, DiO labeling of the embryonic node demonstrates no abnormality of midline axial extension in sulfation-depleted Lp/+ embryos. Positive-control Lp/Lp embryos show severe CE defects. Abnormalities were detected in the size and shape of somites that flank the closing neural tube in sulfation-depleted Lp/+ embryos. We conclude that failure of closure initiation can arise by a mechanism other than faulty neuroepithelial CE, with possible involvement of matrix-mediated somite expansion, adjacent to the closing neural tube

Enrichment of clinically relevant organisms in spontaneous preterm delivered placenta and reagent contamination across all clinical groups in a large UK pregnancy cohort.

In this study differences in the placental microbiota of term and preterm deliveries from a large UK pregnancy cohort were studied using 16S targeted amplicon sequencing. The impact of contamination from DNA extraction, PCR reagents, as well as those from delivery itself were also examined. A total of 400 placental samples from 256 singleton pregnancies were analysed and differences investigated between spontaneous preterm, non-spontaneous preterm, and term delivered placenta. DNA from recently delivered placenta was extracted, and screening for bacterial DNA was carried out using targeted sequencing of the 16S rRNA gene on the Illumina MiSeq platform. Sequenced reads were analysed for presence of contaminating operational taxonomic units (OTUs) identified via sequencing of negative extraction and PCR blank samples. Differential abundance and between sample (beta) diversity metrics were then compared. A large proportion of the reads sequenced from the extracted placental samples mapped to OTUs that were also found in negative extractions. Striking differences in the composition of samples were also observed, according to whether the placenta was delivered abdominally or vaginally, providing strong circumstantial evidence for delivery contamination as an important contributor to observed microbial profiles. When OTU and genus level abundances were compared between the groups of interest, a number of organisms were enriched in the spontaneous preterm cohort, including organisms that have been previously associated with adverse pregnancy outcomes, specifically Mycoplasma spp., and Ureaplasma spp.. However, analyses of overall community structure did not reveal convincing evidence for the existence of a reproducible 'preterm placental microbiome'. IMPORTANCE: Preterm birth is associated with both psychological and physical disabilities and is the leading cause of infant morbidity and mortality worldwide. Infection is known to be an important cause of spontaneous preterm birth, and recent research has implicated variation in the 'placental microbiome' with preterm birth risk. Consistent with previous studies, the abundance of certain clinically relevant species differed between spontaneous preterm and non-spontaneous preterm or term delivered placenta. These results support the view that a proportion of spontaneous preterm births have an intra-uterine infection component. However, an additional observation from this study was that a substantial proportion of reads sequenced were contaminating reads, rather than DNA from endogenous, clinically relevant species. This observation warrants caution in the interpretation of sequencing output from such low biomass samples as the placenta

Rheology of Active-Particle Suspensions

We study the interplay of activity, order and flow through a set of coarse-grained equations governing the hydrodynamic velocity, concentration and stress fields in a suspension of active, energy-dissipating particles. We make several predictions for the rheology of such systems, which can be tested on bacterial suspensions, cell extracts with motors and filaments, or artificial machines in a fluid. The phenomena of cytoplasmic streaming, elastotaxis and active mechanosensing find natural explanations within our model.Comment: 3 eps figures, submitted to Phys Rev Let

FLUORESCENCE AND CIRCULAR DICHROISM STUDIES ON THE PHYCOERYTHROCYANINS FROM THE CYANOBACTERIUM

Two phycoerythrocyanin (PEC) fractions have been obtained from the phycobilisomes of the cyanobac-terium Westiellopsis prolifica ARM 365. They have been characterized by absorption, fluorescence and circular dichroism spectroscopy. One of them is spectroscopically similar to a PEC trimer known from other organisms. Whereas efficient energy transfer from its violin (α-84) to the cyanin (β-84, 155) chromophores is efficient in the trimer (αβ it is impeded after dissociation to the monomer (α,β). A second fraction of PEC which we earlier termed PEC(X) (Maruthi Sai et al., Photochem. Photobiol. 55,119–124, 1992), exhibited the spectral properties similar to that of the α-subunit of PEC from Mastigocladus laminosus. With this highly photoactive fraction, the circular dichroism spectra of the violobilin chromophore in both photoreversible states were obtained

Solar Particle Acceleration at Reconnecting 3D Null Points

Context: The strong electric fields associated with magnetic reconnection in solar flares are a plausible mechanism to accelerate populations of high energy, non-thermal particles. One such reconnection scenario occurs at a 3D magnetic null point, where global plasma flows give rise to strong currents in the spine axis or fan plane. Aims: To understand the mechanism of charged particle energy gain in both the external drift region and the diffusion region associated with 3D magnetic reconnection. In doing so we evaluate the efficiency of resistive spine and fan models for particle acceleration, and find possible observables for each. Method: We use a full orbit test particle approach to study proton trajectories within electromagnetic fields that are exact solutions to the steady and incompressible magnetohydrodynamic equations. We study single particle trajectories and find energy spectra from many particle simulations. The scaling properties of the accelerated particles with respect to field and plasma parameters is investigated. Results: For fan reconnection, strong non-uniform electric drift streamlines can accelerate the bulk of the test particles. The highest energy gain is for particles that enter the current sheet, where an increasing "guide field" stabilises particles against ejection. The energy is only limited by the total electric potential energy difference across the fan current sheet. The spine model has both slow external electric drift speed and weak energy gain for particles reaching the current sheet. Conclusions: The electromagnetic fields of fan reconnection can accelerate protons to the high energies observed in solar flares, gaining up to 0.1 GeV for anomalous values of resistivity. However, the spine model, which gave a harder energy spectrum in the ideal case, is not an efficient accelerator after pressure constraints in the resistive model are included.Comment: 15 pages, 14 figures. Submitted to Astronomy and Astrophysic