CXCL8 Up-Regulated LSECtin through AKT Signal and Correlates with the Immune Microenvironment Modulation in Colon Cancer.

BACKGROUND: The role of CXCL8 and LSECtin in colon cancer liver metastasis and immune checkpoint inhibitors (ICIs) treatment effect were widely recognized. However, the regulatory role of CXCL8 on LSECtin is still unclear. METHODS: The expression of CXCL8 or LSECtin was analyzed by TCGA database, and verified by GES110225 and clinical samples. The relationship between the expression of CXCL8 or LSECtin and immune cells infiltration, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, Gene Ontology (GO) items, stromal score, Estimation of STromal and Immune cells in MAlignant Tumours (ESTIMAT) immune score, tumor mutation burden (TMB), mismatch repair gene and immune checkpoints expression were analyzed by Spearman. The effects of CXCL8 on LSECtin expression, proliferation, and invasion ability were clarified by recombinant CXCL8 or CXCL8 interfering RNA. RESULTS: In colon cancer, the expression of CXCL8 was higher, but LSECtin was lower than that in normal mucosa. The expression of CXCL8 or LSECtin was significantly positively correlated with immune cells infiltration, stromal score, ESTIMATE immune score, TMB, and immune checkpoints expression. The expression of LSECtin was closely related to the cytokine-cytokine receptor interaction pathway and response of chemokine function, such as CXCL8/CXCR1/2 pathway. There was a significant positive correlation between the expression of CXCL8 and LSECtin in colon cancer. CXCL8 up-regulated LSECtin through AKT signal and promoted the proliferation and invasion ability of colon cancer. CONCLUSIONS: CXCL8 up-regulated LSECtin by activating AKT signal and correlated with the immune microenvironment modulation in colon cancer.

Identification of novel single-nucleotide variants altering RNA splicing of PKD1 and PKD2.

The development of sequencing techniques identified numerous genetic variants, and accurate evaluation of the clinical significance of these variants facilitates the diagnosis of Mendelian diseases. In the present study, 549 rare single- nucleotide variants of uncertain significance were extracted from the ADPKD and ClinVar databases. MaxEntScan scoresplice is an in silico splicing prediction tool that was used to analyze rare PKD1 and PKD2 variants of unknown significance. An in vitro minigene splicing assay was used to verify 37 splicing-altering candidates that were located within seven residues of the splice donor sequence excluding canonical GT dinucleotides or within 21 residues of the acceptor sequence excluding canonical AG dinucleotides of PKD1 and PKD2. We demonstrated that eight PKD1 variants alter RNA splicing and were predicted to be pathogenic.

Is BRD7 associated with spermatogenesis impairment and male infertility in humans? A case-control study in a Han Chinese population.

BACKGROUND: Bromodomain-containing protein 7 (BRD7), a member of the bromodomain-containing protein family, plays important roles in chromatin modification and transcriptional regulation. A recent model of Brd7-knockout mice presented azoospermia and male infertility, implying the potential role of BRD7 in spermatogenic failure in humans. This case-control study aimed to explore the association of the BRD7 gene with spermatogenic efficiency and the risk of spermatogenic defects in humans. RESULTS: A total of six heterozygous variants were detected in the coding and splicing regions of the BRD7 gene in patients with azoospermia. For each of four rare variants predicted to potentially damage BRD7 function, we further identified these four variants in oligozoospermia and normozoospermia as well. However, no difference in the allele and genotype frequencies of rare variants were observed between cases with spermatogenic failure and controls with normozoospermia; the sperm products of variant carriers were similar to those of noncarriers. Moreover, similar distribution of the alleles, genotypes and haplotypes of seven tag single nucleotide polymorphisms (tagSNPs) was observed between the cases with azoospermia and oligozoospermia and controls with normozoospermia; associations of tagSNP-distinguished BRD7 alleles with sperm products were not identified. CONCLUSIONS: The lack of an association of BRD7-linked rare and common variants with spermatogenic failure implied a limited contribution of the BRD7 gene to spermatogenic efficiency and susceptibility to male infertility in humans.

