The miR-29 family members induce glioblastoma cell apoptosis by targeting cell division cycle 42 in a p53-dependent manner.

BACKGROUND: Emerging evidence has shown that miR-29 is a promising biomarker and therapeutic target for malignancies. The roles of miR-29a/b/c in glioma pathogenesis remain need further investigation. METHODS: The expression levels of miR-29a/b/c and CDC42 were systematically analysed, and prognostic significance was evaluated by Kaplan-Meier survival and Cox regression analyses. The roles of miR-29a/b/c in apoptosis and the underlying mechanisms were explored via an alkaline single-cell gel electrophoresis assay, caspase 3/7 activity assays and Western blotting. RESULTS: miR-29a/b/c expression decreased progressively with the elevation of the WHO grade in our 147 human glioma specimens, compared with 20 non-tumour control brain tissues, and decreased miR-29a/b/c expression was associated with more aggressive phenotypes. Kaplan-Meier and Cox regression analyses demonstrated that lower miR-29a/b/c expression was correlated with worse prognosis, which was confirmed by analysis of 198 glioma patients from the CGGA cohort. These all indicate that miR-29a/b/c were independent predictors of prognosis in glioma patients. miR-29a/b/c induced apoptosis in GBM cells by silencing CDC42. Further detailed mechanistic investigation revealed that miR-29a/b/c promoted apoptosis in a p53-dependent manner by suppressing the CDC42/PAK/AKT/MDM2 pathway. CONCLUSIONS: miR-29a/b/c are independent predictors of prognosis in glioma patients. They induce glioblastoma cell apoptosis via silencing of CDC42 and suppression of downstream PAK/AKT/MDM2 signalling in a p53-dependent manner.

Metabolomics reveals the mechanism of Antarctic yeast Rhodotorula mucliaginosa AN5 to cope with cadmium stress.

Heavy metal pollution in Antarctica has far exceeded expectations. Antarctic yeast is widely present in polar marine environment. The mechanisms of metabolomics effect of heavy metal on polar yeast have not been reported previously. In this study, gas chromatography-mass spectrometry (GC-MS) wascarried out to performed the metabolite profiling analysis of Antarctic sea-ice yeast Rhodotorula mucilaginosa AN5 exposed to different cadmium (Cd) stresses of 5 mM (HM5), 10 mM (HM10) and 20 mM (HM20), respectively. Metabolic profile analysis showed that the composition and contents of cellular metabolites have been altered by cadmium. 93 different metabolites were identified altogether, among which 23, 58 and 81 different metabolites were found in HM5, HM10 and HM20 group respectively. MetaboAnalyst analysis showed that in HM5, HM10 and HM20 groups, 12, 24 and 31 metabolic pathways were involved in the stress of cadmium to R. mucilaginosa, respectively. By contrasting with Kyoto Encyclopedia of Genes and Genomes database, we discovered that exposure of yeast AN5 to Cd stress resulted in profound biochemical changes including amino acids, organic acids and saccharides. These results will supply a nonnegligible basis of studying the adaptive resistance mechanism of Antarctic yeast Rhodotorula mucilaginosa to heavy metal.

Molecular cloning and sequence analysis of a mitogen-activated protein kinase gene in the Antarctic yeast Rhodotorula mucilaginosa AN5.

BACKGROUND: The mitogen-activated protein kinase (MAPK) cascades play important roles in various signaling transduction networks of biotic and abiotic stress responses. However, MAPK signaling pathways in cold-active yeast Rhodotorula mucilaginosa have not been reported comprehensively. METHODS AND RESULTS: In the present study, MAPK gene (RmMAPK) was first cloned and characterized from Antarctic sea ice yeast R. mucilaginosa AN5. The full length of the RmMAPK gene is 1086 bp and encodes a 361 amino acids protein with a predicted molecular mass of 40.9 kDa and a pI of 5.25. The RmMAPK contains 11 MAPK conserved subdomains and the phosphorylation motif TGY located in the activation loop of the kinase. Quantitative real-time PCR and western blot assay revealed that the expression and phosphorylation level of RmMAPK up-regulated rapidly and significantly when yeast cells were subjected to low temperature (4 °C), high salinity (120‰ NaCl) and heavy metal (2 mmol/L CuCl2). CONCLUSIONS: All data suggested that the MAPK cascades might act as a key function in response to extreme stresses, such as low temperature, high salinity and heavy metal.

