Dominance is common in mammals and is associated with trans-acting gene expression and alternative splicing.

BACKGROUND: Dominance and other non-additive genetic effects arise from the interaction between alleles, and historically these phenomena play a major role in quantitative genetics. However, most genome-wide association studies (GWAS) assume alleles act additively. RESULTS: We systematically investigate both dominance-here representing any non-additive within-locus interaction-and additivity across 574 physiological and gene expression traits in three mammalian stocks: F2 intercross pigs, rat heterogeneous stock, and mice heterogeneous stock. Dominance accounts for about one quarter of heritable variance across all physiological traits in all species. Hematological and immunological traits exhibit the highest dominance variance, possibly reflecting balancing selection in response to pathogens. Although most quantitative trait loci (QTLs) are detectable as additive QTLs, we identify 154, 64, and 62 novel dominance QTLs in pigs, rats, and mice respectively that are undetectable as additive QTLs. Similarly, even though most cis-acting expression QTLs are additive, gene expression exhibits a large fraction of dominance variance, and trans-acting eQTLs are enriched for dominance. Genes causal for dominance physiological QTLs are less likely to be physically linked to their QTLs but instead act via trans-acting dominance eQTLs. In addition, thousands of eQTLs are associated with alternatively spliced isoforms with complex additive and dominant architectures in heterogeneous stock rats, suggesting a possible mechanism for dominance. CONCLUSIONS: Although heritability is predominantly additive, many mammalian genetic effects are dominant and likely arise through distinct mechanisms. It is therefore advantageous to consider both additive and dominance effects in GWAS to improve power and uncover causality.

Effect of Moxibustion Instrument Combined with Intermediate Frequency Electrostatic Therapy on Pain and Joint Function in Elderly Patients with Cold-Dampness Knee Arthritis.

Objective: To explore the effect of a moxibustion instrument combined with intermediate frequency electrostatic therapy on pain and joint function in elderly patients with cold-dampness arthritis (KOA). Method: 200 patients with cold-dampness KOA treated in our hospital from May 2019 to September 2021 were selected. According to the random number table method, they were divided into the observation group (n = 100) and control group (n = 100). The observation group was treated with moxibustion combined with medium-frequency treatment, and the control group was treated with medium-frequency treatment. The clinical effects of the two groups were compared. The joint functions of the two groups were evaluated by the visualization scale of the osteoarthritis index (WOMAC index) of McMaster University in Western Ontario. The TCM symptom scores of the two groups were evaluated according to the guiding principles for clinical research of new traditional Chinese medicine. The visual analogue scale (VAS) was used to evaluate the pain degree of the two groups, and the microcirculatory blood perfusion (MBPU) and interleukin-1 were compared between the two groups, ß (IL-1ß) and tumor necrosis factor-α (TNF-α). The levels of matrix metalloproteinase-1 (MMP-1), serum bone morphogenetic protein-2 (BMP-2), cartilage oligomeric matrix protein (COMP), and serum type II collagen C-terminal peptide (CTX-II) were assessed by the comprehensive quality of life questionnaire-74. Result: The total effective rate of the observation group (92.00%) was higher than that of the control group (76.00%), and the difference was statistically significant (P < 0.05) in ß and TNF-α. The levels of MMP-3, BMP-2, comp, and CTX-II and the improvement of quality of life score in the control group were better than those in the control group (P < 0.05). Conclusion: Moxibustion instrument combined with intermediate frequency electrostatic therapy can effectively improve the knee joint function, pain, blood perfusion, inflammatory reaction, and cartilage damage of the elderly patients with cold-dampness-type knee arthritis, and the therapeutic effect is good.

Human motor learning is robust to control-dependent noise.

