A Critical Role for Glycine Transporters in Hyperexcitability Disorders

Defects in mammalian glycinergic neurotransmission result in a complex motor disorder characterized by neonatal hypertonia and an exaggerated startle reflex, known as hyperekplexia (OMIM 149400). This affects newborn children and is characterized by noise or touch-induced seizures that result in muscle stiffness and breath-holding episodes. Although rare, this disorder can have serious consequences, including brain damage and/or sudden infant death. The primary cause of hyperekplexia is missense and non-sense mutations in the glycine receptor (GlyR) α1 subunit gene (GLRA1) on chromosome 5q33.1, although we have also discovered rare mutations in the genes encoding the GlyR β subunit (GLRB) and the GlyR clustering proteins gephyrin (GPNH) and collybistin (ARHGEF9). Recent studies of the Na+/Cl−-dependent glycine transporters GlyT1 and GlyT2 using mouse knockout models and human genetics have revealed that mutations in GlyT2 are a second major cause of hyperekplexia, while the phenotype of the GlyT1 knockout mouse resembles a devastating neurological disorder known as glycine encephalopathy (OMIM 605899). These findings highlight the importance of these transporters in regulating the levels of synaptic glycine

The Extended Blue Continuum and Line Emission around the Central Radio Galaxy in Abell 2597

We present results from detailed imaging of the centrally dominant radio elliptical galaxy in the cooling flow cluster Abell 2597, using data obtained with the Wide Field and Planetary Camera 2 (WFPC2) on the Hubble Space Telescope (HST). This object is one of the archetypal "blue-lobed" cooling flow radio elliptical galaxies, also displaying a luminous emission-line nebula, a compact radio source, and a significant dust lane and evidence of molecular gas in its center. We show that the radio source is surrounded by a complex network of emission-line filaments, some of which display a close spatial association with the outer boundary of the radio lobes. We present a detailed analysis of the physical properties of ionized and neutral gas associated with the radio lobes, and show that their properties are strongly suggestive of direct interactions between the radio plasma and ambient gas. We resolve the blue continuum emission into a series of knots and clumps, and present evidence that these are most likely due to regions of recent star formation. We investigate several possible triggering mechanisms for the star formation, including direct interactions with the radio source, filaments condensing from the cooling flow, or the result of an interaction with a gas-rich galaxy, which may also have been responsible for fueling the active nucleus. We propose that the properties of the source are plausibly explained in terms of accretion of gas by the cD during an interaction with a gas-rich galaxy, which combined with the fact that this object is located at the center of a dense, high-pressure ICM can account for the high rates of star formation and the strong confinement of the radio source.Comment: Astrophysical Journal, in press, 34 pages, includes 6 PostScript figures. Latex format, uses aaspp4.sty and epsf.sty file

The glycinergic system in human startle disease: a genetic screening approach.

Human startle disease, also known as hyperekplexia (OMIM 149400), is a paroxysmal neurological disorder caused by defects in glycinergic neurotransmission. Hyperekplexia is characterised by an exaggerated startle reflex in response to tactile or acoustic stimuli which first presents as neonatal hypertonia, followed in some with episodes of life-threatening infantile apnoea. Genetic screening studies have demonstrated that hyperekplexia is genetically heterogeneous with several missense and nonsense mutations in the postsynaptic glycine receptor (GlyR) alpha1 subunit gene (GLRA1) as the primary cause. More recently, missense, nonsense and frameshift mutations have also been identified in the glycine transporter GlyT2 gene, SLC6A5, demonstrating a presynaptic component to this disease. Further mutations, albeit rare, have been identified in the genes encoding the GlyR beta subunit (GLRB), collybistin (ARHGEF9) and gephyrin (GPHN) - all of which are postsynaptic proteins involved in orchestrating glycinergic neurotransmission. In this review, we describe the clinical ascertainment aspects, phenotypic considerations and the downstream molecular genetic tools utilised to analyse both presynaptic and postsynaptic components of this heterogeneous human neurological disorder. Moreover, we will describe how the ancient startle response is the preserve of glycinergic neurotransmission and how animal models and human hyperekplexia patients have provided synergistic evidence that implicates this inhibitory system in the control of startle reflexes

A Deep HST Search for Escaping Lyman Continuum Flux at z~1.3: Evidence for an Evolving Ionizing Emissivity

We have obtained deep Hubble Space Telescope far-UV images of 15 starburst galaxies at z~1.3 in the GOODS fields to search for escaping Lyman continuum photons. These are the deepest far-UV images m_{AB}=28.7, 3\sigma, 1" diameter) over this large an area (4.83 arcmin^2) and provide the best escape fraction constraints for any galaxy at any redshift. We do not detect any individual galaxies, with 3\sigma limits to the Lyman Continuum (~700 \AA) flux 50--149 times fainter (in f_nu) than the rest-frame UV (1500 \AA) continuum fluxes. Correcting for the mean IGM attenuation (factor ~2), as well as an intrinsic stellar Lyman Break (~3), these limits translate to relative escape fraction limits of f_{esc,rel}<[0.03,0.21]. The stacked limit is f_{esc,rel}(3\sigma)<0.02. We use a Monte Carlo simulation to properly account for the expected distribution of IGM opacities. When including constraints from previous surveys at z~1.3 we find that, at the 95% confidence level, no more than 8% of star--forming galaxies at z~1.3 can have relative escape fractions greater than 0.50. Alternatively, if the majority of galaxies have low, but non-zero, escaping Lyman Continuum, the escape fraction can not be more than 0.04. Both the stacked limits, and the limits from the Monte Carlo simulation suggest that the average ionizing emissivity (relative to non-ionizing UV emissivity) at z~1.3 is significantly lower than has been observed in Lyman Break Galaxies (LBGs) at z~3. If the ionizing emissivity of star-forming galaxies is in fact increasing with redshift, it would help to explain the high photoionization rates seen in the IGM at z>4 and reionization of the intergalactic medium at z>6. [Abridged]Comment: Submitted to ApJ (Nov. 6) Comments Welcome. 11 pages, 8 figure

