The first case report of CODAS syndrome in Chinese population caused by two LONP1 pathogenic mutations.

Background: CODAS syndrome (MIM 600373) is a multi-system developmental disorder characterized by cerebral, ocular, dental, auricular, and skeletal anomalies. CODAS syndrome is rare in the world and no cases have been reported in Chinese population so far. Mutations in the LONP1 gene can contribute to CODAS syndrome, while the underlying molecular mechanisms requires further investigation. Method: We described a Chinese boy who has suffered from cognition impairment, cataracts, caries, abnormal auricle and skeletal anomalies since birth. The patient's parents are non-consanguineous and healthy. Whole-exome sequencing (WES) was employed to explore the genetic entity of this family. Results: A compound heterozygous missense mutation (NM_004793: c.2009C>T/p.A670V and c.2014C>T/p.R672C) of LONP1 was identified in the patient. Considering the clinical phenotypes and genetic results, the patient was diagnosed as CODAS syndrome. Conclusion: Here we reported the first case with CODAS syndrome in Chinese population. WES identified a compound heterozygous missense mutation of LONP1 gene in the patients. Our study not only provided data for genetic counseling and clinical diagnosis to this family, but also expanded the clinical spectrum of LONP1-related CODAS syndrome.

Case Report: A Novel Heterozygous Mutation of CD2AP in a Chinese Family With Proteinuria Leads to Focal Segmental Glomerulosclerosis.

Idiopathic focal segmental glomerulosclerosis (FSGS) is a relatively frequent kidney disorder that manifest clinically as proteinuria and progressive loss of renal function. Genetic factors play a dominant role in the occurrence of FSGS. CD2-associated protein (CD2AP) is an adapter molecule and is essential for the slit-diaphragm assembly and function. Mutations in the CD2AP gene can contribute to FSGS development. Here, we describe a Chinese family of four generations with unexplained proteinuria. The proband, a 12-year-old boy, was diagnosed as FSGS. Whole-exome sequencing (WES) revealed an unknown frameshift insertion mutation (p.K579Efs*7) of CD2AP gene that leads to a truncation of CD2AP protein. Bioinformatics strategies predicted that the novel mutation was pathogenic. The mutation was absent in either healthy family members or our 200 healthy controls. In summary, we used WES to explore the genetic lesion of FSGS patients and identified a novel mutation in CD2AP gene. This work broadens the mutation spectrum of CD2AP gene and provides data for genetic counseling to additional FSGS patients.

A novel POF1B variant in a Chinese patient is associated with premature ovarian failure.

A novel mutation of POF1B was identified in a patient with premature ovarian failure.

Identification of a novel mutation in the C6 gene of a Han Chinese C6SD child with meningococcal disease.

Deficiency of the sixth complement component (C6D) is a genetic disease associated with increased susceptibility to Neisseria meningitides infection. Individuals with C6D usually present with recurrent meningococcal disease (MD). According to the patients' C6 levels, C6D is divided into complete genetic deficiency of C6 and subtotal deficiency of C6 (C6SD). The present study reported on a Han Chinese pediatric patient with MD, in whom further investigation revealed a C6SD genetic lesion. A heterozygote nonsense mutation (c.1062C>G/p.Y354*) in the C6 gene was identified by Sanger sequencing. The mutation alters the tyrosine codon at position 354 to a termination codon and results in a truncated protein. In conclusion, the genetic lesion of a pediatric patient with C6SD who was diagnosed due to having MD was investigated and a novel pathogenic mutation in the C6 gene was identified. The study confirmed the clinical diagnosis for this patient with C6SD and also expanded the spectrum of C6 mutations.

The Effect of Structural Diversity on Ligand Specificity and Resulting Signaling Differences of Estrogen Receptor α.

Numerous chemicals have been reported to exert estrogen-like endocrine disrupting effects via a receptor binding mechanism that directly interacts with the ligand binding domain of estrogen receptor α (ERα). However, not only their binding affinities to ERα but also their interference in specific cell and tissue functions are clearly different. In this regard, significant regulation differences among three representative estrogenic chemicals (diethylstilbestrol (DES), bisphenol A (BPA), and diarylpropionitrile (DPN)), well-known ERα agonists with very similar structures, have been observed. Molecular dynamics simulation is used to explore the underlying mechanism of different regulation effects induced by the similar estrogen-like chemicals. The DES-induced 12 Å motion of the H9-H10 loop markedly expands the negative electrostatic potential surface of the AF-2 domain, which is consistent with the over-regulation effect of the agonist. In comparison, the 3 Å motion induced by BPA and DPN corresponds to the low-regulation effect of the chemicals. Cross-correlation analysis indicates that the different ERα motions and resulting surface feature of AF-2 domain are brought by the distinguished binding modes of the agonists. Moreover, only hydrophobic DES with estrogen-like size and flexibility has a high binding affinity of -23.47 kcal/mol binding free energy. Both the hydrophilic group in DPN and the small molecular size of BPA dramatically decrease the agonist binding ability, and their binding free energies are only -12.43 kcal/mol and -11.82 kcal/mol, respectively. Our study demonstrates that similar chemicals interact differently with ERα and induce different allosteric effects, which explains the observed regulation diversity.

