LGGA-MPP: Local Geometry-Guided Graph Attention for Molecular Property Prediction.

Molecular property prediction is a fundamental task of drug discovery. With the rapid development of deep learning, computational approaches for predicting molecular properties are experiencing increasing popularity. However, these existing methods often ignore the 3D information on molecules, which is critical in molecular representation learning. In the past few years, several self-supervised learning (SSL) approaches have been proposed to exploit the geometric information by using pre-training on 3D molecular graphs and fine-tuning on 2D molecular graphs. Most of these approaches are based on the global geometry of molecules, and there is still a challenge in capturing the local structure and local interpretability. To this end, we propose local geometry-guided graph attention (LGGA), which integrates local geometry into the attention mechanism and message-passing of graph neural networks (GNNs). LGGA introduces a novel method to model molecules, enhancing the model's ability to capture intricate local structural details. Experiments on various data sets demonstrate that the integration of local geometry has a significant impact on the improved results, and our model outperforms the state-of-the-art methods for molecular property prediction, establishing its potential as a promising tool in drug discovery and related fields.

DDInter: an online drug-drug interaction database towards improving clinical decision-making and patient safety.

Drug-drug interaction (DDI) can trigger many adverse effects in patients and has emerged as a threat to medicine and public health. Despite the continuous information accumulation of clinically significant DDIs, there are few open-access knowledge systems dedicated to the curation of DDI associations. To facilitate the clinicians to screen for dangerous drug combinations and improve health systems, we present DDInter, a curated DDI database with comprehensive data, practical medication guidance, intuitive function interface, and powerful visualization to the scientific community. Currently, DDInter contains about 0.24M DDI associations connecting 1833 approved drugs (1972 entities). Each drug is annotated with basic chemical and pharmacological information and its interaction network. For DDI associations, abundant and professional annotations are provided, including severity, mechanism description, strategies for managing potential side effects, alternative medications, etc. The drug entities and interaction entities are efficiently cross-linked. In addition to basic query and browsing, the prescription checking function is developed to facilitate clinicians to decide whether drugs combinations can be used safely. It can also be used for informatics-based DDI investigation and evaluation of other prediction frameworks. We hope that DDInter will prove useful in improving clinical decision-making and patient safety. DDInter is freely available, without registration, at http://ddinter.scbdd.com/.

The Combined Anti-Aging Effect of Hydrolyzed Collagen Oligopeptides and Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells on Human Skin Fibroblasts.

Stem cell-derived exosomes (SC-Exos) are used as a source of regenerative medicine, but certain limitations hinder their uses. The effect of hydrolyzed collagen oligopeptides (HCOPs), a functional ingredient of SC-Exos is not widely known to the general public. We herein evaluated the combined anti-aging effects of HCOPs and exosomes derived from human umbilical cord mesenchymal stem cells (HucMSC-Exos) using a senescence model established on human skin fibroblasts (HSFs). This study discovered that cells treated with HucMSC-Exos + HCOPs enhanced their proliferative and migratory capabilities; reduced both reactive oxygen species production and senescence-associated ß-galactosidase activity; augmented type I and type III collagen expression; attenuated the expression of matrix-degrading metalloproteinases (MMP-1, MMP-3, and MMP-9), interleukin 1 beta (IL-1ß), and tumor necrosis factor-alpha (TNF-α); and decreased the expression of p16, p21, and p53 as compared with the cells treated with HucMSC-Exos or HCOPs alone. These results suggest a possible strategy for enhancing the skin anti-aging ability of HucMSC-Exos with HCOPs.

Pesticide application behavior in green tea cultivation and risk assessment of tea products: a case study of Rizhao green tea.

