Insulin-like growth factor-2 mRNA-binding protein 3 promotes cell migration, invasion, and epithelial-mesenchymal transition of esophageal squamous cell carcinoma cells by targeting zinc finger E-box-binding homeobox 1 mRNA.

The role and mechanism of insulin-like growth factor-2 mRNA-binding protein 3 (IGF2BP3) in the metastasis of esophageal squamous cell carcinoma (ESCC) remain unclear. In this study, IGF2BP3 mRNA and protein expression levels were evaluated in ESCC tissues. Small interfering RNAs (siRNAs), plasmid overexpression, and stable lentivirus transfection were used to manipulate intracellular IGF2BP3 expression levels. The role of IGF2BP3 in ESCC tumorigenesis was investigated in vitro and in vivo. IGF2BP3 target transcripts were detected, and the acetylation effect ratios of the IGF2BP3 promoter region by H3K27ac were determined. IGF2BP3 mRNA expression levels were significantly higher in ESCC tissues than in normal esophageal tissues. Increased IGF2BP3 expression levels were detected in node-negative ESCC tissues and correlated with greater lesion depth in ESCC. Overexpression of IGF2BP3 promoted ESCC development in vitro and in vivo, and IGF2BP3 knockdown caused an opposite effect. IGF2BP3 was found to directly bind to the zinc finger E-box-binding homeobox 1 (Zeb1) mRNA, and the downregulation of IGF2BP3 reduced the stability of Zeb1 mRNA. IGF2BP3 induced epithelial-mesenchymal transition in ESCC cells in a Zeb1-dependent manner. IGF2BP3 was transcriptionally activated in ESCC cell lines via H3K27 acetylation. Our results demonstrate that IGF2BP3 plays a vital role in ESCC cell proliferation, invasion, and metastasis and is a potential therapeutic target for treating ESCC.

Role of genetics in amyotrophic lateral sclerosis: a large cohort study in Chinese mainland population.

BACKGROUND: A large number of new causative and risk genes for amyotrophic lateral sclerosis (ALS) have been identified mostly in patients of European ancestry. In contrast, we know relatively little regarding the genetics of ALS in other ethnic populations. This study aims to provide a comprehensive analysis of the genetics of ALS in an unprecedented large cohort of Chinese mainland population and correlate with the clinical features of rare variants carriers. METHODS: A total of 1587 patients, including 64 familial ALS (FALS) and 1523 sporadic ALS (SALS), and 1866 in-house controls were analysed by whole-exome sequencing and/or testing for G4C2 repeats in C9orf72. Forty-one ALS-associated genes were analysed. FINDINGS: 155 patients, including 26 (40.6%) FALS and 129 (8.5%) SALS, carrying rare pathogenic/likely pathogenic (P/LP) variants of ALS causative genes were identified. SOD1 was the most common mutated gene, followed by C9orf72, FUS, NEK1, TARDBP and TBK1. By burden analysis, rare variants in SOD1, FUS and TARDBP contributed to the collective risk for ALS (p<2.5e-6) at the gene level, but at the allelic level TARDBP p.Gly294Val and FUS p.Arg521Cys and p.Arg521His were the most important single variants causing ALS. Clinically, P/LP variants in TARDBP and C9orf72 were associated with poor prognosis, in FUS linked with younger age of onset, and C9orf72 repeats tended to affect cognition. CONCLUSIONS: Our data provide essential information for understanding the genetic and clinical features of ALS in China and for optimal design of genetic testing and evaluation of disease prognosis.

The mutation spectrum of Parkinson-disease-related genes in early-onset Parkinson's disease in ethnic Chinese.