CD4(+)CD25(+)FOXP3(+) Regulatory T Cells Suppress Anti-Tumor Immune Responses in Patients with Colorectal Cancer

BACKGROUND: A wealth of evidence obtained using mouse models indicates that CD4(+)CD25(+)FOXP3(+) regulatory T cells (Treg) maintain peripheral tolerance to self-antigens and also inhibit anti-tumor immune responses. To date there is limited information about CD4(+) T cell responses in patients with colorectal cancer (CRC). We set out to measure T cell responses to a tumor-associated antigen and examine whether Treg impinge on those anti-tumor immune responses in CRC patients. METHODOLOGY AND PRINCIPAL FINDINGS: Treg were identified and characterized as CD4(+)CD25(+)FOXP3(+) using flow cytometry. An increased frequency of Treg was demonstrated in both peripheral blood and mesenteric lymph nodes of patients with colorectal cancer (CRC) compared with either healthy controls or patients with inflammatory bowel disease (IBD). Depletion of Treg from peripheral blood mononuclear cells (PBMC) of CRC patients unmasked CD4(+) T cell responses, as observed by IFNγ release, to the tumor associated antigen 5T4, whereas no effect was observed in a healthy age-matched control group. CONCLUSIONS/SIGNIFICANCE: Collectively, these data demonstrate that Treg capable of inhibiting tumor associated antigen-specific immune responses are enriched in patients with CRC. These results support a rationale for manipulating Treg to enhance cancer immunotherapy

The time is now: Achieving FH paediatric screening across Europe – The Prague Declaration

ReviewFamilial Hypercholesterolaemia (FH) is severely under-recognized, under-diagnosed and under-treated in Europe, leading to a significantly higher risk of premature cardiovascular diseases in those affected. FH stands for inherited, very high cholesterol and affects 1:300 individuals regardless of their age, race, sex, and lifestyle, making it the most common inherited metabolic disorder and a non-modifiable cardiovascular disease risk factor in the world..info:eu-repo/semantics/publishedVersio

The GDP-GTP exchange factor collybistin: an essential determinant of neuronal gephyrin clustering

Glycine receptors (GlyRs) and specific subtypes of GABAA receptors are clustered at synapses by the multidomain protein gephyrin, which in turn is translocated to the cell membrane by the GDP-GTP exchange factor collybistin. We report the characterization of several new variants of collybistin, which are created by alternative splicing of exons encoding an N-terminal src homology 3 (SH3) domain and three alternate C termini (CB1, CB2, and CB3). The presence of the SH3 domain negatively regulates the ability of collybistin to translocate gephyrin to submembrane microaggregates in transfected mammalian cells. Because the majority of native collybistin isoforms appear to harbor the SH3 domain, this suggests that collybistin activity may be regulated by protein-protein interactions at the SH3 domain. We localized the binding sites for collybistin and the GlyR {beta} subunit to the C-terminal MoeA homology domain of gephyrin and show that multimerization of this domain is required for collybistin-gephyrin and GlyR-gephyrin interactions. We also demonstrate that gephyrin clustering in recombinant systems and cultured neurons requires both collybistin-gephyrin interactions and an intact collybistin pleckstrin homology domain. The vital importance of collybistin for inhibitory synaptogenesis is underlined by the discovery of a mutation (G55A) in exon 2 of the human collybistin gene (ARHGEF9) in a patient with clinical symptoms of both hyperekplexia and epilepsy. The clinical manifestation of this collybistin missense mutation may result, at least in part, from mislocalization of gephyrin and a major GABAA receptor subtype

Weak or no association of TCF7L2 variants with Type 2 diabetes risk in an Arab population

<p>Abstract</p> <p>Background</p> <p>The rs7903146 and rs12255372 variants of <it>TCF7L2 </it>have been strongly associated with type 2 diabetes (T2D) risk in most populations studied to date. Meta-analysis of 27 different studies has resulted in a global OR of 1.46 [1.42–1.51] (rs7903146 variant). Thus far, despite a high incidence of T2D, the role of this variant in Arabs has not been established.</p> <p>Methods</p> <p>We performed a case-control association study using 522 Saudi T2D patients (WHO criteria), and 346 controls (age > 60; fasting plasma glucose < 7 mmol/L). Genotyping was performed by pyrosequencing. Statistical analyses were performed using SPSS version 13.0 for Windows (SPSS, Chicago, IL, USA).</p> <p>Results</p> <p>For rs7903146, the T allele frequency of the cases (0.415) was not different from that observed in the controls (0.405). The crude odds ratio (OR) was 1.04 with a 95% CI of 0.86–1.27 (P = 0.675). For rs12255372, the T allele frequency of the cases (0.368) was not different from that observed in the controls (0.355). Retrospective power calculations based upon an OR of 1.46 reported in a comprehensive meta-analysis of <it>TCF7L2 </it>risk, indicated this study was sufficiently powered (96.92%; α = 0.05) to detect an effect of similar magnitude to that reported for rs7903146.</p> <p>Conclusion</p> <p>Our study is consistent with weak or no association of T2D in Arabs with the two <it>TCF7L2 </it>variants, however it cannot rule out an effect of other SNPs in this gene. Future studies in this population are required to confirm our findings and may indicate the presence of yet to be defined genetic risk factors for T2D.</p