Previous research on pesticides in green tea mainly focused on detection technology but lacked insights into pesticide use during cultivation. To address this gap, a survey was conducted among Rizhao green tea farmers. The survey results showed that most tea farmers were approximately 60 years old and managed small, scattered tea gardens (< 0.067 ha). Notably, tea farmers who had received agricultural training executed more standardized pesticide application practices. Matrine and thiazinone are the most used pesticides. A total of 16 types of pesticides were detected in the tested green tea samples, with 65% of the samples containing residues of at least one pesticide. Notably, higher levels of residues were observed for bifenthrin, cyfluthrin, and acetamiprid. The presence of pesticide residues varied significantly between seasons and regions. The risk assessment results indicated that the hazard quotient (HQ) values for all 16 pesticides detected in green tea were < 1, suggesting that these residue levels do not pose a significant public health concern.

Photochemical Degradation of the New Nicotine Pesticide Acetamiprid in Water.

Acetamiprid is a novel nicotinic pesticide widely used in modern agriculture because of its low toxicity and specific biological target properties. The objective of this study was to understand the photolysis pattern of acetamiprid in the water column and elucidate its degradation products and mechanism. It was observed that acetamiprid exhibited different photolysis rates under different light source conditions in pure water, with ultraviolet > fluorescence > sunlight; furthermore, its photolysis half-life ranged from 17.3 to 28.6 h. In addition, alkaline conditions (pH 9.0) accelerated its photolysis rate, which increased with pH. Using gas chromatography-mass spectrometry, five direct photolysis products generated during the exposure of acetamiprid to pure water were successfully separated and identified. The molecular structure of acetamiprid was further analyzed using density functional theory, and the active photodegradation sites of acetamiprid were predicted. The mechanism of the photolytic transformation of acetamiprid in water was mainly related to hydroxyl substitution and oxidation. Based on these findings, a comprehensive transformation pathway for acetamiprid was proposed.

Nanopore sequencing for detecting reciprocal translocation carrier status in preimplantation genetic testing.

BACKGROUND: Balanced reciprocal translocation (BRT) is one of the most common chromosomal abnormalities that causes infertility, recurrent miscarriage, and birth defects. Preimplantation genetic testing (PGT) is widely used to select euploid embryos for BRT carriers to increase the chance of a healthy live birth. Several strategies can be used to distinguish reciprocal translocation carrier embryos from those with a normal karyotype; however, these techniques are time-consuming and difficult to implement in clinical laboratories. In this study, nanopore sequencing was performed in two reciprocal translocation carriers, and the results were validated using the next-generation sequencing-based method named, "Mapping Allele with Resolved Carrier Status" (MaReCs). RESULTS: The translocation breakpoints in both reciprocal translocation carriers were accurately identified by nanopore sequencing and were in accordance with the results obtained using MaReCs. More than one euploid non-balanced translocation carrier embryo was identified in both patients. Amniocentesis results revealed normal karyotypes, consistent with the findings by MaReCs and nanopore sequencing. CONCLUSION: Our results suggest that nanopore sequencing is a powerful strategy for accurately distinguishing non-translocation embryos from translocation carrier embryos and precisely localizing translocation breakpoints, which is essential for PGT and aids in reducing the propagation of reciprocal translocation in the population.

Association of body mass index and waist-to-height ratio with outcomes in ischemic stroke: results from the Third China National Stroke Registry.