BACKGROUND AND PURPOSE: Recent genetic progress has shown many causative/risk genes linked to Parkinson's disease (PD), mainly in patients of European ancestry. The study aimed to investigate the PD-related genes and determine the mutational spectrum of early-onset PD in ethnic Chinese. METHODS: In this study, whole-exome sequencing and/or gene dosage analysis were performed in 704 early-onset PD (EOPD) patients (onset age ≤45 years) and 1866 controls. Twenty-six PD-related genes and 20 other genes linked to neurodegenerative and lysosome diseases were analysed. RESULTS: Eighty-two (11.6%, 82/704) EOPD patients carrying rare pathogenic/likely pathogenic variants in PD-related genes were identified. The mutation frequency in autosomal recessive inheritance EOPD (42.9%, 27/63) was much higher than that in autosomal dominant inheritance EOPD (0.9%, 12/110) or sporadic EOPD (8.1%, 43/531). Bi-allelic mutations in PRKN were the most frequent, accounting for 5.1% of EOPD cases. Three common pathogenic variants, p.A53V in SNCA, p.G284R in PRKN and p.P53Afs*38 in CHCHD2, occur exclusively in Asians. The putative damaging variants from GBA, PRKN, DJ1, PLA2G6 and GCH1 contributed to the collective risk for EOPD. Notably, the protein-truncating variants in CHCHD2 were enriched in EOPD, especially for p.P53Afs*38, which was also found in three patients from an independent cohort of patients with late-onset PD (n = 1300). Functional experiments confirmed that truncated CHCHD2 variants cause loss of function and are linked to mitochondrial dysfunction. CONCLUSIONS: Our study reveals that the genetic spectrum of EOPD in Chinese, which may help develop genetic scanning strategies, provided more evidence supporting CHCHD2 in PD.

Molecular characterization, expression analysis and cellular location of IL-4/13 receptors in large yellow croaker (Larimichthys crocea).

Interleukin (IL)-4 and IL-13 are closely related class I cytokines that play key roles in the T helper (Th)-2 immune response via heterodimeric receptors. IL-4 signals via both the type I (IL-4Rα/γc) and type II (IL-4Rα/IL-13Rα1) receptor complexes, while IL-13 signals only via the type II receptor complex. IL-13Rα2 is traditionally considered a "decoy" receptor for IL-13. However, the IL-4/13 system and its response to pathogenic infection are still not fully understood in fish. In this study, we identified four IL-4/13 receptor subunit genes in the large yellow croaker (Larimichthys crocea): LcIL-4Rα1, LcIL-4Rα2, LcIL-13Rα1, and LcIL-13Rα2. Sequence analysis showed that these receptors possessed typical characteristic domains, including a signal peptide, two fibronectin type III (FN III)-like domains, and a transmembrane domain, but their cytoplasmic regions were not well conserved. The mRNA and protein of the four IL-4/13 receptors were constitutively expressed in all examined tissues of large yellow croaker. Their mRNAs were also detected in primary head kidney macrophages (PKMs), primary head kidney granulocytes (PKGs), and primary head kidney lymphocytes (PKLs). Immunofluorescence assay further showed that LcIL-4Rα and LcIL-13Rα1 were expressed on the membrane of IgM + B cells. After stimulation by Vibrio alginolyticus and poly (I:C) (a viral dsRNA mimic), the mRNA levels of LcIL-4/13 receptors were significantly upregulated in the head kidney and spleen. Their mRNA levels were also upregulated in head kidney leukocytes in response to poly (I:C) and lipopolysaccharide (LPS) treatment. Moreover, both recombinant LcIL-4/13A and LcIL-4/13B upregulated LcIL-4Rα1 and LcIL-4Rα2 in primary leukocytes, but only recombinant LcIL-4/13A upregulated LcIL-13Rα1 and LcIL-13Rα2. These results indicated that LcIL-4/13 receptors, containing conserved functional domains, may be involved in the IL-4/13-mediated immune response to pathogenic infections in the large yellow croaker.

Pseudogene KRT17P3 drives cisplatin resistance of human NSCLC cells by modulating miR-497-5p/mTOR.

