The potential up-regulation risk of 3' UTR SNP (rs10787760 G > A) for the VAX1 gene is associated with NSCLP in the northwest Chinese population.

AIMS: To investigate the association between single nucleotide polymorphisms (SNPs) in 3'UTR region of VAX1, SYT14 and PAX7 genes and the risk of non-syndromic cleft palate (NSCLP) in a northwest Chinese population. MAIN METHODS: A case-control study was conducted in 406 normal controls and 399 NSCLP patients. Using iMLDRTM genotyping technology, eight SNPs of three genes ((rs10787760, rs7086344 at VAX1), (rs1010113, rs851114, and rs485874 at PAX7), and (rs61820397, rs4609425, rs12133399 at SYT14)) were genotyped to investigate the differences in alleles and genotype distribution frequencies between NSCLP patients and healthy controls. RNA Folding Form software was used to predict RNA secondary structure and expression vectors were constructed to explore the function of the relevant SNP. The effect of SNP polymorphism of gene transcription and translation was assessed using qPCR and Western blot analysis. KEY FINDINGS: Among the eight SNPs of three genes, rs10787760 of VAX1 gene was found to be associated with an increased risk of NSCLP (OR = 1.341, CI = 1.004-1.790) and the GA genotype of rs10787760 increased the risk of cleft lip and/or palate (CL/P) about 1.42 times (p < 0.05), and carrying the A allele might increase the risk of NSCL/P in male (OR = 1.356, 95 % CI = 1.010-1.823). But there was no association observed with cleft palate only (CPO). Cell function experiments revealed that the G to A mutation in rs10787760 up-regulated GFP-VAX1 transcriptional level by 2.39 and 3.13 times in two cell lines respectively, and enhance the protein expression of the VAX1 gene further. RNA secondary structure study showed that the rs10787760 (G > A) had two different secondary structures in 3'UTR region. SIGNIFICANCE: The rs10787760 variant in the 3'UTR region of VAX1 gene is associated with CL/P in northwest Chinese population. We hypothesize that the machanism of it might be caused by the RNA differenct fold in the 3'UTR region caused by the polymorphism of the gene. LEVEL OF EVIDENCE: Original Reports.

Disulfiram: A novel repurposed drug for cancer therapy.

ABSTRACT: Cancer is a major global health issue. Effective therapeutic strategies can prolong patients' survival and reduce the costs of treatment. Drug repurposing, which identifies new therapeutic uses for approved drugs, is a promising approach with the advantages of reducing research costs, shortening development time, and increasing efficiency and safety. Disulfiram (DSF), a Food and Drug Administration (FDA)-approved drug used to treat chronic alcoholism, has a great potential as an anticancer drug by targeting diverse human malignancies. Several studies show the antitumor effects of DSF, particularly the combination of DSF and copper (DSF/Cu), on a wide range of cancers such as glioblastoma (GBM), breast cancer, liver cancer, pancreatic cancer, and melanoma. In this review, we summarize the antitumor mechanisms of DSF/Cu, including induction of intracellular reactive oxygen species (ROS) and various cell death signaling pathways, and inhibition of proteasome activity, as well as inhibition of nuclear factor-kappa B (NF-κB) signaling. Furthermore, we highlight the ability of DSF/Cu to target cancer stem cells (CSCs), which provides a new approach to prevent tumor recurrence and metastasis. Strikingly, DSF/Cu inhibits several molecular targets associated with drug resistance, and therefore it is becoming a novel option to increase the sensitivity of chemo-resistant and radio-resistant patients. Studies of DSF/Cu may shed light on its improved application to clinical tumor treatment.

Decreased lipid levels in adult with congenital heart disease: a systematic review and Meta-analysis.