BACKGROUND AND PURPOSE: Conflicting reports of obesity paradox have led to confusion about weight management strategies for post-stroke patients. The main purpose of this study is to determine whether the obesity paradox measured by body mass index (BMI) or by waist-to-height ratio (WHtR) is real. METHODS: We evaluated the association of general obesity measured by BMI, and abdominal obesity measured by WHtR with 1-year all-cause mortality, recurrence of stroke and combined vascular events of acute ischemic stroke (AIS) patients in a cohort -- the Third China National Stroke Registry (CNSR-III). Cox proportional hazards models and restricted cubic splines were performed to investigate the association between obesity and clinical outcomes. RESULTS: A total of 14,146 patients with ischemic stroke were included. When BMI was used as a measure of obesity, compared to the normal weight patients, mortality decreased in overweight patients (hazard ratio [HR] 0.74 [95% confidence interval (CI) 0.61-0.91], P = 0.0035) and obese patients (HR 0.54 [0.40-0.73], P < 0.0001); and increased in underweight patients (HR 2.55 [1.75-3.73], P < 0.0001). After adjustment for confounding factors, the protective effect of obesity and overweight disappeared. BMI had no association with recurrence of stroke or combined vascular events. When WHtR was used as a measure of obesity, obese patients had lower 1-year all-cause mortality (HR 0.64 [0.43-0.97], P = 0.0357). After adjustment for confounding factors, this difference disappeared; overweight patients still had lower all-cause mortality (adjusted hazard ratio [aHR] 0.42 [0.26-0.67], P = 0.0003), recurrence of stroke (aHR 0.77 [0.60-0.99], P = 0.0440) and combined vascular events (aHR 0.75 [0.58-0.95], P = 0.0198). CONCLUSIONS: Among Chinese patients with AIS, our study does not support the BMI paradox; overweight patients measured by WHtR had a more favorable prognosis. TOAST subtypes did not modify the association.

An I2-DMSO catalytic manifold enabled aromatization for C-ring editing of podophyllotoxone.

The precise aromatization of the C-ring of podophyllotoxone to access value-added dehydropodophyllotoxin derivatives conventionally requires the use of equivalent amounts of unsustainable oxidants and suffers from inefficiencies. Taking advantage of the hydridic character of the C8 and C8' of podophyllotoxone, we have developed an I2-DMSO catalytic manifold that enables a green and selective dehydrogenative aromatization to overcome these synthetic challenges. An unprecedented dehydrogenative amination of podophyllotoxone derivatives was also realized using aniline as the reaction partner.

Infantile Internal and External Exposure to Neonicotinoid Insecticides: A Comparison of Levels across Various Sources.

Little is known about exposure of infants to neonicotinoid insecticides (NEOs). In this study, concentrations of six parent NEOs (p-NEOs) and N-desmethyl-acetamiprid (N-dm-ACE) were measured in urine and whole blood samples from infants, in addition to breast milk, infant formula, and tap water collected in South China. The p-NEO with the highest median concentration in urine (0.25 ng/mL) and blood (1.30) samples was dinotefuran (DIN), while imidacloprid (IMI) was abundant in breast milk (median: 0.27 ng/mL), infant formula (0.22), and tap water (0.028). The older infants (181-360 days) might face higher NEO and N-dm-ACE exposure than younger infants (0-180 days). Blood samples contained a significantly (p < 0.01) higher median concentration of ∑6p-NEOs (2.03 ng/mL) than that of urine samples (0.41), similar to acetamiprid (ACE), IMI, thiacloprid (THD), DIN, and N-dm-ACE, suggesting that NEOs readily partition into blood. Furthermore, breast-fed infants tend to have higher exposure levels than formula-fed infants. Infant formula prepared with tap water augmented the daily intake of ∑NEOs. The external sources contributed 80% of the total dose to IMI and clothianidin (CLO) exposure, while other unknown sources contributed to ACE, THD, and DIN exposure in infants. To the best of our knowledge, this is the first study to assess levels and sources of infantile exposure to NEOs through internal and external exposure assessment.

Sirt1 regulates microglial activation and inflammation following oxygen-glucose deprivation/reoxygenation injury by targeting the Shh/Gli-1 signaling pathway.