Chemoresistance is a major obstacle in non-small cell lung cancer (NSCLC) treatment. The pseudogene keratin 17 pseudogene 3 (KRT17P3) has been previously shown to be upregulated in lung cancer tissues of patients with cisplatin resistance. In the present study, RT-qPCR was performed to evaluate KRT17P3 levels in plasma samples collected from 30 cisplatin-resistant and 32 cisplatin-sensitive patients. We found that the plasma level of KRT17P3 is upregulated in cisplatin-resistant patients, and the increased expression of plasma KRT17P3 is associated with poor chemotherapy response. Functional studies demonstrated that KRT17P3 overexpression in cultured NSCLC cells increases cell viability and decreases apoptosis upon cisplatin treatment in vitro and in vivo, while KRT17P3 knockdown has the opposite effect. Mechanistically, bioinformatics analysis, RNA immunoprecipitation, and dual luciferase reporter assay indicated that KRT17P3 acts as a molecular sponge for miR-497-5p and relieves the binding of miR-497-5p to its target gene mTOR. Rescue experiments validated the functional interaction between KRT17P3, miR-497-5p, and mTOR. Taken together, our findings indicate that KRT17P3/miR-497-5p/mTOR regulates the chemosensitivity of NSCLC, suggesting a potential therapeutic target for cisplatin-resistant NSCLC patients. KRT17P3 may be a potential peripheral blood marker of NSCLC patients resistant to cisplatin.

ATG12 is involved in the antiviral immune response in large yellow croaker (Larimichthys crocea).

ATG12, a core autophagy protein, forms a conjugate with ATG5 to promote the formation of autophagosome membrane, and plays an important role in antiviral immunity. However, little is known about the function of ATG12 in fish. Here, we cloned the open reading frame (ORF) of large yellow croaker (Larimichthys crocea) ATG12 (LcATG12), which is 354 nucleotides long and encodes a protein of 117 amino acids. The deduced LcATG12 possesses a conserved APG12 domain (residues 31 to 117), and shares 91.45% identities with ATG12 in orange-spotted grouper (Epinephelus coioides). LcATG12 was constitutively expressed in all examined tissues, with the highest level in intestine. Its transcript was also detected in primary head kidney granulocytes (PKG), primary head kidney macrophages (PKM), primary head kidney lymphocytes (PKL), and large yellow croaker head kidney (LYCK) cell line, and was significantly up-regulated by poly(I:C). LcATG12 was regularly distributed in both cytoplasm and nucleus of LYCK and epithelioma papulosum cyprinid (EPC) cells. Overexpression of LcATG12 in EPC cells significantly inhibited the replication of spring viremia of carp virus (SVCV). Further studies reveled that LcATG12 could induce the occurrence of autophagy in LYCK cells. Furthermore, overexpression of LcATG12 in LYCK cells increased the expression levels of large yellow croaker type I interferons (IFNs, IFNc, IFNd, and IFNh), IFN regulatory factors (IRF3 and IRF7), and IFN-stimulated genes (PKR, Mx, and Viperin). All these data indicated that LcATG12 plays a role in the antiviral immunity possibly by inducing both autophagy and type I IFN response in large yellow croaker.

Different resting-state network disruptions in newly diagnosed drug-naïve Parkinson's disease patients with mild cognitive impairment.

