Genome-wide association study on serum alkaline phosphatase levels in a Chinese population

Background: Serum alkaline phosphatase (ALP) is a complex phenotype influenced by both genetic and environmental factors. Recent Genome-Wide Association Studies (GWAS) have identified several loci affecting ALP levels; however, such studies in Chinese populations are limited. We performed a GWAS analyzing the association between 658,288 autosomal SNPs and serum ALP in 1,461 subjects, and replicated the top SNPs in an additional 8,830 healthy Chinese Han individuals. The interactions between significant locus and environmental factors on serum ALP levels were further investigated. Results: The association between ABO locus and serum ALP levels was replicated (P = 2.50 × 10-21, 1.12 × 10-56 and 2.82 × 10-27 for SNP rs8176720, rs651007 and rs7025162 on ABO locus, respectively). SNP rs651007 accounted for 2.15% of the total variance of serum ALP levels independently of the other 2 SNPs. When comparing our findings with previously published studies, ethnic differences were observed across populations. A significant interaction between ABO rs651007 and overweight and obesity was observed (FDR for interaction was 0.036); for individuals with GG genotype, those with normal weight and those who were overweight or obese have similar serum ALP concentrations; minor allele A of rs651007 remarkably reduced serum ALP levels, but this effect was attenuated in overweight and obese individuals. Conclusions: Our findings indicate that ABO locus is a major determinant for serum ALP levels in Chinese Han population. Overweight and obesity modifies the effect of ABO locus on serum ALP concentrations

A genome-wide association study identifies common variants influencing serum uric acid concentrations in a Chinese population

Background: Uric acid (UA) is a complex phenotype influenced by both genetic and environmental factors as well as their interactions. Current genome-wide association studies (GWASs) have identified a variety of genetic determinants of UA in Europeans; however, such studies in Asians, especially in Chinese populations remain limited. Methods: A two-stage GWAS was performed to identify single nucleotide polymorphisms (SNPs) that were associated with serum uric acid (UA) in a Chinese population of 12,281 participants (GWAS discovery stage included 1452 participants from the Dongfeng-Tongji cohort (DFTJ-cohort) and 1999 participants from the Fangchenggang Area Male Health and Examination Survey (FAMHES). The validation stage included another independent 8830 individuals from the DFTJ-cohort). Affymetrix Genome-Wide Human SNP Array 6.0 chips and Illumina Omni-Express platform were used for genotyping for DFTJ-cohort and FAMHES, respectively. Gene-environment interactions on serum UA levels were further explored in 10,282 participants from the DFTJ-cohort. Results: Briefly, we identified two previously reported UA loci of SLC2A9 (rs11722228, combined P = 8.98 × 10-31) and ABCG2 (rs2231142, combined P = 3.34 × 10-42). The two independent SNPs rs11722228 and rs2231142 explained 1.03% and 1.09% of the total variation of UA levels, respectively. Heterogeneity was observed across different populations. More importantly, both independent SNPs rs11722228 and rs2231142 were nominally significantly interacted with gender on serum UA levels (P for interaction = 4.0 × 10-2 and 2.0 × 10-2, respectively). The minor allele (T) for rs11722228 in SLC2A9 has greater influence in elevating serum UA levels in females compared to males and the minor allele (T) of rs2231142 in ABCG2 had stronger effects on serum UA levels in males than that in females. Conclusions: Two genetic loci (SLC2A9 and ABCG2) were confirmed to be associated with serum UA concentration. These findings strongly support the evidence that SLC2A9 and ABCG2 function in UA metabolism across human populations. Furthermore, we observed these associations are modified by gender

A Genome Wide Association Study Identifies Common Variants Associated with Lipid Levels in the Chinese Population

Plasma lipid levels are important risk factors for cardiovascular disease and are influenced by genetic and environmental factors. Recent genome wide association studies (GWAS) have identified several lipid-associated loci, but these loci have been identified primarily in European populations. In order to identify genetic markers for lipid levels in a Chinese population and analyze the heterogeneity between Europeans and Asians, especially Chinese, we performed a meta-analysis of two genome wide association studies on four common lipid traits including total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL) and high-density lipoprotein cholesterol (HDL) in a Han Chinese population totaling 3,451 healthy subjects. Replication was performed in an additional 8,830 subjects of Han Chinese ethnicity. We replicated eight loci associated with lipid levels previously reported in a European population. The loci genome wide significantly associated with TC were near DOCK7, HMGCR and ABO; those genome wide significantly associated with TG were near APOA1/C3/A4/A5 and LPL; those genome wide significantly associated with LDL were near HMGCR, ABO and TOMM40; and those genome wide significantly associated with HDL were near LPL, LIPC and CETP. In addition, an additive genotype score of eight SNPs representing the eight loci that were found to be associated with lipid levels was associated with higher TC, TG and LDL levels (P = 5.52×10-16, 1.38×10-6 and 5.59×10-9, respectively). These findings suggest the cumulative effects of multiple genetic loci on plasma lipid levels. Comparisons with previous GWAS of lipids highlight heterogeneity in allele frequency and in effect size for some loci between Chinese and European populations. The results from our GWAS provided comprehensive and convincing evidence of the genetic determinants of plasma lipid levels in a Chinese population