BACKGROUND: Cerebral ischemic injury leads to over-activation of microglia, which release pro-inflammatory factors that deteriorate neurological function during the acute phase of stroke. Thus, inhibiting microglial over-activation is crucial for reducing ischemic injury. Sirtuin 1 (Sirt1) has been shown to play a critical role in stroke, neurodegenerative diseases and aging. However, the effect of Sirt1 on the regulation of microglial activation following cerebral ischemic injury, as well as the underlying mechanism, remain unknown. Therefore, the purpose of the present study is to mainly investigate the effect of Sirt1 on oxygen-glucose deprivation/reoxygenation (OGD/R)-treated N9 microglia following treatment with the Sirt1 agonists resveratrol and SRT1720 and the Sirt1 antagonist sirtinol. METHODS: Cell viability, Apoptosis, activation and inflammatory responses of microglia, expressions and activity of Shh signaling pathway proteins were detected by Cell Counting Kit 8, Flow Cytometry, immunocytochemistry, ELISA, and Western blotting, respectively. RESULTS: The results demonstrated that treatment with resveratrol or SRT1720 could inhibit the activation of microglia and inflammation during OGD/R. Moreover, these treatments also led to the translocation of the GLI family zinc finger-1 (Gli-1) protein from the cytoplasm to the nucleus and upregulated the expression of Sonic hedgehog (Shh), Patched homolog-1 (Ptc-1), smoothened frizzled class receptor and Gli-1. By contrast, the inhibition of Sirt1 using sirtinol had the opposite effect. CONCLUSION: These findings suggested that Sirt1 may regulate microglial activation and inflammation by targeting the Shh/Gli-1 signaling pathway following OGD/R injury. Schematic representation of Sirt1 regulating the microglial activation and inflammation following oxygen-glucose deprivation/reoxygenation injury via mediation of Shh/Gli-1 signaling pathway.

Plasma Reference Ranges for Brain Injury Biomarkers (NfL, NfH, MCP-1, and MMP-9) in Healthy Chinese.

BACKGROUND: Brain injury triggers neuroaxonal injury and neural death, that leads to the development of secondary sequelae. Throughout this process, brain injury factors released into circulation via the injured neurovascular unit are important prognostic parameters. Plasma NfL, NfH, MCP-1, and MMP-9 have been identified as potential indicators in this regard. METHODS: Using a microfluidic ELISA platform, we measured plasma from 273 healthy subjects that underwent quantifications of NfL, NfH, MCP-1, and MMP-9 levels. We investigated the possible associations between biomarkers and basic demographics. RESULTS: The median concentration of plasma NfL was 10.40 (IQR = 6.73 - 16.60) pg/mL, NfH was 70.70 (IQR = 39.75 - 125.50) pg/mL, MCP-1 was 191.0 (IQR = 162.0 - 237.5) pg/mL, and MMP-9 was 169,255 (IQR = 107,657 - 231,276) pg/mL. Among all four biomarkers, plasma NfL and NfH levels were positively correlated with age (r = 0.557, p < 0.001, r = 0.364, p = 0.003). NfL was also correlated with NfH (r = 0.391, p = 0.002). CONCLUSIONS: These data provide a basis for the potential application of a brain-injury biomarker panel in routine clinical practice. It lays a significant foundation in supporting circulating CNS-biomarkers as noninvasive biomarkers for neurological disorders.

Arctigenin derivatives improve exercise performance in mice: synthesis and biological evaluation.

Arctigenin (ARG) has potent antifatigue activity, but its clinical application has been restricted for its poor water solubility. In this study, seven ARG derivatives containing different amino acids coupled via an ethoxy linker were synthesized, and tested for their solubility, as well as activities to improve exercise performance in mice. All of the derivatives showed improved solubility compared to that of ARG. Derivative Z-A-6 exhibited the highest activity, showing that the mice ran a 4.88-fold greater distance in the running wheel test and swam a 2.86-fold greater time in the swimming test than those in the blank control group. Z-A-6 treatment increased the plasma superoxide dismutase and catalase concentrations as well as reduced lactic acid and blood urea nitrogen accumulation during exercise. Z-A-6 treatment enhanced the phosphorylation of adenosine monophosphate-activated protein kinase, and no acute toxicity was observed. The results will contribute to the development of potential antifatigue agents.

Identification of six novel mutations in EDA from 20 hypohidrotic ectodermal dysplasia families.