BACKGROUND: Cognitive impairment is a common non-motor symptom in patients with Parkinson's disease (PD). Mild cognitive impairment (MCI) is also prevalent in nondemented PD patients, even in newly diagnosed PD patients. The possible impacts of MCI on brain function activities for PD patients need more investigation, and the potential of emerging technologies for detecting underlying pathophysiology of cognitive signs in PD can be further improved. METHOD: Forty-seven newly diagnosed drug-naïve PD patients (28 PD-MCI patients and 19 PD patients with cognitively unimpaired (PD-CU)) and 28 healthy controls (HCs) underwent resting-state functional MRI. The connectivity patterns of specific networks were investigated through the independent component analysis among PD-MCI, PD-CU and HCs groups. RESULTS: The independent component analysis revealed significantly decreased functional connectivity (FC) of the default mode network, visual network and sensorimotor network in the PD-MCI subgroup compared with the HC group. Furthermore, FC of the default mode network was positively correlated with memory scores from the brief visuospatial memory test-revised, and FC of the visual network was positively correlated with visuospatial scores from the clock copying test in the PD-MCI group. In all patients with PD, FC of the sensorimotor network negatively correlated with motor severity scores from the Unified PD Rating Scale (UPDRS) part III. On the other hand, the potential damage was more likely to occur in FC between the sensorimotor network and limbic network, and between the ventral attention network and visual network in all PD patients. CONCLUSIONS: Newly diagnosed drug-naïve PD-MCI patients showed characteristic damage of FC within the default mode network, visual network and sensorimotor network, and all PD patients presented impaired FC between the sensorimotor network and limbic network, and FC between the ventral attention network and visual network. These network-wide functional aberrations may underline the pathophysiology of PD.

Chinese families with autosomal recessive hereditary spastic paraplegia caused by mutations in SPG11.

BACKGROUND: Spastic paraplegia type 11 (SPG11) mutations are the most frequent cause of autosomal recessive hereditary spastic paraplegia (ARHSP). We are aiming to identify the causative mutations in SPG11 among families referred to our center with ARHSP in a Chinese population. METHODS: Targeted next-generation sequencing was performed on the patients to identify disease-causing mutations. Variants were analyzed according to their predicted pathogenicity and their relevance to the clinical phenotypes. The segregation in the family members was validated by Sanger sequencing. RESULTS: A total of 12 mutations in SPG11 gene from 9 index cases were identified, including 6 frameshift mutations, 3 missense mutations, 1 nonsense mutation, 1 splicing mutation, and 1 intron deletion mutation. In 6 of these patients, the mutations were homozygous, and the other 3 patients carried two compound heterozygous mutations. Six mutations were novel; 2 were classified as pathogenic, 1 were considered as likely pathogenic, and the other 3 were variants of unknown significance. Additionally, 1 missense heterozygous variant we found was also carried by amyotrophic lateral sclerosis (ALS) patient. Clinically and electrophysiologically, some of our ARHSP patients partially shared various features of autosomal-recessive juvenile amyotrophic lateral sclerosis (ARJALS), including combination of both UMN and LMN degeneration. CONCLUSIONS: The results contribute to extending of the SPG11 gene mutation spectrum and emphasizing a putative link between ARHSP and ARJALS.

Primary disruption of the default mode network subsystems in drug-naïve Parkinson's disease with mild cognitive impairments.

PURPOSE: Mild cognitive impairment (MCI) in Parkinson's disease (PD) is related to the disrupted connectivity in networks involved in cognition, primarily in the default mode network (DMN). The DMN contains a midline core and two distinct subsystems (dorsal medial prefrontal cortex (DMPFC) and medial temporal lobe (MTL) subsystems). METHODS: The strength of functional connectivity (FCS) in intra- and inter-subsystems of DMN and the regional FCS were compared between any two groups from 28 drug-naïve PD patients with MCI (PD-MCI), 19 drug-naïve PD patients with cognitive unimpaired (PD-CU), and 28 age- and sex-matched healthy controls (HCs) by using the nonparametric permutation method (10,000 permutations) with age, sex, and education as covariates and False Discovery Rate (FDR) correction. RESULTS: For intra-subsystems, the decreased FCS was only detected in the DMPFC subsystem of PD-MCI patients compared with HCs. For inter-subsystems, PD-MCI patients displayed decreased FCS between the posterior cingulate cortex (PCC) and DMPFC subsystem compared with HCs. Furthermore, the temporal parietal junction (TPJ) in the DMPFC subsystem showed decreased regional FCS in the PD-MCI subgroup relative to the HC group. No significant change of FCS was found between PD-MCI and PD-CU patients, and between PD-CU patients and HCs. The sum of FCS values within the DMPFC subsystem and FCS values between the PCC and DMPFC subsystem had a significant power to distinguish PD-MCI patients from PD-CU patients (area under curve (AUC) = 0.703). CONCLUSION: The DMPFC subsystem was predominantly disrupted in the PD-MCI subgroup and may have the potential to discriminate PD with MCI.

