ADNP modulates SINE B2-derived CTCF-binding sites during blastocyst formation in mice.

CTCF is crucial for chromatin structure and transcription regulation in early embryonic development. However, the kinetics of CTCF chromatin occupation in preimplantation embryos have remained unclear. In this study, we used CUT&RUN technology to investigate CTCF occupancy in mouse preimplantation development. Our findings revealed that CTCF begins binding to the genome prior to zygotic genome activation (ZGA), with a preference for CTCF-anchored chromatin loops. Although the majority of CTCF occupancy is consistently maintained, we identified a specific set of binding sites enriched in the mouse-specific short interspersed element (SINE) family B2 that are restricted to the cleavage stages. Notably, we discovered that the neuroprotective protein ADNP counteracts the stable association of CTCF at SINE B2-derived CTCF-binding sites. Knockout of Adnp in the zygote led to impaired CTCF binding signal recovery, failed deposition of H3K9me3, and transcriptional derepression of SINE B2 during the morula-to-blastocyst transition, which further led to unfaithful cell differentiation in embryos around implantation. Our analysis highlights an ADNP-dependent restriction of CTCF binding during cell differentiation in preimplantation embryos. Furthermore, our findings shed light on the functional importance of transposable elements (TEs) in promoting genetic innovation and actively shaping the early embryo developmental process specific to mammals.

gutMGene v2.0: an updated comprehensive database for target genes of gut microbes and microbial metabolites.

The gut microbiota is essential for various physiological functions in the host, primarily through the metabolites it produces. To support researchers in uncovering how gut microbiota contributes to host homeostasis, we launched the gutMGene database in 2022. In this updated version, we conducted an extensive review of previous papers and incorporated new papers to extract associations among gut microbes, their metabolites, and host genes, carefully classifying these as causal or correlational. Additionally, we performed metabolic reconstructions for representative gut microbial genomes from both human and mouse. gutMGene v2.0 features an upgraded web interface, providing users with improved accessibility and functionality. This upgraded version is freely available at http://bio-computing.hrbmu.edu.cn/gutmgene. We believe that this new version will greatly advance research in the gut microbiota field by offering a comprehensive resource.

Spatom: a graph neural network for structure-based protein-protein interaction site prediction.

Accurate identification of protein-protein interaction (PPI) sites remains a computational challenge. We propose Spatom, a novel framework for PPI site prediction. This framework first defines a weighted digraph for a protein structure to precisely characterize the spatial contacts of residues, then performs a weighted digraph convolution to aggregate both spatial local and global information and finally adds an improved graph attention layer to drive the predicted sites to form more continuous region(s). Spatom was tested on a diverse set of challenging protein-protein complexes and demonstrated the best performance among all the compared methods. Furthermore, when tested on multiple popular proteins in a case study, Spatom clearly identifies the interaction interfaces and captures the majority of hotspots. Spatom is expected to contribute to the understanding of protein interactions and drug designs targeting protein binding.

Consensus-based clustering of single cells by reconstructing cell-to-cell dissimilarity.

The development of single-cell ribonucleic acid (RNA) sequencing (scRNA-seq) technology has led to great opportunities for the identification of heterogeneous cell types in complex tissues. Clustering algorithms are of great importance to effectively identify different cell types. In addition, the definition of the distance between each two cells is a critical step for most clustering algorithms. In this study, we found that different distance measures have considerably different effects on clustering algorithms. Moreover, there is no specific distance measure that is applicable to all datasets. In this study, we introduce a new single-cell clustering method called SD-h, which generates an applicable distance measure for different kinds of datasets by optimally synthesizing commonly used distance measures. Then, hierarchical clustering is performed based on the new distance measure for more accurate cell-type clustering. SD-h was tested on nine frequently used scRNA-seq datasets and it showed great superiority over almost all the compared leading single-cell clustering algorithms.

Advanced drive laser system for a high-brightness continuous-wave photocathode electron gun.