RéSUMé: CONTEXTE: Le bromodomaine contenant la protéine 7 (BRD7), un membre de la famille du bromodomaine contenant des protéines, joue des rôles importants dans la modification de la chromatine et la régulation transcriptionnelle. Un modèle récent de souris Brd7-knockout présentait une azoospermie et une infertilité mâle, ce qui implique un rôle potentiel de BRD7 dans l'altération de la spermatogenèse chez l'homme. Cette étude cas-témoins visait à explorer l'association du gène BRD7 avec l'efficacité de la spermatogenèse et le risque d'altérations spermatogéniques chez l'homme. RéSULTATS: Un total de six variants hétérozygotes ont été détectés dans les régions de codage et d'épissage du gène BRD7 chez les patients présentant une azoospermie. Pour chacun des quatre variants rares prédits pour potentiellement endommager la fonction BRD7, nous avons en outre identifié ces quatre variants dans l'oligozoospermie et la normozoospermie. Cependant, nous n'avons observé aucune différence dans les fréquences d'allèle et de génotype des variants rares entre les cas avec altérations de la spermatogenèse et les témoins avec normozoospermie ; les produits du sperme des porteurs de variants étaient semblables à ceux des non-porteurs. Par ailleurs, on a observé une distribution semblable des allèles, des génotypes et des haplotypes de sept polymorphismes simples de nucléotide de balise (tagSNPs) entre les cas avec azoospermie ou oligozoospermie et les témoins normozoospermiques; aucune association n'a pas été identifiée entre les allèles BRD7 tagSNP-distingués et des produits du sperme. CONCLUSION: L'absence d'association des variants rares liés à BRD7 et des variants communs liés à BRD7 avec les altérations de la spermatogenèse implique une contribution limitée du gène BRD7 à l'efficacité spermatogénique et à la susceptibilité à l'infertilité masculine chez l'homme.

Stroke risk in arthritis: A systematic review and meta-analysis of cohort studies.

BACKGROUND AND OBJECTIVE: Stroke is a major contributor to the global burden of disease. Although numerous modifiable risk factors (RF) for stroke have been identified, some remain unexplained. Increasing studies have investigated stroke risk in arthritis, but their results are inconsistent. We aimed to synthesize, quantify, and compare the risk of stroke for the major types of arthritis in cohort studies by using a systematic review and meta-analysis approach. METHODS: We searched Chinese and English databases to identify relevant studies from inception to April 30, 2020. Only studies adjusting at least for age and sex were included. We calculated pooled effect estimates for relative risk (RR) and 95% confidence interval (CI) and identified potential sources of heterogeneity and publication bias. RESULTS: A total of 1,348 articles were retrieved, and after an preliminary screening of titles and abstracts, 69 were reviewed for full text, and finally, 32 met the criteria for meta-analysis. Stroke risk in arthritis was significantly increased in studies adjusting for age and sex (RR = 1.36, 95% CI: 1.27-1.46) and for at least one traditional risk factor (RR = 1.40, 95% CI: 1.28-1.54). The results of studies stratified by stroke subtype were consistent with the main finding (ischemic stroke: RR = 1.53, 95% CI: 1.32-1.78; hemorrhagic stroke: RR = 1.45, 95% CI: 1.15-1.84). In subgroup analysis by arthritis type, stroke risk was significantly increased in rheumatoid arthritis (RR = 1.38, 95% CI: 1.29-1.48), ankylosing spondylitis (RR = 1.49, 95% CI: 1.25-1.77), psoriatic arthritis (RR = 1.33, 95% CI: 1.22-1.45), and gout (RR = 1.40, 95% CI: 1.13-1.73) but not osteoarthritis (RR = 1.03, 95% CI: 0.91-1.16). Age and sex subgroup analyses indicated that stroke risk was similar by sex (women: RR = 1.47, 95% CI: 1.31-1.66; men: RR = 1.44, 95% CI: 1.28-1.61); risk was higher with younger age (<45 years) (RR = 1.46, 95% CI: 1.17-1.82) than older age (≥65 years) (RR = 1.17, 95% CI: 1.08-1.26). CONCLUSIONS: Stroke risk was increased in multiple arthritis and similar between ischemic and hemorrhagic stroke. Young patients with arthritis had the highest risk.