LUCAT1 promotes colorectal cancer tumorigenesis by targeting the ribosomal protein L40-MDM2-p53 pathway through binding with UBA52.

Colorectal cancer (CRC) is the third most commonly diagnosed cancer in both men and women in the USA. However, the underlying molecular mechanisms that drive CRC tumorigenesis are still not clear. Several studies have reported that long noncoding RNAs (lncRNAs) have important roles in tumor development. Here, we undertook a transcriptome microarray analysis in 6 pairs of CRC tissues and their corresponding adjacent normal tissues. A total of 1705 differentially expressed lncRNAs were detected in CRC tissues at stages I/II and III/IV (fold change greater than or equal to 2 or less than or equal to 0.5). Among them, we found that the lncRNA lung cancer-associated transcript 1 (LUCAT1) was upregulated in CRC tissues and was closely associated with poor overall survival of CRC patients, through analysis of clinical data and The Cancer Genome Atlas. Functional studies indicated that LUCAT1 promoted CRC cell proliferation, apoptosis, migration, and invasion in vitro and in vivo. Furthermore, knockdown of LUCAT1 rendered CRC cells hypersensitive to oxaliplatin treatment. Mechanistically, bioinformatic analysis indicated that low expression of LUCAT1 was associated with the p53 signaling pathway. Chromatin isolation by RNA purification followed by mass spectrometry and RNA immunoprecipitation revealed that LUCAT1 bound with UBA52, which encodes ubiquitin and 60S ribosomal protein L40 (RPL40). We found that RPL40 functions in the ribosomal protein-MDM2-p53 pathway to regulate p53 expression. Taken together, our findings indicate that suppression of LUCAT1 induces CRC cell cycle arrest and apoptosis by binding UBA52 and activating the RPL40-MDM2-p53 pathway. These results implicate LUCAT1 as a potential prognostic biomarker and therapeutic target for CRC.

Development of monoclonal antibody against IgM of large yellow croaker (Larimichthys crocea) and characterization of IgM+ B cells.

In the present study, a monoclonal antibody (mAb) against large yellow croaker IgM was produced by immunizing mice with purified large yellow croaker serum IgM. Western blotting showed that this mAb could specifically react with the heavy chain of large yellow croaker serum IgM. Indirect immunofluorescence assay (IFA) analysis suggested that the resulting mouse anti-IgM mAb could recognize membrane-bound IgM (mIgM) molecules of large yellow croaker. This mouse anti-IgM mAb also can be used for sorting of large yellow croaker IgM+ B cells through the magnetic-activated cell sorting (MACS) method, which was further confirmed by RT-PCR analysis of specific marker genes for B cells. Flow cytometry analysis showed that the percentages of IgM+ B cells in head kidney, spleen and peripheral blood lymphocytes were 29.00 ±â€¯1.58%, 33.00 ±â€¯1.64%, and 16.50 ±â€¯2.39%, respectively. Additionally, the phagocytosis rates of IgM+ B cells for 0.5 µm beads in head kidney, spleen and peripheral blood were calculated to be 7.56 ±â€¯0.58%, 4.053 ±â€¯0.62% and 23.17 ±â€¯2.26%, respectively, while only 2.36 ±â€¯0.23%, 1.16 ±â€¯0.44% and 6.41 ±â€¯0.45 of IgM+ B cells in these three tissues ingested 1 µm beads. Taken together, our data demonstrated that the mouse anti-IgM mAb produced in this study could be used as a tool to characterize IgM+ B cells and to study functions of IgM in large yellow croaker.

