Glycine Cleavage System H Protein Is Essential for Embryonic Viability, Implying Additional Function Beyond the Glycine Cleavage System

Glycine cleavage system H protein (GCSH) is a component of the glycine cleavage system (GCS), a conserved protein complex that acts to decarboxylate glycine. Mutation of AMT or GLDC, encoding the GCS components aminomethyltransferase and glycine decarboxylase, can cause malformations of the developing CNS (neural tube defects (NTDs) and ventriculomegaly) as well as a post-natal life-limiting neurometabolic disorder, Non-Ketotic Hyperglycinemia. In contrast, it is unclear whether mutation of GCSH contributes to these conditions and we therefore investigated GCSH loss of function in mice. Mice that were heterozygous for a Gcsh null allele were viable and did not exhibit elevated plasma glycine. Moreover, heterozygous mutation of Gcsh did not increase the frequency of NTDs in Gldc mutant embryos. Homozygous Gcsh null mice were not recovered at post-natal stages. Analysis of litters at E8.5-10.5, revealed the presence of homozygous null embryos which were much smaller than littermates and had failed to develop beyond early post-implantation stages with no visible somites or head-folds. Hence, unlike null mutations of Gldc or Amt, which are compatible with embryonic survival despite the presence of NTDs, loss of Gcsh causes embryonic death prior to mid-gestation. Maternal supplementation with formate did not restore embryonic development beyond E7.5, suggesting that the primary cause of lethality was not loss of glycine cleavage activity or suppression of folate one-carbon metabolism. These findings suggest that GCSH has additional roles beyond function in the glycine cleavage system. We hypothesize that GCSH potentially acts in lipoylation of 2-oxoacid dehydrogenase proteins, as reported in bacteria

Subtracted Geometry From Harrison Transformations

We consider the rotating non-extremal black hole of N=2 D=4 STU supergravity carrying three magnetic charges and one electric charge. We show that its subtracted geometry is obtained by applying a specific SO(4,4) Harrison transformation on the black hole. As previously noted, the resulting subtracted geometry is a solution of the N=2 S=T=U supergravity.Comment: 11 pages main text; total 24 pages; Latex file; v2 typos corrected + ref added; v3 results significantly strengthened, changes in section 3.1 and appendix C, version to appear in JHE

First-order flows and stabilisation equations for non-BPS extremal black holes

We derive a generalised form of flow equations for extremal static and rotating non-BPS black holes in four-dimensional ungauged N = 2 supergravity coupled to vector multiplets. For particular charge vectors, we give stabilisation equations for the scalars, analogous to the BPS case, describing full known solutions. Based on this, we propose a generic ansatz for the stabilisation equations, which surprisingly includes ratios of harmonic functions.Comment: 27 pages; v2: presentation improved and references added as in the published versio

Numerical study of circulation on the inner Amazon Shelf

Author Posting. © Springer, 2008. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Ocean Dynamics 58 (2008): 187-198, doi:10.1007/s10236-008-0139-4.We studied the circulation on the coastal domain of the Amazon Shelf by applying the hydrodynamic module of the Estuarine and Coastal Ocean Model and Sediment Transport - ECOMSED. The first barotropic experiment aimed to explain the major bathymetric effects on tides and those generated by anisotropy in sediment distribution. We analyzed the continental shelf response of barotropic tides under realistic bottom stress parametrization (Cd), considering sediment granulometry obtained from a faciologic map, where river mud deposits and reworked sediments areas are well distinguished, among others classes of sediments. Very low Cd values were set in the fluid mud regions off the Amapa coast (1.0 10-4 ), in contrast to values around 3:5 10-3 for coarser sediment regions off the Para coast. Three-dimensional experiments represented the Amazon River discharge and trade winds, combined to barotropic tide influences and induced vertical mixing. The quasi-resonant response of the Amazon Shelf to the M2 tide act on the local hydrodynamics by increasing tidal admittance, along with tidal forcing at the shelf break and extensive fluid mud regions. Harmonic analysis of modeled currents agreed well with analysis of the AMASSEDS observational data set. Tidal-induced vertical shear provided strong homogenization of threshold waters, which are subject to a kind of hydraulic control due to the topographic steepness. Ahead of the hydraulic jump, the low-salinity plume is disconnected from the bottom and acquires negative vorticity, turning southeastward. Tides act as a generator mechanism and topography, via hydraulic control, as a maintainer mechanism for the low-salinity frontal zone positioning. Tidally induced southeastward plume fate is overwhelmed by northwestward trade winds so that, along with background circulation, probably play the most important role on the plume fate and variability over the Amazon Shelf

