Phenotypic and genetic analysis of cognitive performance in Major Depressive Disorder in the Generation Scotland:Scottish Family Health Study

Abstract Lower performances in cognitive ability in individuals with Major Depressive Disorder (MDD) have been observed on multiple occasions. Understanding cognitive performance in MDD could provide a wider insight in the aetiology of MDD as a whole. Using a large, well characterised cohort (N = 7012), we tested for: differences in cognitive performance by MDD status and a gene (single SNP or polygenic score) by MDD interaction effect on cognitive performance. Linear regression was used to assess the association between cognitive performance and MDD status in a case-control, single-episode–recurrent MDD and control-recurrent MDD study design. Test scores on verbal declarative memory, executive functioning, vocabulary, and processing speed were examined. Cognitive performance measures showing a significant difference between groups were subsequently analysed for genetic associations. Those with recurrent MDD have lower processing speed versus controls and single-episode MDD (β =  −2.44, p = 3.6 × 10−04; β =  -2.86, p = 1.8 × 10−03, respectively). There were significantly higher vocabulary scores in MDD cases versus controls (β = 0.79, p = 2.0 × 10−06), and for recurrent MDD versus controls (β = 0.95, p  = 5.8 × 10−05). Observed differences could not be linked to significant single-locus associations. Polygenic scores created from a processing speed meta-analysis GWAS explained 1% of variation in processing speed performance in the single-episode versus recurrent MDD study (p = 1.7 × 10−03) and 0.5% of variation in the control versus recurrent MDD study (p = 1.6 × 10−10). Individuals with recurrent MDD showed lower processing speed and executive function while showing higher vocabulary performance. Within MDD, persons with recurrent episodes show lower processing speed and executive function scores relative to individuals experiencing a single episode

Efficient control of atmospheric sulfate production based on three formation regimes

The formation of sulfate (SO₄²⁻) in the atmosphere is linked chemically to its direct precursor, sulfur dioxide (SO₂), through several key oxidation paths for which nitrogen oxides or NO_x (NO and NO₂) play essential roles. Here we present a coherent description of the dependence of SO₄²⁻ formation on SO₂ and NO_x under haze-fog conditions, in which fog events are accompanied by high aerosol loadings and fog-water pH in the range of 4.7–6.9. Three SO₄²⁻ formation regimes emerge as defined by the role played by NO_x. In the low-NO_x regime, NO_x act as catalyst for HO_x, which is a major oxidant for SO₂, whereas in the high-NO_x regime, NO₂ is a sink for HO_x. Moreover, at highly elevated NO_x levels, a so-called NO₂-oxidant regime exists in which aqueous NO₂ serves as the dominant oxidant of SO₂. This regime also exists under clean fog conditions but is less prominent. Sensitivity calculations using an emission-driven box model show that the reduction of SO₄²⁻ is comparably sensitive to the reduction of SO₂ and NO_x emissions in the NO₂-oxidant regime, suggesting a co-reduction strategy. Formation of SO₄²⁻ is relatively insensitive to NO_x reduction in the low-NO_x regime, whereas reduction of NO_x actually leads to increased SO₄²⁻ production in the intermediate high-NO_x regime

Knockdown of ZNF268, which Is Transcriptionally Downregulated by GATA-1, Promotes Proliferation of K562 Cells

The human ZNF268 gene encodes a typical KRAB-C2H2 zinc finger protein that may participate in hematopoiesis and leukemogenesis. A recent microarray study revealed that ZNF268 expression continuously decreases during erythropoiesis. However, the molecular mechanisms underlying regulation of ZNF268 during hematopoiesis are not well understood. Here we found that GATA-1, a master regulator of erythropoiesis, repressed the promoter activity and transcription of ZNF268. Electrophoretic mobility shift assays and chromatin immunoprecipitation assays showed that GATA-1 directly bound to a GATA binding site in the ZNF268 promoter in vitro and in vivo. Knockdown of ZNF268 in K562 erythroleukemia cells with specific siRNA accelerated cellular proliferation, suppressed apoptosis, and reduced expression of erythroid-specific developmental markers. It also promoted growth of subcutaneous K562-derived tumors in nude mice. These results suggest that ZNF268 is a crucial downstream target and effector of GATA-1. They also suggest the downregulation of ZNF268 by GATA-1 is important in promoting the growth and suppressing the differentiation of K562 erythroleukemia cells

The association of two single nucleotide polymorphisms (SNPs) in growth hormone (GH) gene with litter size and superovulation response in goat-breeds