Capability of four sigmoidoscopy-based screening strategies to predict proximal neoplasia in an asymptomatic Chinese population.

BACKGROUND AND AIM: A proper colonoscopy referral criterion is essential for flexible sigmoidoscopy-based colorectal cancer screening. We aimed to compare the predictive capability of four existing criteria to detect proximal neoplasia (PN) and advanced proximal neoplasia (APN) in a Chinese population. METHODS: Asymptomatic Chinese participants aged 50-75 years, who received screening colonoscopy, were consecutively recruited. The four criteria included (i) UK flexible sigmoidoscopy; (ii) Italian Screening for COlon REctum; (iii) NORwegian Colorectal Cancer Prevention trial; and (iv) US clinical index. The sensitivity, specificity, positive/negative predictive value, and the number of subjects needed to screen (NNS)/refer (NNR) to detect one APN/PN were examined. The area under receiver operating characteristic curve was evaluated. RESULTS: Among 5833 subjects, 749 (12.8%) and 151 (2.6%) cases were found to have PN and APN, respectively. US criteria achieved the highest sensitivity for PN (49%) and APN (66%), while UK criteria attained the highest specificity (93%) for PN/APN. The lowest NNS was required by US criteria for PN (16 vs 19-38) and APN (58 vs 69-86), while the lowest NNR was required by UK criteria for PN (3.2 vs 4.0-4.8) and APN (7 vs 10-16). The receiver operating characteristic of all four criteria was 0.57-0.61 for PN and 0.68-0.70 for APN. CONCLUSIONS: Among all the four criteria, US criteria had the highest sensitivity and lowest NNS, while UK criteria achieved the highest specificity and lowest NNR. Their limited discriminatory capability highlighted the need for a new score to predict PN/APN in Chinese populations.

1,25-Dihydroxy vitamin D prevents tumorigenesis by inhibiting oxidative stress and inducing tumor cellular senescence in mice.

Human epidemiological studies suggest that 1,25(OH)2 D3 deficiency might increase cancer incidence, but no spontaneous tumors have been reported in mice lacking 1,25(OH)2 D3 or deficient in its receptor. In our study, we detected, for the first time, diverse types of spontaneous tumors in l,25(OH)2 D3 deficient mice more than 1 year of age. This was associated with increased oxidative stress, cellular senescence and senescence-associated secretory phenotype molecules, such as hepatocyte growth factor, mediated via its receptor c-Met. Furthermore, 1,25(OH)2 D3 prevented spontaneous tumor development. We also demonstrated that l,25(OH)2 D3 deficiency accelerates allograft tumor initiation and growth by increasing oxidative stress and DNA damage, activating oncogenes, inactivating tumor suppressor genes, stimulating malignant cell proliferation and inhibiting their senescence; in contrast, supplementation with exogenous l,25(OH)2 D3 or antioxidant, or knock-down of the Bmi1 or c-Met oncogene, largely rescued the phenotypes of allograft tumors. Results from our study suggest that 1,25(OH)2 D3 deficiency enhances tumorigenesis by increasing malignant cell oxidative stress and DNA damage, stimulating microenvironmental cell senescence and a senescence-associated secretory phenotype, and activating oncogenes and inactivating tumor suppressor genes, thus increasing malignant cell proliferation. Our study provides direct evidence supporting the role of vitamin D deficiency in increasing cancer incidence. Conversely, 1,25(OH)2 D3 prevented spontaneous tumor development, suggesting that this inhibitory effect prevents the initiation and progression of tumorigenesis, thus provides a mechanistic basis for 1,25(OH)2 D3 to prevent tumorigenesis in an aging organism.

Diagnostic yield is not influenced by the timing of screening endoscopy: morning versus afternoon.