A rare mutant of OFD1 gene responsible for Joubert syndrome with significant phenotype variation.

Joubert syndrome (JBTS), a rare genetic disorder resulted from primary cilium defects or basal-body dysfunction, is characterized by agenesis of cerebellar vermis and abnormal brain stem. Both genotypes and phenotypes of JBTS are highly heterogeneous. The identification of pathogenic gene variation is essential for making a definite diagnosis on JBTS. Here, we found that hypoplasia of cerebellar vermis occurred in three male members in a Chinese family. Then, we performed whole exome sequencing to identify a novel missense mutation c.599T > C (p. L200P) in the OFD1 gene which is the candidate gene of X-linked JBTS (JBST10). The following analysis showed that the variant was absent in the 1000 Genomes, ExAC and the 200 female controls; the position 200 Leucine residue was highly conserved across species; the missense variant was predicted to be deleterious using PolyPhen-2, PROVEAN, SIFT and Mutation Taster. The OFD1 expression was heavily lower in the proband and an induced male fetus compared with a healthy male with a wild-type OFD1 gene. The in vitro expression analysis of transiently transfecting c.599T or c.599C plasmids into HEK-293T cells confirmed that the missense mutation caused OFD1 reduction at the protein level. And further the mutated OFD1 decreased the level of Gli1 protein, a read-out of Sonic hedgehog (SHH) signaling essential for development of central neural system. A known pathogenic variant c.515T > C (p. L172P) showed the similar results. All of these observations suggested that the missense mutation causes the loss function of OFD1, resulting in SHH signaling impairs and brain development abnormality. In addition, the three patients have Dandy-Walker malformation, macrogyria and tetralogy of Fallot, respectively, the latter two of which are firstly found in JBTS10 patients. In conclusion, our findings expand the context of genotype and phenotype in the JBTS10 patients.

Epigenetic modification-dependent androgen receptor occupancy facilitates the ectopic TSPY1 expression in prostate cancer cells.

Testis-specific protein Y-encoded 1 (TSPY1), a Y chromosome-linked oncogene, is frequently activated in prostate cancers (PCa) and its expression is correlated with the poor prognosis of PCa. However, the cause of the ectopic transcription of TSPY1 in PCa remains unclear. Here, we observed that the methylation status in the CpG islands (CGI) of the TSPY1 promoter was negatively correlated with its expression level in different human samples. The acetyl-histone H4 and trimethylated histone H3-lysine 4, two post-translational modifications of histones occupying the TSPY1 promoter, facilitated the TSPY1 expression in PCa cells. In addition, we found that androgen accelerated the TSPY1 transcription on the condition of hypomethylated of TSPY1-CGI and promoted PCa cell proliferation. Moreover, the binding of androgen receptor (AR) to the TSPY1 promoter, enhancing TSPY1 transcription, was detected in PCa cells. Taken together, our findings identified the regulation of DNA methylation, acting as a primary mechanism, on TSPY1 expression in PCa, and revealed that TSPY1 is an androgen-AR axis-regulated oncogene, suggesting a novel and potential target for PCa therapy.

Is the primary AZFc duplication a potential risk for male infertility?: A systematic review and meta-analysis.