BACKGROUND: Metabolic disorders were a health problem for many adults with congenital heart disease, however, the differences in metabolic syndrome-related metabolite levels in adults with congenital heart disease compared to the healthy population were unknown. METHODS: We collected 18 studies reporting metabolic syndrome-associated metabolite levels in patients with congenital heart disease. Data from different studies were combined under a random-effects model using Cohen's d values. RESULTS: The results found that the levels of total cholesterol (Cohen's d -0.68, 95% CI: -0.91 to -0.45), high-density lipoprotein cholesterol (Cohen's d -0.63, 95% CI: -0.89 to -0.37), and low-density lipoprotein cholesterol (Cohen's d -0.32, 95% CI: -0.54 to -0.10) were significantly lower in congenital heart disease patients compared with controls. Congenital heart disease patients also had a lower body mass index (Cohen's d -0.27, 95% CI: -0.42 to -0.12) compared with controls. On the contrary, congenital heart disease patients had higher levels of hemoglobin A1c (Cohen's d 0.93, 95% CI: 0.17 to 1.70) than controls. Meanwhile, there were no significant differences in triglyceride (Cohen's d 0.07, 95% CI: -0.09 to 0.23), blood glucose (Cohen's d -0.12, 95% CI: -0.94 to 0.70) levels, systolic (Cohen's d 0.07, 95% CI: -0.30 to 0.45) and diastolic blood pressure (Cohen's d -0.10, 95% CI: -0.39 to 0.19) between congenital heart disease patients and controls. CONCLUSIONS: The lipid levels in patients with congenital heart disease were significantly lower than those in the control group. These data will help in the health management of patients with congenital heart disease and guide clinicians. PROSPERO REGISTRATION NUMBER: CRD42022228156.

Single-cell RNA sequencing reveals the transcriptomic characteristics of peripheral blood mononuclear cells in hepatitis B vaccine non-responders.

The emergence of a vaccine against hepatitis B has proven to be an important milestone in the prevention of this disease; however, 5%-10% of vaccinated individuals do not generate an immune response to the vaccine, and its molecular mechanism has not been clarified. In this study, single-cell RNA sequencing was performed on peripheral blood mononuclear cells (PBMCs) from three volunteers with a high immune response (HR) and three with no immune response (NR) to the hepatitis B vaccine. We found that the antigen-presenting activity scores of various antigen-presenting cells, the mitogen-activated protein kinase (MAPK) pathway activity scores of naive B cells, and the cell activity scores of three types of effector T cells were significantly decreased, whereas the cytotoxicity scores of CD3highCD16lowKLRG1high natural killer T (NKT) cells were significantly increased in the NR group compared with those in the HR group. Additionally, the expression levels of some classical molecules associated with distinct signaling pathways-including HLA-B, HLA-DRB5, BLNK, BLK, IL4R, SCIMP, JUN, CEBPB, NDFIP1, and TXNIP-were significantly reduced in corresponding subsets of PBMCs from the NR group relative to those of the HR group. Furthermore, the expression of several cytotoxicity-related effector molecules, such as GNLY, NKG7, GZMB, GZMM, KLRC1, KLRD1, PRF1, CST7, and CTSW, was significantly higher in CD3highCD16lowKLRG1high NKT cells derived from non-responders. Our study provides a molecular basis for the lack of response to the hepatitis B vaccine, including defective antigen presentation, decreased T cell activity, and reduced IL-4 secretion, as well as novel insight into the role of NKT cells in the immune response to the hepatitis B vaccine.

Pharmaceuticals Promoting Premature Termination Codon Readthrough: Progress in Development.

Around 11% of all known gene lesions causing human genetic diseases are nonsense mutations that introduce a premature stop codon (PTC) into the protein-coding gene sequence. Drug-induced PTC readthrough is a promising therapeutic strategy for treating hereditary diseases caused by nonsense mutations. To date, it has been found that more than 50 small-molecular compounds can promote PTC readthrough, known as translational readthrough-inducing drugs (TRIDs), and can be divided into two major categories: aminoglycosides and non-aminoglycosides. This review summarizes the pharmacodynamics and clinical application potential of the main TRIDs discovered so far, especially some newly discovered TRIDs in the past decade. The discovery of these TRIDs brings hope for treating nonsense mutations in various genetic diseases. Further research is still needed to deeply understand the mechanism of eukaryotic cell termination and drug-induced PTC readthrough so that patients can achieve the greatest benefit from the various TRID treatments.