BACKGROUND: Previous studies have shown the colonoscopy quality affected by the endoscopist's fatigue. This study was aimed to evaluate this potential factor in a colorectal cancer-screening cohort of Chinese patients. METHODS: The attendances at department of gastroenterology for colorectal cancer screening between 2013 and 2015 were retrospectively analyzed. The procedure time-of-day and hours elapse were recorded. The primary outcome was defined as adenoma detection rate (ADR). RESULTS: A total of 1342 screening colonoscopies were performed by 19 gastroenterologists in the study. Detection rates were 7.7% for all polyps and 20.0% for adenomas. Time-of-day was not significantly associated with ADR. With time elapsing, the first climax for ADR was presented at 09:00-10:00, and persistently rose again after the lunch break. Significant inclined trend in ADR was noted for each hour blocks of a full day (p = .0021). CONCLUSIONS: The procedure time-of-day, morning versus afternoon, did not affect the diagnostic efficacy of screening endoscopy in Chinese patients.

[Identification of compound heterozygous mutations of SACS gene in two patients from a pedigree with spastic ataxia of Charlevoix-Saguenay].

OBJECTIVE: To detect potential mutations of the spastic ataxia of Charlevoix-Saguenay (SACS) gene in a pedigree affected with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). METHODS: Genomic DNA was extracted from peripheral blood samples of the proband and her family members. All exons and flanking sequences of the SACS gene were analyzed by high-throughput sequencing. Suspected mutations were verified with Sanger sequencing. RESULTS: Next generation sequencing revealed novel compound heterozygous mutations of the SACS gene, namely c.13085T to G (p.I4362R) and c.5236dupA (p.T1746fs), in the proband, which were respectively derived from her parents. The mutations were confirmed by Sanger sequencing. CONCLUSION: The c.5236dupA (p.T1746fs) and c.13085T to G (p.I4362R) mutations of the SACS gene probably underlie the ocular symptoms and hearing loss in the proband.

No association of FAM47E rs6812193, SCARB2 rs6825004 and STX1B rs4889603 polymorphisms with Parkinson's disease in a Chinese Han population.

Recently, a series of studies found that the single-nucleotide polymorphisms (SNPs) rs6812193 in the family with sequence similarity 47, member E (FAM47E), rs6825004 in the scavenger receptor class B member 2 (SCARB2) and rs4889603 in the Syntaxin1B (STX1B) genes increase the risk for Parkinson's disease (PD). However, the results of subsequent independent studies were inconsistent. To explore the associations between the three SNPs and PD in the Chinese population, a large cohort was analyzed in a case-control study. A total of 1994 subjects, including 1179 PD and 815 healthy controls (HCs), were investigated. All subjects were genotyped for rs6812193, rs6825004 and rs4889603 using the Sequenom iPLEX Assay. There was no significant difference in additive genetic model of rs6812193, rs6825004 and rs4889603 between PD and controls, even after being stratified by sex and age. In addition, no significant differences were found between other subgroups of PD patients with regard to clinical presentation. Our findings suggested that FAM47E rs6812193, SCARB2 rs6825004 and STX1B rs4889603 do not confer a significant risk for PD in Chinese population.

A novel mutation in SORD gene associated with distal hereditary motor neuropathies.