Noises are ubiquitous in sensorimotor interactions and contaminate the information provided to the central nervous system (CNS) for motor learning. An interesting question is how the CNS manages motor learning with imprecise information. Integrating ideas from reinforcement learning and adaptive optimal control, this paper develops a novel computational mechanism to explain the robustness of human motor learning to the imprecise information, caused by control-dependent noise that exists inherently in the sensorimotor systems. Starting from an initial admissible control policy, in each learning trial the mechanism collects and uses the noisy sensory data (caused by the control-dependent noise) to form an imprecise evaluation of the performance of the current policy and then constructs an updated policy based on the imprecise evaluation. As the number of learning trials increases, the generated policies mathematically provably converge to a (potentially small) neighborhood of the optimal policy under mild conditions, despite the imprecise information in the learning process. The mechanism directly synthesizes the policies from the sensory data, without identifying an internal forward model. Our preliminary computational results on two classic arm reaching tasks are in line with experimental observations reported in the literature. The model-free control principle proposed in the paper sheds more lights into the inherent robustness of human sensorimotor systems to the imprecise information, especially control-dependent noise, in the CNS.

Electrochemical degradation of vanillin using lead dioxide electrode: influencing factors and reaction pathways.

In this study, a novel PbO2-CeO2 composite electrode was applied it to the electrocatalytic degradation of vanillin. The operating parameters such as applied current density, initial vanillin concentration, supporting electrolyte concentration and pH value were investigated and optimised. After 120 min, in a 0.10 mol L-1 Na2SO4 solution with a current density of 50 mA cm-2 and a pH value of 5.0 containing 30 mg L-1 vanillin, the vanillin removal efficiency can reach 98.03%, the COD removal efficiency is up to 73.28%. The results indicate that electrochemical degradation has a high ability to remove vanillin in aqueous solution. The reaction follows a pseudo-first-order reaction kinetics model with rate constants of 0.03036 min-1. In the process of electrochemical degradation, up to eight hydroxylated or polyhydroxylated oxidation by-products were identified through hydroxylation, dealkylation and substitution reactions. Furthermore, the degradation pathways were proposed, which eventually mineralised into inorganic water and carbon dioxide.

A large-scale comparison of meat quality and intramuscular fatty acid composition among three Chinese indigenous pig breeds.

Derived from the long historical natural and artificial selection, Chinese indigenous pigs have formed their own special meat characteristics. We herein systematically evaluated 14 meat characteristics and 15 fatty acid composition traits on three Chinese local pig breeds. The experimental pigs were produced by crossing design covering all sire genealogy and most of dam genealogy in each of the three breeds' seed conservation farms. All animals were reared in the same standardized housing and feeding conditions. A Comparison study showed that most of the investigated meat quality traits present significant differences among Bamaxiang, Erhualian and Laiwu breeds. While Erhualian pigs outperformed pH traits, the Laiwu pigs showed extremely high intramuscular fat content, better meat color and lower drip loss (P < .05). The highest contents of total saturated fatty acids and total polyunsaturated fatty acids were found in Laiwu and Erhualian, respectively. These results will benefit the future breeding utilization of these genetic resources for worldwide swine meat quality improvement.

Correction to: Genome-wide SNP data unveils the globalization of domesticated pigs.

An amendment to this paper has been published and can be accessed via the original article.

ADDO: a comprehensive toolkit to detect, classify and visualize additive and non-additive quantitative trait loci.

