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Single domain antibodies (sdAb) are promising candidates in cancer and anti-virus biotherapies for their unique structure characters. Though VHH and IgNAR have been discovered in camelidae and nurse shark (Ginlymostoma cirratum) respectively serval decades ago, expense of these large animals still limits the studies and applications of sdAb. Recently, IgNAR has been found in whitespotted bamboo shark (Chiloscyllium plagiosum), a small-sized sharks, while how to characterize and achieved the IgNAR of whitespotted bamboo shark is still unclear. In our research, we identified four IgNAR coding gene loci in whitespotted bamboo shark chromosome 44 (NC_057753.1), and primers were designed for single domain variable regions of IgNAR (VNAR) libraries preparation. Following sequencing results revealed that all plasmids constructed with our predicted VNAR libraries contained VNAR coding sequences, which confirmed the specificities of our primers in VNAR amplification. To our surprise, ≥90% VNAR sequences were encoded by IgNAR1, which suggests IgNAR1 is the most active IgNAR transcription locus in whitespotted bamboo shark. Interestingly, we found IgNAR(ΔC2-C3) were encoded by IgNAR3. Our findings gave a new sight of whitespotted bamboo shark IgNAR, which would broad the way of IgNAR studies and applications in biotherapies., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Current research suggests that hundreds to thousands of single nucleotide polymorphisms (SNPs) with small to modest effect sizes contribute to the genetic basis of many disorders, a phenomenon labeled as polygenicity. Additionally, many such disorders demonstrate polygenic overlap, in which risk alleles are shared at associated genetic loci. A simple strategy to detect polygenic overlap between two phenotypes is based on rank-ordering the univariate p -values from two genome-wide association studies (GWASs). Although high-dimensional variable selection strategies such as Lasso and elastic nets have been utilized in other GWAS analysis settings, they are yet to be utilized for detecting shared polygenicity. In this paper, we illustrate how elastic nets, with polygenic scores as the dependent variable and with appropriate adaptation in selecting the penalty parameter, may be utilized for detecting a subset of SNPs involved in shared polygenicity. We provide theory to better understand our approaches, and illustrate their utility using synthetic datasets. Results from extensive simulations are presented comparing the elastic net approaches with the rank ordering approach, in various scenarios. Results from simulations studies exhibit one of the elastic net approaches to be superior when the correlations among the SNPs are high. Finally, we apply the methods on two real datasets to illustrate further the capabilities, limitations and differences among the methods., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Intranuclear position of several genes is dynamically altered during development concordant with their activation. To understand this dynamic, but non-random, nuclear organization, it is important to identify the relevant regulatory elements and trans acting factors. Murine TCRb locus gets activated during thymic development. Enhancer Eb is important for VDJ recombination at TCRb locus as it is critically required for establishment of recombination center. Our analysis revealed that TCRb locus gets located out of the chromosome territory specifically in developing thymocytes. Further, CRISPR/Cas9 based deletion mutagenesis established an unambiguous role of enhancer Eb in defining TCRb location relative to chromosome territory. The ability to reposition the target locus relative to chromosome territory highlights a novel aspect pertaining to activity of enhancers which may contribute to their ability to regulate gene expression. Additionally, our observations have implications for understanding the role of enhancers in three-dimensional genome organization and function., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Bw4 and Bw6 are strongly immunogenic epitopes routinely assigned based on HLA-B typing results per Organ Procurement and Transplantation Network (OPTN) policies. These public epitopes and their variants are shared by some cross-reactive HLA-A and -C antigens. Although epitope mismatch has been associated with poor transplant outcomes, previous studies did not find such associations for Bw4/6 mismatch as defined by HLA-B antigens only. We hypothesized that a broader definition for Bw4/Bw6 mismatch that includes cross-reactive HLA-A and -C antigens may reveal the risk associated with these epitopes. In this retrospective cohort study, we examined kidney