In order to enhance the performance of a continuous-wave photocathode electron gun at Peking University, and to achieve electron beams with higher current and brightness, a multifunctional drive laser system named PULSE (Peking University drive Laser System for high-brightness Electron source) has been developed. This innovative system is capable of delivering an average output power of 120 W infrared laser pulse at 81.25 MHz, as well as approximately 13.8 W of green power with reliable stability. The utilization of two stages of photonic crystal fibers plays a crucial role in achieving this output. Additionally, the incorporation of two acousto-optic modulators enables the selection of macro-pulses with varying repetition frequencies and duty cycles, which is essential for effective electron beam diagnosis. Furthermore, the system employs a series of birefringent crystals for temporal pulse shaping, allowing for stacking Gaussian pulses into multiple types of distribution. Overall, the optical schematic and operating performance of PULSE are detailed in this paper.

NHPI-Mediated FeTiO3-Photocatalyzed Semiheterogeneous Decarboxylative Acylarylation of Acrylamides with α-Oxocarboxylic Acids under Nitrogen.

FeTiO3 has emerged as an interesting semiconductor photocatalyst in organic synthesis. We herein describe a visible-light-induced semiheterogeneous strategy for the synthesis of 3-(2-oxoethyl)indolin-2-ones with moderate to good yields and good functional group compatibility using recyclable FeTiO3 as a photocatalyst and NHPI as a redox catalyst.

The risk profiles of pregnancy-related cerebral venous thrombosis: a retrospective study in a comprehensive hospital.

OBJECTIVES: To investigate the risk factors and underlying causes of pregnancy-related cerebral venous thrombosis (PCVT). METHODS: A retrospective cohort of 16 patients diagnosed with CVT during pregnancy and postpartum (within six weeks after delivery) in a comprehensive hospital in China between 2009 and 2022 were carefully reviewed, focusing on demographic, clinical, and etiological characteristics, especially underlying causes. We matched 16 PCVT patients with 64 pregnant and puerperal women without PCVT to explore risk factors and clinical susceptibility to PCVT. RESULTS: PCVT occurred commonly during the first trimester (43.75%) and the puerperium (37.5%). The frequency of anemia, thrombocytosis and thrombocytopenia during pregnancy, dehydration, and pre-pregnancy anemia was significantly higher in women with PCVT than in those without PCVT (P < 0.05). Among the 16 patients, five were diagnosed with antiphospholipid syndrome and one was diagnosed with systemic lupus erythematosus. Three patients had distinct protein S deficiency and one had protein C deficiency. Whole Exome Sequencing (WES) was performed for five patients and revealed likely pathogenic mutations associated with CVT, including heterozygous PROC c.1218G > A (p. Met406Ile), heterozygous PROS1 c.301C > T (p. Arg101Cys), composite heterozygous mutation in the F8 gene (c.144-1259C > T; c.6724G > A (p. Val2242Met)) and homozygous MTHFR c.677C > T (p. Ala222Val). CONCLUSIONS: The occurrence of anemia, thrombocytopenia and thrombocytosis during pregnancy, dehydration and pre-pregnancy anemia suggested a greater susceptibility to PCVT. For confirmed PCVT patients, autoimmune diseases, hereditary thrombophilia, and hematological disorders were common causes. Screening for potential etiologies should be paid more attention, as it has implications for treatment and long-term management.

Protective effect of tretinoin on cervical cancer growth and proliferation through downregulation of pFAK2 expression.

BACKGROUND: Cervical cancer, a life-threatening disease, is the seventh most commonly detected cancer among women throughout the world. The present study investigated the effect of tretinoin on cervical cancer growth and metastasis in vitro and in vivo in the mice model. MATERIALS AND METHODS: Cell Counting Kit-8, clonogenic survival, and transwell chamber assays were used for determination cells proliferation, colony formation, and invasiveness. Western blotting assay was used for assessment of protein expression whereas AutoDock Vina and Discovery studio software for in silico studies. RESULTS: Tretinoin treatment significantly (p < .05) reduced the proliferation of HT-3 and Caski cells in concentration-based manner. Incubation with tretinoin caused a significant decrease in clonogenic survival of HT-3 and Caski cells compared with the control cultures. The invasive potential of HT-3 cells was decreased to 18%, whereas that of Caski cells to 21% on treatment with 8 µM concentration of tretinoin. In HT-3 cells, tretinoin treatment led to a prominent reduction in p-focal adhesion kinase (FAK), matrix metalloproteinases (MMP)-2, and MMP-9 expression in HT-3 cells. Treatment of the cervical cancer mice model with tretinoin led to a prominent decrease in tumor growth. The metastasis of tumor in model cervical cancer mice group was effectively inhibited in spleen, intestines, and peritoneal cavity. In silico studies showed that tretinoin interacts with alanine, proline, isoleucine, and glycine amino acid residues of FAK protein to block its activation. The 2-dimensional diagram of interaction of tretinoin with FAK protein revealed that tretinoin binds to alanine and glycine amino acids through conventional hydrogen bonding. CONCLUSION: In summary, tretinoin suppressed the proliferation, colony formation, and invasiveness of cervical cancer cells in vitro. It decreased the expression of activated focal adhesion kinase, MMP-2, and MMP-9 in HT-3 cells in dose-dependent manner. In silico studies showed that tretinoin interacts with alanine and glycine amino acids through conventional hydrogen bonding. In vivo data demonstrated that treatment of the cervical cancer mice model with tretinoin led to a prominent decrease in tumor growth. Therefore, tretinoin can be developed as an effective therapeutic agent for cervical cancer treatment.