OBJECTIVE: To investigate the genetic causes of 22 patients with clinically high suspicion of X-linked hypohidrotic ectodermal dysplasia from 20 unrelated Chinese families, expand the spectrum of ectodysplasin-A mutations, and provide more evidence for variants of uncertain significance. SUBJECTS AND METHODS: Whole-exome sequencing was performed and potentially pathogenic variants were verified by Sanger sequencing. Western blotting, real-time PCR and immunofluorescence analyses were performed to investigate the preliminary functions of the candidate variants. RESULTS: Nineteen ectodysplasin-A variants were identified, six of which were not previously reported. Among these variants, we identified a patient who carried two mutations in ectodysplasin-A and exhibited more severe phenotypes. Additionally, mutant protein expression levels decreased, whereas mRNA transcription levels increased. Cellular sublocalisation of the variants located in the tumour necrosis factor homologous domain showed that the proteins accumulated in the nucleus, whereas wild-type proteins remained in the cell membrane. A rare indel variant and two classical splicing variants that lead to exon 7 skipping were detected. CONCLUSIONS: This study provides definitive diagnoses for 20 families with suspected X-linked hypohidrotic ectodermal dysplasia and additional information on clinical heterogeneity and genotype-phenotype relationships.

Knowledge, attitude, and practice regarding sarcopenia: a survey between orthopedic and geriatric professionals in China.

BACKGROUND: In elderly patients with fractures, sarcopenia impairs recovery and even increases mortality. Both orthopedic and geriatric professionals are at the forefront of treating sarcopenic patients with fractures. However, it is not clear to what extent they have knowledge and skills to diagnose and treat sarcopenia. AIMS: This study aimed to analyze and compare knowledge, attitude, and practice regarding sarcopenia between orthopedic and geriatric professionals. METHODS: An online cross-sectional survey was conducted in June 2022 targeting professionals in orthopedic and geriatric departments in two largest tertiary general hospitals in Taizhou, southeastern China. Results on knowledge, attitude, and practice of sarcopenia were analyzed. Variables with significance were then included in a stepwise multiple linear regression analysis. RESULTS: A total of 220 professionals, 176 from orthopedic departments and 44 from geriatric departments, participated in this study. Orthopedic professionals scored lower than geriatrics in knowledge, attitude and practice (P < 0.001). The attitude score was high in both orthopedic and geriatric professionals. Stepwise multiple linear regression analysis showed that participants who had contact with sarcopenia patients had higher knowledge score (ß = 1.941, P < 0.001); participants who had attended sarcopenia training in the past 6 months (ß = 4.305, P < 0.001) had higher practice score. DISCUSSION: Orthopedic professionals have deficiencies in the screening and diagnosis of sarcopenia. Improving the knowledge and training of professionals can strengthen practice. It is necessary to formulate diagnostic criteria and improve practice of sarcopenia through training. CONCLUSION: Orthopedic professionals had limited knowledge and practice regarding sarcopenia compared with geriatric professionals. To improve sarcopenia practice, the use of diagnostic tools to formally diagnose sarcopenia and regular training on sarcopenia should be encouraged.

Control Method of Cold and Hot Shock Test of Sensors in Medium.

In order to meet the latest requirements for sensor quality test in the industry, the sample sensor needs to be placed in the medium for the cold and hot shock test. However, the existing environmental test chamber cannot effectively control the temperature of the sample in the medium. This paper designs a control method based on the support vector machine (SVM) classification algorithm and K-means clustering combined with neural network correction. When testing sensors in a medium, the clustering SVM classification algorithm is used to distribute the control voltage corresponding to temperature conditions. At the same time, the neural network is used to constantly correct the temperature to reduce overshoot during the temperature-holding phase. Eventually, overheating or overcooling of the basket space indirectly controls the rapid rise or decrease in the temperature of the sensor in the medium. The test results show that this method can effectively control the temperature of the sensor in the medium to reach the target temperature within 15 min and stabilize when the target temperature is between 145 °C and -40 °C. The steady-state error is less than 0.31 °C in the high-temperature area and less than 0.39 °C in the low-temperature area, which well solves the dilemma of the current cold and hot shock test.