Comparison of the size of bilateral testis in children with unilateral non-communicating hydrocele and its correlation with age.

BACKGROUND: Opinions on the optimal age for surgical management of hydroceles in young boys are not uniform. Scrotal ultrasonography can be used to diagnose hydroceles and measure testicular size. A comparison of bilateral testicular size with hydrocele and the change in trend with age has not been reported. We therefore aimed to analyze the bilateral testicular size of children with unilateral non-communicating hydroceles and examine the correlation between age and testicular volume. METHODS: Non-communicating hydrocele cases in children were included. Ultrasound results, age, and diagnose time were retrospectively recorded. The bilateral testicular size was compared, and the correlation between age and testicular volume was analyzed. RESULTS: There were 138 cases of non-communicating hydrocele, ranging in age from 11 to 72 months. The diagnose time ranged from 3 days to 54 months. The volume of the testis on the side of the hydrocele was larger than that on the normal side (P < 0.001). Testicular length was not different bilaterally. Testicular width and height were greater on the hydrocele side than on the normal testicular side (P<0.001). Age was positively correlated with testicular volume on the normal side (P = 0.004) but not on the hydrocele side. CONCLUSIONS: An important finding was that when the contralateral normal testicular volume increases with age, the testicular volume does not increase on the hydrocele side. This finding confirms the adverse effects of hydrocele on testicular growth and provides a basis for early treatment.

A novel mutation in the UBAP1 gene causing hereditary spastic paraplegia: A case report and overview of the genotype-phenotype correlation.

Hereditary Spastic Paraplegia (HSP) is considered to be one of the common neurodegenerative diseases with marked genetic heterogeneity. Recently, the mutations in ubiquitin-associated protein 1 (UBAP1) have been described in patients with HSP, known as spastic paraplegias 80 (SPG80). Here, we reported a Chinese HSP family presenting a frameshift mutation in the UBAP1 gene leading to complex HSP. Their clinical features encompassed spastic paraparetic gait, exaggerated patellar tendon reflexes, bilateral Babinski signs, and hyperactive Achilles tendon reflex. The proband also had severe urinary incontinence and a dermoid cyst at the lumbar 4-5 spinal cord, which rarely occurs in HSP patients. Following whole-exome sequencing, a novel heterozygous mutation (c.437dupG, NM_016,525) was identified in the UBAP1 that segregated with the family's phenotype and resulted in truncating UBAP1 protein (p.Ser146ArgfsTer13). Moreover, we reviewed the genotypes of UBAP1 and the phenotypic variability in 90 HSP patients reported in the literature. We found that the age of onset in UBAP1-related patients was juvenile, and there were population differences in the age of onset. The main complications were lower extremity spasticity, hyperreflexia, and the Babinski sign. Exon 4 of UBAP1 was identified as a mutation hotspot region. Our study expands the knowledge of UBAP1 mutations, which will aid in HSP patient counseling. Further molecular biological research is needed to explore the genotype-phenotype correlations of UBAP1-related HSP.

Analysis of trends in testicular atrophy index values with age in patients with unilateral palpable cryptorchidism.