TransBorrow: genome-guided transcriptome assembly by borrowing assemblies from different assemblers.

RNA-seq technology is widely used in various transcriptomic studies and provides great opportunities to reveal the complex structures of transcriptomes. To effectively analyze RNA-seq data, we introduce a novel transcriptome assembler, TransBorrow, which borrows the assemblies from different assemblers to search for reliable subsequences by building a colored graph from those borrowed assemblies. Then, by seeding reliable subsequences, a newly designed path extension strategy accurately searches for a transcript-representing path cover over each splicing graph. TransBorrow was tested on both simulated and real data sets and showed great superiority over all the compared leading assemblers.

TransRef enables accurate transcriptome assembly by redefining accurate neo-splicing graphs.

RNA-seq technology is widely employed in various research areas related to transcriptome analyses, and the identification of all the expressed transcripts from short sequencing reads presents a considerable computational challenge. In this study, we introduce TransRef, a new computational algorithm for accurate transcriptome assembly by redefining a novel graph model, the neo-splicing graph, and then iteratively applying a constrained dynamic programming to reconstruct all the expressed transcripts for each graph. When TransRef is utilized to analyze both real and simulated datasets, its performance is notably better than those of several state-of-the-art assemblers, including StringTie2, Cufflinks and Scallop. In particular, the performance of TransRef is notably strong in identifying novel transcripts and transcripts with low-expression levels, while the other assemblers are less effective.

SERPINA1 and plasminogen as novel biomarkers in obstetric antiphospholipid syndrome patients.

OBJECTIVES: To explore the potential biomarkers and mechanisms in obstetric antiphospholipid syndrome (OAPS) patients by placental proteomics. METHODS: Among 212 follow-up pregnancy patients based on the Chinese Rheumatism Data Center database (CRDC), we continuously recruited 30 pregnancy patients at the late stage of pregnancy for proteomics study. Fresh placental tissues were collected and 4D label-free technologies were used to analyse the placental proteome in patients. Bioinformatic analysis was applied to identify differentially expressed proteins (DEPs) and crucial pathways. Placental tissues were also stained with haematoxylin and eosin (H & E) for histological analysis. RESULTS: We collected 7 OAPS patients (33.85±1.57 years), 4 SAPS patients (34.25 ± 3.86 years), 8 SLE patients (30.38±2.56 years), and 11 healthy controls (31.45±3.01 years). All patients in the SAPS and OAPS group had adverse pregnancy history. A total of 7040 proteins containing at least one unique peptide were identified. There were 214 DEPs between the healthy group and the OAPS group, of which 82 proteins were upregulated and 132 proteins were downregulated in the OAPS group based on fold change ≥1.5 and p-values ≤0.05. We found that the complement and coagulation pathway played a significant role in OAPS patients. Several key proteins (C1Q, C4b, SERPINA1, plasminogen) highly expressed in placental tissues, that may serve as biomarkers for OAPS patients. CONCLUSIONS: The complement and coagulation pathway and related DEPs (SERPINA1 and plasminogen) were of crucial importance in OAPS patients.

Nontargeted metabolomics reveals the potential mechanism underlying the association between birthweight and metabolic disturbances.