A Twist in the Dyon Partition Function

In four dimensional string theories with N=4 and N=8 supersymmetries one can often define twisted index in a subspace of the moduli space which captures additional information on the partition function than the ones contained in the usual helicity trace index. We compute several such indices in type IIB string theory on K3 x T^2 and T^6, and find that they share many properties with the usual helicity trace index that captures the spectrum of quarter BPS states in N=4 supersymmetric string theories. In particular the partition function is a modular form of a subgroup of Sp(2,Z) and the jumps across the walls of marginal stability are controlled by the residues at the poles of the partition function. However for large charges the logarithm of this index grows as 1/n times the entropy of a black hole carrying the same charges where n is the order of the symmetry generator that is used to define the twisted index. We provide a macroscopic explanation of this phenomenon using quantum entropy function formalism. The leading saddle point corresponding to the attractor geometry fails to contribute to the twisted index, but a Z_n orbifold of the attractor geometry produces the desired contribution.Comment: LaTeX file, 35 pages; v2: references adde

The effect of the electric field on lag phase, β-galactosidase production and plasmid stability of a recombinant Saccharomyces cerevisiae strain growing on lactose

Ethanol and β-galactosidase production from cheese whey may significantly contribute to minimise environmental problems while producing value from lowcost raw materials. In this work, the recombinant Saccharomyces cerevisiae NCYC869-A3/pVK1.1 flocculent strain expressing the lacA gene (coding for β-galactosidase) of Aspergillus niger under ADHI promoter and terminator was used. This strain shows high ethanol and β-galactosidase productivities when grown on lactose. Batch cultures were performed using SSlactose medium with 50 gL−1 lactose in a 2-L bioreactor under aerobic and microaerophilic conditions. Temperature was maintained at 30 °C and pH 4.0. In order to determine the effect of an electric field in the fermentation profile, titanium electrodes were placed inside the bioreactor and different electric field values (from 0.5 to 2 Vcm−1) were applied. For all experiments, β-galactosidase activity, biomass, protein, lactose, glucose, galactose and ethanol concentrations were measured. Finally, lag phase duration and specific growth rate were calculated. Significant changes in lag phase duration and biomass yield were found when using 2 Vcm−1. Results show that the electric field enhances the early stages of fermentation kinetics, thus indicating that its application may improve industrial fermentations’ productivity. The increase in electric field intensity led to plasmid instability thus decreasing β-galactosidase production.The authors gratefully acknowledge Fundacao para a Ciencia e a Tecnologia (Portugal) for the scholarships SFRH/BD/11230/2002 and SFRH/BDP/63831/2009 granted to authors I. Castro and C. Oliveira, respectively

Persistent DNA strand breaks induce a CAF-like phenotype in normal fibroblasts.

Cancer-associated fibroblasts (CAFs) are an emerging target for cancer therapy as they promote tumour growth and metastatic potential. However, CAF targeting is complicated by the lack of knowledge-based strategies aiming to selectively eliminate these cells. There is a growing body of evidence suggesting that a pro-inflammatory microenvironment (e.g. ROS and cytokines) promotes CAF formation during tumorigenesis, although the exact mechanisms involved remain unclear. In this study, we reveal that a prolonged pro-inflammatory stimulation causes a de facto deficiency in base excision repair, generating unrepaired DNA strand breaks and thereby triggering an ATF4-dependent reprogramming of normal fibroblasts into CAF-like cells. Based on the phenotype of in vitro-generated CAFs, we demonstrate that midostaurin, a clinically relevant compound, selectively eliminates CAF-like cells deficient in base excision repair and prevents their stimulatory role in cancer cell growth and migration