The Reading Palaeofire Database : an expanded global resource to document changes in fire regimes from sedimentary charcoal records

Sedimentary charcoal records are widely used to reconstruct regional changes in fire regimes through time in the geological past. Existing global compilations are not geographically comprehensive and do not provide consistent metadata for all sites. Furthermore, the age models provided for these records are not harmonised and many are based on older calibrations of the radiocarbon ages. These issues limit the use of existing compilations for research into past fire regimes. Here, we present an expanded database of charcoal records, accompanied by new age models based on recalibration of radiocarbon ages using IntCal20 and Bayesian age-modelling software. We document the structure and contents of the database, the construction of the age models, and the quality control measures applied. We also record the expansion of geographical coverage relative to previous charcoal compilations and the expansion of metadata that can be used to inform analyses. This first version of the Reading Palaeofire Database contains 1676 records (entities) from 1480 sites worldwide. The database (RPDv1b - Harrison et al., 2021) is available at https://doi.org/10.17864/1947.000345.Peer reviewe

Ploidy level and performance in meiotic gynogenetic offsprings of grass carp using UV-irradiated blunt snout bream sperm

Diploid (2n) gynogens, triploid (3n) hybrids and 2n hybrids fish were produced in meiotic gynogenetic offsprings of grass carp (Ctenopharyngodon idella) eggs using UV-irradiated blunt snout bream (Megalobrama amblycephala) sperm. Flow cytometry revealed that a total of 306 (54.2%) 2n gynogens, 157 (27.7%) 2n hybrids and 102 (18.1%) 3n hybrids were identified at one year old stage examined. Chromosome analysis showed that 2n gynogens and 2n hybrid individuals had the same chromosome number as their parents (2n = 48), while the chromosome number of 3n hybrids was 3n = 72. The morphological characters of 2n hybrids and 3n hybrids were intermediate between their parents, and the 2n gynogens were similar to grass carp. Microsatellite genetic analysis showed that the expected heterozygosity (He) of 2n gynogens, 2n hybrids, 3n hybrids and grass carp control were 0.3775, 0.6518, 0.6601, 0.6502, respectively, and the polymorphism information content (PIC) was 0.3791, 0.5749, 0.5907, 0.5738, respectively. Compared with 2n and 3n hybrids, the He and PIC of 2n gynogens were significantly decreased, indicating that high homozygous could be obtained by the gynogenetic method. The 3n hybrids grew faster than both 2n gynogens and 2n hybrid individuals, suggesting that 3n hybrids had an obvious growth advantage

Prokaryotic expression of goldfish Tgf2 transposase with optimal codons and its enzyme activity

Tgf2 transposase (Tgf2-TPase), a hAT transposase from goldfish, plays an important role in fish transgenic applications. Previously, the production of the recombinant Tgf2-TPase protein required rigorous fermentation at low temperatures (22 °C) and early log phase induction (OD600 = 0.3–0.4) in Rosetta 1 (DE3) Escherichia coli lines. In order to better express the Tgf2-TPase and detect its enzyme activity, 83 rare codons in Tgf2-TPase were optimized and designated Tgf2-TPase83. The expression results showed that the soluble recombinant Tgf2-TPase83 was highly expressed at 30 °C and was inducible at an OD600 of 0.5–0.6 in the same prokaryotic expression system. After purification by affinity chromatography, Tgf2-TPase83 with codon optimization had higher enzyme activity than the Tgf2-TPase control. Comparison of different preservation methods (freeze-drying at −80 °C, storage in 20%-glycerol, 8%-sucrose, 4%-mannitol), revealed storage of Tgf2-TPase83 in glycerol helped to preserve its DNase digestion activity. Furthermore, size exclusion chromatography suggested that the purified Tgf2-TPase83 could recognize and bind to DNA probes containing a terminal inverted repeat (TIR) and a subterminal repeat (STR) sequence of the Tgf2 transposon. Overall, the results showed that optimizing the 83 codons of Tgf2 transposase can simplify the fermentation process and improve the enzyme activity. We propose that the production of the Tgf2-Tpase83 protein in a soluble and active form could provide an alternative tool for genetic modification of fish. Keywords: Codon optimization, Enzyme activity, Prokaryotic expression, Tgf2 transposas

Thermally Bonded PET–Basalt Sandwich Composites for Heat Pipeline Protection: Preparation, Stab Resisting, and Thermal-Insulating Properties

In order to solve the cost and bulky problems of buried thermal pipeline insulating materials, this study adopts basalt fabric and low-melting PET nonwoven to construct low-cost and light-weight pipeline thermal-insulating composites after needle punching and thermal bonding processes. Research result shows that thermal-bonded temperature affected the stab resistance and burst energy more significantly. As thermal-bonded temperature increased, knife resistance and spike resistance presented the upward and then downward trends, but the burst energy gradually decreased. Yarn pull-out result shows that the enhancement of stab resistance of intra-/inter-thermal-bonded structure resulted from the increment in the coefficient of friction between yarns. When PET–basalt sandwich composites were thermal-bonded at 140 °C for 5 min, the maximum knife and spike resistance were 147.00 N (1.99 J) and 196.30 N (1.11 J), respectively, and burst energy was 4.79 J, thermal conductivity reduced to 0.0073 W/(m∙K). The resultant thermally bonded sandwich composites can be used as thermal-insulating protection for buried thermal pipeline