miR-135a-5p Functions as a Glioma Proliferation Suppressor by Targeting Tumor Necrosis Factor Receptor-Associated Factor 5 and Predicts Patients' Prognosis.

miR-135a-5p has been reported as a tumor suppressor in several extracranial tumors. However, its exact roles in gliomagenesis and relevance to the patients' prognoses are largely unknown. Herein, we detected the miR-135a-5p and tumor necrosis factor receptor-associated factor 5 (TRAF5) levels in 120 human glioma specimens and 20 nontumoral brain tissues; we found the miR-135a-5p level decreased, whereas the TRAF5 level increased, with the elevation of glioma grade. Their labeling indexes were inversely correlated with each other and showed strong negative (miR-135a-5p) and positive (TRAF5) correlation with the Ki-67 index. Cox regression demonstrated that both of their expression levels were independent survival predictors, whereas Kaplan-Meier analysis showed that subgrouping the glioma patients according to their levels could perfectly reflect the patients' prognoses regardless of the similarities in pathologic, molecular, and clinical features. In the following in vitro and in vivo studies, it was demonstrated that miR-135a-5p induced G1 arrest and inhibited the proliferation of glioma cells by targeting TRAF5 and subsequently blocking AKT phosphorylation as well as c-Myc and cyclin D1 expression. These effects could be reversed by TRAF5 overexpression and simulated by specific TRAF5 silencing. This study highlights the importance of miR-135a-5p and TRAF5 in gliomagenesis and progression and implies their potential prognostic and therapeutic values in malignant glioma.

Cloning, characterization and expression analysis of glutathione S-transferase from the Antarctic yeast Rhodotorula mucilaginosa AN5.

The gene for glutathione S-transferase (GST) in Antarctic sea-ice yeast Rhodotorula mucilaginosa AN5 was cloned and expressed in Escherichia coli and named RmGST. Sequence analysis showed that the RmGST gene contained a 843 bp open reading frame, which encoded 280 amino acid residues with a calculated molecular mass of 30.4 kDa and isoelectric point of 5.40. RmGST has the typical C- and N-terminal double domains of glutathione S-transferase. Recombinant RmGST (rRmGST) was expressed in E. coli to produce heterologous protein that had a high specific activity of 60.2 U/mg after purification. The apparent Km values of rRmGST for glutathione and 1-chloro-2,4-dinitrobenzene were 0.35 mM and 0.40 mM, respectively. Optimum enzyme activity was measured at 35 °C and at pH 7.0 and complete inactivation was observed after incubation at 55 °C for 60 min rRmGST tolerated high salt concentrations (1.0 M NaCl) and was stable at pH 3.0. Additionally, the recombinant protein nearly kept whole activity in Hg2+ and Mn2+, and could tolerate Ca2+, Cu2+, Mg2+, Cd2+, EDTA, thiourea, urea, Tween-80, H2O2 and Triton X-100. Real-time quantitative PCR showed that relative expression of the GST gene was significantly increased under Cu2+ and low temperature stress. These results indicate that rRmGST is a typical low thermostable enzyme, while its other characteristics, heavy metal and low temperature tolerance, might be related to its Antarctic home environment.

Purification and characterization of a novel wild-type α-amylase from Antarctic sea ice bacterium Pseudoalteromonas sp. M175.

A novel wild-type α-amylase named wtAmy175 from Pseudoalteromonas sp. M175 strain was purified through ammonium sulphate precipitation, DEAE cellulose, and Sephadex G-75 sequentially (25.83-fold, 7.67%-yield) for biochemical characterization. SDS-PAGE and zymographic activity staining of purified enzyme showed a single band with a predicted molecular mass of about 61 kDa. The optimum temperature and pH for enzyme activity were 30 °C and 7.5, respectively. Additionally, the enzyme exhibited high activity and remarkable stability in 0-10 mM SDS. The values of Km and Vmax for soluble starch as substrate were 2.47 mg/ml and 0.103 mg/ml/min, respectively. Analysis of hydrolysis products of soluble starch and maltooligosaccharides showed that wtAmy175 cleaved the interior and the terminal α-1,4-glycosidic linkage in starch, and had transglycosylation activity. The result of fluorescence spectroscopy showed that wtAmy175 had strong binding affinity with soluble starch. In brief, this study discovered the first wild-type α-amylase so far with several distinctive properties of cold activity, SDS-resistance, and the mixed activity of α-amylase and α-glucosidase, suggesting that wtAmy175 possess high adaptive capability to endure harsh industrial conditions and would be an excellent candidate in detergent and textile industries.