Cryptorchidism affects the growth of testicular volume. Testicular volume is associated with reproductive function. The testicular atrophy index evaluates the degree of damage caused by cryptorchidism, but it remains unclear whether changes in testicular atrophy index are related to age. We selected patients who underwent surgery for unilateral palpable cryptorchidism. Testicular volume was measured using ultrasonography. The testicular atrophy indices of the undescended testes were then reviewed, and their correlation with age was analyzed. We studied 228 cases (age range: 6-53 months). Scatter plots were constructed, and Loess curves were fitted, revealing a turning point at 24 months of age. The patients were divided into age groups of 6-24 months and 25-53 months. The testicular volume of the cryptorchid side was smaller than that of the normal side in both groups (both P < 0.001). In the 6-24-month group, the testicular atrophy index was positively correlated with age, testicular volume on the cryptorchid side was not correlated with age, and testicular volume was positively correlated with age on the normal side. In the 25-53-month group, testicular atrophy index and testicular volumes on either side were not correlated with age. A palpable unilateral cryptorchid testis is smaller than the contralateral testis. The testicular atrophy index increases with age between 6 months and 24 months, but not between 25 months and 53 months. Testicular volume increased with age on the normal side between 6 months and 24 months, but not on the cryptorchid side. Trends in testicular atrophy index with age contribute to the decision of operation time.

Regulating the Entire Journey of Pesticide Application on Surfaces of Hydrophobic Leaves Modified by Pathogens at Different Growth Stages.

Under the background of the strategy of reducing pesticide application and increasing efficiency, the mechanism and common technology of efficient and accurate target deposition of chemical pesticides are the key development direction. The interaction between pesticide droplets and a leaf surface affects the deposition behavior of pesticides. However, cucumber leaf surface modified by powdery mildew pathogens at different growth stages is more hydrophobic than a normal leaf surface, which hinders the accurate deposition of pesticides on cucumber powdery mildew leaves. Here, an effective strategy for controlling pesticide efficiency for the entire journey of pesticide application is proposed. Based on the impact dynamics of droplets, the dynamic direction of droplet bounce is determined, the trajectory of droplet rebound is preliminarily determined, and the pinning sites formed by droplets on the surface of cucumber leaves with powdery mildew are confirmed. By analyzing the dynamics in the retraction stage and the energy dissipation rate for droplets after impact, the basic parameters that can be used to simply characterize droplet rebound are screened out, and the effect of addition of an effective surfactant is determined by characterizing the basic parameters (energy dissipation rate, retraction rate, recovery coefficient). The molecular structure formed by the addition of nonionic surfactant in pesticide solution is more appropriate to the interaction between the powdery mildew layer and the pesticide solution, which ensured that the droplets are well wet and deposited on cucumber powdery mildew leaves. Meanwhile, a force balance model for the pesticide droplet wetting state is established to calculate the pinning force for the droplet and predict the transition direction for the droplet wetting state. Impact dynamics combined with force balance model analysis provides a constructive method to improve pesticide utilization during the entire journey for pesticide application on hydrophobic plant surfaces.

Regulating Droplet Wetting and Pinning Behaviors on Pathogen-Modified Hydrophobic Surfaces: Strategies and Working Mechanisms.

Hydrophobic surfaces modified by pathogens in agricultural production are one of the main reasons to reduce the utilization of pesticides. Adding surfactants to pesticide solutions is a common method to improve their wetting and spreading properties. In this work, the interaction mechanism between pathogen-modified hydrophobic surfaces and mixtures of surfactants and a pesticide was studied in detail. The interaction mechanism was determined by characterizing the wetting and spreading behaviors of droplets on cucumber powdery mildew leaves at different growth stages. When surfactants were added, droplets on cucumber powdery mildew leaves were in the Wenzel wetting state, the pinning force weakened, the contact line speed accelerated, and the adhesion force increased. We explained the micellar state and aggregation behavior of surfactant molecules in a pesticide solution that was applied to the surface of cucumber powdery mildew leaves. Droplets of solutions containing nonionic surfactants easily formed semibald micelles, binding to the pathogen of powdery mildew, whereas droplets containing cationic surfactants did not do so. Because of the electrostatic interaction between cationic surfactant molecules and powdery mildew pathogens, cationic surfactant molecules did not wet the pathogens very well, so we suggest adding nonionic surfactants rather than cationic surfactants to improve the wetting and spreading of pesticide solutions on cucumber powdery mildew leaves. This study provides new insights into enhancing the wetting and deposition of droplets on pathogen-modified hydrophobic surfaces.

