Safety and effectiveness of lurasidone in the treatment of Chinese schizophrenia patients: An interim analysis of post-marketing surveillance.

BACKGROUND: Schizophrenia is a psychiatric disorder characterized by chronic or recurrent symptoms. Lurasidone was licensed in China in 2019 for the treatment of adult schizophrenia in adults with a maximum dose of 80 mg/d. However, post-market surveillance (PMS) with an adequate sample size is required for further validation of the drug's safety profile and effectiveness. AIM: To conduct PMS in real-world clinical settings and evaluate the safety and effectiveness of lurasidone in the Chinese population. METHODS: A prospective, multicenter, open-label, 12-wk surveillance was conducted in mainland China. All patients with schizophrenia from 10 sites who had begun medication with lurasidone between September 2019 and August 2022 were eligible for enrollment. Safety assessments included adverse events (AEs), adverse drug reactions (ADRs), extrapyramidal symptoms (EPS), akathisia, use of EPS drugs, weight gain, and laboratory values as metabolic parameters and the QTc interval. The effectiveness was assessed using the brief psychiatric rating scale (BPRS) from baseline to the end of treatment. RESULTS: A total of 965 patients were enrolled in the full analysis set and 894 in the safety set in this interim analysis. The average daily dose was 61.7 ± 19.08 mg (mean ± SD) during the treatment. AEs and ADRs were experienced by 101 patients (11.3%) and 78 patients (8.7%), respectively, which were mostly mild. EPS occurred in 25 individuals with a 2.8% incidence, including akathisia in 20 individuals (2.2%). Moreover, 59 patients received drugs for treating EPS during the treatment, with an incidence of 6.6% which dropped to 5.4% at the end of the treatment. The average weight change was 0.20 ± 2.36 kg (P = 0.01687) with 0.8% of patients showing a weight gain of ≥ 7% at week 12 compared with that at the baseline. The mean values of metabolic parameters and the QTc interval at baseline and week 12 were within normal ranges. The mean changes in total BPRS scores were -8.9 ± 9.76 (n = 959), -13.5 ± 12.29 (n = 959), and -16.8 ± 13.97 (n = 959) after 2/4, 6/8, and 12 wk, respectively (P < 0.001 for each visit compared with the baseline) using the last-observation-carried-forward method. CONCLUSION: The interim analysis of the PMS of adult patients with schizophrenia demonstrate the safety and effectiveness of lurasidone in the Chinese population. No new safety or efficacy concerns were identified.

Identification of Potential miRNA-mRNA Regulatory Network Associated with Growth and Development of Hair Follicles in Forest Musk Deer.

In this study, sRNA libraries and mRNA libraries of HFs of FMD were constructed and sequenced using an Illumina HiSeq 2500, and the expression profiles of miRNAs and genes in the HFs of FMD were obtained at the anagen and catagen stages. In total, 565 differentially expressed unigenes (DEGs) were identified, 90 of which were upregulated and 475 of which were downregulated. In the BP category of GO enrichment, the DEGs were enriched in the processes related to HF development and differentiation, including the hair cycle regulation and processes, HF development, skin epidermis development, regulation of HF development, skin development, the Wnt signaling pathway, and the BMP signaling pathway. Through KEGG analysis it was found that DEGs were significantly enriched in pathways associated with HF development and growth. A total of 186 differentially expressed miRNAs (DEmiRNAs) were screened (p < 0.05) in the HFs of FMD at the anagen stage vs. the catagen stage, 33 of which were upregulated and 153 of which were downregulated. Through DEmiRNA-mRNA association analysis, we found DEmiRNAs and target genes that mainly play regulatory roles in HF development and growth. The enrichment analysis of DEmiRNA target genes revealed similarities with the enrichment results of DEGs associated with HF development. Notably, both sets of genes were enriched in key pathways such as the Notch signaling pathway, melanogenesis, the cAMP signaling pathway, and cGMP-PKG. To validate our findings, we selected 11 DEGs and 11 DEmiRNAs for experimental verification using RT-qPCR. The results of the experimental validation were consistent with the RNA-Seq results.