Cloning and functional characterization of a novel metallothionein gene in Antarctic sea-ice yeast (Rhodotorula mucilaginosa).

Metallothionein (MT) is a low-molecular-weight protein with a high metal binding capacity and plays a key role in organism adaptation to heavy metals. In this study, a metallothionein gene was successfully cloned and sequenced from Antarctic sea-ice yeast Rhodotorula mucilaginosa AN5. Nucleotide sequencing and analysis revealed that the gene had four exons interrupted by three introns. MTs complementary DNA (named as RmMT) had an open reading frame of 321 bp encoding a 106 amino acid protein with a predicted molecular weight of 10.3 kDa and pI of 8.49. The number of amino acids and distribution of cysteine residues indicated that RmMT was a novel family of fungal MTs. Quantitative real-time polymerase chain reaction analysis showed that RmMT expression was elevated under copper-induced stress. The RmMT gene was transferred into E. coli and the RmMT expressing bacteria showed improved tolerance to copper ion and increased accumulation of heavy metals, such as Cu2+ , Pb2+ , Zn2+ , Cd2+ , and Ag+ . Moreover, in vitro studies, purified recombinant RmMT demonstrated that it could be used as a good scavenger of superoxide anion, hydroxyl, and 1,1-Diphenyl-2-picrylhydrazyl (DPPH) radicals. In summary, these results demonstrate that RmMT plays a key role in the tolerance and bioaccumulation of heavy metals.

miR-29a/b/c function as invasion suppressors for gliomas by targeting CDC42 and predict the prognosis of patients.

BACKGROUND: The lethality and poor outcome of high-grade gliomas result from the tumour relentless invasion. miR-29a/b/c downexpressions contribute to several human tumourigenesis. However, their relevance to prognosis and invasion in gliomas remains unclear. METHODS: Relationships of miR-29a/b/c and CDC42 expressions to grade and survival-time in 147 human gliomas were analysed by in situ hybridisation and immunohistochemistry. Dual-luciferase reporter assay was used to identify CDC42 as a target of miR-29a/b/c. Underlining mechanisms by which miR-29a/b/c inhibited glioma cell migration and invasion were studied by in vitro and in vivo assays. RESULTS: miR-29a/b/c expressions were inversely correlated with glioma grades, but positively correlated with patients' survival. Two distinct subgroups of grade I-IV glioma patients with different prognoses were identified according to miR-29a/b/c expressions. miR-29a/b/c overexpressions suppressed glioma cell migration and invasion through targeting CDC42 and subsequently decreasing phosphorylated PAK1/2/3, LIMK1/2 and cofilin, the pivotal downstream effectors of CDC42. Moreover, CDC42 expression was positively correlated with glioma grades, but inversely correlated with miR-29a/b/c expressions and patients' survival. In glioblastoma cell lines, CDC42-knockdown could mimic the anti-tumour effects of miR-29a/b/c. CONCLUSIONS: miR-29a/b/c are important tumour suppressors and novel prognostic biomarkers of gliomas, and miR-29a/b/c and CDC42 are potential therapeutic candidates for malignant gliomas.

Cloning and characterization of iron-superoxide dismutase in Antarctic yeast strain Rhodotorula mucilaginosa AN5.

A novel superoxide dismutase gene from Antarctic yeast Rhodotorula mucilaginosa AN5 was cloned, sequenced, and then expressed in Escherichia coli. The R. mucilaginosa AN5 SOD (RmFeSOD) gene was 639 bp open reading frame in length, which encoded a protein of 212 amino acids with a deduced molecular mass of 23.5 kDa and a pI of 7.89. RmFeSOD was identified as iron SOD type with a natural status of homodimer. The recombinant RmFeSOD showed good pH stability in the pH 1.0-9.0 after 1 h incubation. Meanwhile, it was found to behave relatively high thermostability, and maintained more than 80% activity at 50 °C for 1 h. By addition of 1 mM metal ions, the enzyme activity increased by Zn2+ , Cu2+ , Mn2+ , and Fe3+ , and inhibited only by Mg2+ . RmFeSOD showed relatively low tolerance to some compounds, such as PMSF, SDS, Tween-80, Triton X-100, DMSO, ß-ME, and urea. However, DTT showed no inhibition to enzyme activity. Using copper stress experiment, the RmFeSOD recombinant E. coli exhibited better growth than non-recombinant bacteria, which revealed that RmFeSOD might play an important role in the adaptability of heavy metals.