MOTIVATION: During the past decade, genome-wide association studies (GWAS) have been used to map quantitative trait loci (QTLs) underlying complex traits. However, most GWAS focus on additive genetic effects while ignoring non-additive effects, on the assumption that most QTL act additively. Consequently, QTLs driven by dominance and other non-additive effects could be overlooked. RESULTS: We developed ADDO, a highly efficient tool to detect, classify and visualize QTLs with additive and non-additive effects. ADDO implements a mixed-model transformation to control for population structure and unequal relatedness that accounts for both additive and dominant genetic covariance among individuals, and decomposes single-nucleotide polymorphism effects as either additive, partial dominant, dominant or over-dominant. A matrix multiplication approach is used to accelerate the computation: a genome scan on 13 million markers from 900 individuals takes about 5 h with 10 CPUs. Analysis of simulated data confirms ADDO's performance on traits with different additive and dominance genetic variance components. We showed two real examples in outbred rat where ADDO identified significant dominant QTL that were not detectable by an additive model. ADDO provides a systematic pipeline to characterize additive and non-additive QTL in whole genome sequence data, which complements current mainstream GWAS software for additive genetic effects. AVAILABILITY AND IMPLEMENTATION: ADDO is customizable and convenient to install and provides extensive analytics and visualizations. The package is freely available online at https://github.com/LeileiCui/ADDO. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Landscape of Loci and Candidate Genes for Muscle Fatty Acid Composition in Pigs Revealed by Multiple Population Association Analysis.

Genome wide association analyses in diverse populations can identify complex trait loci that are specifically present in one population or shared across multiple populations, which help to better understand the genetic architecture of complex traits in a broader genetic context. In this study, we conducted genome-wide association studies and meta-analysis for 38 fatty acid composition traits with 12-19 million imputed genome sequence SNPs in 2446 pigs from six populations, encompassing White Duroc × Erhualian F2, Sutai, Duroc-Landrace-Yorkshire (DLY) three-way cross, Laiwu, Erhualian, and Bamaxiang pigs that were originally genotyped with 60 K or 1.4 million single nucleotide polymorphism (SNP) chips. The analyses uncovered 285 lead SNPs (P < 5 × 10-8), among which 78 locate more than 1 Mb to the lead chip SNPs were considered as novel, largely augmented the landscape of loci for porcine muscle fatty acid composition. Meta-analysis enhanced the association significance at loci near FADS2, ABCD2, ELOVL5, ELOVL6, ELOVL7, SCD, and THRSP genes, suggesting possible existence of population shared mutations underlying these loci. Further haplotype analysis at SCD loci identified a shared 3.7 kb haplotype in F2, Sutai and DLY pigs showing consistent effects of decreasing C18:0 contents in the three populations. In contrast, at FASN loci, we found an Erhualian specific haplotype explaining the population specific association signals in Erhualian pigs. This study refines our understanding on landscape of loci and candidate genes for fatty acid composition traits of pigs.

Rational discovery of novel type-III FTF antagonists to competitively suppress TIF-2 coactivation in liver cancer.

The α-fetoprotein transcription factor (FTF) is a member of the nuclear receptor NR5A subfamily, which is involved in the pathogenesis of liver cancer and some other gastrointestinal cancers. The protein's transcriptional activity is regulated by binding TIF-2 coactivator at its coactivator-interacting site (CIS); suppression of the transcriptional activity has been recognized as a potential therapeutic strategy against cancer. Previously, small-molecule antagonists have been developed to target the ligand-binding site (LBS) of FTF ligand-binding domain, which simply occupy the site to exclusively block natural ligand entry (type-I antagonists) or destabilize the agonist conformation of activation helix 12 of the domain (type-II antagonists). Here, we describe the use of small-molecule competitors (type-III antagonists) to directly disrupt FTF-TIF-2 interaction by competitively targeting FTF CIS site. High-throughput virtual screening is performed against a structurally diverse, commercially available compound library to identify FTF CIS binders as competitor candidates, from which 12 hits are manually selected and their competitive potency with TIF-2 core binding sequence for FTF CIS site is tested with CC50 values up to 2.5 µM. Structural modeling analysis revealed that the competitive ligands can form a complicated network of noncovalent interactions to specifically or nonspecifically pack against FTF CIS site, thus preventing TIF-2 from binding to the site.

Electrocatalytic degradation of the herbicide metamitron using lead dioxide anode: influencing parameters, intermediates, and reaction pathways.

