Sigma-1 receptor (σ ₁R) has become a focus point of drug discovery for central nervous system (CNS) diseases. A series of novel 1-phenylethan-1-one O-(2-aminoethyl) oxime derivatives were synthesized. In vitro biological evaluation led to the identification of 1a, 14a, 15d and 16d as the most high-affinity (K _i < 4 nmol/L) and selective σ ₁R agonists. Among these, 15d, the most metabolically stable derivative exhibited high selectivity for σ ₁R in relation to σ ₂R and 52 other human targets. In addition to low CYP450 inhibition and induction, 15d also exhibited high brain permeability and excellent oral bioavailability. Importantly, 15d demonstrated effective antipsychotic potency, particularly for alleviating negative symptoms and improving cognitive impairment in experimental animal models, both of which are major challenges for schizophrenia treatment. Moreover, 15d produced no significant extrapyramidal symptoms, exhibiting superior pharmacological profiles in relation to current antipsychotic drugs. Mechanistically, 15d inhibited GSK3β and enhanced prefrontal BDNF expression and excitatory synaptic transmission in pyramidal neurons. Collectively, these in vivo proof-of-concept findings provide substantial experimental evidence to demonstrate that modulating σ ₁R represents a potential new therapeutic approach for schizophrenia. The novel chemical entity along with its favorable drug-like and pharmacological profile of 15d renders it a promising candidate for treating schizophrenia.

OBJECTIVETo detect potential mutation in a large Chinese pedigree affected with congenital corneal dystrophy.

METHODSTwo patients from the pedigree were subjected to whole exome sequencing to determine the candidate gene. Suspected mutation was verified in 13 additional members by directional Sanger sequencing. Ccorrelation between genotype and phenotype was explored.

RESULTSA missense mutation, c.1877A>C (p.His626Pro), was detected in exon 14 of the TGFBI gene in 8 patients from the pedigree, but not in five unaffected members and 100 unrelated healthy controls. Respectively, the mutation was predicted as "affecting protein function", "probably damaging" and "disease causing" by SIFT, PolyPhen-2 and MutationTaster.

CONCLUSIONThe c.1877A>C mutation of the TGFBI gene probably underlies the disease in this pedigree.

Objective To initially map the gene responsible for autosomal dominant familial IgA nephropathy of a Chinese family by exclusive the five loci that had been reported with linkage analysis.Methods The genetic pattern of the familial IgA nephropathy was identified and the genomic DNA was extracted from the blood samples collected from the family members.Short tandem repeat (STR) inside the loci that had been reported was selected,such as 2q36,3p23-24,4q26-31,6q22-23,17q12-22,and the data with two-point linkage analysis were performed.Results Autosomal dominant inheritance pattern was demonstrated in phenotypes of the family and there was no linkage relationship in the above five loci of chromosomes because the maximum two-point LOD score was 0.39 at D17S1868.Conclusion Following exclusion of the loci which had been reported,there are other new pathopoiesis loci of FIgAN and it reveals that FIgAN has the genetic heterogeneity according to initial result at the same time.

BACKGROUNDOver-expression of RAB5A gene has been proved to be associated with neoplasia metastasis. This study is to explore the effect of RAB5A gene on invasion and metastasis of human lung adenocarcinoma cell lines.

METHODSConstituted basement membrane invasion technique, adhesion capability of tumor cell assay, the chemotactic migration of tumor cells assay, and gelatinases SDS-PAGE analysis method were used to detect the changes of invasive and metastatic capability of Anip973 (with high metastatic capability) and its parent AGZY83-a cell lines (with low metastatic capability).

RESULTSAfter AGZY83-a cells were transfected by PcDNA3.1-RAB5A plasmid, its invasion was significantly increased (t=24.36, P < 0.000 5); adhesion capability of cell was promoted (P < 0.05); the chemotactic migration of cells was higher than that of the parent lines (t=14.18, P < 0.000 5); and the activity of gelatinases secreted from transfected AGZY83-a was enhanced. The invasion of the transfected Anip973 cells with PcDNA3-AntiRAB5A was lower (t= 16.510 4, P < 0.002 5); adhesion capability of cell was decreased (P < 0.05); the chemotactic migration of cells was lower than that of the parent lines (t=6.062, P < 0.005); and the activity of gelatinases was obviously decreased.

CONCLUSIONSThis study in vitro indicates that over-expression of RAB5A genes plays an important role in tumor invasion and metastatic phenotype formation of human lung adenocarcinoma cells; and antisense RNA can interrupt the translation of RAB5A gene.