The identification of AMZ2 as a candidate causative gene in a severe teratozoospermia patient characterized by vacuolated spermatozoa.

Teratozoospermia with cephalic defects is one of the most severe types of sperm defects known to date. While several monogenic factors are linked to cephalic abnormalities, such as globozoospermia and macrozoospermia, the genetic cause of vacuolated spermatozoa remains inadequately described. Here, we analyzed whole-exome sequencing (WES) data for an individual from a consanguineous family with severely vacuolated spermatozoa. The analysis revealed a novel homozygous c.520A>G (p.Thr174Ala) variant in the archaelysin family metallopeptidase 2 (AMZ2), a gene that encodes a zinc metalloprotease previously shown to be highly expressed in the testes and sperm. Multiple algorithms predicted this variant to be a damaging mutation. Consistent with an autosomal recessive mode of inheritance, this variant was inherited from heterozygous parental carriers. To investigate the potential pathogenicity of the identified variant, we compared the AMZ2 expression in sperm cells from the patient with the AMZ2 variant and from a healthy control. Immunoblot analysis revealed that the homozygous missense variant in AMZ2 abolished AMZ2 expression in the spermatozoa. Our findings reveal a candidate causative gene for vacuolated spermatozoa.

Distribution patterns of microsatellites and development of its marker in different genomic regions of forest musk deer genome based on high throughput sequencing.

Forest musk deer (Moschus berezovskii, FMD) is an endangered artiodactyl species, male FMD produce musk. We have sequenced the whole genome of FMD, completed the genomic assembly and annotation, and performed bioinformatic analyses. Our results showed that microsatellites (SSRs) displayed nonrandomly distribution in genomic regions, and SSR abundances were much higher in the intronic and intergenic regions compared to other genomic regions. Tri- and hexanucleotide perfect (P) SSRs predominated in coding regions (CDSs), whereas, tetra- and pentanucleotide P-SSRs were less abundant. Trifold P-SSRs had more GC-contents in the 5'-untranslated regions (5'UTRs) and CDSs than other genomic regions, whereas mononucleotide P-SSRs had the least GC-contents. The repeat copy numbers (RCN) of the same mono- to hexanucleotide P-SSRs had different distributions in different genomic regions. The RCN of trinucleotide P-SSRs had increased significantly in the CDSs compared to the transposable elements (TEs), intronic and intergenic regions. The analysis of coefficient of variability (CV) of P-SSRs showed that the RCN of mononucleotide P-SSRs had relative higher variation in different genomic regions, followed by the CV pattern of RCN: dinucleotide P-SSRs > trinucleotide P-SSRs > tetranucleotide P-SSRs > pentanucleotide P-SSRs > hexanucleotide P-SSRs. The CV variations of RCN of the same mono- to hexanucleotide P-SSRs were relative higher in the intron and intergenic regions, followed by that in the TEs, and the relative lower was in the 5'UTR, CDSs and 3'UTRs. 58 novel polymorphic SSR loci were detected based on genotyping DNA from 36 captive FMD and 22 SSR markers finally showed polymorphism, stability, and repetition.

[Microbial diversity of musk across its maturation process in forest musk deer].

Musk,with unique and intense perfume,was a kind of deep brown precious medicinal material in traditional Chinese medicine. However,the immature musk in musk pot was white and stench. Given the fact that bacterial diversity generated odorous metabolites in animal hosts,in this study,musk samples at three different mature stages,including MJ( the end of June),MA( the end of August) and MO( the end of October) were harvested from three male forest musk deer,and then next-generation sequencing was used to intensively survey the bacterial communities in musk harvested at different mature stages. RESULTS: indicated that the average OTUs per sample at the end of June,August and October were 47 116. 00 ± 1 567. 24( SE),52 009. 00 ± 8 958. 75( SE) and50 004. 67±4 135. 57( SE),respectively. Feature of the musk 16 S rRNA gene showed a total of 418 genera belonging to 52 phyla were observed in all samples. The main microbiota was bacteria,which accounted for 98. 82%,99. 95% and 99. 58% in MJ,MA and MO,respectively. At phylum level,Firmicutes was the most abundant bacterial of MA( 32. 75%) and MO( 39. 19%). While,the major bacterial in MJ was Proteobacteria( 49. 14%). PICRUSt analysis revealed the functions of bacterial in MJ were mainly involved in secretion,while bacterial functions of MA and MO were mainly involved in amino acid or other substance metabolism,which was in accord with the musk secretion physiological process of forest musk deer. This is the first study involved in the bacterial diversity in musk of forest musk deer across the maturation process,while may provide a new insight into the musk generation mechanism.