Two active mutations (A 781 G and A 1575 G) in growth hormone (GH) gene, and their associations with litter size (LS), were investigated in both a high prolificacy (Matou, n = 182) and a low prolificacy breed (Boer, n = 352) by using the PCR-RFLP method. Superovulation experiments were designed in 57 dams, in order to evaluate the effect of different genotypes of the GH gene on superovulation response. Two genotypes (AA and AB, CC and CD) in each mutation were detected in these two goat breeds. Neither BB nor DD homozygous genotypes were observed. The genotypic frequencies of AB and CC were significantly higher than those of AA and CD. In the third parity, Matou dams with AB or CC genotypes had significantly larger litter sizes than those with AA and CD (p < 0.05). On combining the two loci, both Matou and Boer dams with ABCD genotype had the largest litter sizes when compared to the other genotypes (p < 0.05). When undergoing like superovulation treatments, a significantly higher number of corpora lutea and ova, with a lower incidence of ovarian cysts, were harvested in the AB and CC genotypes than in AA and CD. These results show that the two loci of GH gene are highly associated with abundant prolificacy and superovulation response in goat breeds

A Fine-Mapping Study of 7 Top Scoring Genes from a GWAS for Major Depressive Disorder

Major depressive disorder (MDD) is a psychiatric disorder that is characterized -amongst others- by persistent depressed mood, loss of interest and pleasure and psychomotor retardation. Environmental circumstances have proven to influence the aetiology of the disease, but MDD also has an estimated 40% heritability, probably with a polygenic background. In 2009, a genome wide association study (GWAS) was performed on the Dutch GAIN-MDD cohort. A non-synonymous coding single nucleotide polymorphism (SNP) rs2522833 in the PCLO gene became only nominally significant after post-hoc analysis with an Australian cohort which used similar ascertainment. The absence of genome-wide significance may be caused by low SNP coverage of genes. To increase SNP coverage to 100% for common variants (m.a.f.>0.1, r2>0.8), we selected seven genes from the GAIN-MDD GWAS: PCLO, GZMK, ANPEP, AFAP1L1, ST3GAL6, FGF14 and PTK2B. We genotyped 349 SNPs and obtained the lowest P-value for rs2715147 in PCLO at P = 6.8E−7. We imputed, filling in missing genotypes, after which rs2715147 and rs2715148 showed the lowest P-value at P = 1.2E−6. When we created a haplotype of these SNPs together with the non-synonymous coding SNP rs2522833, the P-value decreased to P = 9.9E−7 but was not genome wide significant. Although our study did not identify a more strongly associated variant, the results for PCLO suggest that the causal variant is in high LD with rs2715147, rs2715148 and rs2522833

Optical control of L-Type Ca2+ channels using a diltiazem photoswitch

L-type Ca2+ channels (LTCCs) play a crucial role in excitation-contraction coupling and release of hormones from secretory cells. They are targets of antihypertensive and antiarrhythmic drugs such as diltiazem. Here, we present a photoswitchable diltiazem, FHU-779, which can be used to reversibly block endogenous LTCCs by light. FHU-779 is as potent as diltiazem and can be used to place pancreatic β-cell function and cardiac activity under optical control

Hot disc of the Swift J0243.6+6124 revealed by Insight-HXMT

We report on analysis of observations of the bright transient X-ray pulsar (XRP) Swift J0243.6+6124 obtained during its 2017-2018 giant outburst with Insight-HXMT, NuSTAR, and Swift observatories. We focus on the discovery of a sharp state transition of the timing and spectral properties of the source at super-Eddington accretion rates, which we associate with the transition of the accretion disc to a radiation pressure dominated state, the first ever directly observed for magnetized neutron star. This transition occurs at slightly higher luminosity compared to already reported transition of the source from sub- to supercritical accretion regime associate with onset of an accretion column. We argue that this scenario can only be realized for comparatively weakly magnetized neutron star, not dissimilar to other ultra-luminous X-ray pulsars, which accrete at similar rates. Further evidence for this conclusion is provided by the non-detection of the transition to the propeller state in quiescence which strongly implies compact magnetosphere and thus rules out magnetar-like fields

Switches between accretion structures during flares in 4U 1901+03

We report on our analysis of the 2019 outburst of the X-ray accreting pulsar 4U 1901+03 observed with Insight-HXMT and NICER. Both spectra and pulse profiles evolve significantly in the decaying phase of the outburst. Dozens of flares are observed throughout the outburst. They are more frequent and brighter at the outburst peak. We find that the flares, which have a duration from tens to hundreds of seconds, are generally brighter than the persistent emission by a factor of similar to 1.5. The pulse-profile shape during the flares can be significantly different from that of the persistent emission. In particular, a phase shift is clearly observed in many cases. We interpret these findings as direct evidence of changes of the pulsed beam pattern, due to transitions between the sub- and supercritical accretion regimes on a short time-scale. We also observe that at comparable luminosities the flares' pulse profiles are rather similar to those of the persistent emission. This indicates that the accretion on the polar cap of the neutron star is mainly determined by the luminosity, i.e. the mass accretion rate