Two-stage resection of a disseminated mixed endometrial stromal sarcoma and smooth muscle tumor with intravascular and intracardiac extension.

OBJECTIVE: Mixed endometrial stromal and smooth muscle tumor (MESSMT)-a rare mesenchymal uterine tumor of the uterus with atypical clinical symptoms-is susceptible to misdiagnosis and missed diagnosis. We report a case of a disseminated MESSMT with intravenous and intracardiac extensions treated with staging surgery and review previously documented cases of such tumors with intracardiac extension. CASE REPORT: The case involves a 45-year-old woman with disseminated MESSMT that originated in the uterus and progressed through the iliac vein, inferior vena cava, right atrium, and into the right ventricle, which closely resembled intravenous leiomyomatosis (IVL) grossly and microscopically. She presented with a 1-year history of dyspnea on exertion. IVL was highly suspected preoperatively based on computed tomography and magnetic resonance imaging findings. Two-stage surgeries were performed successfully. The postoperative pathology indicated a disseminated MESSMT. CONCLUSION: This case illustrates the important role of pathology and immunohistochemistry in the differential diagnosis of a rare tumor that mimics the characteristics of IVL with intracardiac involvement and demonstrates the therapeutic strategy for this rare entity.

Bioaccumulation, maternal transfer and elimination of polybrominated diphenyl ethers in wild frogs.

To investigate bioaccumulation, maternal transfer and elimination of polybrominated diphenyl ethers (PBDEs) in amphibians, we collected adult frogs (Rana limnocharis) from a rice field in an e-waste recycling site in China. We found that ∑PBDEs in the whole frogs and various tissues (brain, liver, testis and egg) ranged from 17.10 to 141.11 ng g(-1) wet weight. Various tissues exhibited a similar PBDE congener profile, which was characterized by intermediate brominated congeners (BDE-99 and BDE-153) as the largest contributors, with less lower brominated congeners (BDE-28 and BDE-47) and higher brominated congeners (BDE-209). The maternal transfer capacity of PBDEs declined with the increase in bromine numbers of PBDE congeners. We suggest that the bromine atom number (the molecular size, to some degree) might be a determining factor for the maternal transport of a PBDE congener rather than K(ow) (Octanol-Water partition coefficient), which expresses a compound's lipophilicity. ∑PBDEs concentrations in frogs decreased over time during a depuration period of 54 days when these wild frogs were brought to the lab from the e-waste recycling site. The half-life of ∑PBDEs was 35 days, with about 14 days for BDE-47, and 36 and 81 days for BDE-99 and BDE-153, respectively. The data shows that the elimination of PBDEs has no essential difference from aquatic and terrestrial species.

Evaluation of the noncovalent binding interactions between polycyclic aromatic hydrocarbon metabolites and human p53 cDNA.

The binding of reactive polycyclic aromatic hydrocarbon (PAH) metabolites, formed enzymatically, to DNA is a crucial step in PAH carcinogenesis in vivo. We investigated the noncovalent binding interactions between 11 PAH metabolites and human p53 complementary DNA (p53 cDNA) using the fluorescence displacement method and molecular docking analysis. All of the examined metabolites predominantly interacted with p53 cDNA by intercalation instead of groove binding. The dissociation constants ranged from 0.02 to 12.34µM. Of the metabolites tested, 1-hydroxypyrene and 3-hydroxybenzo[a]pyrene showed the strongest binding affinities to DNA, while 2-naphthol was the weakest DNA intercalator. The intercalation of the metabolites was stabilized by stacking the PAH phenyl rings with the DNA base pairs and the formation of hydrogen bonds between the oxide or hydroxyl groups on the metabolites, and DNA bases or backbones. The binding of the metabolites to DNA showed some sequence selectivity. The binding affinities and hydrogen bonds for 3-hydroxybenzo[a]pyrene, benzo[a]pyrene-4,5-dihydroepoxide (BPE) and benzo[a]pyrene-r-7,t-8-dihydrodiol-t-9,10-epoxide (BPDE) differed. It seems that the functional groups on the periphery of the PAH aromatic ring play crucial roles in regulating its binding affinity with DNA. Although it was difficult to determine the correlation between DNA noncovalent binding affinity and carcinogenicity for some of the PAH metabolites, the present study improved our understanding of the formation of PAH metabolite-DNA adducts.