Temporomandibular joint disc repositioning and occlusal splint for adolescents with skeletal class II malocclusion: a single-center, randomized, open-label trial.

BACKGROUND: Temporomandibular joint (TMJ) disc repositioning through open suturing (OSu) is a new disc repositioning method. Its result for adolescents with condylar resorption and dentofacial deformities combined with and without postoperative occlusal splints (POS) has not been well studied. OBJECTIVE: This study was to evaluate and compare the effects of OSu with and without POS in the treatment of TMJ anterior disc displacement without reduction (ADDwoR) in adolescent skeletal Class II malocclusion. METHODS: A total of 60 adolescents with bilateral ADDwoR were enrolled in this study. They were randomly allocated into two groups: OSu with and without POS. Magnetic resonance imaging (MRI) and lateral cephalometric radiographs were used to measure changes in condylar height and the degree of skeletal Class II malocclusion from before operation and at 12 months postoperatively. Changes in these indicators were compared within and between the two groups. RESULTS: After OSu, both groups exhibited significant improvements in condylar height and occlusion at the end of 12 months follow-up (P < 0.05). The group of OSu with POS had significantly more new bone formation (2.83 ± 0.75 mm vs. 1.42 ± 0.81 mm, P < 0.001) and improvement in dentofacial deformity than the group of OSu only (P < 0.05). The new bone height was significantly correlated with POS (P < 0.001), the changes of SNB (P = 0.018), overjet (P = 0.012), and Wits appraisal (P < 0.001). CONCLUSION: These findings indicated that OSu can effectively stimulate condylar regeneration and improve skeletal Class II malocclusion in adolescents with bilateral ADDwoR. The results are better when combined with POS. TRIAL REGISTRATION: This trial was prospectively registered on the chictr.org.cn registry with ID: ChiCTR1900021821 on 11/03/2019.

FPIA: A database for gene fusion profiling and interactive analyses.

As one of the hallmarks of cancer, gene fusions play an important role in tumorigenesis, and have been established as biomarkers and therapeutic targets. Although recent years have witnessed the development of gene fusion databases, a tool with interactive analytic functions remains lacking. Here, we introduce fusion profiling interactive analysis (FPIA), a web server to perform interactive and customizable analysis on fusion genes. With this platform, researchers can easily explore fusion-associated biological and molecular differences including gene expression, tumor purity and ploidy, mutation, copy number variations, protein expression, immune cell infiltration, stemness, telomere length, microsatellite instability, survival and novel peptides based on 33 cancer types from The Cancer Genome Atlas (TCGA) data. Currently, it contains 31 633 fusion events from 6910 patients. FPIA complements the existing gene fusion annotation databases with its multiomics analytic capacity, integrated analysis features, customized analysis selection and user-friendly design. The comprehensive data analyses by FPIA will greatly facilitate data mining, hypothesis generation and therapeutic target discovery. FPIA is available at http://bioinfo-sysu.com/fpia.

Comprehensive Analysis of Congenital Adrenal Hyperplasia Using Long-Read Sequencing.