Identification of Novel Single-Nucleotide Variants With Potential of Mediating Malfunction of MicroRNA in Congenital Heart Disease.

Congenital heart defects (CHDs) represent the most common human birth defects. Our previous study indicates that the malfunction of microRNAs (miRNAs) in cardiac neural crest cells (NCCs), which contribute to the development of the heart and the connected great vessels, is likely linked to the pathogenesis of human CHDs. In this study, we attempt to further search for causative single-nucleotide variants (SNVs) from CHD patients that mediate the mis-regulating of miRNAs on their downstream target genes in the pathogenesis of CHDs. As a result, a total of 2,925 3'UTR SNVs were detected from a CHD cohort. In parallel, we profiled the expression of miRNAs in cardiac NCCs and found 201 expressed miRNAs. A combined analysis with these data further identified three 3'UTR SNVs, including NFATC1 c.*654C>T, FGFRL1 c.*414C>T, and CTNNB1 c.*729_*730insT, which result in the malfunction of miRNA-mediated gene regulation. The dysregulations were further validated experimentally. Therefore, our study indicates that miRNA-mediated gene dysregulation in cardiac NCCs could be an important etiology of congenital heart disease, which could lead to a new direction of diagnostic and therapeutic investigation on congenital heart disease.

[Online and offline mixed teaching mode of medical genetics].

Online courses are an indispensable part of medical teaching in the new era. Online courses have good prospects, although also with certain problems in practice. As an important basic medical course, medical genetics has both basic theoretical knowledge and clinical cases, involving basic principles and the latest developments. A single online course or offline teaching model cannot meet the needs of subject development and training a new generation of medical professionals. Therefore, actively exploring the online and offline hybrid teaching model is one of the important topics in the current medical teaching reform.

Optimization Strategy to Inhibit Droplets Rebound on Pathogen-Modified Hydrophobic Surfaces.

The deposition and retention of pesticide sprays on the surface of hydrophobic plant leaves is a major agricultural challenge, and the deposition of hydrophobic surfaces caused by plant leaf diseases is also a major agricultural problem. Many recent studies have focused on evaluating the effect of adding surfactants to water rather than to pesticide solutions to increase the deposition and retention of spray liquids. Here, we report a strategy to solve the problem of deposition and retention by studying the impact of the behavior of pesticide droplets with added surfactants and performing kinetic analysis on cucumber leaves with powdery mildew. The reduction in the bounce and splash of the pesticide droplets was analyzed by combining the pinning site formed in the retraction stage and the viscous dissipation in the rebound stage. In the practical application of the pesticide spray, we can clearly see that the bounce, splash, and powdery mildew spore ejection decreased when surfactants were added to the pesticide spray that was used on the cucumber leaves, and the adhesion and retention increased. The proposed comprehensive method is helpful for understanding the interactions between pesticide spray droplets and the surface of cucumber leaves with powdery mildew.

Primary intratracheal schwannoma misdiagnosed as severe asthma in an adolescent: A case report.

BACKGROUND: Primary intratracheal schwannoma is an extremely rare type of benign airway tumor, especially in adolescents. The presenting symptoms are typically prolonged cough and wheezing that can be misdiagnosed as asthma in adolescent patients. CASE: A 16-year-old adolescent girl admitted to a local hospital with symptoms of an irritating cough and wheezing was diagnosed with bronchial asthma and treated with budesonide and formoterol. Over the next year, the patient's wheezing and coughing symptoms gradually worsened and the antiasthma treatment was ineffective. One week prior to this admission, the patient developed dyspnea after catching a cold and was transferred to our hospital with a diagnosis of severe asthma. However, chest computed tomography and bronchoscopy showed a mass in the trachea. Primary intratracheal schwannoma was diagnosed by biopsy. Her symptoms were relieved by endoscopic resection by electrosurgical snaring combined with argon plasma coagulation. No relapse occurred during an 18 mo follow-up. CONCLUSION: Primary intratracheal schwannoma should be considered in the differential diagnosis in adolescents with recurrent asthma-like attacks.

