To evaluate the contribution of non-synonymous-coding variants of known familial and genome-wide association studies (GWAS)-linked genes for Parkinson's disease (PD) to PD risk in the East Asian ...population, we sequenced all the coding exons of 39 PD-related disease genes and evaluated the accumulation of rare non-synonymous-coding variants in 375 early-onset PD cases and 399 controls. We also genotyped 782 non-synonymous-coding variants of these genes in 710 late-onset PD cases and 9046 population controls. Significant enrichment of LRRK2 variants was observed in both early- and late-onset PD (odds ratio = 1.58; 95% confidence interval = 1.29-1.93; P = 8.05 × 10(-6)). Moderate enrichment was also observed in FGF20, MCCC1, GBA and ITGA8. Half of the rare variants anticipated to cause loss of function of these genes were present in healthy controls. Overall, non-synonymous-coding variants of known familial and GWAS-linked genes appear to make a limited contribution to PD risk, suggesting that clinical sequencing of these genes will provide limited information for risk prediction and molecular diagnosis.
Dapsone is an important medication for the treatment of leprosy, but a life-threatening drug hypersensitivity syndrome develops in some patients. In this report from China, an
HLA-B
locus is ...identified as a strong genetic risk factor for the syndrome.
Dapsone (4-4′-sulfonyldianiline), which was first synthesized in 1908,
1
is both an antibiotic and an antiinflammatory agent. Dapsone alone or in combination with other drugs has been used for the prevention and treatment of infectious diseases (e.g., leprosy, malaria, and actinomycetoma, as well as
Pneumocystis jirovecii
pneumonia in persons with human immunodeficiency virus HIV infection) and chronic inflammatory diseases characterized by the infiltration of neutrophils or eosinophils (e.g., dermatitis herpetiformis, linear IgA dermatosis, subcorneal pustular dermatosis, and erythema elevatum diutinum).
2
,
3
About 0.5 to 3.6% of persons treated with dapsone have a drug hypersensitivity syndrome,
3
–
5
which was first described by . . .
The new magnetic photocatalysts HT/TiO2/Fe and HT-DS/TiO2/Fe, modified with the anionic surfactant sodium dodecylsulfate (DS) were successfully synthesized in this work. Titanium dioxide (anatase) ...followed by iron oxide were deposited on the hydrotalcite support. Several catalyst samples were prepared with different amounts of titanium and iron. The photocatalysts were characterized by infrared and Raman spectroscopy, X-ray diffraction, scanning electron microscopy. Photocatalytic performance was analyzed by UV–visible radiation (filter cutoff, λ > 300 nm) of an aqueous solution (24 mg/L) of methylene blue (MB). The most efficient catalyst was obtained at an iron oxide:TiO2 molar ratio of 2:3. This catalyst showed high photocatalytic activity, removing 96% of the color and 61% of total organic carbon from the MB solution after 120 min. It was easily removed from solution after use because of its magnetic properties. The reuse of the HT-DS/TiO2/Fe23 catalyst was viable and the catalyst was structurally stable for at least four consecutive photocatalytic cycles.
Display omitted
•The catalysts, HT/TiO2/Fe and HT-DS/TiO2/Fe, are unpublished in the literature.•HT-DS/TiO2/Fe23 exhibited the adsorption of light displacing the greater wavelength.•Synergistic effect between constituents of the catalyst increases the photocatalysis.•The catalyst HT-DS/TiO2/Fe23 can be reused for consecutive cycles.•The magnetic characteristic of the catalysts allows them to be easily removed.
Five new compounds with the general formula of (Bu
4N)
2M(RSO
2N
CS
2)
2, where Bu
4N
=
tetrabutylammonium cation, (M
=
Ni, R
=
4-FC
6H
4) (
1), (M
=
Zn, R
=
4-FC
6H
4, 4-ClC
6H
4, 4-BrC
6H
4, 4-IC
...6H
4), (
2), (
3), (
4) and (
5), respectively, were obtained by the reaction of the appropriate potassium
N-R-sulfonyldithiocarbimate (RSO
2N
CS
2K
2) with nickel(II) chloride hexahydrate or zinc(II) acetate dihydrate in metanol:water 1:1. The elemental analyses and the IR data are consistent with the formation of the expected bis(dithiocarbimato)metal(II) complexes. The
1H and
13C NMR spectra showed the signals for the tetrabutylammonium cation and the dithiocarbimate moieties. The compounds
1,
2 and
5 were also characterized by X-ray diffraction techniques. The nickel(II) is coordinated by two
N-4-fluorophenylsulphonyldithiocarbimato(2-) ligands forming a planar coordination. The zinc(II) exhibits distorted tetrahedral configuration in compounds
2 and
5 due to the chelation effect of two sulfur atoms of the
N-R-sulfonyldithiocarbimate ligands. The antifungal activities of the compounds were tested
in vitro against
Colletotrichum gloeosporioides, an important fungus that causes the plant disease known as anthracnose in fruit trees. All the complexes were active.
Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by epigenetic silencing of FMR1 and loss of FMRP expression. Efforts to understand the molecular underpinnings of the disease have ...been largely performed in rodent or nonisogenic settings. A detailed examination of the impact of FMRP loss on cellular processes and neuronal properties in the context of isogenic human neurons remains lacking.
Using CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 to introduce indels in exon 3 of FMR1, we generated an isogenic human pluripotent stem cell model of FXS that shows complete loss of FMRP expression. We generated neuronal cultures and performed genome-wide transcriptome and proteome profiling followed by functional validation of key dysregulated processes. We further analyzed neurodevelopmental and neuronal properties, including neurite length and neuronal activity, using multielectrode arrays and patch clamp electrophysiology.
We showed that the transcriptome and proteome profiles of isogenic FMRP-deficient neurons demonstrate perturbations in synaptic transmission, neuron differentiation, cell proliferation and ion transmembrane transporter activity pathways, and autism spectrum disorder–associated gene sets. We uncovered key deficits in FMRP-deficient cells demonstrating abnormal neural rosette formation and neural progenitor cell proliferation. We further showed that FMRP-deficient neurons exhibit a number of additional phenotypic abnormalities, including neurite outgrowth and branching deficits and impaired electrophysiological network activity. These FMRP-deficient related impairments have also been validated in additional FXS patient–derived human-induced pluripotent stem cell neural cells.
Using isogenic human pluripotent stem cells as a model to investigate the pathophysiology of FXS in human neurons, we reveal key neural abnormalities arising from the loss of FMRP.
Psoriasis is a common inflammatory skin disease with complex genetics and different degrees of prevalence across ethnic populations. Here we present the largest trans-ethnic genome-wide meta-analysis ...(GWMA) of psoriasis in 15,369 cases and 19,517 controls of Caucasian and Chinese ancestries. We identify four novel associations at LOC144817, COG6, RUNX1 and TP63, as well as three novel secondary associations within IFIH1 and IL12B. Fine-mapping analysis of MHC region demonstrates an important role for all three HLA class I genes and a complex and heterogeneous pattern of HLA associations between Caucasian and Chinese populations. Further, trans-ethnic comparison suggests population-specific effect or allelic heterogeneity for 11 loci. These population-specific effects contribute significantly to the ethnic diversity of psoriasis prevalence. This study not only provides novel biological insights into the involvement of immune and keratinocyte development mechanism, but also demonstrates a complex and heterogeneous genetic architecture of psoriasis susceptibility across ethnic populations.
ABSTRACT
MED13L is a component subunit of the Mediator complex, an important regulator of transcription that is highly conserved across eukaryotes. Here, we report MED13L disruption in a ...translocation t(12;19) breakpoint of a patient with Pierre–Robin syndrome, moderate intellectual disability, craniofacial anomalies, and muscular defects. The phenotype is similar to previously described patients with MED13L haploinsufficiency. Knockdown of MED13L orthologue in zebrafish, med13b, showed early defective migration of cranial neural crest cells (NCCs) that contributed to cartilage structure deformities in the later stage, recapitulating craniofacial anomalies seen in human patients. Notably, we observed abnormal distribution of developing neurons in different brain regions of med13b morphant embryos, which could be rescued upon introduction of full‐length human MED13L mRNA. To compare with mammalian system, we suppressed MED13L expression by short‐hairpin RNA in ES‐derived human neural progenitors, and differentiated them into neurons. Transcriptome analysis revealed differential expression of components of Wnt and FGF signaling pathways in MED13L‐deficient neurons. Our finding provides a novel insight into the mechanism of overlapping phenotypic outcome targeting NCCs derivatives organs in patients with MED13L haploinsufficiency, and emphasizes a clinically recognizable syndromic phenotype in these patients.
Several reports have identified structural variants and mutations affecting MED13L in patients with heart defects, craniofacial anomalies, and intellectual disability. In this study we functionally demonstrated that depletion of its orthologue in zebrafish model could recapitulate the craniofacial abnormalities in human and the observed phenotype can be reversed by introducing intact human mRNA, suggesting that gene dosage is required for normal gene function.
The new magnetic photocatalysts HT/TiO.../Fe and HT-DS/TiO.../Fe, modified with the anionic surfactant sodium dodecylsulfate (DS) were successfully synthesized in this work. Titanium dioxide ...(anatase) followed by iron oxide were deposited on the hydrotalcite support. Several catalyst samples were prepared with different amounts of titanium and iron. The photocatalysts were characterized by infrared and Raman spectroscopy, X-ray diffraction, scanning electron microscopy. Photocatalytic performance was analyzed by UV-visible radiation (filter cutoff, ... > 300 nm) of an aqueous solution (24 mg/L) of methylene blue (MB). The most efficient catalyst was obtained at an iron oxide:TiO... molar ratio of 2:3. This catalyst showed high photocatalytic activity, removing 96% of the color and 61% of total organic carbon from the MB solution after 120 min. It was easily removed from solution after use because of its magnetic properties. The reuse of the HT-DS/TiO.../Fe23 catalyst was viable and the catalyst was structurally stable for at least four consecutive photocatalytic cycles. (ProQuest: ... denotes formulae/symbols omitted.)
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