BACKGROUND: Numerous studies have been performed to investigate the association between the primary AZFc duplication and male infertility risk; however, the sample sizes have been small and the results have been controversial. A meta-analysis was performed to assess these associations. METHODS: A systematic search was conducted to identify all relevant studies from the PubMed, Web of Science, Medline, CNKI, and Wanfang databases up to October 22, 2019. The odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess the strength of associations. All of the statistical analyses were conducted by using RevMan 5.3. RESULTS: Eleven studies were identified that involved 3140 infertile men and 2280 fertile men. Overall, there was a statistically significant association between the primary AZFc duplication and male infertility (OR = 1.66, 95% CI  = 1.29-2.14, P < .0001). In the subgroup analysis by ethnic group, a statistically significant association between the primary AZFc duplication and male infertility was observed in Asian men (OR  =  2.26, 95% CI  = 1.64-3.12, P < .00001), but not in European men (OR  =  0.90, 95% CI = 0.59-1.38, P = .64). For subtypes of the primary AZFc duplication, a statistically significant association was observed between the gr/gr duplication-only (OR  = 2.71, 95% CI  = 1.38-5.32, P = .004) and infertility in Asian men. Asian men with the primary AZFc duplication resulting in more than four DAZ genes were found to be at an increased risk for infertility (OR  = 2.70, 95% CI  = 1.49-4.89, P = .001). CONCLUSION: Our meta-analysis provides an unprecedented illustration of how the association between the primary AZFc duplication and male infertility may be dependent on ethnicity or geographic location. Furthermore, gr/gr duplication or increased DAZ copy number can be detrimental to spermatogenesis in Asian men.

Experimental study for effects of terrain features and rainfall intensity on infiltration rate of modelled permeable pavement.

In order to investigate the effects of the terrain slopes and rainfall intensity on the steady infiltration rate of permeable pavement, an experiment with the combinations of three types of permeability, three kinds of rainfall intensity, different cross slope and longitudinal slope are undertaken. Through analyzing the experimental data, it is indicated that: (1) the relation between the steady infiltration rate and the cross and longitudinal slopes can be described by power functions, i.e. as the slopes increase, the steady infiltration rate decreases. The steady infiltration rate can be reduced by 23.3%-72.2% and 12.6%-22.2% for the slopes ranging from 0° to 5° and from 5° to 10°, respectively, illustrating the infiltration is more sensitive to the 0°-5° slope; (2) Under the same conditions, the effect of the cross slope on the steady infiltration rate is about 1.1-1.4 times as high as that of the longitudinal slope, i.e. the cross slope varying could lead to more obvious infiltration change, comparing to the longitudinal slope; (3) The relation between the rainfall intensity and the infiltration rate can be reflected by power function as well. The higher the rainfall intensity, the more the steady infiltration rate increases; (4) The comprehensive effect of the cross slope, longitudinal slope and rainfall intensity on steady infiltration rate can be expressed by quadratic polynomial functions. The main purpose of the manuscript is to determine how the slopes and the rainfall intensities affect the infiltration process and guide the plan and design of the permeable pavement in practical engineering.

Ising Superconductivity and Quantum Phase Transition in Macro-Size Monolayer NbSe2.

Two-dimensional (2D) transition metal dichalcogenides (TMDs) have a range of unique physics properties and could be used in the development of electronics, photonics, spintronics, and quantum computing devices. The mechanical exfoliation technique of microsize TMD flakes has attracted particular interest due to its simplicity and cost effectiveness. However, for most applications, large-area and high-quality films are preferred. Furthermore, when the thickness of crystalline films is down to the 2D limit (monolayer), exotic properties can be expected due to the quantum confinement and symmetry breaking. In this paper, we have successfully prepared macro-size atomically flat monolayer NbSe2 films on bilayer graphene terminated surface of 6H-SiC(0001) substrates by a molecular beam epitaxy (MBE) method. The films exhibit an onset superconducting critical transition temperature (Tconset) above 6 K and the zero resistance superconducting critical transition temperature (Tczero) up to 2.40 K. Simultaneously, the transport measurements at high magnetic fields and low temperatures reveal that the parallel characteristic field Bc//(T = 0) is above 5 times of the paramagnetic limiting field, consistent with Zeeman-protected Ising superconductivity mechanism. Besides, by ultralow temperature electrical transport measurements, the monolayer NbSe2 film shows the signature of quantum Griffiths singularity (QGS) when approaching the zero-temperature quantum critical point.