Performance matching between the surface structure of cucumber powdery mildew in different growth stages and the properties of surfactant solution.

BACKGROUND: Understanding performance matching of pesticide droplets on the surface of cucumber leaves modified by powdery mildew is of practical importance for the agricultural sector. Here, the surface texture and wettability of cucumber leaves covered by powdery mildew were systematically examined using parameters such as micromorphology, physicochemical properties, and liquid droplet contact angle measurements. RESULTS: Our results show that powdery mildew growth can be divided into four distinct stages according to the surface texture characteristics of the diseased cucumber leaves. The three-dimensional (3D) surface structures of powdery mildew layers on cucumber leaves had individual characteristics at different mildew growth stages, among which powdery mildew was more easily spread in the last growth stage, and powdery mildew height was greatest in the NO. 2 growth stage (Sa  = 425.35 µm). Surface free energy values, static contact angle, and contact angle hysteresis all correlated strongly with the surface characteristics of powdery mildew layers at different growth stages. When the concentration of surfactant reached the critical micelle concentration, the wetting state of AEO-5 solution droplets on the surface of cucumber powdery mildew leaves reached the Wenzel state more easily. The wettability of a droplet on the leaf surface depends on the state of the monomer and micelle in the surfactant solution and the surface characteristics of the powdery mildew-covered leaf. CONCLUSION: The 3D structure and relative dielectric constant of powdery mildew-covered leaves influenced surface texture characteristics, which in turn controlled the wetting and matching ability of surfactant droplets on diseased leaves. This work provides valuable new insights into the matching of the structure of powdery mildew-covered plant leaves with the properties of surfactant solutions. © 2021 Society of Chemical Industry.

[Effect of Enteromorpha prolifera Biochar on the Adsorption Characteristics and Adsorption Mechanisms of Ammonia Nitrogen in Rainfall Runoff].

In order to study the performance and mechanisms of bioretention pond media (Enteromorpha prolifera biochar) for NH4+-N removal in rainfall runoff, three kinds of alkali modified biochars (marked as BC1, BC2, and BC3) were prepared with various concentrations of NaOH solution (1, 2, and 3 mol·L-1) to explore their adsorption performance for NH4+-N. The results showed that:① Appropriate modifications of the NaOH concentration increased the specific surface area and surface microstructure of biochar, with the content of O and the surface functional groups being enriched. In addition, BC2 possessed the best adsorption performance. ② The adsorption capacity reached a maximum when the pH was 9.0 and the dosage of biochar was 0.5 g·L-1. Compared with BC, the adsorption capacity of BC1 and BC2 increased by 6.4% and 10.8%, respectively, while BC3 decreased by 13.7%. Moreover, BC2 had an optimal adsorption efficiency with a saturated adsorption capacity of 16.76mg·g-1. ③ The adsorption mechanism of biochar belonged to chemical adsorption with a monomolecular layer. The adsorption process was promoted by the high pH of biochar, the electrostatic attraction of biochar pores, the complexation and oxidization of the functional groups of hydroxyl (-OH), carboxyl (-COOH), and carbon-oxygen single bond (C-O). To sum up, the proper amount of NaOH to modify biochar can improve the adsorption performance of NH4+-N, and the modified biochar can be used as media of the bioretention pond to remove NH4+-N.

Highly Efficient Photoelectrocatalytic Reduction of CO2 to Methanol by a p-n Heterojunction CeO2/CuO/Cu Catalyst.