In the present study, the electrocatalytic degradation of triazine herbicide metamitron using Ti/PbO2-CeO2 composite anode was studied in detail. The effects of the current density, initial metamitron concentration, supporting electrolyte concentration, and initial pH value were investigated and optimized. The results revealed that an electrocatalytic approach possessed a high capability of metamitron removal in aqueous solution. After 120 min, the removal ratio of metamitron could reach 99.0% in 0.2 mol L-1 Na2SO4 solution containing 45 mg L-1 metamitron with the current density at 90 mA cm-2 and pH value at 5.0. The reaction followed the pseudo-first-order kinetics model. HPLC and HPLC-MS were employed to analyze the degradation by-products in the metamitron oxidization process, and the degradation pathway was also proposed, which was divided into two sub-routes according to the different initial attacking positions on metamitron by hydroxyl radicals. Therefore, the electrocatalytic approach was considered as a very promising technology in practical application for herbicide wastewater treatment.

Electrochemical degradation of insecticide hexazinone with Bi-doped PbO2 electrode: Influencing factors, intermediates and degradation mechanism.

Electrochemical degradation of hexazinone in aqueous solution using Bi-doped PbO2 electrodes as anodes was investigated. The main influencing parameters on the electrocatalytic degradation of hexazinone were analyzed as function of initial hexazinone concentration, current density, initial pH value and Na2SO4 concentration. The experiment results showed that the electrochemical oxidization reaction of hexazinone fitted pseudo-first-order kinetics model. 99.9% of hexazinone can be decontaminated using Bi-doped PbO2 electrode as anode for 120 min. Comparing with pure PbO2 electrode, the Bi-doped PbO2 electrodes possess higher hexazinone and COD removal ratio, higher ICE and lower energy consumption in the electrocatalytic degradation process. The results revealed that electrochemical oxidation using Bi-doped PbO2 anodes was an efficient method for the elimination of hexazinone in aqueous solution. The electrocatalytic oxidization mechanism of hexazinone with Bi-doped PbO2 anode was discussed, then the possible degradation pathway of hexazinone with two parallel sub-routes was elucidated according to 15 intermediates identified using HPLC-MS.

Genetic correlation of fatty acid composition with growth, carcass, fat deposition and meat quality traits based on GWAS data in six pig populations.

This study investigated genetic correlations of longissimus muscle fatty acid composition with 32 traits related to growth, carcass, fat deposition and meat quality in 2448 pigs from six populations using genome wide SNP data. Most of significant loci for saturated (C14:0, C16:0 and C18:0) and mono-saturated fatty acids (C18:1n9 and C16:1n7) identified in GWAS, including those near ELOVL6, SCD and FASN genes, displayed negligible or weak effects on all the 32 traits. Fat deposition traits were the most relevant traits for fatty acid composition in genetic correlations. Backfat thickness and intramuscular fat content consistently showed strong negative genetic correlations with C18:2n6, and positive genetic correlations with C18:1n9 at least five populations. Intramuscular fat content consistently has positive correlations with saturated fatty acids (SFA) in six populations. This study provided insights into shared genetic control of fatty acid composition and the other economic traits, which is helpful in design of breeding strategies to genetically improve fatty acid composition in pork.

Correlation between tripartite motif-containing protein 44 protein expression and the prognosis of postoperative patients exhibiting skin squamous cell carcinoma.