Identification of a novel M-superfamily conotoxin with the ability to enhance tetrodotoxin sensitive sodium currents

In this work, a novel M-superfamily conotoxin, designated lt3a, was purified from the crude venom of Conus litteratus. Combined with peptide sequencing, MALDI-TOF mass spectrometry and cDNA cloning techniques, the amino acid sequence of lt3a was supposed to be DgammaCCgamma OQWCDGACDCCS, where O is hydroxyproline and gamma is carboxyglutamate. The Cys framework of lt3a (-CC-C-C-CC-) is similar to that of psi-, mu-, kappaM-conotoxins, which are representatives of M-conotoxins. Peptide lt3a is categorized into M1 branch based on the number of residues in the last Cys loop. Whole cell patch-clamp study on adult rat dorsal root ganglion neurons indicated that lt3a could enhance tetrodotoxin-sensitive sodium currents. This is a previously unknown function of M-superfamily conotoxins

Higher Levels of Tumour-Infiltrating Lymphocytes (TILs) are Associated with a Better Prognosis, While CDK5 Plays a Different Role Between Nonmetastatic and Metastatic Colonic Carcinoma

Objective We investigated the prognostic value of cyclin-dependent kinase 5 (CDK5) in a true population-based cohort of patients with colon cancer. Methods 1. Immunohistochemical (IHC) staining was used to retrospectively analyse the expression of CDK5 in colon cancer tissue samples of 296 patients. The χ2 test, Kaplan-Meier method and Cox proportional regression model were used to analyse the difference between the patients with differential expression of CDK5 and with different stages (metastatic and nonmetastatic); 2. The number of tumour-infiltrating lymphocytes (TILs) in tumour sections was determined, and its relationship with prognosis was explored. Results 1. Among 296 patients stained for CDK5, 18 cases (6.09%) showed negative expression, 77 cases (26.01%) showed weak expression (+1), 124 cases (41.89%) showed medium positive expression (2+), and 77 cases (26.01%) showed strong positive expression (3+). The expression of CDK5 was neither related to mismatch repair nor TILs ( p > .05 ). In non-metastatic patients, longer progression-free survival (PFS) and cancer-specific survival (CSS) were observed in patients with high CDK5 expression (2+ or 3+) than low CDK5 expression (- or 1+), while in metastatic disease, the opposite was true ( p < .001 ). 2. TILs in 226 patients were detected in the study. Among them, 115 cases (50.88%) showed a low number of TILs (TILs-L), and 111 cases (49.12%) showed a high number of TILs (TILs-H). Patients with a TIL ratio greater than .2 had a significantly better CSS ( p < .001 ) or PFS ( p = .008 ) than patients with a lower TIL ratio. By multivariate analysis, TILs-H was a protective factor for CSS, however failed to reach a significant difference (hazard ratio: .59, 95% CI: .33∼1.06, p = .079 ), and so was the PFS (HR: .65, 95% CI: .29∼1.43, p = .279 ). Conclusion High expression of CDK5 indicates a good prognosis in nonmetastatic colon cancer, while it is the opposite in metastatic colon cancer, and the expression of CDK5 is unrelated to TILs. Patients with TIL-H have a better prognosis, with a proper cut-off value of 20% for colon cancer

Downregulation of AC092894.1 promotes oxaliplatin resistance in colorectal cancer via the USP3/AR/RASGRP3 axis

Abstract Background Oxaliplatin resistance is a complex process and has been one of the most disadvantageous factors and indeed a confrontation in the procedure of colorectal cancer. Recently, long non-coding RNAs (lncRNAs) have emerged as novel molecules for the treatment of chemoresistance, but the specific molecular mechanisms mediated by them are poorly understood. Methods The lncRNAs associated with oxaliplatin resistance were screened by microarray. lncRNA effects on oxaliplatin chemoresistance were then verified by gain- and loss-of-function experiments. Finally, the potential mechanism of AC092894.1 was explored by RNA pull-down, RIP, and Co-IP experiments. Results AC092894.1 representation has been demonstrated to be drastically downregulated throughout oxaliplatin-induced drug-resistant CRC cells. In vivo and in vitro experiments revealed that AC092894.1 functions to reverse chemoresistance. Studies on the mechanism suggested that AC092894.1 served as a scaffold molecule that mediated the de-ubiquitination of AR through USP3, thereby increasing the transcription of RASGRP3. Finally, sustained activation of the MAPK signaling pathway induced apoptosis in CRC cells. Conclusions In conclusion, this study identified AC092894.1 as a suppressor of CRC chemoresistance and revealed the idea that targeting the AC092894.1/USP3/AR/RASGRP3 signaling axis is a novel option for the treatment of oxaliplatin resistance