Search

Background: Mutations in CD40 ligand gene (CD40L) affecting immunoglobulin class-switch recombination and somatic hypermutation can result in X-Linked Hyper IgM Syndrome (HIGM1, XHIGM), a kind of rare serious primary immunodeficiency disease (PID) characterized by the deficiency of IgG, IgA and IgE and normal or increased serum concentrations of IgM. The objective of this study is to explain genotype-phenotype correlation and highlight the mutation responsible for a Chinese male patient with XHIGM. Methods: Whole exome sequencing (WES) and Sanger sequencing validation were performed to identify and validate the likely pathogenic mutation in the XHIGM family. Results: The results of the sequencing revealed that a new causative mutation in CD40L (c.714delT in exon 5, p.F238Lfs*4) which leads to the change in amino acids (translation terminates at the third position after the frameshift mutation) appeared in the proband. As his mother in the family was carrier with this heterozygous mutation, the hemizygous mutation in this patient came from his mother indicating that genetic mode of XHIGM is X-linked recessive inheritance. Conclusion: This study broadens our knowledge of the mutation in CD40L and lays a solid foundation for prenatal diagnosis and genetic counseling for the XHIGM family. [ABSTRACT FROM AUTHOR]

In this study, we aimed to determine the effects of dietary supplementation with chitosan nanoparticles (CNP) on growth performance, immune status, gut microbiota and immune responses after lipopolysaccharide challenge in weaned pigs. A total of 144 piglets were assigned to four groups receiving different dietary treatments, including basal diets supplemented with 0, 100, 200 and 400 mg/kg CNP fed for 28 days. Each treatment group included six pens (six piglets per pen). The increase in supplemental CNP concentration improved the average daily gain (ADG) and decreased the feed and gain (F/G) and diarrhoea rate (p <.05). However, significant differences in the average daily feed intake (ADFI) among different CNP concentrations were not observed. CNP also increased plasma immunoglobulin (Ig)A and IgG, and C3 and C4 concentrations in piglets in a dose‐dependent manner on day 28, whereas IgM concentration was not affected by CNP. A total of 24 piglets in the control diet and control diet with 400 mg/kg CNP supplementation groups were randomly selected for the experiment of immunological stress. Half of the pigs in each group (n = 6) were injected i.p. with Escherichia coli lipopolysaccharide (LPS) at a concentration of 100 μg/kg. The other pigs in each group were injected with sterile saline solution at the same volume. Plasma concentrations of cortisol, prostaglandin E2 (PEG2), interleukin (IL)‐6, tumour necrosis factor (TNF)‐α and IL‐1β dramatically increased after LPS challenge. However, CNP inhibited the increase in cortisol, PEG2, IL‐6 and IL‐1β levels in plasma, whereas TNF‐α level slightly increased. Moreover, the effects of CNP on the gut microbiota were also evaluated. Our results showed that dietary supplementation with CNP modified the composition of colonic microbiota, where it increased the amounts of some presumably beneficial intestinal bacteria and suppressed the growth of potential bacterial pathogens. These findings suggested CNP supplementation improved the growth performance and immune status, alleviated immunological stress and regulated intestinal ecology in weaned piglets. Based on these beneficial effects, CNP could be applied as a functional feed additives supplemented in piglets diet. [ABSTRACT FROM AUTHOR]

The present study was conducted to assess the effects of a mixture of essential oils and organic acids on the growth performance, immune system, major fecal volatile fatty acids (VFAs), and microflora community in the weaned piglets. We also evaluated the antibacterial activity of the essential oil mixture on Escherichia coli and Staphylococcus aureus. Three hundred weaned piglets (Duroc × Landrace × Yorkshire) were randomly divided into the following 3 treatment groups: basal diet (C), basal diet supplemented with the mixture of essential oils and organic acids (T1), and basal diet supplemented with antibiotics (T2). The mixture of essential oils and organic acids comprised of cinnamaldehyde (15%), thymol (5%), citric acid (10%), sorbic acid (10%), malic acid (6.5%), and fumaric acid (13.5%). In vitro studies showed that the mixture of essential oils extremely damaged the cell structure of pathogenic bacteria by deforming the membranes and disorganizing the intracellular components. In vivo studies revealed that diet supplementation with a mixture of essential oils and organic acids improved the final body weight and ADG of piglets (P < 0.05), increased the concentration of serum complement 4 (P < 0.05), and enhanced the fecal level of isovaleric acid (P < 0.05) compared with controls on day 28. Result of high-throughput sequencing revealed that: 1) a total of 1,177 and 1,162 observed taxonomic units (OTUs) were shared between all treatment groups on day 14 and 28, respectively; 2) the T1 exhibited higher (P < 0.05) beta diversity (unweighted UniFrac distance) than control and antibiotics treatment on day 28; 3) the samples in principle component analysis plot and tree of relative abundance were separated from each other based on dietary treatments and age; 4) Firmicutes and Bacteroidetes were the most 2 dominate phyla; Lactobacillus and Streptococcus were the 2 top species among the recognized microbiota; 5) T1 had higher (P < 0.05) relative abundance of Lactobacillus mucosae than control and antibiotics treatment on day 28. To conclude, the mixture of cinnamaldehyde and citric acids damaged the structure of pathogens in vitro; the mixture of essential oils and organic acids improved the growth performance, increased the fecal concentration of isovaleric acid, and modulated the microflora community in weaned piglets. [ABSTRACT FROM AUTHOR]