Tripartite motif-containing protein 44 (TRIM44) plays an important role in the development and progression of some human cancers; however, its role in skin squamous cell carcinoma (SCC) remains unknown. The aim of the present study was to investigate TRIM44 expression and clinicopathological significance of TRIM44 in SCC.Immunohistochemistry (IHC) technique, reverse transcriptase-polymerase chain reaction (RT-PCR) and western blot were performed to evaluate differences in TRIM44 protein expression in SCC and normal skin tissues.IHC showed that the positive rate of TRIM44 staining in SCC tissues 26.00% (9/30), while the positive rate of normal control group was 83.33% (25/30). The positive rate of TRIM44 staining in SCC tissues is significantly lower than normal skin tissue (P <.01). RT-PCR showed that the positive rates of TRIM44 mRNA expression in SCC tissues were 16.67% (5/30), but the positive rate of normal control group was 86.67% (26/30). TRIM44 mRNA expression in SCC group was significantly lower than that in the normal group (P <.01). Kaplan-Meier survival analysis showed that low expression was associated with poor overall survival in SCC patients (P =.004). Multi-factor survival analysis indicated that both low TRIM44 expression and tumor stage were independent factors affecting the overall survival of patients with SCC (P =.038 and P =.001, respectively). Low expression of TRIM44 in SCC was associated with staging (P =.009 and P =.008, respectively) and metastasis (P =.003 and P =.004, respectively).The levels of TRIM44 protein and TRIM44 mRNA in SCC are both lowly expressed which is strongly associated with tumor staging, metastasis, and poor survival. And it also is an independent factor affecting the overall survival of patients with SCC.

Genetic Fine-Mapping and Identification of Candidate Genes and Variants for Adiposity Traits in Outbred Rats.

OBJECTIVE: Obesity is a major risk factor for multiple diseases and is in part heritable, yet the majority of causative genetic variants that drive excessive adiposity remain unknown. Here, outbred heterogeneous stock (HS) rats were used in controlled environmental conditions to fine-map novel genetic modifiers of adiposity. METHODS: Body weight and visceral fat pad weights were measured in male HS rats that were also genotyped genome-wide. Quantitative trait loci (QTL) were identified by genome-wide association of imputed single-nucleotide polymorphism (SNP) genotypes using a linear mixed effect model that accounts for unequal relatedness between the HS rats. Candidate genes were assessed by protein modeling and mediation analysis of expression for coding and noncoding variants, respectively. RESULTS: HS rats exhibited large variation in adiposity traits, which were highly heritable and correlated with metabolic health. Fine-mapping of fat pad weight and body weight revealed three QTL and prioritized five candidate genes. Fat pad weight was associated with missense SNPs in Adcy3 and Prlhr and altered expression of Krtcap3 and Slc30a3, whereas Grid2 was identified as a candidate within the body weight locus. CONCLUSIONS: These data demonstrate the power of HS rats for identification of known and novel heritable mediators of obesity traits.

Genome-wide SNP data unveils the globalization of domesticated pigs.

BACKGROUND: Pigs were domesticated independently in Eastern and Western Eurasia early during the agricultural revolution, and have since been transported and traded across the globe. Here, we present a worldwide survey on 60K genome-wide single nucleotide polymorphism (SNP) data for 2093 pigs, including 1839 domestic pigs representing 122 local and commercial breeds, 215 wild boars, and 39 out-group suids, from Asia, Europe, America, Oceania and Africa. The aim of this study was to infer global patterns in pig domestication and diversity related to demography, migration, and selection. RESULTS: A deep phylogeographic division reflects the dichotomy between early domestication centers. In the core Eastern and Western domestication regions, Chinese pigs show differentiation between breeds due to geographic isolation, whereas this is less pronounced in European pigs. The inferred European origin of pigs in the Americas, Africa, and Australia reflects European expansion during the sixteenth to nineteenth centuries. Human-mediated introgression, which is due, in particular, to importing Chinese pigs into the UK during the eighteenth and nineteenth centuries, played an important role in the formation of modern pig breeds. Inbreeding levels vary markedly between populations, from almost no runs of homozygosity (ROH) in a number of Asian wild boar populations, to up to 20% of the genome covered by ROH in a number of Southern European breeds. Commercial populations show moderate ROH statistics. For domesticated pigs and wild boars in Asia and Europe, we identified highly differentiated loci that include candidate genes related to muscle and body development, central nervous system, reproduction, and energy balance, which are putatively under artificial selection. CONCLUSIONS: Key events related to domestication, dispersal, and mixing of pigs from different regions are reflected in the 60K SNP data, including the globalization that has recently become full circle since Chinese pig breeders in the past decades started selecting Western breeds to improve local Chinese pigs. Furthermore, signatures of ongoing and past selection, acting at different times and on different genetic backgrounds, enhance our insight in the mechanism of domestication and selection. The global diversity statistics presented here highlight concerns for maintaining agrodiversity, but also provide a necessary framework for directing genetic conservation.