Androgen Receptor Promotes Gastric Carcinogenesis via Upregulating Cell Cycle-Related Kinase Expression.

Gastric cancer (GC) is a leading global health problem as it is the fifth most common cancer type and the third most common cause of cancer-related deaths worldwide. In most areas of the world, the incidence rate of GC is 1.5- to 3-fold higher in males than in females. The androgen receptor (AR) is an independent adverse prognostic factor in patients with GC. However, the mechanism by which AR regulates the progression of GC remains unclear. In this study, we found that AR expression was upregulated in 6/8 GC cell lines, and this expression was higher than that in immortalized gastric cells. AR expression was also higher in GC tissues than in adjacent tissues. Moreover, the ectopic expression of AR promoted the colony formation ability, migration and invasion of GC cells. In contrast, AR knockdown had the opposite effects on GC cell lines. Remarkably, we found that AR regulated cell cycle-related kinase (CCRK) expression through transcriptional mechanisms. The AR-CCRK axis promoted GC development through the phosphorylation of GSK3ß and ß-catenin. Furthermore, TCGA data revealed that high expression of AR or CCRK was related to poor prognosis in GC patients. The prognosis was significantly worse in patients with concurrent high AR and CCRK expression than in patients with low AR and CCRK expression. In conclusion, our study demonstrated that AR and CCRK acted as oncogenes in GC progression. However, their clinical roles require further exploration.

MT1G is Silenced by DNA Methylation and Contributes to the Pathogenesis of Hepatocellular Carcinoma.

Using genome-wide screening and TCGA-based data analysis, we identified a DNA methylation-related gene named metallothionein-1G (MT1G), which may play an important role in hepatocellular carcinoma (HCC). In this study, we found that MT1G expression was silenced in 4/6 HCC cell lines and negatively related to aberrant promoter hypermethylation. Its mRNA level was restored with demethylation treatment. Moreover, MT1G downregulation at both the transcriptional and protein level was also detected in 8 pairs of clinical HCC samples compared with its expression in adjacent normal tissues. Ectopic expression of MT1G in silenced HCC cell lines inhibited colony formation, suppressed cell migration and invasion, and repressed xenograft tumor growth in nude mice. In contrast, knockdown of MT1G by short hairpin RNA showed the opposite effect on cell proliferation and the malignant phenotype. Moreover, our data showed that MT1G suppressed tumor invasion and metastasis mainly through regulating the expression of proteins in the matrix metalloproteinase family (MMP) and modulating the epithelial-mesenchymal transition (EMT) process. To our surprise, the data from TCGA showed that hypermethylation of MT1G is associated with good survival of HCC patients. In conclusion, our study demonstrated that MT1G acts as a tumor suppressor gene in HCC development, but its clinical potential in HCC requires further evaluation.

[Research progress on molecular genetics of forest musk deer].

Forest musk deer is one of the large-scale farming musk deer animals with the largest population at the same time. The male musk deer can secrete valuable medicines, which has high medicinal and economic value. Due to the loss of habitat and indiscriminate hunting, the numbers of wild population specie and the distribution have been drastically reduced. Therefore, in-depth understanding of the molecular genetics progress of forest musk deer will pave a way for musk deer protection and breeding. In this review, the progress associated with the molecular marker, genetic classification, artificial breeding, musk secretion and disease in past decades were reviewed, in order to provide a theoretical basis for subsequent molecular genetic researches in forest musk deer.

[Research progress on musk secretion mechanism of forest musk deer].