Photoelectrocatalytic reduction of CO2 to fuels has great potential for reducing anthropogenic CO2 emissions and also lessening our dependence on fossil fuel energy. Herein, we report the successful development of a novel photoelectrocatalytic catalyst for the selective reduction of CO2 to methanol, comprising a copper catalyst modified with flower-like cerium oxide nanoparticles (CeO2 NPs) (a n-type semiconductor) and copper oxide nanoparticles (CuO NPs) (a p-type semiconductor). At an applied potential of - 1.0 V (vs SCE) under visible light irradiation, the CeO2 NPs/CuO NPs/Cu catalyst yielded methanol at a rate of 3.44 µmol cm-2 h-1, which was approximately five times higher than that of a CuO NPs/Cu catalyst (0.67 µmol cm-2 h-1). The carrier concentration increased by ~ 108 times when the flower-like CeO2 NPs were deposited on the CuO NPs/Cu catalyst, due to synergistic transfer of photoexcited electrons from the conduction band of CuO to that of CeO2, which enhanced both photocatalytic and photoelectrocatalytic CO2 reduction on the CeO2 NPs. The facile migration of photoexcited electrons and holes across the p-n heterojunction that formed between the CeO2 and CuO components was thus critical to excellent light-induced CO2 reduction properties of the CeO2 NPs/CuO NPs/Cu catalyst. Results encourage the wider application of composite semiconductor electrodes in carbon dioxide reduction.

A novel homozygous FBXO43 mutation associated with male infertility and teratozoospermia in a consanguineous Chinese family.

OBJECTIVE: To identify the genetic causes of male infertility characterized by teratozoospermia. DESIGN: Genetic studies. SETTING: Medical university. PATIENT(S): Two infertile brothers with teratozoospermia in a consanguineous Chinese family, another 124 sporadic infertile male patients presenting with teratozoospermia, and 200 male controls with normal fertility. INVENTION(S): None. MAIN OUTCOME MEASURE(S): Whole exome sequencing and genotype analysis to identify the potential pathogenic mutation, Sanger sequencing to validate the mutation in family members, in silico structural modeling to predict the functional consequences of mutation, and targeted next-generation sequencing to validate the mutation in sporadic cases. RESULT(S): A novel homozygous nonsynonymous mutation (C1991T, p.G664D) in FBXO43 (F-box only protein 43) was observed in two brothers from a consanguineous Chinese family. The mutation was segregated with the disease phenotype and was predicted to be a disease causing protein by SIFT, PolyPhen-2, and Mutation Taster. An in silico mutant FBXO43 model predicts that the mutation p.G664D causes shortening of two ß-sheets, an additional α-helix, and change in loops, which may result in loss of function of the protein. The homozygous mutation of FBXO43 was absent in the 1000 Genomes Project (1000 G) and the Exome Aggregation Consortium (ExAC) databases. Subsequent mutation screening of FBXO43 in a cohort of 124 cases identified four additional cases with heterozygous FBXO43 mutations. No mutations were found in FBXO43 in 200 fertile controls. CONCLUSION(S): The mutation in FBXO43 is a causative factor of male infertility and teratozoospermia.

Novel mutations of AXIN2 identified in a Chinese Congenital Heart Disease Cohort.

Congenital heart defects (CHDs), the most common congenital human birth anomalies, involves complex genetic factors. Wnt/ß-catenin pathway is critical for cardiogenesis and proved to be associated with numerous congenital heart abnormities. AXIN2 has a unique role in Wnt/ß-catenin pathway, as it is not only an important inhibitor but also a direct target of Wnt/ß-catenin pathway. However, whether AXIN2 is associated with human CHDs has not been reported. In our present study, we found a differential expression of Axin2 mRNA during the development of mouse heart, indicating its importance in mouse cardiac development. Then using targeted next-generation sequencing, we found two novel case-specific rare mutations [c.28 C > T (p.L10F), c.395 A > G (p.K132R)] in the sequencing region of AXIN2. In vitro functional analysis suggested that L10F might be a loss-of-function mutation and K132R is a gain-of-function mutation. Both mutations disrupted Wnt/ß-catenin pathway and failed to rescue CHD phenotype caused by Axin2 knockdown in zebrafish model. Collectively, our study indicates that rare mutations in AXIN2 might contribute to the risk of human CHDs and a balanced canonical Wnt pathway is critical for cardiac development process. To our knowledge, it is the first study of AXIN2 mutations associated with human CHDs, providing new insights into CHD etiology.