[Genetic analysis of a fetus with Coffin-Siris syndrome 2 due to a novel variant of ARID1A gene].

OBJECTIVE: To explore the genetic etiology of a fetus with Coffin-Siris syndrome (CSS). METHODS: A fetus with abnormal ultrasound findings detected at Luoyang Maternal and Child Health Care Hospital in July 2023 was selected as the study subject. Clinical data were analyzed retrospectively. Whole exome sequencing was carried out on fetal tissue and parental peripheral blood samples, and candidate variant was verified by Sanger sequencing and pathogenicity analysis. This study was approved by the Luoyang Maternal and Child Health Care Hospital (Ethics No. LYFY-YCCZ-2023011). RESULTS: Color Doppler ultrasound at 16+ gestational weeks revealed bilateral ventriculomegaly and cerebellar hypoplasia in the fetus. Trio-WES found that the fetus has harbored a heterozygous c.553C>T (p.Gln185Ter) variant of the ARID1A gene, which was verified by Sanger sequencing to have a de novo origin. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.553C>T (p.Gln185Ter) variant of the ARID1A gene was classified as pathogenic (PVS1+PS2_Supporting+PM2_Supporting). CONCLUSION: The fetus was diagnosed with CSS type 2, and the heterozygous c.553C>T (p.Gln185Ter) variant of the ARID1A gene probably underlay its brain malformations.

DRD4 promotes chemo-resistance and cancer stem cell-like phenotypes by mediating the activation of the Akt/ß-catenin signaling axis in liver cancer.

BACKGROUND: Liver cancer stem cells (LCSCs) significantly impact chemo-resistance and recurrence in liver cancer. Dopamine receptor D4 (DRD4) is known to enhance the cancer stem cell (CSC) phenotype in glioblastoma and correlates with poor prognosis in some non-central nervous system tumors; however, its influence on LCSCs remains uncertain. METHODS: To investigate the gene and protein expression profiles of DRD4 in LCSCs and non-LCSCs, we utilized transcriptome sequencing and Western blotting analysis. Bioinformatics analysis and immunohistochemistry were employed to assess the correlation between DRD4 expression levels and the pathological characteristics of liver cancer patients. The impact of DRD4 on LCSC phenotypes and signaling pathways were explored using pharmacological or gene-editing techniques. Additionally, the effect of DRD4 on the protein expression and intracellular localization of ß-catenin were examined using Western blotting and immunofluorescence. RESULTS: DRD4 expression is significantly elevated in LCSCs and correlates with short survival in liver cancer. The expression and activity of DRD4 are positive to resistance, self renewal and tumorigenicity in HCC. Mechanistically, DRD4 stabilizes ß-catenin and promotes its entry into the nucleus via activating the PI3K/Akt/GSK-3ß pathway, thereby enhancing LCSC phenotypes. CONCLUSIONS: Inhibiting DRD4 expression and activation offers a promising targeted therapy for eradicating LCSCs and relieve chemo-resistance.

Cat eye syndrome caused by 22q11.1q11.21 duplication: case report in a Chinese family.

PURPOSE:  This paper presents a report on two uncommon instances of cat eye syndrome in a Chinese family. CASE PRESENTATION: The proband, a 23-year-old female, exhibited a diminutive cornea and complete blindness in her right eye, and the uncorrected distance visual acuity of her left eye was 0.7 LogMAR. Peripheral blood chromosome karyotyping reveal a karyotype of 47, XX, + mar. Subsequent analysis of chromosome copy number variation unveiled a 1.5 Mb duplication in the 22q11.1q11.21 region of the proband. The proband's mother,aged 49, displayed small eyes, wide-set eyes, downward slanting eyelids, and congenital heart disease. Chromosome copy number variation analysis also showed a 1.55 Mb duplication in the 22q11.1q11.21 region of chromosome 22 in the proband's mother. Ultimately, both members of this family were diagnosed with cat eye syndrome. CONCLUSION:  Cat eye syndrome is a rare genetic disorder that greatly affects patients' lives and requires personalized treatment. This study provides new evidence for a better understanding of the diagnosis of cat eye syndrome and emphasizes the importance of genetic counseling and supervision.

Synthesis of a covalent organic framework with hetero-environmental pores and its medicine co-delivery application.

The topology type and the functionalization of pores play an important role in regulating the performance of covalent organic frameworks. Herein, we designed and synthesized the covalent organic framework with hetero-environmental pores using predesigned asymmetrical dialdehyde monomer. According to the results of structural characterization, crystallinity investigation, and theoretical calculation, the hetero-environmental pores of the obtained framework are regarded as the alternant arrangement. The distinctive hetero pore structure leads the designed material to show more advantages as compared with control materials in loading both hydrophobic and hydrophilic antibiotics for wound healing. This dual-antibiotic strategy can expand the antibacterial range as compared with the single antibiotic one, and reduce the generation of drug resistance. In summary, this strategy for designing covalent organic frameworks with hetero-environmental pores can extend the structural variety and provide a pathway for improving the practical application performance of these materials.