Association between EHD3 gene and the cognitive function of patients with major depressive disorder.

OBJECTIVE: To analyze the potential association between the EHD3 gene and the cognitive function of patients with major depressive disorder (MDD). METHODS: A total of 47 MDD patients and 40 healthy controls were enrolled in this study. After their cognitive functions were analyzed, the scores of the MDD patients were used as the quantitative traits; by using the quantitative trait module in the UNPHASED software, we analyzed the potential association of the cognitive traits with the EHD3 gene. RESULTS: The cognitive scores (WAIS-RC and WMS-R) of MDD patients were significantly lower than those of controls (P<0.05). The rs3769621 allele and genotype of EHD3 gene were significantly associated with the raw score and scaled score of WAIS-RC (Χ(2)=10.561, P=0.001; Χ(2)=7.922, P=0.019; Χ(2)=12.627, P=0.00038; Χ(2)=11.775, P=0.0027)and WMS-R (Χ(2)=8.762, P=0.003; Χ(2)=17.399, P=0.00016; Χ(2)=10.356, P=0.001; Χ(2)=14.958, P=0.00056). Such associations remained statistically significant after Bonferroni correction. CONCLUSION: The EHD3 gene may be associated with the endophenotype of cognitive function in MDD patients.

Identification of SRSF10 as a promising prognostic biomarker with functional significance among SRSFs for glioma.

AIMS: The serine/arginine-rich splicing factor (SRSF) protein family members are essential mediators of the alternative splicing (AS) regulatory network, which is tightly implicated in cancer progression. However, the expression, clinical correlation, immune infiltration, and prognostic value of SRSFs in gliomas remain unclear. MATERIALS AND METHODS: Glioma samples were extracted from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) datasets. Several databases, such as HPA, DAVID, UALCAN were used to comprehensively explore the roles of SRSFs. In addition, experimental validation of SRSF10 was also conducted. KEY FINDINGS: Here, we found the expression alterations of the SRSF family in glioma samples using data from the TCGA and CGGA_325 datasets. Among the 12 genes, most were found to be closely associated with glioma clinical features, which linked to poor prognosis in glioma patients. Interestingly, survival analysis identified only SRSF10 as a potential independent risk prognostic biomarker for glioma patients. Immune analysis indicated that glioma patients with high SRSF10 expression may respond well to immunotherapies targeting immune checkpoint (ICP) genes. Finally, knocking down SRSF10 reduced glioma cell viability, induced G1 cell cycle arrest, and induced the exclusion of bcl-2-associated transcription factor 1 (BCLAF1) exon 5a. SIGNIFICANCE: Overall, this study uncovers the oncogenic roles of most SRSF family members in glioma, with the exception of SRSF5, while highlighting SRSF10 as a potential novel independent prognostic biomarker for glioma.

Evaluation of the ovarian reserve in women and adolescent girls with Hashimoto's thyroiditis by serum anti-Müllerian hormone level: A systematic review and meta-analysis.

Objectives: Several researchers performed case-control studies to explore the relationship between Hashimoto's thyroiditis(HT) and ovarian reserve using anti-Müllerian hormone(AMH) in adolescent girls and women. But the results among these studies are inconsistent and the relationship between HT and ovarian reserve is still controversial. The study aimed to conduct the meta analysis of case-control studies to confirm the relationship between HT and ovarian reserve using AMH. Methods: 6 electronic databases including PubMed, EMBASE, the Cochrane Library, China National Knowledge Internet(CNKI), SinoMed and Wanfang were searched from inception to December 2021. Endnote X7.0 software was applied to managing all the relevant records. Then data extraction and evaluation of methodological quality of included studies were conducted after two-step selection.Review manager 5.4 version software and Stata 12.0 version software were used to perform all statistical analyses. Results: 10 case-control studies involving 1202 individuals were included in the present study. The preliminary results revealed AMH values were significantly higher in adolescent girls with euthyroid HT compared with healthy adolescent girls(MD = 1.97; 95%CI, 1.43-2.51; P < 0.001; I2 = 0%). The pooled results in the subgroup of female adults with euthyroid HT showed AMH values were not significantly different between patients with HT and healthy women(MD = -0.21; 95%CI, -0.51-0.09; P = 0.18; I2 = 38%). The pooled results in the two subgroups of female adults with subclinical hypothyroidism and overt hypothyroidism both showed AMH values were significantly lower in the HT group compared with healthy women [(MD = -0.60; 95%CI, -0.86 to -0.34; P < 0.001; I2 = 0%), (MD = -1.34; 95%CI, -1.94 to -0.74; P < 0.001; I2 = 65%)]. Conclusions: Ovarian reserve evaluated by serum AMH concentration is affected by female adults with subclinical hypothyroidism and overt hypothyroidism. The AMH level was significantly higher in euthyroid adolescent girls.

