KDM2 proteins constrain transcription from CpG island gene promoters independently of their histone demethylase activity

Wellcome Trust [102349/Z/13/Z to A.H.T., 099677/Z/12/Z to H.W.K., 098024/Z/11/Z, 209400/Z/17/Z to R.J.K.]; Lister Institute of Preventive Medicine; European Research Council [681440]; Japan Agency for Medical Research and Development, AMEDCREST Programme. Funding for open access charge: Wellcome Trus

TOPORS (topoisomerase I binding, arginine/serine-rich)

Review on TOPORS (topoisomerase I binding, arginine/serine-rich), with data on DNA, on the protein encoded, and where the gene is implicated

Development and operational experience of magnetic horn system for T2K experiment

A magnetic horn system to be operated at a pulsed current of 320 kA and to survive high-power proton beam operation at 750 kW was developed for the T2K experiment. The first set of T2K magnetic horns was operated for over 12 million pulses during the four years of operation from 2010 to 2013, under a maximum beam power of 230 kW, and $6.63\times10^{20}$ protons were exposed to the production target. No significant damage was observed throughout this period. This successful operation of the T2K magnetic horns led to the discovery of the $\nu_{\mu}\rightarrow\nu_e$ oscillation phenomenon in 2013 by the T2K experiment. In this paper, details of the design, construction, and operation experience of the T2K magnetic horns are described.Comment: 22 pages, 40 figures, also submitted to Nuclear Instrument and Methods in Physics Research,

Self-Diffusion of a Polymer Chain in a Melt

Self-diffusion of a polymer chain in a melt is studied by Monte Carlo simulations of the bond fluctuation model, where only the excluded volume interaction is taken into account. Polymer chains, each of which consists of $N$ segments, are located on an $L \times L \times L$ simple cubic lattice under periodic boundary conditions, where each segment occupies $2 \times 2 \times 2$ unit cells. The results for $N=32, 48, 64, 96, 128, 192, 256, 384$ and 512 at the volume fraction $\phi \simeq 0.5$ are reported, where $L = 128$ for $N \leq 256$ and L=192 for $N \geq 384$. The $N$-dependence of the self-diffusion constant $D$ is examined. Here, $D$ is estimated from the mean square displacements of the center of mass of a single polymer chain at the times larger than the longest relaxation time. From the data for $N = 256$, 384 and 512, the apparent exponent $x_{\rm d}$, which describes the apparent power law dependence of $D$ on $N$ as $D \propto N^{- x_{\rm d}}$, is estimated as $x_{\rm d} \simeq 2.4$. The ratio $D \tau /$ seems to be a constant for $N = 192, 256, 384$ and 512, where $\tau$ and $$ denote the longest relaxation time and the mean square end-to-end distance, respectively.Comment: 4 pages, 3 figures, submitted to J. Phys. Soc. Jp

EFA6 regulates selective polarised transport and axon regeneration from the axon initial segment

Central nervous system (CNS) axons lose their intrinsic ability to regenerate upon maturity, whereas peripheral nervous system (PNS) axons do not. A key difference between these neuronal types is their ability to transport integrins into axons. Integrins can mediate PNS regeneration, but are excluded from adult CNS axons along with their Rab11 carriers. We reasoned that exclusion of the contents of Rab11 vesicles including integrins might contribute to the intrinsic inability of CNS neurons to regenerate, and investigated this by performing laser axotomy. We identify a novel regulator of selective axon transport and regeneration, the ARF6 guanine-nucleotide-exchange factor (GEF) EFA6 (also known as PSD). EFA6 exerts its effects from a location within the axon initial segment (AIS). EFA6 does not localise at the AIS in dorsal root ganglion (DRG) axons, and in these neurons, ARF6 activation is counteracted by an ARF GTPase-activating protein (GAP), which is absent from the CNS, ACAP1. Depleting EFA6 from cortical neurons permits endosomal integrin transport and enhances regeneration, whereas overexpressing EFA6 prevents DRG regeneration. Our results demonstrate that ARF6 is an intrinsic regulator of regenerative capacity, implicating EFA6 as a focal molecule linking the AIS, signalling and transport.The study was funded by grants from the Christopher and Dana Reeve Foundation, the Medical Research Council, the ERC advanced grant ECMneuro, the International Spinal Research Trust, Glaxo Smith Kline International Scholarship, Honjo International Scholarship, Bristol-Myers Squibb Graduate Studentship and the NIHR Cambridge Biomedical Research Centre

