New roles for the major human 3'-5' exonuclease TREX1 in human disease

Aicardi-Goutières syndrome (AGS), Systemic Lupus Erythematosus (SLE), Familial Chilblain Lupus (FCL) and Retinal Vasculopathy and Cerebral Leukodystrophy (RVCL) {a new term encompassing three independently described conditions with a common etiology—Cerebroretinal Vasculopathy (CRV), Hereditary Vascular Retinopathy (HVR) and Hereditary Endotheliopathy, Retinopathy and Nephropathy (HERNS)}—have previously been regarded as distinct entities. However, recent genetic analysis has demonstrated that each of these diseases maps to chromosome 3p21 and can be caused by mutations in TREX1, the major human 3'–5' exonuclease. In this review, we discuss the putative functions of TREX1 in relationship to the clinical, genetic and functional characteristics of each of these conditions

Association Analysis of Canonical Wnt Signalling Genes in Diabetic Nephropathy

Several studies have provided compelling evidence implicating the Wnt signalling pathway in the pathogenesis of diabetic nephropathy. Gene expression profiles associated with renal fibrosis have been attenuated through Wnt pathway modulation in model systems implicating Wnt pathway members as potential therapeutic targets for the treatment of diabetic nephropathy. We assessed tag and potentially functional single nucleotide polymorphisms (SNPs; n = 31) in four key Wnt pathway genes (CTNNB1, AXIN2, LRP5 and LRP6) for association with diabetic nephropathy using a case-control design.SNPs were genotyped using Sequenom or Taqman technologies in 1351 individuals with type 1 diabetes (651 cases with nephropathy and 700 controls without nephropathy). Cases and controls were white and recruited from the UK and Ireland. Association analyses were performed using PLINK, to compare allele and haplotype frequencies in cases and controls. Adjustment for multiple testing was performed by permutation testing.Following logistic regression analysis adjusted by collection centre, duration of T1D, and average HbA1c as covariates, a single SNP in LRP6 (rs1337791) was significantly associated with DN (OR = 0.74; CI: 0.57-0.97; P = 0.028), although this was not maintained following correction for multiple testing. Three additional SNPs (rs2075241 in LRP6; rs3736228 and rs491347 both in LRP5) were marginally associated with diabetic nephropathy, but none of the associations were replicated in an independent dataset. Haplotype and subgroup analysis (according to duration of diabetes, and end-stage renal disease) also failed to reveal an association with diabetic nephropathy.Our results suggest that analysed common variants in CTNNB1, AXIN2, LRP5 and LRP6 are not strongly associated with diabetic nephropathy in type 1 diabetes among white individuals. Our findings, however, cannot entirely exclude these genes or other members of the Wnt pathway, from involvement in the pathogenesis of diabetic nephropathy as our study had limited power to detect variants with small effect size

The psychiatric risk gene transcription factor 4 (TCF4) regulates neurodevelopmental pathways associated with schizophrenia, autism, and intellectual disability

Background Common genetic variants in and around the gene encoding transcription factor 4 (TCF4) are associated with an increased risk of schizophrenia. Conversely, rare damaging TCF4 mutations cause Pitt–Hopkins syndrome and have also been found in individuals with intellectual disability (ID) and autism spectrum disorder (ASD). Methods Chromatin immunoprecipitation and next generation sequencing were used to identify the genomic targets of TCF4. These data were integrated with expression, epigenetic and disease gene sets using a range of computational tools. Results We identify 10604 TCF4 binding sites in the genome that were assigned to 5437 genes. De novo motif enrichment found that most TCF4 binding sites contained at least one E-box (5′-CAtcTG). Approximately 77% of TCF4 binding sites overlapped with the H3K27ac histone modification for active enhancers. Enrichment analysis on the set of TCF4 targets identified numerous, highly significant functional clusters for pathways including nervous system development, ion transport and signal transduction, and co-expression modules for genes associated with synaptic function and brain development. Importantly, we found that genes harboring de novo mutations in schizophrenia (P = 5.3 × 10−7), ASD (P = 2.5 × 10−4), and ID (P = 7.6 × 10−3) were also enriched among TCF4 targets. TCF4 binding sites were also found at other schizophrenia risk loci including the nicotinic acetylcholine receptor cluster, CHRNA5/CHRNA3/CHRNB4 and SETD1A. Conclusions These data demonstrate that TCF4 binding sites are found in a large number of neuronal genes that include many genetic risk factors for common neurodevelopmental disorders

Analytical characterization of bioactive N-benzyl-substituted phenethylamines and 5-methoxytryptamines

RATIONALE: Substances based on the N-(2-methoxybenzyl)phenethylamine template (‘NBOMe’ derivatives) play an important role in medicinal research but some of these derivatives have also appeared as ‘research chemicals’ for recreational use which attracted attention worldwide. A major challenge associated with newly emerging substances includes the lack of analytical data and the ability to correctly identify positional isomers. METHODS: Six N-benzylphenethylamines based on the 2,5-dimethoxy-4-iodophenethylamine structure (‘25I’) and twelve substituted N-benzyl-5-methoxytryptamines (‘5MT’) have been prepared and extensively characterized. Techniques used for characterization were gas chromatography ion trap mass spectrometry in electron and chemical ionization mode, liquid chromatography diode array detection (DAD), infrared spectroscopy, electrospray high mass accuracy quadrupole time-of-flight tandem mass spectrometry, and triple quadrupole tandem mass spectrometry. RESULTS: The characterization of eighteen ‘NBOMe’ analogs provided a comprehensive collection of chromatographic and spectral data. Four groups of three positional isomers, i.e. 25I-NB2OMe, 25I-NB3OMe, 25I-NB4OMe, 25I-NB2B, 25INB3B, 25I-NB4B and their 5-methoxytryptamine counterparts, were included and assessed for ability to differentiate between them. Six meta-substituted N-benzyl derivatives of 5-methoxytryptamine (CF3, F, CH3, Cl, I, SCH3) were also studied. CONCLUSIONS: The implementation of mass spectral techniques was helpful for the differentiation between isomers, for example, when considering the difference in a number of ion ratios. This was considered beneficial in cases where chromatographic separation was only partially achieved under liquid chromatography (LC) conditions. The use of LC/DAD analysis was also found to be valuable for this particular purpose, which confirmed the integrative value of complementary techniques for areas related to forensic toxicology

