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, r(2)>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.     

Family-Environmental Factors Associated with Attention Deficit Hyperactivity Disorder in Chinese Children: A Case-Control Study

Background

Attention deficit hyperactivity disorder (ADHD) is one of the most common psychiatric disorders, affecting an estimated 5 to 12% of school-aged children worldwide. From 15 to 19 million Chinese children suffer from ADHD. The aim of this study was to investigate the association between family-environmental factors and ADHD in a sample of Chinese children.

Methods

A pair-matched, case-control study was conducted with 161 ADHD children and 161 non-ADHD children of matching age and sex, all from 5–18 years of age. The ADHD subjects and the normal controls were all evaluated via structured diagnostic interviews. We examined the association between family-environmental factors and ADHD using the conditional multiple logistic regression with backward stepwise selection to predict the associated factors of ADHD.

Results

Having experienced emotional abuse and being a single child were both significant factors associated with children diagnosed with ADHD. ADHD subjects were more likely to have suffered from emotional abuse (OR = 11.09, 95% CI = 2.15–57.29, P = 0.004) and have been a single child in the family (OR = 6.32, 95% CI = 2.09–19.14, P = 0.001) when compared to normal controls. The results were not modified by other confounding factors.

Conclusion

Our findings provide evidence that family-environmental factors are associated with ADHD among children in China. These findings, if confirmed by future research, may help to decrease ADHD by increasing the awareness of the effects of childhood emotional abuse.     

Functional amyloids in insect immune response

The innate immune system of insects consists of humoural and cellular responses that provide protection against invading pathogens and parasites. Defence reactions against these latter include encapsulation by immune cells and targeted melanin deposition, which is usually restricted to the surface of the foreign invader, to prevent systemic damage. Here we show that a protein produced by haemocytes of Heliothis virescens (Lepidoptera, Noctuidae) larvae, belonging to XendoU family, generates amyloid fibrils, which accumulate in large cisternae of the rough endoplasmic reticulum and are released upon immune challenge, to form a layer coating non-self objects entering the haemocoel. This amyloid layer acts as a molecular scaffold that promotes localised melanin synthesis and the adhesion of immune cells around the non-self intruder during encapsulation response. Our results demonstrate a new functional role for these protein aggregates that are commonly associated with severe human diseases. We predict that insects will offer new powerful experimental systems for studying inducible amyloidogenesis, which will likely provide fresh perspectives for its prevention.     

SIRT3 gene expression: a link between inherited mitochondrial DNA variants and oxidative stress

Signaling pathways between mitochondrial and nuclear genomes are activated to preserve cellular homeostasis, especially in the event of stress. Using cybrid cell lines, we investigated whether inherited mitochondrial DNA (mtDNA) variants modulate the expression profiles of mammalian sirtuins (SIRT1-7) under oxidative stress conditions. We found that the expression of the SIRT3 gene was down-regulated in cybrids harboring mtDNA of the J haplogroup, which correlated with mitochondrial function, resulting in a decline of NAD(+)/NADH and ATP levels. Overall, the data reported here highlight a link between SIRT3, mitochondrial DNA variability and mitochondrial functionality, three fundamental components of the cellular stress response.     

The usefulness of combining traditional sperm assessments with in vitro heterospermic insemination to identify bulls of low fertility as estimated in vivo

To date, no single in vitro assessment can estimate bull fertility. This research was aimed at evaluating the ability of a series of laboratory assessments to assign 50 Holstein Friesian bulls grouped as low (ER-NRR<-1.5), medium (-0.5相似文献   

First chemoenzymatic synthesis of (+)-2-carboxypyrrolidine-3-acetic acid, the nucleus of kainoid amino acids

The distinctive nucleus of kainoid amino acids, (2S,3R)-(+)-2-carboxypyrrolidine-3-acetic acid 6, was synthesized by a chemoenzymatic process, exploiting the diastereomeric cis/trans methyl pyroglutamate derivatives 10a-c/11a-c as key intermediates. These mixtures, when subjected to a kinetic resolution mediated by α-chymotrypsin, reacted diastereo-, regio-, and enantioselectively to give the trans derivatives (+)-10a-c possessing the correct (2S,3R) configuration. Subsequently, the desired product (2S,3R)-(+)-6 could be obtained after well-established transformations.     

Isolation of Squarebop I bacteriorhodopsin from biomass of coastal salterns

Squarebop I bacteriorhodopsin is a light-activated proton pump present in the membranes of the archeon Haloquadratum walsbyi, a square-shaped organism representing 50-60% of microbial population in the crystallizer ponds of the coastal salterns. Here we describe: (1) the operating mode of a bioreactor designed to concentrate the saltern biomass through a microfiltration process based on polyethersulfone hollow fibers; (2) the isolation of Squarebop I bacteriorhodopsin from solubilized biomass by means of a single chromatographic step; (3) tightly bound lipids to the isolated and purified protein as revealed by MALDI-TOF/MS analysis; (4) the photoactivity of Squarebop I bacteriorhodopsin isolated from environmental samples by flash spectroscopy. Yield of the isolation process is 150 μg of Squarebop I bacteriorhodopsin from 1l of 25-fold concentrated biomass. The possibility of using the concentrated biomass of salterns, as renewable resource for the isolation of functional bacteriorhodopsin and possibly other valuable bioproducts, is briefly discussed.     

Skin langerin+ dendritic cells transport intradermally injected anti-DEC-205 antibodies but are not essential for subsequent cytotoxic CD8+ T cell responses

Incorporation of Ags by dendritic cells (DCs) increases when Ags are targeted to endocytic receptors by mAbs. We have previously demonstrated in the mouse that mAbs against C-type lectins administered intradermally are taken up by epidermal Langerhans cells (LCs), dermal Langerin(neg) DCs, and dermal Langerin(+) DCs in situ. However, the relative contribution of these skin DC subsets to the induction of immune responses after Ag targeting has not been addressed in vivo. We show in this study that murine epidermal LCs and dermal DCs transport intradermally injected mAbs against the lectin receptor DEC-205/CD205 in vivo. Skin DCs targeted in situ with mAbs migrated through lymphatic vessels in steady state and inflammation. In the skin-draining lymph nodes, targeting mAbs were found in resident CD8α(+) DCs and in migrating skin DCs. More than 70% of targeted DCs expressed Langerin, including dermal Langerin(+) DCs and LCs. Numbers of targeted skin DCs in the nodes increased 2-3-fold when skin was topically inflamed by the TLR7 agonist imiquimod. Complete removal of the site where OVA-coupled anti-DEC-205 had been injected decreased endogenous cytotoxic responses against OVA peptide-loaded target cells by 40-50%. Surprisingly, selective ablation of all Langerin(+) skin DCs in Langerin-DTR knock-in mice did not affect such responses independently of the adjuvant chosen. Thus, in cutaneous immunization strategies where Ag is targeted to DCs, Langerin(+) skin DCs play a major role in transport of anti-DEC-205 mAb, although Langerin(neg) dermal DCs and CD8α(+) DCs are sufficient to subsequent CD8(+) T cell responses.