Forest musk deer (Moschus berezovskii), a rare wild medicinal animal, is listed under the category of the state key protected wildlife list of China. Musk, secreted by the musk glands, is with high economic and medicinal value and used as precious traditional medicine in China. In order to meet the needs of musk in Chinese traditional medicine, forest musk deer farming was conducted in 1950s, but the research progress on musk secretion mechanism was slow. Therefore, by reviewing the histological and anatomical structure of forest musk deer musk gland, the relationship between sex hormones and the musk secretion process, and the molecular mechanism of the musk secretion, the existing problems in investigating the musk secretion mechanism were analyzed and the development trends in this field were also discussed, in order to provide a reference for further studies on the musk secretion mechanism and improve musk production of forest musk deer.

Prediction of protein cleavage site with feature selection by random forest.

Proteinases play critical roles in both intra and extracellular processes by binding and cleaving their protein substrates. The cleavage can either be non-specific as part of degradation during protein catabolism or highly specific as part of proteolytic cascades and signal transduction events. Identification of these targets is extremely challenging. Current computational approaches for predicting cleavage sites are very limited since they mainly represent the amino acid sequences as patterns or frequency matrices. In this work, we developed a novel predictor based on Random Forest algorithm (RF) using maximum relevance minimum redundancy (mRMR) method followed by incremental feature selection (IFS). The features of physicochemical/biochemical properties, sequence conservation, residual disorder, amino acid occurrence frequency, secondary structure and solvent accessibility were utilized to represent the peptides concerned. Here, we compared existing prediction tools which are available for predicting possible cleavage sites in candidate substrates with ours. It is shown that our method makes much more reliable predictions in terms of the overall prediction accuracy. In addition, this predictor allows the use of a wide range of proteinases.

Establishment of an orthotopic transplantation tumor model of hepatocellular carcinoma in mice.

AIM: To improve the outcome of orthotopic transplantation in a mouse model, we used an absorbable gelatin sponge (AGS) in nude mice to establish an orthotopic implantation tumor model. METHODS: MHCC-97L hepatocellular carcinoma (HCC) cells stably expressing the luciferase gene were injected into the subcutaneous region of nude mice. One week later, the ectopic tumors were harvested and transplanted into the left liver lobe of nude mice. The AGS was used to establish the nude mouse orthotopic implantation tumor model. The tumor suppressor gene, paired box gene 5 (PAX5), which is a tumor suppressor in HCC, was transfected into HCC cells to validate the model. Tumor growth was measured by bioluminescence imaging technology. Semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) and histopathology were used to confirm the tumorigenicity of the implanted tumor from the MHCC-97L cell line. RESULTS: We successfully developed an orthotopic transplantation tumor model in nude mice with the use of an AGS. The success rate of tumor transplantation was improved from 60% in the control group to 100% in the experimental group using AGS. The detection of fluorescent signals showed that tumors grew in all live nude mice. The mice were divided into 3 groups: AGS-, AGS+/PAX5- and AGS+/PAX5+. Tumor size was significantly smaller in PAX5 transfected nude mice compared to control mice (P < 0.0001). These fluorescent signal results were consistent with observations made during surgery. Pathologic examination further confirmed that the tissues from the ectopic tumor were HCC. Results from RT-PCR proved that the HCC originated from MHCC-97L cells. CONCLUSION: Using an AGS is a convenient and efficient way of establishing an indirect orthotopic liver transplantation tumor model with a high success rate.

Cell cycle-related kinase is a direct androgen receptor-regulated gene that drives ß-catenin/T cell factor-dependent hepatocarcinogenesis.