transplantations between 2000 and 2016 in the OPTN database and determined the association of Bw4/6 mismatch across all class I HLA antigens and renal graft outcomes. Even by this broader definition, Bw4/6 mismatch was not independently associated with 1-year graft rejection (adjusted OR: 0.99, 95%CI 0.93-1.06) or death-censored graft survival (adjusted HR: 1.02, 95%CI 1.00-1.05). There was no significant association among recipients who were already sensitized at transplant either. Our findings suggest that Bw4/6 mismatch alone is not associated with poor renal graft outcomes despite their strong immunogenicity, and the load of epitope mismatches over a certain threshold is likely required to cause adverse clinical consequences., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Maize (Zea mays L.) is one of the world's staple food crops. In order to feed the growing world population, improving maize yield is a top priority for breeding programs. Ear traits are important determinants of maize yield, and are mostly quantitatively inherited. To date, many studies relating to the genetic and molecular dissection of ear traits have been performed; therefore, we explored the genetic loci of the ear traits that were previously discovered in the genome-wide association study (GWAS) and quantitative trait locus (QTL) mapping studies, and refined 153 QTL and 85 quantitative trait nucleotide (QTN) clusters. Next, we shortlisted 19 common intervals (CIs) that can be detected simultaneously by both QTL mapping and GWAS, and 40 CIs that have pleiotropic effects on ear traits. Further, we predicted the best possible candidate genes from 71 QTL and 25 QTN clusters that could be valuable for maize yield improvement. [ABSTRACT FROM AUTHOR]

Achieving high-yield potential is always the ultimate objective of any breeding program. However, various abiotic stresses such as salinity, drought, cold, flood, and heat hampered rice productivity tremendously. Salinity is one of the most important abiotic stresses that adversely affect rice grain yield. The present investigation was undertaken to dissect new genetic loci, which are responsible for salt tolerance at the early seedling stage in rice. A bi-parental mapping population (F2:3) was developed from the cross between BRRI dhan28/Akundi, where BRRI dhan28 (BR28) is a salt-sensitive irrigated (boro) rice mega variety and Akundi is a highly salinity-tolerant Bangladeshi origin indica rice landrace that is utilized as a donor parent. We report reliable and stable QTLs for salt tolerance from a common donor (Akundi) irrespective of two different genetic backgrounds (BRRI dhan49/Akundi and BRRI dhan28/Akundi). A robust 1k-Rice Custom Amplicon (1k-RiCA) SNP marker genotyping platform was used for genome-wide analysis of this bi-parental population. After eliminating markers with high segregation distortion, 886 polymorphic SNPs built a genetic linkage map covering 1526.5 cM of whole rice genome with an average SNP density of 1.72 cM for the 12 genetic linkage groups. A total of 12 QTLs for nine different salt tolerance-related traits were identified using QGene and inclusive composite interval mapping of additive and dominant QTL (ICIM-ADD) under salt stress on seven different chromosomes. All of these 12 new QTLs were found to be unique, as no other map from the previous study has reported these QTLs in the similar chromosomal location and found them different from extensively studied Saltol, SKC1, OsSalT, and salT locus. Twenty-eight significant digenic/epistatic interactions were identified between chromosomal regions linked to or unlinked to QTLs. Akundi acts like a new alternate donor source of salt tolerance except for other usually known donors such as Nona Bokra, Pokkali, Capsule, and Hasawi used in salt tolerance genetic analysis and breeding programs worldwide, including Bangladesh. Integration of the seven novel, reliable, stable, and background independent salinity-resilient QTLs (qSES1, qSL1, qRL1, qSUR1, qSL8, qK8, qK1) reported in this investigation will expedite the cultivar development that is highly tolerant to salt stress. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Could the direct contribution of genetic variants to the pathophysiology of uterine fibroids and the contribution mediated by age at menarche be different? SUMMARY ANSWER Age at menarche plays a mediation role in the genetic influence on uterine fibroids, and four causal genetic mechanisms underlying the age at menarche-mediated effects of common genetic loci on uterine fibroid development were identified. WHAT IS KNOWN ALREADY Uterine fibroids are common benign tumors developing from uterine smooth muscle. Genome-wide association studies (GWASs) have identified over 30 genetic loci associated with uterine fibroids in different ethnic populations. Several genetic variations in or nearby these identified loci were also associated with early age at menarche, one of the major risk factors of uterine fibroids. Although the results of GWASs reveal how genetic variations affect uterine fibroids, the genetic mechanism of uterine fibroids mediated by age at menarche remains elusive. STUDY DESIGN, SIZE, DURATION In this study, we conducted a genome-wide causal mediation analysis in two cohorts covering a total of 69 552 females of Han Chinese descent from the Taiwan Biobank (TWB). TWB is an ongoing community- and hospital-based cohort aiming to enroll 200 000 individuals from the general Taiwanese population between 30 and 70 years old. It has been enrolling Taiwanese study participants since 2012 and has extensive phenotypic data collected from 148 291 individuals as of May 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS We recruited individuals in two cohorts, with 13 899 females in TWB1 and 55 653 females in TWB2. The two sets of individuals are almost distinct, with only 730 individuals enrolled in both cohorts. Over 99% of the participants are Han Chinese. Approximately 21% of participants developed uterine fibroids. DNA samples from both cohorts were genotyped using two different customized chips (TWB1 and TWB2 arrays). After quality control and genotype imputation, 646 973 TWB1 single-nucleotide polymorphisms (SNPs) and 686 439 TWB2 SNPs were assessed in our analysis. There were 99 939 SNPs which overlapped between the TWB1 and TWB2 arrays, 547 034 TWB1 array-specific SNPs and 586 500 TWB2 array-specific SNPs. We performed GWASs for screening potential risk SNPs for age at menarche and for uterine fibroids. We subsequently identified causal mediation effects of risk SNPs on uterine fibroids mediated by age at menarche. MAIN RESULTS AND THE ROLE OF CHANCE In addition to known loci at LIN28B associated with age at menarche and loci at WNT4 associated with uterine fibroids, we identified 162 SNPs in 77 transcripts that were associated with menarche-mediated causal effects on uterine fibroids via four different causal genetic mechanisms: a both-harmful group with 52 SNPs, a both-protective group with 34 SNPs, a mediator-harmful group with 22 SNPs and a mediator-protective group with 54 SNPs. Among these SNPs, rs809302 in SLK significantly increased the risk of developing uterine fibroids by 3.92% through a mechanism other than age at menarche (P  <   10−10), and rs371721345 in HLA-DOB was associated with a 2.70% decreased risk (P  <   10−10) in the occurrence of uterine fibroids, mediated by age at menarche. These findings provide insights into the mechanism underlying the effect of genetic loci on uterine fibroids mediated by age at menarche. LIMITATIONS, REASONS FOR CAUTION A potential issue is that the present study relied upon self-reported age at menarche and uterine fibroid information. Due to the experimental design, the consistency between self-reports and medical records for uterine fibroids in Taiwan cannot be checked. Fortunately, the literature support that self-reporting even years later remains a practical means for collecting data on menarche and uterine fibroids. We found that the impact of under-reporting of uterine fibroids is less in our study. In addition, the rate of reporting a diagnosis of uterine fibroids was within the rates of medical diagnosis based on national health insurance data. Future work investigating the consistency between self-reports and medical records in Taiwan can remedy this issue. WIDER IMPLICATIONS OF THE FINDINGS This study is the first to investigate whether and to what extent age at menarche mediates the causal effects of genetic variants on uterine fibroids by using genome-wide causal mediation analysis. By treating age at menarche as a mediator, this report provides an insight into the genetic risk factors for developing uterine fibroids. Thus, this article represents a step forward in deciphering the role of intermediated risk factors in the genetic mechanism of disease. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the China Medical University, Taiwan (CMU110-ASIA-13 and CMU107-Z-04), the Ministry of Science and Technology, Taiwan (MOST 110-2314-B-039-058) and the International Joint Usage/Research Center, the Institute of Medical Science, the University of Tokyo, Japan (K2104). The authors have no competing interests. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