BACKGROUND: Distal hereditary motor neuropathy (dHMN) is a heterogeneous group of hereditary diseases caused by the gradual degeneration of the lower motor neuron. More than 30 genes associated with dHMN have been reported, while 70-80% of those with the condition are still unable to receive a genetic diagnosis. METHODS: A 26-year-old man experiencing gradual weakness in his lower limbs was referred to our hospital, and data on clinical features, laboratory tests, and electrophysiological tests were collected. To identify the disease-causing mutation, we conducted whole exome sequencing (WES) and then validated it through Sanger sequencing for the proband and his parents. Silico analysis was performed to predict the pathogenesis of the identified mutations. A literature review of all reported mutations of the related gene for the disease was performed. RESULTS: The patient presented with dHMN phenotype harboring a novel homozygous variant c.361G > C (p.Ala121Pro) in SORD, inherited from his parents, respectively. A121 is a highly conserved site and the mutation was categorized as "likely pathogenic" according to the criteria and guidelines of the American College of Medical Genetics and Genomics (ACMG). A total of 13 published articles including 101 patients reported 18 SORD variants. Almost all described cases have the homozygous deletion variant c.757delG (p.A253Qfs*27) or compound heterozygous state of a combination of c.757delG (p.A253Qfs*27) with another variant. The variant c.361G > C (p.Ala121Pro) detected in our patient was the second homozygous variant in SORD-associated hereditary neuropathy. CONCLUSION: One novel homozygous variant c.361G > C (p.Ala121Pro) in SORD was identified in a Chinese patient with dHMN phenotype, which expands the mutation spectrum of SORD-associated hereditary neuropathy and underscores the significance of screening for SORD variants in patients with undiagnosed hereditary neuropathy patients.

Molecular Dynamic and Dissipative Particle Dynamic Simulation on the Miscibility of NR/CR Blends.

Natural rubber (NR) exhibits good elasticity, flexural resistance, wear resistance, and excellent mechanical properties, and it has been widely used in aerospace, transportation, medical, and health fields. For NR, however, the resistance to thermal-oxidation and ozone aging is fairly poor. Although aging properties of NR can be significantly improved with the incorporation of chloroprene rubber (CR) according to some references, the miscibility between NR and CR, the morphologies of the binary blends, and so on are revealed ambiguously. In this work, molecular dynamics simulation (MD) and dissipative particle dynamics (DPD) simulation were carried out to predict the compatibility between natural rubber and chloroprene rubber in view of Flory-Huggins parameters. The morphologies of the blends were obtained with the use of the DPD method. The simulation results were furtherly examined by means of Fourier transform infrared spectroscopy (FT-IR) and dynamic mechanical analysis (DMA). It was found that the miscibility between NR and CR is poor. Nevertheless, the miscibility could be improved when the content of CR is 50% or 90%. In addition, spinodal decomposition with a critical temperature of 390 K would take place according to the phase diagram. Microphase structure such as spherical, lamellar, and bicontinuous phases can be found with different contents of CR in the blends with the results of morphologies analysis.

RANBP1 promotes colorectal cancer progression by regulating pre-miRNA nuclear export via a positive feedback loop with YAP.

Colorectal cancer (CRC) is among the top five most common malignant tumors worldwide and has a high mortality rate. Identification of the mechanism of CRC and potential therapeutic targets is critical for improving survival. In the present study, we observed high expression of RAN binding protein 1 (RANBP1) in CRC tissues. Upregulated RANBP1 expression was strongly associated with TNM stages and was an independent risk factor for poor prognosis. In vitro and in vivo functional experiments demonstrated that RANBP1 promoted the proliferation and invasion of CRC cells and inhibited the apoptosis of CRC cells. Low RANBP1 expression reduced the expression levels of hsa-miR-18a, hsa-miR-183, and hsa-miR-106 microRNAs (miRNAs) by inhibiting the nucleoplasmic transport of precursor miRNAs (pre-miRNAs), thereby promoting the accumulation of the latter in the nucleus and reducing the expression of mature miRNAs. Further experiments and bioinformatic analyses demonstrated that RANBP1 promoted the expression of YAP by regulating miRNAs and the Hippo pathway. We also found that YAP acted as a transcriptional cofactor to activate RANBP1 transcription in combination with TEAD4 transcription factor. Thus, RANBP1 further promoted the progression of CRC by forming a positive feedback loop with YAP. Our results revealed the biological role and mechanism of RANBP1 in CRC for the first time, suggesting that RANBP1 can be used as a diagnostic molecule and a potential therapeutic target in CRC.