Bioinspired, Robust, and Absorbable Cellulose Nanofibrils/Chitosan Filament with Remarkable Cytocompatibility and Wound Healing Properties.

Surgical threads are of great importance to prevent wound infection and accelerate tissue healing in surgical treatment. Cellulose nanofibrils (CNF) and chitosan (CS) are attracting increasing attention to be employed as biomedicine materials due to their nontoxicity, cytocompatibility, and biodegradability. However, a robust and absorbable cellulose-based surgical thread has not been explored. Therefore, in this work, a bioinspired CNF/CS composite thread containing 5% cationic polyacrylamide (CPAM) by the mass of CS was prepared, and the obtained CNF/CS-5C thread exhibited excellent mechanical properties and low swelling ratio in water due to the high cross-link degree. Especially, the tensile strength (1877 ± 107 MPa) of this thread was much higher than that of most reported CNF-based threads. Meanwhile, compared with commercial silk and Vicryl surgical threads, the CNF/CS-5C thread exhibited better in vitro cytocompatibility toward endothelial and fibroblast cells and lower inflammatory response in vivo to subcutaneous tissues of rats. In addition, the obtained thread could be regarded as a promising absorbable suture, which exhibited excellent wound healing performances in vivo. Therefore, the prepared absorbable thread will open a new window to prepare novel and advanced cellulose-based threads for medical applications.

Reductase-Labile Peptidic Supramolecular Hydrogels Aided in Oral Delivery of Probiotics.

Oral delivery of probiotics has been a promising method for treatment of inflammatory bowel diseases (IBDs). However, probiotics always suffer from substantial loss of viability due to the harsh gastrointestinal conditions, especially the highly acidic environment in the stomach and bile salts in the intestine. In addition, to overcome the challenging conditions, an ideal delivery of probiotics requires the on-demand release of probiotics upon environmental response. Herein, a novel nitroreductase (NTR) labile peptidic hydrogel based on supramolecular self-assembly is demonstrated. The efficient encapsulation of typical probiotic Escherichia coli Nissle 1917 (EcN) into supramolecular assemblies yielded a probiotic-loaded hydrogel (EcN@Gel). Such a hydrogel adequately protected EcN to improve its viability against harsh acid and bile salt environments during oral delivery. The upregulated NTR in the intestinal tract triggered the disassembly of the hydrogel and accomplished the controlled release of EcN locally. In ulcerative colitis (UC)-bearing mice, EcN@Gel showed significantly enhanced therapeutic efficacy by downregulating proinflammatory cytokines and repairing the intestinal barrier. Moreover, EcN@Gel remolded the gut microbiome by increasing the diversity and abundance of indigenous probiotics, contributing to ameliorated therapies of IBDs. The NTR-labile hydrogel provided a promising platform for the on-demand delivery of probiotics into the intestinal tract.

A novel variant of the SOX10 gene associated with Waardenburg syndrome type IV.

BACKGROUND: Waardenburg syndrome (WS) is a rare genetic disorder characterized by varying degrees of sensorineural hearing loss and accumulated pigmentation in the skin, hair and iris. The syndrome is classified into four types (WS1, WS2, WS3, and WS4), each with different clinical phenotypes and underlying genetic causes. The aim of this study was to identify the pathogenic variant in a Chinese family with Waardenburg syndrome type IV. METHODS: The patient and his parents underwent a thorough medical examination. We applied whole exome sequencing to identify the causal variant on the patient and other family members. RESULTS: The patient presented with iris pigmentary abnormality, congenital megacolon and sensorineural hearing loss. The clinical diagnosis of the patient was WS4. The whole exome sequencing (WES) revealed a novel variant (c.452_456dup) in the SOX10 gene, which could be responsible for the observed pathogenic of WS4 in this patient. Our analysis suggests that this variant produces a truncated protein that contributes to the development of the disease. The genetic test confirmed the diagnosis of WS4 in the patient from the studied pedigree. CONCLUSIONS: This present study demonstrated that genetic test based on WES, an effective alternative to regular clinical examinations, helps diagnose WS4. The newly identified SOX10 gene variant can expand the understanding of WS4.

Synthesis and evaluation of naphthalene derivatives as potent STAT3 inhibitors and agents against triple-negative breast cancer growth and metastasis.