Structure-based investigation on the binding interaction of hydroxylated polybrominated diphenyl ethers with thyroxine transport proteins.

Polybrominated diphenyl ethers (PBDEs) have been shown to alter thyroid hormone level in experimental animals. One of the possible mechanisms for hormone disruption is the competitive binding of hydroxylated PBDEs (OH-PBDEs) with hormone transport proteins. In this study, binding interaction of 14 diversely structured OH-PBDEs with two thyroxine transport proteins was investigated by fluorescence displacement assay, circular dichroism, and molecular docking. Binding affinity of the 14 OH-PBDEs with transthyretin (TTR) and thyroxine-binding globulin (TBG) was measured by competitive fluorescence displacement assay. The binding constant was found to fall in the range of 1.4 x 107 M and 6.9 x 108 M⁻¹ for TTR, and between 6.5 x 106 M⁻¹ and 2.2 x 108 M⁻¹ for TBG. Binding affinity increased significantly with bromination number from 1 to 4, whereas 5- and 6-brominated diphenyl ethers did not show any further increase. Protein secondary structural change of TTR and TBG upon binding with 5-OH-BDE-047 was investigated by circular dichroism. The spectral change displayed a pattern similar to the one with thyroxine, suggesting that the environmental chemical binds to the two proteins at the same sites as the hormone. In molecular docking analysis, a ligand-binding channel in TTR was revealed for OH-PBDEs binding, which appeared to be mostly hydrophobic inside but guarded by positively charged residue Lys15 at the entrance. Binding affinity of the 14 OH-PBDEs with TTR could be rationalized reasonably well by their pocket binding mode and hydrophobic characteristics. Based on the binding constant obtained in this work, possibility of in vitro competitive displacement of thyroid hormones from the transport proteins by OH-PBDEs was evaluated.

Immunotoxicity of bisphenol A to Carassius auratus lymphocytes and macrophages following in vitro exposure.

Bisphenol A (BPA) is the monomer component of polycarbonate plastics and classified as an endocrine disrupting chemical (EDC). The reproductive toxicity of BPA has been extensively studied in mammals; however, relatively little information is available on the immunotoxic responses of fish to BPA. In this study, we investigated the effects of BPA on the immune functions of lymphocytes and macrophages in Carassius auratus. The effects of BPA were compared with those of two natural steroid hormones, estradiol and hydrocortisone. Proliferation of the two types of cells in response to PHA was measured using colorimetric MTT assay. Macrophage respiratory burst stimulated by Con A was measured using chemiluminescence assay. Results showed that BPA (0.054-5.4 mg/L), estradiol (0.0002-2.0 mg/L) and hydrocortisone (5-50 mg/L) significantly induced Carassius auratus lymphocyte proliferation while higher doses of hydrocortisone (500-5000 mg/L) appeared to be inhibitory. BPA (0.005-50 mg/L), estradiol (0.005-800 mg/L) and hydrocortisone (0.005-500 mg/L) markedly enhanced macrophage proliferation, whereas higher doses of BPA (500-1000 mg/L) appeared to inhibit cell proliferation. Furthermore, higher dosage of BPA (50 mg/L) and hydrocortisone (50 and 500 mg/L) suppressed the macrophages respiratory burst while estradiol is stimulative all the doses tested (0.05-500 mg/L). In conclusion, BPA could have immunotoxicity to Carassius auratus and functional changes of lymphocyte and macrophage in Carassius auratus may be different between low and high dosages.

[Photodegradation of bisphenol A in presence of Suwannee River fulvic acid].

Under simulated solar irradiation, the degradation of bisphenol A (BPA) was studied in the presence of Suwannee River Fulvic Acid (SRFA). The results demonstrate that the photodegradation of BPA followed a pseudo-first-order kinetics and the photodegradation rate increased rapidly with increasing initial concentration of SRFA. Hydroxyl radical, singlet oxygen were found in the SRFA solutions of BPA with molecular probes and the technique of electronic spin resonance. The electronic energy transfer of triplet state fulvic acid was also studied with various aerated conditions. The results showed that the photodegradation of BPA was related with triplet state fulvic acid. The photodegradation products of BPA in the presence of SRFA were identified with GC/MS methods. The photodegradation pathways of BPA were also discussed.

Surface microlayer enrichment of volatile organic compounds and semi-volatile organic compounds in drinking water source.

Enrichment of volatile organic compounds(VOC) and semi-volatility organic compounds(SVOC) in surface microlayer(SM) of three drinking water sources were studied. The enrichment factor(EFs) were 0.67 to 13.37 and 0.16 to 136, respectively. The results showed some VOC and most SVOC could enrich in SM. Some EFs of SVOC was quite high. Suspension and temperature could affect EFs of SVOC, slim wind and water movement do not destroy enrichment of organic in SM.