BACKGROUND: Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder that has been included in newborn screening programs. Current approaches to gene testing for CAH are facing challenges because of the complexity of the CYP21A2 locus and genetic heterogeneity of the disease. METHODS: A comprehensive analysis of CAH (CACAH) combining long-range locus-specific PCR and long-read sequencing (LRS) was developed to perform full sequence analysis of 5 common CAH candidate genes, including CYP21A2, CYP11B1, CYP17A1, HSD3B2, and StAR. In a blind retrospective study, the clinical utility of CACAH was evaluated in 37 samples by comparing to standard CAH testing using multiplex ligation-dependent probe amplification (MLPA) plus Sanger sequencing. RESULTS: Of the 37 clinical samples, a total of 69 pathogenic variants were identified, comprising 65 CYP21A2 variants, 2 HSD3B2 variants, and 2 CYP17A1 variants. For CYP21A2, the most frequent variant was c.518T > A (29.2%), followed by c.293-13C/A > G (21.5%). Compared with the current CAH testing using MLPA plus Sanger sequencing, the CACAH assay showed 100% specificity and 100% sensitivity, and precisely determined the junction sites of deletions/insertions and cis-trans configuration of multiple variants without analyzing family samples. Moreover, CACAH identified a case carrying 2 copies of CYP21A1 with the c.1451_1452delinsC variant on the same chromosome, which was not confirmed by MLPA plus Sanger sequencing. CONCLUSION: LRS-based CACAH can determine all genotypes of CAH accurately and reliably in one assay, presenting a comprehensive approach for CAH genetic diagnosis and carrier screening.

Resveratrol pretreatment protects neurons from oxygen-glucose deprivation/reoxygenation and ischemic injury through inhibiting ferroptosis.

Ferroptosis, a newly discovered iron-dependent cell death, is involved in brain ischemia-reperfusion injury. Iron scavengers or ferroptosis inhibitors could reduce infarct volume and improve neurological function in mice. Resveratrol has neuroprotective and neurorestorative effects. However, it is unclear whether resveratrol can play a neuroprotective role via inhibiting ferroptosis. Our study showed that resveratrol pretreatment had a similar effect with ferrostatin­1, which inhibited neuronal ferroptosis-related changes, such as iron overload, damages of oxidation-reduction system, and destruction of mitochondrial structure, after oxygen-glucose deprivation/reoxygenation (OGD/R) and application of ferroptosis inducers. In addition, middle cerebral artery occlusion/reperfusion (MCAO/R) injury in vivo also induced ferroptosis, and resveratrol pretreatment could inhibit ferroptosis and reduce degenerative neurons, cerebral ischemic damage and infarction volume. Our results are the first to indicate that resveratrol pretreatment might inhibit ferroptosis induced by OGD/R and ferroptosis inducers in neurons, and MCAO/R in rats.

A novel homozygous mutation in the PADI6 gene causes early embryo arrest.

BACKGROUND: It has been proved that mutations in the PADI6 gene can cause early embryo arrest. This study describes a newly discovered mutation in PADI6 that expands the genetic spectrum of early embryo arrest. METHODS: Peripheral blood of a patient diagnosed with early embryo arrest was collected for whole-exome sequencing. Sanger sequencing was performed to confirm this mutation. The effects of the variant were investigated in human embryonic kidney 293T (HEK293T) cells using western blotting, real-time quantitative polymerase chain reaction, and immunofluorescence. RESULTS: A novel homozygous mutation in PADI6 was identified in the proband. The patient carried a frameshift insertion mutation c.558dupA (p.Thr187Asnfs*48), which was located in the protein arginine deiminase middle domain. The variant destroyed PADI6 protein expression and reduced PADI6 mRNA expression in HEK293T cells. CONCLUSIONS: The newly identified mutation in PADI6 accounts for early embryo arrest. It expands the spectrum of genetic causes and phenotypes of infertility in humans. These findings also provide an additional possible diagnostic marker for patients with recurrent in vitro fertilization/intracytoplasmic sperm injection failure.

Some infertile patients experience multiple in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) failure owing to recurrent early embryo arrest. However, the underlying mechanisms remain largely unknown. Due to the development of whole-exome sequencing, early embryo arrest has been confirmed as a type of Mendelian disease. This study aimed to identify the genetic cause of early embryo arrest in patients and to expand the genetic spectrum. Furthermore, it can help doctors offer better suggestions to such patients and prevent patients from suffering from multiple IVF/ICSI failures.