Frontogenesis of the Angola–Benguela Frontal Zone

A diagnostic analysis of the climatological annual mean and seasonal cycle of the Angola–Benguela Frontal Zone (ABFZ) is performed by applying an ocean frontogenetic function (OFGF) to the ocean mixing layer (OML). The OFGF reveals that the meridional confluence and vertical tilting terms are the most dominant contributors to the frontogenesis of the ABFZ. The ABFZ shows a well-pronounced semiannual cycle with two maximum (minimum) peaks in April–May and November–December (February–March and July–August). The development of the two maxima of frontogenesis is due to two different physical processes: enhanced tilting from March to April and meridional confluence from September to October. The strong meridional confluence in September to October is closely related to the seasonal southward intrusion of tropical warm water to the ABFZ that seems to be associated with the development of the Angola Dome northwest of the ABFZ. The strong tilting effect from March to April is attributed to the meridional gradient of vertical velocities, whose effect is amplified in this period due to increasing stratification and shallow OML depth. The proposed OFGF can be viewed as a tool to diagnose the performance of coupled general circulation models (CGCMs) that generally fail at realistically simulating the position of the ABFZ, which leading to huge warm biases in the southeastern Atlantic.</p

Average Structures of a Single Knotted Ring Polymer

Two types of average structures of a single knotted ring polymer are studied by Brownian dynamics simulations. For a ring polymer with N segments, its structure is represented by a 3N -dimensional conformation vector consisting of the Cartesian coordinates of the segment positions relative to the center of mass of the ring polymer. The average structure is given by the average conformation vector, which is self-consistently defined as the average of the conformation vectors obtained from a simulation each of which is rotated to minimize its distance from the average conformation vector. From each conformation vector sampled in a simulation, 2N conformation vectors are generated by changing the numbering of the segments. Among the 2N conformation vectors, the one closest to the average conformation vector is used for one type of the average structure. The other type of the averages structure uses all the conformation vectors generated from those sampled in a simulation. In thecase of the former average structure, the knotted part of the average structure is delocalized for small N and becomes localized as N is increased. In the case of the latter average structure, the average structure changes from a double loop structure for small N to a single loop structure for large N, which indicates the localization-delocalization transition of the knotted part.Comment: 15 pages, 19 figures, uses jpsj2.cl

Local modulation of the Wnt/β‐catenin and bone morphogenic protein (BMP) pathways recapitulates rib defects analogous to cerebro‐costo‐mandibular syndrome

Ribs are seldom affected by developmental disorders, however, multiple defects in rib structure are observed in the spliceosomal disease cerebro‐costo‐mandibular syndrome (CCMS). These defects include rib gaps, found in the posterior part of the costal shaft in multiple ribs, as well as missing ribs, shortened ribs and abnormal costotransverse articulations, which result in inadequate ventilation at birth and high perinatal mortality. The genetic mechanism of CCMS is a loss‐of‐function mutation in SNRPB, a component of the major spliceosome, and knockdown of this gene in vitro affects the activity of the Wnt/β‐catenin and bone morphogenic protein (BMP) pathways. The aim of the present study was to investigate whether altering these pathways in vivo can recapitulate rib gaps and other rib abnormalities in the model animal. Chick embryos were implanted with beads soaked in Wnt/β‐catenin and BMP pathway modulators during somitogenesis, and incubated until the ribs were formed. Some embryos were harvested in the preceding days for analysis of the chondrogenic marker Sox9, to determine whether pathway modulation affected somite patterning or chondrogenesis. Wnt/β‐catenin inhibition manifested characteristic rib phenotypes seen in CCMS, including rib gaps (P < 0.05) and missing ribs (P < 0.05). BMP pathway activation did not cause rib gaps but yielded missing rib (P < 0.01) and shortened rib phenotypes (P < 0.05). A strong association with vertebral phenotypes was also noted with BMP4 (P < 0.001), including scoliosis (P < 0.05), a feature associated with CCMS. Reduced expression of Sox9 was detected with Wnt/β‐catenin inhibition, indicating that inhibition of chondrogenesis precipitated the rib defects in the presence of Wnt/β‐catenin inhibitors. BMP pathway activators also reduced Sox9 expression, indicating an interruption of somite patterning in the manifestation of rib defects with BMP4. The present study demonstrates that local inhibition of the Wnt/β‐catenin and activation of the BMP pathway can recapitulate rib defects, such as those observed in CCMS. The balance of Wnt/β‐catenin and BMP in the somite is vital for correct rib morphogenesis, and alteration of the activity of these two pathways in CCMS may perturb this balance during somite patterning, leading to the observed rib defects