AIMS: The aim of this study was to characterize the metabolites associated with small- and large-gestational-age newborns in maternal and cord blood, and to investigate potential mechanisms underlying the association between birthweight and metabolic disturbances. RESEARCH DESIGN AND METHODS: We recorded detailed anthropometric data of mother-offspring dyads. Untargeted metabolomic assays were performed on 67 pairs of cord blood and maternal fasting plasma samples including 16 pairs of small-for-gestational (SGA, < 10th percentile) dyads, 28 pairs of appropriate-for-gestational (AGA, approximate 50 percentile) dyads, and 23 pairs of large-for-gestational (LGA, > 90th percentile) dyads. The association of metabolites with newborn birthweight was conducted to screen for metabolites with U-shaped and line-shaped distributions. The association of metabolites with maternal and fetal phenotypes was also performed. RESULTS: We found 2 types of metabolites that changed in different patterns according to newborn birthweight. One type of metabolite exhibited a "U-shaped" trend of abundance fluctuation in the SGA-AGA-LGA groups. The results demonstrated that cuminaldehyde level was lower in the SGA and LGA groups, and its abundance in cord blood was negatively correlated with maternal BMI (r = -0.352 p = 0.009) and weight gain (r = -0.267 p = 0.043). 2-Methoxy-estradiol-17b 3-glucuronide, which showed enrichment in the SGA and LGA groups, was positively correlated with homocysteine (r = 0.44, p < 0.001) and free fatty acid (r = 0.42, p < 0.001) in maternal blood. Serotonin and 13(S)-HODE were the second type of metabolites, denoted as "line-shaped", which both showed increasing trends in the SGA-AGA-LGA groups in both maternal and cord blood and were both significantly positively correlated with maternal BMI before pregnancy. Moreover, cuminaldehyde, serotonin, 13(S)-HODE and some lipid metabolites showed a strong correlation between maternal and cord blood. CONCLUSIONS: These investigations demonstrate broad-scale metabolomic differences associated with newborn birthweight in both pregnant women and their newborns. The U-shaped metabolites associated with both the SGA and LGA groups might explain the U-shaped association between birthweight and metabolic dysregulation. The line-shaped metabolites might participate in intrauterine growth regulation. These observations might help to provide new insights into the insulin resistance and the risk of metabolic disturbance of SGA and LGA babies in adulthood and might identify potential new markers for adverse newborn outcomes in pregnant women.

Abdominal pregnancy: a case report and review of 17 cases.

PURPOSE: To analyze the clinical characteristics of abdominal pregnancy, and to explore the diagnosis and prognosis of different treatment methods. METHODS: The cases of patients with abdominal pregnancy admitted to Peking Union Medical College Hospital between January 1, 1989 and January 1, 2021, were analyzed retrospectively. RESULTS: The median age of 17 patients was 34 years (22-42 years); the median gestational duration was 57 days (from 41 days to 32 weeks). Among all 17 patients, 15 (88.24%) presented with abdominal pain. The implantation sites of the gestational sac included the bladder peritoneal reflection, anterior wall of the rectum, omentum, serous membrane of the uterus, and inside or on the surface of uterosacral ligament. In all, only 29.41% cases (5/17) were diagnosed before surgery. All 17 patients were treated via surgery. Further, 58.82% (10/17) patients recovered without complications, 29.41% (5/17) developed fever, 5.88% (1/17) underwent reoperation because of intra-abdominal bleeding, and 5.88% (1/17) developed double lower limb venous thrombosis. All 17 patients survived. CONCLUSION: The preoperative diagnosis rate of abdominal pregnancy is low. Planting sites in the pelvic peritoneum and pelvic organs are more common than the others. Laparoscopic surgery in the first trimester of pregnancy can achieve better therapeutic effects. However, the blood supply of the placenta should be fully evaluated before surgery. When it is expected that attempts to remove the placenta will cause fatal bleeding, the placenta can be left in place, but long-term close follow-up should be paid attention to.

[Guidelines for the application of chromosomal microarray analysis in prenatal diagnosis (2023)].