Objectives: Twin and family analyses have revealed a genetic contribution to Tourette syndrome (TS) and post-mortem studies have raised the intriguing possibility of a reduction in cholinergic interneuronsin TS patients. Methods: We selected five tag SNPs (rs100824791, rs12264845, rs1880676, rs3793790 and rs3793798) of choline acetyltransferase (CHAT) from the Han Chinese population Hapmap database. Genotyping was conducted on 401 TS nuclear family trios and 405 control subjects. Transmission disequilibrium test (TDT) and haplotype relative risk (HRR) analyses were used to analyse the family-based study and a case-control study was also used to assess the genetic susceptibility to TS. Results: The results revealed a significant over-transmission of rs3793790 (TDT, χ2 = 9.121, P = 0.003; HRR, χ2 = 6.579, P = 0.01), while case-control analysis found no differences between the two groups (genotype, χ2 = 0.436, P = 0.804; allele, χ2 = 0.149, P = 0.700). Also, rs3793798 also indicated a positive association associated with TS (TDT, χ2 = 5.025, P = 0.028; HRR, χ2 = 0.250, P = 0.617). However, the other three SNPs investigated were found not to be associated with TS in both in the family-based and case-control studies. Conclusions: Our association analysis demonstrates that CHAT may contribute to TS susceptibility in the Han Chinese population. This gives strong support to the involvement of cholinergic interneurons in the aetiology of TS and reveals a potential therapeutic target. [ABSTRACT FROM AUTHOR]

Background: Autosomal recessive congenital ichthyosis (ARCI) is a rare genetically heterogeneous cutaneous disease predominantly characterized by erythroderma, generalized abnormal scaling of the whole body and a collodion membrane at birth. Numerous causative genes have been demonstrated to be responsible for ARCI including PNPLA1 which can cause ARCI type 10. The objectives of this study are to describe clinical features of three ARCI patients from two Chinese unrelated families and to identify the underlying causative mutations. Methods: Genomic DNA was extracted from peripheral venous blood obtained from the two Chinese ARCI families in Shandong province. Subsequently, targeted regions sequencing (TRS) followed by Sanger sequencing was conducted to identify and validate the likely pathogenic mutations of the ARCI families. Results: Genetic analyses revealed four novel PNPLA1 variants that are predicted to be probably to lead to ARCI in three patients of two families. Patient 1 in one family was in compound heterozygous status for c.604delC/p.Arg202Glyfs*27 and c.820dupC/p.Arg274Profs*15, whereas c.738_742delinsCCCACAGATCCTGC/ p.Gly247_Tyr248delinsProGlnIleLeuHis, and c.816dupC/p.Arg274Profs*15 were found in patient 2 and 3 of the other family. In addition, these variants cosegregate in the two pedigrees and are all within highly conserved regions of the PNPLA1 protein, which indicate that the four mutations are likely pathogenic. Conclusion: Our findings not only broaden the mutational spectrum of PNPLA1, but also contribute to establishing genotype–phenotype correlations for different forms of ARCI. [ABSTRACT FROM AUTHOR]

High dose of zinc oxide (ZnO) could improve growth performance and alleviate disease status, whereas it caused serious environmental pollution and bacterial resistance. This study was to investigate whether low doses of sodium alginate-coated nano zinc oxide (saZnO), a new type of zinc resource, could serve as a potential alternative to pharmacological doses of traditional ZnO in weaned piglets. A total of 144 crossbred piglets were randomly allocated into three groups, including a basal diet without the addition of Zn (CON), a basal diet with 1600 mg Zn/kg from traditional ZnO (ZnO), and a basal diet with 500 mg Zn/kg from saZnO (saZnO). The experiment lasted for 28 days. The results showed that supplementing with ZnO and saZnO for 14 and 28 days significantly improved body weight (BW) and average daily gain (ADG) ( p < 0.01) and markedly reduced the feed intake-to-gain ratio (F/G) ( p < 0.05) and diarrhea rate. In addition, dietary ZnO and saZnO significantly increased the activities of the total antioxidant capacity (T-AOC) and alkaline phosphatase (ALP) ( p < 0.01). Supplementing with saZnO also promoted the levels of superoxide dismutase (SOD), IgM and copper- and zinc-containing superoxide dismutase (Cu/Zn-SOD) in serum ( p < 0.05), whereas a ZnO addition decreased the concentration of malondialdehyde (MDA) ( p < 0.05), indicating the beneficial effect of Zn on antioxidant and immune functions. Piglets fed the ZnO diet showed higher serum Zn accumulations than those fed the CON and saZnO diets at d 28 ( p < 0.01), and supplementing with ZnO and saZnO markedly contributed to Zn excretion in feces, especially in the ZnO diet ( p < 0.01). Additionally, piglets fed the saZnO diet had greater valeric acid concentrations ( p < 0.05) in their feces, while other short chain fatty acids (SCFAs) were not affected by different treatments ( p > 0.05). Microbial alpha diversity was reduced in the saZnO group compared with the CON group ( p < 0.05), while an obvious separation of microbial composition, the marker of beta diversity, was shown among the three groups ( p < 0.05). At the genus level, six genera, including Clostridium&#95;sensu&#95;stricto&#95;1 , Terrisporobacter , f&#95;Muribaculaceae, Subdoligranulum and Intestinibacter , were pronouncedly increased in the ZnO and saZnO groups ( p < 0.05); another nine species were dramatically downregulated, such as f&#95;Lachnospiraceae, f&#95;Prevotellaceae, f&#95;Butyricicoccaceae and f&#95;Ruminococcaceae ( p < 0.05). Finally, a functional analysis indicated that altered microbes significantly changed the "Metabolism" pathway ( p < 0.05). These findings suggested that saZnO could act as a feasible substitute for ZnO to reduce Zn emission and enhance growth performance, antioxidant and immune functions, and to adjust the structure of gut microbiota in piglets.