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. It is more prevalent in men than women. Related to this, recent genetic studies have revealed a causal role for androgen receptor (AR) in hepatocarcinogenesis, but the underlying molecular mechanism remains unclear. Here, we used genome-wide location and functional analyses to identify a critical mediator of AR signaling - cell cycle-related kinase (CCRK) - that drives hepatocarcinogenesis via a signaling pathway dependent on ß-catenin and T cell factor (TCF). Ligand-bound AR activated CCRK transcription and protein expression via direct binding to the androgen-responsive element of the CCRK promoter in human HCC cell lines. In vitro analyses showed that CCRK was critical in human cell lines for AR-induced cell cycle progression, hepatocellular proliferation, and malignant transformation. Ectopic expression of CCRK in immortalized human liver cells activated ß-catenin/TCF signaling to stimulate cell cycle progression and to induce tumor formation, as shown in both xenograft and orthotopic models. Conversely, knockdown of CCRK decreased HCC cell growth, and this could be rescued by constitutively active ß-catenin or TCF. In primary human HCC tissue samples, AR, CCRK, and ß-catenin were concordantly overexpressed in the tumor cells. Furthermore, CCRK overexpression correlated with the tumor staging and poor overall survival of patients. Our results reveal a direct AR transcriptional target, CCRK, that promotes hepatocarcinogenesis through the upregulation of ß-catenin/TCF signaling.

Establishment of the methods for searching eukaryotic gene cis-regulatory modules.

On the basis of the knowledge of eukaryotic gene regulation, we modified the method in three aspects: (1) Searching the cis-regulatory modules (CRM) according Fasta or Blast sequence with multiple sequence and low E value, followed by mutual scoring of these sequence with Smith-Waterman algorithms and finally by clustering analysis; (2) Searching the transcription factor-binding site using International Union of Pure and Applied Chemistry, Position-Weight Matrix(PWM) and Dyed method; (3) Designing and implementation of data analysis based on the software in Windows 2000 and UNIX using object-oriented technology. The results of analysis of the major histocompatibility complex gene family show that this procedure may accurately locate the regions that contain some of the CRMs.

Comparing the base usage frequency between bacteria DNA double strand.

During the Evolution, effected by select pressure or nature mutation, the compositions of bacteria genomes is various. And many experiences prove that the genes between leading strand and lagging strand is distinctly in copy, transcription and repair. Some scholars presume that the bases distribution is difference between the two strand, to verify the guess, we using the technology of bioinformatics, compare the base usage between the DNA double strand in 17 species bacteria. The result show: 1. there is same bases usage frequency in coding sequence between leading strand and lagging strand 2. There also same bases usage frequency in first codon, second codon and third codon. It suggest that there is a equilibrium between the two strand by the effect of select pressure and nature mutation.

[Advance in the entire balance and local unbalance of base distribution in genome].

With more and more genome have been completely sequenced, scientists find the Partial Rule 2 (PR2) in entire single strand that A approximately equal to T, G approximately equal to C. But from the scope of thousands to hundreds of thousand bases, A not = T, G not = C. From the view of math, if the mutational rate of one strand is equal to others, it could be proved that A approximately equal to T, G approximately equal to C, but from the view of experience, that premise doesn't exist, so the solution of the problem needs the deeply combination of biology and math.

Diversity of PLA(2) Genes from Sea Snake Lapemis hardwickii Gray Venom.

Three full-length cDNA from Lapemis hardwickii Gray, (namely PLA(2)-8, PLA(2)-9 and PLA(2)-384), encoding phospholipase A(2) (PLA(2)), were isolated and sequenced. These cDNA sequences were composed of 456 bp, 438 bp and 438 bp, encoding a signal peptide of 27 amino acids and a mature peptide of 125, 119 and 119 amino acids, respectively. The analysis results by computer indicated PLA(2)-8, PLA(2)-9and PLA(2)-384 has a pI of ca. 4.8, 7.8 and 8.4, respectively. Sequence analysis of amino acid and prediction of secondary structure suggested that these isoforms of PLA(2) belong to class I PLA(2) family. PLA(2)-8 was highly homologous (81%) to Notechis scutatus scutatus (Australian tiger snake) PLA(2), PLA(2)-9 and PLA(2)-384 showed fairly high sequence homology (90%) to Enhydrina schistosa (beaked sea snake) PLA(2), indicating that they might have similar functions. These results reflect the diversity of Lapemis hardwickii Gray PLA(2) genes. The successful cloning of these isoenzyme genes of sea snake PLA(2) may provide new information for the study on structure-function relationship of PLA(2) family and its possible molecular mechanism.