Purpose: Genetic factors play an indispensable role in the pathogenesis of lifelong premature ejaculation (LPE). The susceptibility genes/SNPs that have been discovered are very limited and can only explain part of the genetic effects of LPE. Therefore, discovering more genetic polymorphisms associated with the occurrence and development of LPE will help reveal the pathogenesis of LPE. Materials and Methods: We conducted a genome-wide association study of LPE in 486 Chinese male Han people (cases and controls). We used Gene Titan multi-channel instrument and Axiom Analysis Suite 6.0 software for genotyping. Imputation was performed by IMPUTE2 software and the 1000 Genomes Project (Phase3) was used as reference for haplotype. Finally, logistic regression analysis was performed on all loci that passed the quality control. The odds ratio and 95% confidence interval were calculated to determine the association between each SNPs and Chinese male Han population LPE risk. Results: The results showed that a total of 33 genetic variants in 13 genes (LACTBL1, SSBP3, ACOT11, LINC02486, TMEM154, LINC01098, NONE, HCG27, HLA-C, TNFSF8, TNC, FAM53B, SULF2) have a suggestively significant genomewide association with LPE risk (p<5×10-6). Conclusions: This study is the first to conduct a GWAS on LPE in Chinese male Han population 33 genetic polymorphisms have a suggestive genome-wide association with LPE risk. This study have provided data supplement for the genetic loci of LPE risk, and laid a scientific foundation for the pathogenesis and the targeted therapy of LPE. [ABSTRACT FROM AUTHOR]

Aims: Studies on polymorphisms of the cytotoxic T lymphocytes associated antigen‐4 (CTLA‐4) genes in rheumatic disease patients are limited in Southeast Asia. This pilot study aimed to determine CTLA‐4 polymorphisms in Thai patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and systemic sclerosis (SSc), and correlate them with serology. Method: One‐hundred RA, 70 SLE and 50 SSc patients, and 99 healthy controls (HCs) were included in this study. Polymorphisms of the CTLA‐4 gene at +49A/G, −318C/T, −1661A/G and −1722T/C loci were determined by polymerase chain reaction restriction fragment length polymorphism methods. Patient serum samples were determined as follows: RA (rheumatoid factor [RF] and anticyclic citrullinated peptide [anti‐CCP]), SLE (antinuclear antibodies [ANA], anti‐double‐stranded DNA [anti‐dsDNA], anti‐Smith [anti‐Sm], anti‐ribonucleoprotein [anti‐RNP], and anti‐Sjögren's syndrome antigen A [SSA]), and SSc (ANA, anti‐RNP, anti‐SSA, anti‐topoisomerase‐1 [anti‐Scl70], and anti‐centromere antibodies [ACA]). Results: Among the 4 loci studied (+49A/G, −318C/T, −1661A/G and −1722T/C) only the A allele frequency at the +49A/G was significantly higher in the RA patients than their HCs (47.25% vs 35.86%, P =.029, odds ratio [OR] 1.60; 95% CI 1.04‐2.47). It also was significantly higher in the subgroup of RA patients with positive RF and anti‐CCP than their HCs (47.50% vs 35.86%, P =.020, OR 1.62; 95% CI 1.06‐2.47 and 48.89% vs 35.86%, P =.012, OR 1.71; 95% CI 1.11‐2.64, respectively). No polymorphisms at these 4 loci were observed in SLE or SSc patients. Conclusion: The A allele at +49A/G locus of the CTLA‐4 gene was associated with RA in Thais. [ABSTRACT FROM AUTHOR]

Summary: Salt stress is a major devastating abiotic factor that affects the yield and quality of maize. However, knowledge of the molecular mechanisms of the responses to salt stress in maize is limited. To elucidate the genetic basis of salt tolerance traits, a genome‐wide association study was performed on 348 maize inbred lines under normal and salt stress conditions using 557 894 single nucleotide polymorphisms (SNPs). The phenotypic data for 27 traits revealed coefficients of variation of >25%. In total, 149 significant SNPs explaining 6.6%–11.2% of the phenotypic variation for each SNP were identified. Of the 104 identified quantitative trait loci (QTLs), 83 were related to salt tolerance and 21 to normal traits. Additionally, 13 QTLs were associated with two to five traits. Eleven and six QTLs controlling salt tolerance traits and normal root growth, respectively, co‐localized with QTL intervals reported previously. Based on functional annotations, 13 candidate genes were predicted. Expression levels analysis of 12 candidate genes revealed that they were all responsive to salt stress. The CRISPR/Cas9 technology targeting three sites was applied in maize, and its editing efficiency reached 70%. By comparing the biomass of three CRISPR/Cas9 mutants of ZmCLCg and one zmpmp3 EMS mutant with their wild‐type plants under salt stress, the salt tolerance function of candidate genes ZmCLCg and ZmPMP3 were confirmed. Chloride content analysis revealed that ZmCLCg regulated chloride transport under sodium chloride stress. These results help to explain genetic variations in salt tolerance and provide novel loci for generating salt‐tolerant maize lines. [ABSTRACT FROM AUTHOR]