A study of the combined effects of the EHD3 and FREM3 genes in patients with major depressive disorder.

Major depressive disorder (MDD) is a common chronic mental disease with diverse clinical presentation. Although the genome-wide association study (GWAS) has remarkably facilitated the understanding of genetic mechanisms of MDD at a deep molecular level, the combined effect of these disease-underlying genes still needs further investigation. A total of 1,062 unrelated patients with MDD and 992 unrelated healthy subjects were recruited from a Chinese Han population to test 16 MDD-associated genes identified by GWAS. A tag SNP-based linkage-disequilibrium map was then constructed over the loci that showed MDD association in the study sample. Of the 16 genes tested, EHD3 and FREM3 were associated with MDD in the Chinese population. The conditional test showed disease association for the rs619002(EHD3)-rs1112714(FREM3) combination (P = 0.0059) and for the rs644926(EHD3)-rs13130123(FREM3) combination (P = 0.007), of which a reduced risk was found for the rs619002(G)-rs1112714(T) combination (OR = 0, P = 4.02 × 10(-6) ) and for the rs644926(A)-rs11938298(G) combination (OR = 0.12, 95% CI = 0.035-0.39, P = 3.85 × 10(-6) ). Quantitative trait analysis revealed that rs13130123 in the FREM3 locus was strongly associated with the insomnia early symptom in patients carrying the rs619002(G) allele (P = 0.001) and those carrying the rs644926(A) allele (P = 0.00077). The combined effect of the EHD3 and FREM3 genes may play an important role in developing MDD. © 2012 Wiley Periodicals, Inc.

ZNF804A and schizophrenia susceptibility in Asian populations.

ZNF804A, a recently identified risk gene for schizophrenia, has been extensively investigated and the principle finding for this locus has been the association with SNP rs1344706 in populations of European ancestries. However, in Asian populations, only a few studies have been conducted for rs1344706 and the results were inconsistent. Here, we studied rs1344706 and schizophrenia susceptibility in multiple Asian case-control samples (10 Chinese and 2 Japanese samples; N = 21,062), and the meta-analyses indicated non-significant association of rs1344706 with schizophrenia (P = 0.26), suggesting the same SNP identified in European samples is not predisposing risk in Asians. Further genotyping and association analyses of a set of SNPs spanning the entire genomic region of ZNF804A (520 kb) identified no association except for SNP rs359895 (P = 7.8 x 10(-5) , N = 5,172), a newly reported risk SNP located in the ZNF804A promoter region with functional implications. This suggests that ZNF804A may also contribute to schizophrenia susceptibility in Asians although the risk SNP is different from that in Europeans, and it was supported by the detected up-regulation of ZNF804A mRNA expression in the blood cells of Chinese schizophrenia patients compared with normal controls (P = 0.004). Additionally, the linkage disequilibrium (LD) structure analyses using data from HapMap indicated distinct LD blocks across ZNF804A between Chinese and Europeans, which may explain the different association patterns between them, and also highlight the compounding difficulty of genetic studies of complex diseases like schizophrenia when studying multiple ethnic populations.

Biochemical and Metabolomic Responses of Antarctic Bacterium Planococcus sp. O5 Induced by Copper Ion.