Estimating nitrogen oxides emissions at city scale in China with a nightlight remote sensing model.

Increasing nitrogen oxides (NOx) emissions over the fast developing regions have been of great concern due to their critical associations with the aggravated haze and climate change. However, little geographically specific data exists for estimating spatio-temporal trends of NOx emissions. In order to quantify the spatial and temporal variations of NOx emissions, a spatially explicit approach based on the continuous satellite observations of artificial nighttime stable lights (NSLs) from the Defense Meteorological Satellite Program/Operational Linescan System (DMSP/OLS) was developed to estimate NOx emissions from the largest emission source of fossil fuel combustion. The NSL based model was established with three types of data including satellite data of nighttime stable lights, geographical data of administrative boundaries, and provincial energy consumptions in China, where a significant growth of NOx emission has experienced during three policy stages corresponding to the 9th-11th)Five-Year Plan (FYP, 1995-2010). The estimated national NOx emissions increased by 8.2% per year during the study period, and the total annual NOx emissions in China estimated by the NSL-based model were approximately 4.1%-13.8% higher than the previous estimates. The spatio-temporal variations of NOx emissions at city scale were then evaluated by the Moran's I indices. The global Moran's I indices for measuring spatial agglomerations of China's NOx emission increased by 50.7% during 1995-2010. Although the inland cities have shown larger contribution to the emission growth than the more developed coastal cities since 2005, the High-High clusters of NOx emission located in Beijing-Tianjin-Hebei regions, the Yangtze River Delta, and the Pearl River Delta should still be the major focus of NOx mitigation. Our results indicate that the readily available DMSP/OLS nighttime stable lights based model could be an easily accessible and effective tool for achieving strategic decision making toward NOx reduction.

Z-scan measurement of nonlinear optical properties of BiOCl nanosheets.

Bismuth oxyhalides, such as bismuth oxychlorides (BiOCl), are layered materials with [Bi2O2]2+ layers sandwiched between two sheets of Cl ions. Much work has focused on the potential for bismuth oxyhalides to be a photocatalyst, but their nonlinear optical properties are rarely studied. In this work, the nonlinear refractive index of BiOCl nanosheets has been characterized with Z-scan measurement under 800 nm femtosecond pulsed laser excitation. A shift from saturable absorption to reverse saturable absorption was observed at higher input pump intensities in the experiments. The transition process was analyzed using a phenomenological model based on saturable absorption and two-photon absorption.

Z-scan measurement of the nonlinear refractive index of monolayer WS(2).

Transition metal dichalcogenides (TMDCs), such as tungsten disulfide (WS(2)), are layered materials with strong in-plane bonding and weak out-of-plane interactions enabling exfoliation into two-dimensional layers of single unit cell thickness. Recent advances in nanoscale materials characterization and few layer TMDCs' unique optical properties make them a research hot-spot in nonlinear optics. In this work, the nonlinear refractive index of monolayer WS(2) has been characterized with Z-scan measurement under 800nm femtosecond pulsed laser excitation, and a value of n2 ≃ (8.1 ± 0.41) × 10(-13)m(2)/W is obtained. A shift from saturable absorption to reverse saturable absorption was observed at higher input pump intensities in the experiments. The transition process was analyzed using a phenomenological model based on two photon absorption, and the two photon absorption coefficient was estimated about (3.7±0.28)×10(-6)m/W.

Construction of high-capacitance 3D CoO@polypyrrole nanowire array electrode for aqueous asymmetric supercapacitor.