'This is what democracy looks like' : New Labour's blind spot and peripheral vision

New Labour in government since 1997 has been roundly criticized for not possessing a clear, coherent and consistent democratic vision. The absence of such a grand vision has resulted, from this critical perspective, in an absence of 'joined-up' thinking about democracy in an evolving multi-level state. Tensions have been all too apparent between the government's desire to exert central direction - manifested in its most pathological form as 'control freakery' - and its democratising initiatives derived from 'third-way' obsessions with 'decentralising', 'empowering' and 'enabling'. The purpose of this article is to examine why New Labour displayed such apparently impaired democratic vision and why it appeared incapable of conceiving of democratic reform 'in the round'. This article seeks to explain these apparent paradoxes, however, through utilising the notion of 'macular degeneration'. In this analysis, the perceived democratic blind spot of New Labour at Westminster is connected to a democratic peripheral vision, which has envisaged innovative participatory and decentred initiatives in governance beyond Westminster

Sources, perceived usefulness and understanding of information disseminated to families who entered home quarantine during the H1N1 pandemic in Victoria, Australia: a cross-sectional study

Background Voluntary home quarantine of cases and close contacts was the main non-pharmaceutical intervention used to limit transmission of pandemic (H1N1) 2009 influenza (pH1N1) in the initial response to the outbreak of the disease in Australia. The effectiveness of voluntary quarantine logically depends on affected families having a clear understanding of what they are being asked to do. Information may come from many sources, including the media, health officials, family and friends, schools, and health professionals. We report the extent to which families who entered home quarantine received and used information on what they were supposed to do. Specifically, we outline their sources of information; the perceived usefulness of each source; and associations between understanding of recommendations and compliance. Methods Cross-sectional survey administered via the internet and computer assisted telephone interview to families whose school children were recommended to go into home quarantine because they were diagnosed with H1N1 or were a close contact of a case. The sample included 314 of 1157 potentially eligible households (27% response rate) from 33 schools in metropolitan Melbourne. Adjusting for clustering within schools, we describe self-reported \u27understanding of what they were meant to do during the quarantine period\u27; source of information (e.g. health department) and usefulness of information. Using logistic regression we examine whether compliance with quarantine recommendations was associated with understanding and the type of information source used. Results Ninety per cent understood what they were meant to do during the quarantine period with levels of understanding higher in households with cases (98%, 95% CI 93%-99% vs 88%, 95% CI 84%-91%, P = 0.006). Over 87% of parents received information about quarantine from the school, 63% from the health department and 44% from the media. 53% of households were fully compliant and there was increased compliance in households that reported that they understood what they were meant to do (Odds Ratio 2.27, 95% CI 1.35-3.80). Conclusions It is critical that public health officials work closely with other government departments and media to provide clear, consistent and simple information about what to do during quarantine as high levels of understanding will maximise compliance in the quarantined population

JWST MIRI flight performance: The Medium-Resolution Spectrometer

The Medium-Resolution Spectrometer (MRS) provides one of the four operating modes of the Mid-Infrared Instrument (MIRI) on board the James Webb Space Telescope (JWST). The MRS is an integral field spectrometer, measuring the spatial and spectral distributions of light across the 5-28 $\mu m$ wavelength range with a spectral resolving power between 3700-1300. We present the MRS's optical, spectral, and spectro-photometric performance, as achieved in flight, and we report on the effects that limit the instrument's ultimate sensitivity. The MRS flight performance has been quantified using observations of stars, planetary nebulae, and planets in our Solar System. The precision and accuracy of this calibration was checked against celestial calibrators with well-known flux levels and spectral features. We find that the MRS geometric calibration has a distortion solution accuracy relative to the commanded position of 8 mas at 5 $\mu m$ and 23 mas at 28 $\mu m$. The wavelength calibration is accurate to within 9 km/sec at 5 $\mu m$ and 27 km/sec at 28 $\mu m$. The uncertainty in the absolute spectro-photometric calibration accuracy was estimated at 5.6 +- 0.7 %. The MIRI calibration pipeline is able to suppress the amplitude of spectral fringes to below 1.5 % for both extended and point sources across the entire wavelength range. The MRS point spread function (PSF) is 60 % broader than the diffraction limit along its long axis at 5 $\mu m$ and is 15 % broader at 28 $\mu m$. The MRS flight performance is found to be better than prelaunch expectations. The MRS is one of the most subscribed observing modes of JWST and is yielding many high-profile publications. It is currently humanity's most powerful instrument for measuring the mid-infrared spectra of celestial sources and is expected to continue as such for many years to come.Comment: 16 pages, 21 figure