Heavy metal pollution in the Antarctic has gone beyond our imagination. Copper toxicity is a selective pressure on Planococcus sp. O5. We observed relatively broad tolerance in the polar bacterium. The heavy metal resistance pattern is Pb2+ > Cu2+ > Cd2+ > Hg2+ > Zn2+. In the study, we combined biochemical and metabolomics approaches to investigate the Cu2+ adaptation mechanisms of the Antarctic bacterium. Biochemical analysis revealed that copper treatment elevated the activity of antioxidants and enzymes, maintaining the bacterial redox state balance and normal cell division and growth. Metabolomics analysis demonstrated that fatty acids, amino acids, and carbohydrates played dominant roles in copper stress adaptation. The findings suggested that the adaptive mechanisms of strain O5 to copper stress included protein synthesis and repair, accumulation of organic permeable substances, up-regulation of energy metabolism, and the formation of fatty acids.

Promotive effects of four herbal medicine ARCC on wound healing in mice and human.

Background: Traditional Chinese medicine (TCM) had been extensively used in China for wound management and had shown great potential in wound treatment while its mechanism is still needed to be addressed. Objective: The present study sought to investigate the therapuetic effect of the TCM ARCC on acute and chronic wounds. Methods: Here, using the ultra-low temperature preparation method, the mixed ultramicro powder prepared with Angelica (A), Angelica (R), Calcined Gypsum (C) and Caleramide (C) named as ARCC. The effects of ARCC on wound healing in adult and aged mice were comparatively evaluated through a full-thickness skin defect model. In addition, we randomly selected 10 patients aged 55 to 70 years from a cohort of 500 patients with diabetic feet to assess their prognosis. Results: As the results showed that the healing rate had delayed in aged mice compared to adult mice, while ARCC prominently augmented the healing process in aged mice. Moreover, ARCC treatment wounds in aged mice showed accelerated re-epithelization, enhanced granulation tissue formation, and increased vascularization, which was similar to that of adult mice. Furthermore, ARCC also achieved therapeutic effects in diabetic foot patients, accelerating wound healing. The results found that foot ulcers improved significantly 7 days after the ARCC administration, and 80% of patients were healed within 1 month. Discussion: In the present study, ARCC was found to have therapeutic effects on both acute and chronic wounds in animal models. ARCC also demonstrated therapeutic effects in diabetic feet, which promoted wound healing, prevented wound infection, and avoided the risk of further surgery or amputation. All these evidences suggested ARCC was a promising approach for wound treatment. Conclusions: ARCC might be recommended as a promising therapeutic medication in diabetic and chronic refractory wounds.

Recruitment of LEF1 by Pontin chromatin modifier amplifies TGFBR2 transcription and activates TGFß/SMAD signalling during gliomagenesis.

Synergies of transcription factors, chromatin modifiers and their target genes are vital for cell fate determination in human cancer. Although the importance of numerous epigenetic machinery for regulating gliomagenesis has been previously recognized, how chromatin modifiers collaborate with specific transcription factors remains largely elusive. Herein we report that Pontin chromatin remodelling factor acts as a coactivator for LEF1 to activate TGFß/SMAD signalling, thereby contributing to gliomagenesis. Pontin is highly expressed in gliomas, and its overexpression paralleled the grade elevation and poor prognosis of patients. Functional studies verified its oncogenic roles in GBM cells by facilitating cell proliferation, survival and invasion both in vitro and in vivo. RNA sequencing results revealed that Pontin regulated multiple target genes involved in TGFß/SMAD signalling. Intriguingly, we found that Pontin amplified TGFßR2 gene transcription by recruiting LEF1, thereby activating TGFß/SMAD signalling and facilitating gliomagenesis. Furthermore, higher TGFßR2 expression conferred worse patient outcomes in glioma. To conclude, our study revealed that the Pontin-LEF1 module plays a crucial role in driving TGFßR2 gene transcription, which could be exploited to target TGFß/SMAD signalling for anti-glioma therapy.

[Association between protein tyrosine phosphatase receptor type R gene and major depressive disorder].