We have developed a supercapacitor electrode composed of well-aligned CoO nanowire array grown on 3D nickel foam with polypyrrole (PPy) uniformly immobilized onto or firmly anchored to each nanowire surface to boost the pseudocapacitive performance. The electrode architecture takes advantage of the high electrochemical activity from both the CoO and PPy, the high electronic conductivity of PPy, and the short ion diffusion pathway in ordered mesoporous nanowires. These merits together with the elegant synergy between CoO and PPy lead to a high specific capacitance of 2223 F g(-1) approaching the theoretical value, good rate capability, and cycling stability (99.8% capacitance retention after 2000 cycles). An aqueous asymmetric supercapacitor device with a maximum voltage of 1.8 V fabricated by using our hybrid array as the positive electrode and activated carbon film as the negative electrode has demonstrated high energy density (~43.5 Wh kg(-1)), high power density (~5500 W kg(-1) at 11.8 Wh kg(-1)) and outstanding cycleability (~20,000 times). After charging for only ~10 s, two such 4 cm(2) asymmetric supercapacitors connected in series can efficiently power 5 mm diameter red, yellow, and green round LED indicators (lasting for 1 h for red LED) and drive a mini 130 rotation-motor robustly.

RNA interference-mediated inhibition of wild-type Torsin A expression increases apoptosis caused by oxidative stress in cultured cells.

To assess RNAi mediated inhibition of the expression of wt-DYT1 on H(2)O(2)-induced toxicity in NIH 3T3 cells and primary cortical neurons. To detect the function of wild-type Torsin A and the effect of SiRNA on the wt-DYT1 gene. The shRNA expression vector was constructed by ligating annealed complementary shRNA oligonucleotides into the down-stream of the human U6 promoter (PU6) of the RNAi-ready pSIREN-Shuttle vector. Then, the pSIREN-Shuttle-DYT1-shRNA cassette was ligated to Adeno-X Viral DNA to construct the recombinant adenoviral vector pAd-DYT1-shRNA. Cultured cerebral cortical neurons and NIH 3T3 cells were transfected with pAd-DYT1-shRNA and pSIREN-Shuttle-DYT1-shRNA. We evaluated NIH 3T3 cells and neurons in the presence of oxidative stress using a TUNEL assay under different conditions. The knockdown efficacy of the DYT1 was confirmed by real-time RT-PCR and Western Blot analysis. After exposure to H(2)O(2,) the quantity of NIH 3T3 cells transfected with pSIREN-Shuttle-DYT1-shRNA, which stained positively in the TUNEL assay, was significantly higher than the cells transfected with pSIREN-Shuttle-negative control-shRNA. (44.85 +/- 1.81% vs. 8.98 +/- 2.73%, t = 26.168). There were significantly more apoptotic neurons infected with pAd-DYT1-shRNA (45.63 +/- 7.53%) than neurons infected with pAd-X-negative control-shRNA (17.33 +/- 2.43%) (t = 9.816). The observed silencing of wild-type Torsin A expression by DYT1-shRNA was sequence-specific. RNAi-mediated inhibition of the expression of wild-type Torsin A increases apoptosis caused by oxidative stress. It is reasonable to consider that wild-type Torsin A has the capacity to protect cortical neurons against oxidative stress, and in the development of DYT1-delta GAG-dystonia the neuroprotective function of wild-type Torsin A may be compromised.

A novel mutation of the epsilon-sarcoglycan gene in a Chinese family with myoclonus-dystonia syndrome.

In a Chinese myoclonus-dystonia syndrome (MDS) family presented with a phenotype including a typical MDS, cervical dystonia, and writer's cramp, genetic analyses revealed a novel 662 + 1insG heterozygous mutation in exon 5 in the epsilon-sarcoglycan (SGCE) gene, leading to a frameshift with a down stream stop codon. Low SGCE mRNA levels were detected in the mutation carriers by real-time PCR, suggesting that the nonsense mutation might interfere with the stability of SGCE mRNA. This is the first report on Chinese with a SGCE mutation leading to MDS. Our data support the fact that same mutation of SGCE gene can lead to a varied phenotype, even in the same family.