Clinical significance of the phosphorylation of MAPK and protein expression of cyclin D1 in human osteosarcoma tissues.

The aim of the present study was to investigate the significance of the phosphorylation of mitogen-activated protein kinase (MAPK) and the protein expression of cyclin D1 in human osteosarcoma tissues. Human osteosarcoma tissue samples were collected from 30 patients, benign bone tumor samples were collected from 30 patients, and normal bone tissues were collected from 10 individuals as controls. Immunohistochemistry was performed to measure the levels of phosphorylated (p)-MAPK and cyclin D1 protein in cases of human osteosarcoma. The results showed that the positive rates of MAPK and cyclin D1 in osteosarcoma were 86.67% (26/30) and 73.00% (22/30), respectively. The positive staining rates of MAPK and cyclin D1 in benign bone tumor tissues were 10.00% (3/30) and 3.30% (1/30), respectively. The positive rate in the normal bone tissues was 0% (0/30), which was significantly lower, compared with that of the cancerous bone tissue. The positive rates of MAPK and cyclin D1 in osteosarcoma were increased (P<0.05), and the expression of cyclin D1 and p­MAPK were positively correlated. The phosphorylation of MAPK may be important in the development of osteosarcoma, and the overactivation of MAPK may induce high expression of cyclin D1 and induce tumor cells to proliferate continuously.

Identification of loci affecting teat number by genome-wide association studies on three pig populations.

OBJECTIVE: Three genome-wide association studies (GWAS) and a meta-analysis of GWAS were conducted to explore the genetic mechanisms underlying variation in pig teat number. METHODS: We performed three GWAS and a meta-analysis for teat number on three pig populations, including a White Duroc×Erhualian F2 resource population (n = 1,743), a Chinese Erhualian pig population (n = 320) and a Chinese Sutai pig population (n = 383). RESULTS: We detected 24 single nucleotide polymorphisms (SNPs) that surpassed the genome-wide significant level on Sus Scrofa chromosomes (SSC) 1, 7, and 12 in the F2 resource population, corresponding to four loci for pig teat number. We highlighted vertnin (VRTN) and lysine demethylase 6B (KDM6B) as two interesting candidate genes at the loci on SSC7 and SSC12. No significant associated SNPs were identified in the meta-analysis of GWAS. CONCLUSION: The results verified the complex genetic architecture of pig teat number. The causative variants for teat number may be different in the three populations.

Construction and optimization of an efficient amplification method of a random ssDNA library by asymmetric emulsion PCR.

Construction of a random ssDNA sublibrary is an important step of the aptamer screening process. The available construction methods include asymmetric PCR, biotin-streptavidin separation, and lambda exonuclease digestions, in which PCR amplification is a key step. The main drawback of PCR amplification is overamplification increasing nonspecific hybridization among different products and by-products, which may cause the loss of potential high-quality aptamers, inefficient screening, and even screening failure. Cycle number optimization in PCR amplification is the main way to avoid overamplification but does not fundamentally eliminate the nonspecific hybridization, and the decreased cycle number may lead to insufficient product amounts. Here, we developed a new method, "asymmetric emulsion PCR," which could overcome the shortcomings of conventional PCR. In asymmetric emulsion PCR, different templates were separated by emulsion particles, allowing single-molecule PCR, in which each template was separately amplified, and the nonspecific hybridization was avoided. Overamplification or formation of by-products was not observed. The method is so simple that direct amplification of 40 or more cycles can provide a high-quality ssDNA library. Therefore, the asymmetric emulsion PCR would improve the screening efficiency of systematic evolution of ligands by exponential enrichment.