OBJECTIVE: To explore the genetic association between protein tyrosine phosphatase receptor type R (PTPRR) gene polymorphism and major depressive disorder (MDD) and its endophenotype. METHODS: A total of 517 unrelated MDD patients and 455 unrelated healthy subjects were recruited in this study to detect 11 single nucleotide polymorphisms (SNPs) in the PTPRR locus. They all were of the Chinese Han origin. Genotyping of SNPs was performed by matrix assisted laser desorption ionisation time-of-flight mass spectrometry (MALDI-TOF-MS) -based genotyping approach. The UNPHASED program was applied to analyze the genotyping data. RESULTS: Of the 11 selected SNPs, no significant allelic and genotypic association was found between MDD patients and the normal controls (corrected P > 0.05). However, analysis of haplotypes showed that the three SNPs haplotype rs1398599 (C) -rs2175711 (A) - rs4489789 (T) (P = 0.0023, OR = 1.334, 95% CI = 1.104-1.612) and four SNPs haplotype rs11178391 (C) -rs1398599 (C) -rs2175711 (A)-rs4489789(T) (P = 0.0063, OR = 1.281, 95% CI = 1.059-1.549) were associated with increased risk of MDD. Quantitative trait analysis revealed that rs2203231 in the PTPRR locus had strong allelic and genotypic association with the raw score of long-term memory (P = 0.0038 for allelic association, P = 0.0024 for genotypic association), the scaled score of long-term memory (P = 0.0057 for allelic association, P = 0.0038 for genotypic association), the raw score of short-term memory (P = 0.0027 for allelic association, P = 0.0015 for genotypic association), and the scaled score of short-term memory (P = 0.0035 for allelic association, P = 0.002 for genotypic association) in MDD patients. CONCLUSION: The polymorphism of PTPRR gene rs2203231 may be associated with the impairment of long-term and short-term memories in MDD patients.

Diversity and Antiaflatoxigenic Activities of Culturable Filamentous Fungi from Deep-Sea Sediments of the South Atlantic Ocean.

Despite recent studies, relatively few are known about the diversity of fungal communities in the deep Atlantic Ocean. In this study, we investigated the diversity of fungal communities in 15 different deep-sea sediments from the South Atlantic Ocean with a culture-dependent approach followed by phylogenetic analysis of ITS sequences. A total of 29 fungal strains were isolated from the 15 deep-sea sediments. These strains belong to four fungal genera, including Aspergillus, Cladosporium, Penicillium, and Alternaria. Penicillium, accounting for 44.8% of the total fungal isolates, was a dominant genus. The antiaflatoxigenic activity of these deep-sea fungal isolates was studied. Surprisingly, most of the strains showed moderate to strong antiaflatoxigenic activity. Four isolates, belonging to species of Penicillium polonicum, Penicillium chrysogenum, Aspergillus versicolor, and Cladosporium cladosporioides, could completely inhibit not only the mycelial growth of Aspergillus parasiticus mutant strain NFRI-95, but also the aflatoxin production. To our knowledge, this is the first report to investigate the antiaflatoxigenic activity of culturable deep-sea fungi. Our results provide new insights into the community composition of fungi in the deep South Atlantic Ocean. The high proportion of strains that displayed antiaflatoxigenic activity demonstrates that deep-sea fungi from the Atlantic Ocean are valuable resources for mining bioactive compounds.

Improved Antiglioblastoma Activity and BBB Permeability by Conjugation of Paclitaxel to a Cell-Penetrative MMP-2-Cleavable Peptide.

In order to solve the problems of receptor promiscuity and poor blood-brain barrier (BBB) penetration in the treatment of glioblastomas (GBM), a novel dual-functional nanocomplex drug delivery system is developed based on the strategy of peptide-drug conjugates. In this study, SynB3-PVGLIG-PTX is designed and screened out by matrix metalloproteinase-2 (MMP-2), to which it exhibits the best affinity. The MMP-2-sensitive peptide (PVGLIG) and a cell-penetration peptide (SynB3) are combined to form a dual-functional peptide. Moreover, as a drug-peptide nanocomplex, SynB3-PVGLIG-PTX exhibited a high potential to form an aggregation with good solubility that can release paclitaxel (PTX) through the cleavage of MMP-2. From a functional perspective, it is found that SynB3-PVGLIG-PTX can specifically inhibit the proliferation, migration, and invasion of GBM cells in vitro in the presence of MMP-2, in contrast to that observed in MMP-2 siRNA transfected cells. Further investigation in vivo shows that SynB3-PVGLIG-PTX easily enters the brain of U87MG xenograft nude mice and can generate a better suppressive effect on GBM through a controlled release of PTX from SynB3-PVGLIG-PTX compared with PTX and temozolomide. Thus, it is proposed that SynB3-PVGLIG-PTX can be used as a novel drug-loading delivery system to treat GBM due to its specificity and BBB permeability.