After the promulgation of the first edition of expert consensus on the application of chromosomal microarray analysis (CMA) technology in prenatal diagnosis in 2014, after 8 years of clinical and technical development, CMA technology has become a first­line diagnosis technology for fetal chromosome copy number deletion or duplication abnormalities, and is widely used in the field of prenatal diagnosis in China. However, with the development of the industry and the accumulation of experience in case diagnosis, the application of CMA technology in many important aspects of prenatal diagnosis, such as clinical diagnosis testimony, data analysis and genetic counseling before and after testing, needs to be further standardized and improved, so as to make the application of CMA technology more in line with clinical needs. The revision of the guideline was led by the National Prenatal Diagnostic Technical Expert Group, and several prenatal diagnostic institutions such as Peking Union Medical College Hospital were commissioned to write, discuss and revise the first draft, which was discussed and reviewed by all the experts of the National Prenatal Diagnostic Technical Expert Group, and was finally formed after extensive review and revision. This guideline is aimed at the important aspects of the application of CMA technology in prenatal diagnosis and clinical diagnosis, from the clinical application of evidence, test quality control, data analysis and interpretation, diagnosis report writing, genetic counseling before and after testing and other work specifications are elaborated and introduced in detail. It fully reflects the integrated experience, professional thinking and guidance of the current Chinese expert team on the prenatal diagnosis application of CMA technology. The compilation of the guideline for the application of CMA technology in prenatal diagnosis will strive to promote the standardization and advancement of prenatal diagnosis of fetal chromosome diseases in China.

[Accidental discovery of copy number variation on chromosome 1 in a fetus with high risk of trisomy 13 suggested by NIPT].

OBJECTIVE: To validate a fetus with high risk for trisomy 13 suggested by non-invasive prenatal testing (NIPT). METHODS: The fetus was selected as the study subject after the NIPT detection at Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences on February 18, 2019. Clinical data of the pregnant woman was collected. Fluorescence in situ hybridization (FISH), chromosomal karyotyping analysis and chromosomal microarray analysis (CMA) were carried out on amniotic fluid and umbilical cord blood and the couple's peripheral blood samples. Copy number variation sequencing (CNV-seq) was also performed on the placental and amniotic fluid samples following induced labor. RESULTS: The pregnant woman, a 38-year-old G4P1 gravida, was found to have abnormal fetal development by prenatal ultrasonography. NIPT test suggested that the fetus has a high risk for trisomy 13. Chromosomal karyotyping analysis of fetal amniotic fluid and umbilical cord blood were 46,XN,add(13)(p10). The result of CMA was arr[hg19]1q41q44(223937972_249224684)×3, with the size of the repeat fragment being approximately 25.29 Mb, the fetal karyotype was thereby revised as 46,XN,der(13)t(1;13)(q41;p10). Chromosomal karyotyping analysis and CMA of the parents' peripheral blood samples showed no obvious abnormality. The CNV-seq analysis of induced placenta revealed mosaicisms of normal karyotype and trisomy 13. The CNV-seq test of induced amniotic fluid confirmed a duplication of chr1:22446001_249220000 region spanning approximately 24.75 Mb, which was in keeping with the CMA results of amniotic fluid and umbilical cord blood samples. CONCLUSION: NIPT may yield false positive result due to placenta mosaicism. Invasive prenatal diagnosis should be recommended to women with a high risk by NIPT test. And analysis of placenta can explain the inconsistency between the results of NIPT and invasive prenatal diagnosis.

Clinical efficiency of simultaneous CNV-seq and whole-exome sequencing for testing fetal structural anomalies.

BACKGROUND: Birth defects are responsible for approximately 7% of neonatal deaths worldwide by World Health Organization in 2004. Many methods have been utilized for examining the congenital anomalies in fetuses. This study aims to investigate the efficiency of simultaneous CNV-seq and whole-exome sequencing (WES) in the diagnosis of fetal anomaly based on a large Chinese cohort. METHODS: In this cohort study, 1800 pregnant women with singleton fetus in Hubei Province were recruited from 2018 to 2020 for prenatal ultrasonic screening. Those with fetal structural anomalies were transferred to the Maternal and Child Health Hospital of Hubei Province through a referral network in Hubei, China. After multidisciplinary consultation and decision on fetal outcome, products of conception (POC) samples were obtained. Simultaneous CNV-seq and WES was conducted to identify the fetal anomalies that can compress initial DNA and turnaround time of reports. RESULTS: In total, 959 couples were finally eligible for the enrollment. A total of 227 trios were identified with a causative alteration (CNV or variant), among which 191 (84.14%) were de novo. Double diagnosis of pathogenic CNVs and variants have been identified in 10 fetuses. The diagnostic yield of multisystem anomalies was significantly higher than single system anomalies (32.28% vs. 22.36%, P = 0.0183). The diagnostic rate of fetuses with consistent intra- and extra-uterine phenotypes (172/684) was significantly higher than the rate of these with inconsistent phenotypes (17/116, P = 0.0130). CONCLUSIONS: Simultaneous CNV-seq and WES analysis contributed to fetal anomaly diagnosis and played a vital role in elucidating complex anomalies with compound causes.