Objective: To explore the genetic basis for a child with metachromatic leukodystrophy (MLD)., Methods: Clinical data of the patient was collected. Genomic DNA was extracted from peripheral blood samples of the child and his family members. Potential variant was screened by whole exome sequencing (WES), and candidate variant was verified by Sanger sequencing. The pathogenicity the variant was analyzed by multiple sequence alignment of the amino acid sequence and three-dimensional model prediction of its protein product., Results: The child was found to harbor compound heterozygous variants c.257G>A (p.R86Q) and c.467del (p.G156Afs*6) of the ARSA gene, among which the c.467del (p.G156Afs*6) frameshift variation was unreported previously. Multiple sequence alignment showed that the site of the c.257G>A (p.R86Q) missense variant is highly conserved. Three-dimensional structure modeling analysis showed that the partial deletion due to the p.G156Afs*6 variant may cause significant alteration of the structure of ARSA protein., Conclusion: The discovery of novel variant in ARSA has enriched the mutational spectrum of MLD and may facilitate the understanding of the genotype-phenotype correlation of MLD.

The TGF-β superfamily members are indicated to play key roles in ovarian follicular development, such as granulosa cell proliferation, estrogens, and progesterone production. However, little is known about the roles of TGF-β3 in follicular development. In this study, we found that TGF-β3 was predominantly expressed in granulosa cells of mouse ovarian follicles, and it significantly promoted 17β-estradiol (E(2)) release in a dose-dependent manner. The orphan nuclear receptor steroidogenic factor-1 (SF-1) was required in TGF-β3-induced Cyp19a1 (a key rate-limiting enzyme for estrogen biosynthesis) expression and E(2) release. Additionally, TGF-β3 enhanced the binding of SF-1 to endogenous ovary-specific Cyp19a1 type II promoter, as evidenced by chromatin immunoprecipitation assays. The enhanced effect of SF-1 by TGF-β3 may be mediated through functional interactions between SF-1 and mothers against decapentaplegic homolog (Smad)3 (a mediator of TGF-β signaling pathway), because disruption of the interaction abolished the synergistic effects of SF-1, Smad3, and TGF-β3 on Cyp19a1 mRNA expression. RNA interference and chromatin immunoprecipitation studies also demonstrated that Smad3 was required for SF-1 binding to Cyp19a1 type II promoter and activation of Cyp19a1. Smad3 thus acts as a point of convergence that involves integration of SF-1 and TGF-β signaling in affecting E(2) production. Taken together, our data provide mechanistic insights into the roles of SF-1 in TGF-β3-mediated E(2) synthesis. Understanding of potential cross-points between extracellular signals affecting estrogen production will help to discover new therapeutic targets in estrogen-related diseases.

Chitosan nanoparticles (CNP) have demonstrated anticancer activity in vitro and in vivo by a few recent researches. However, the mechanisms involved in their potential anticancer activity remain to be elucidated. In this study, the effects of CNP on tumor growth were investigated using a model of nude mice xenografted with human hepatocellular carcinoma (HCC) (BEL-7402) cells. The results demonstrated that the treatment of these nude mice with CNP significantly inhibited tumor growth and induced tumor necrosis. Furthermore, microvessel density (MVD) determination by counting immunohistologically stained tumor microvessels suggested that CNP dose-dependent tumor suppression was correlated with the inhibition of tumor angiogenesis. Mechanistically, immunohistochemical and quantitative real-time reverse transcription-polymerase reaction assays provided evidence that CNP-mediated inhibition of tumor angiogenesis was linked to impaired levels of vascular endothelial growth factor receptor 2 (VEGFR2). Due to their low or non-toxicity, CNP and their derivatives may represent a novel class of anti-cancer drug.