Low-intensity ultrasound promotes uterine involution after cesarean section: the first multicenter, randomized, controlled clinical trial.

OBJECTIVE: To evaluate the clinical efficacy and safety of low-intensity ultrasound (LIUS) in promoting uterine involution and relieving postpartum pain. METHODS: The randomized controlled clinical trial in this study was conducted at five centers in three regions across China from June 2014 to December 2014. A total of 498 subjects were randomly divided into two groups. The LIUS group received ultrasound treatment, and the control group received sham ultrasound treatment. The fundal height and visual analogue scale (VAS) scores of the subjects following cesarean section were recorded separately before and after five treatments. The incidence of adverse events was recorded, while the records on lochia duration were obtained by telephone follow-up. The Full Analysis Set (FAS) comprised all subjects randomized who received at least one treatment. The Per-Protocol Set (PPS) comprised all patients who did not seriously violate the study protocol and had good compliance with complete report forms. Efficacy analyses were performed based on the FAS and PPS. All safety analyses were performed based on the safety set (SS), which included all patients who received at least one treatment. RESULTS: In the analysis of PPS and FAS, the LIUS group performed better than the control group in reducing the fundal height, shortening the duration of lochia, and relieving postpartum pain, with a significant difference between the two groups (p < 0.0001). In the SS analysis, there were no treatment-related adverse events observed in either group. CONCLUSIONS: The LIUS therapy is safe and effective, which contributes to uterine involution and the alleviation of postpartum pain.

Management of hemophagocytic lymphohistiocytosis in pregnancy: Case series study and literature review.

AIM: The diagnosis and treatment of hemophagocytic lymphohistiocytosis (HLH) in pregnancy is challenging due to its rarity. We aim to analyze and summarize the clinical characteristics of HLH in pregnancy, and to discuss effective diagnostic and treatment options. METHODS: Thirteen patients with HLH during pregnancy who were diagnosed and treated at the Peking Union Medical College Hospital of the Chinese Academy of Medical Sciences from January 2000 to December 2019 were studied retrospectively. We collected data on treatment regimens and on maternal and pregnancy outcomes. RESULTS: All patients had a singleton pregnancy, with a median age of 28 years (range, 22-33 years) and a median gestational age of 23 weeks (7-36 weeks). Twelve patients received corticosteroids, and four patients (with/without intravenous immunoglobulin) showed a curative effect. Two patients who were treated with dexamethasone and etoposide after termination of pregnancy achieved complete remission. Two patients attained remission after termination of pregnancy. Four pregnant women died, and the mortality rate was 30.8% (4/13). Fetal or neonatal death up to 1 week after delivery occurred in eight (61.5%) pregnancies. CONCLUSIONS: Early diagnosis and treatment are important for maternal survival, and corticosteroids are the first choice for most patients with HLH during pregnancy. For patients who do not respond to corticosteroids, etoposide and termination of pregnancy may be life-saving.

Phthalide metabolites produced by mangrove endophytic fungus Pestalotiopsis sp. SAS4.

Two new phthalide derivatives (1-2) and four known phthalide compounds (3-6) were purified from the culture of a mangrove endophytic fungus Pestalotiopsis sp. SAS4. Their chemical structures were established by analyses of 1D and 2D nuclear magnetic resonance (NMR) and high resolution mass spectrometry (HR-MS) spectroscopic data. All of these compounds were evaluated in vitro for antibacterial, cytotoxicity, and resistance to hypoxic-ischemic injury activities.

Production Review of Accelerator-Based Medical Isotopes.

The production of reactor-based medical isotopes is fragile, which has meant supply shortages from time to time. This paper reviews alternative production methods in the form of cyclotrons, linear accelerators and neutron generators. Finally, the status of the production of medical isotopes in China is described.