PURPOSE: Triple-negative breast cancer (TNBC) represents the worst prognostic subtype of breast cancer and lacks targeted therapeutic drugs. Signal transducer and activator of transcription 3 (STAT3) is overexpressed and constitutively activated in TNBCs and associated with poor patient outcomes. However, no agents targeting STAT3 have been successfully developed and marketed. Selective Estrogen Receptor Modulators (SERMs) have been reported as potential inhibitors of the IL-6/STAT3 signaling pathway. Naphthalene compounds have good pharmacological activity and significant anti-cancer activity. In this study, we synthesized a new series of naphthalene derivatives with the general structure of SERM and evaluated their effects on TNBC and STAT3 signals. METHODS: A new series of compounds based on the scaffold of SERMs and an amino group were designed and screened based on the structure-activity relationship by MTT assay. The binding activity of SMY002 to STAT3 was predicted and validated by docking and SPR. The STAT3 signaling target and anti-cancer effects of SMY002 were evaluated with three TNBC cell lines and the mice transplanted tumor model. RESULTS: Among the compounds, SMY002 displayed the most potent activity, which could directly interact with STAT3 SH2-domain, and strongly inhibit the phosphorylation, dimerization, nuclear distribution, transcriptional activity, and target genes expression of STAT3. Furthermore, SMY002 markedly suppressed migration, invasion, survival, growth, and metastasis of TNBC cells in vitro and in vivo via down-regulating the expression of Cyclin D1 and MMP9. CONCLUSIONS: SMY002 can significantly inhibit the growth and metastasis of TNBC cells by targeting the STAT3 signal.

Crosstalk between heat shock factor 1 and signal transducer and activator of transcription 3 mediated by interleukin-8 autocrine signaling maintains the cancer stem cell phenotype in liver cancer.

BACKGROUND AND AIM: Liver cancer stem cells (LCSCs) cause therapeutic refractoriness and relapse in hepatocellular carcinoma. Heat shock factor 1 (HSF1) plays versatile roles in multiple cancers. However, the role of HSF1 in LCSCs is not well understood. This study investigated the function and signal mechanisms of HSF1 in maintaining LCSC phenotypes. METHODS: We established two LCSC lines, HepG2-R and HuH-7-R. Constitutive activation of HSF1 was observed in these LCSCs. Specific short hairpin RNAs (shRNAs) and chemical inhibitors were used to identify the relationship between HSF1 expression and LCSCs phenotypes. RESULTS: We revealed a concomitant activation modality involving HSF1 and STAT3 in LCSCs and liver cancer tissues. We also found that liver cancer patients whose HSF1 and STAT3 mRNA expression levels were high presented with unfavorable clinicopathological characteristics. Moreover, the secretion of interleukin-8 (IL-8) was elevated in the LCSC medium and was directly regulated by HSF1 at the transcriptional level. In turn, IL-8 activated HSF1 and STAT3 signaling, and a neutralizing IL-8 antibody inhibited HSF1 and STAT3 activity, reduced cancer stem cell marker expression, and decreased LCSC microsphere formation. Simultaneous intervention with HSF1 and STAT3 led to synergistically suppressed stemness acquisition and growth suppression in the LCSCs in vivo and in vitro. CONCLUSIONS: Our study indicates that IL-8 mediates the crosstalk between the HSF1 and Stat3 signaling pathways in LCSCs and that the combined targeting of HSF1 and STAT3 is a promising treatment strategy for patients with advanced liver cancer.

Prenatal diagnosis of fetuses with ultrasound anomalies by whole-exome sequencing in Luoyang city, China.

Background: There is a great obstacle in prenatal diagnosis of fetal anomalies due to their considerable genetic and clinical heterogeneity. Whole-exome sequencing (WES) has been confirmed as a successful option for genetic diagnosis in pediatrics, but its clinical utility for prenatal diagnosis remains to be limited. Methods: A total of 60 fetuses with abnormal ultrasound findings underwent karyotyping or chromosomal microarray analysis (CMA), and those with negative results were further subjected to WES. The identified variants were classified as pathogenic or likely pathogenic (P/LP) and the variant of uncertain significance (VUS). Pregnancy outcomes were obtained through a telephone follow-up. Results: Twelve (20%, 12/60) fetuses were diagnosed to have chromosomal abnormalities using karyotyping or CMA. Of the remaining 48 cases that underwent WES, P/LP variants were identified in 14 cases (29.2%), giving an additional diagnostic yield of 23.3% (14/60). The most frequently affected organ referred for prenatal WES was the head or neck system (40%), followed by the skeletal system (39.1%). In terms of pathogenic genes, FGFR3 was the most common diagnostic gene in this cohort. For the first time, we discovered five P/LP variants involved in SEC24D, FIG4, CTNNA3, EPG5, and PKD2. In addition, we identified three VUSes that had been reported previously. Outcomes of pregnancy were available for 54 cases, of which 24 cases were terminated. Conclusion: The results confirmed that WES is a powerful tool in prenatal diagnosis, especially for fetuses with ultrasonographic anomalies that cannot be diagnosed using conventional prenatal methods. Additionally, newly identified variants will expand the phenotypic spectrum of monogenic disorders and greatly enrich the prenatal diagnostic database.

Nitroreductase-instructed supramolecular assemblies for microbiome regulation to enhance colorectal cancer treatments.

The development of human microbiome has collectively correlated the sophisticated interactions between Fusobacterium nucleatum and colorectal cancers (CRCs). However, the treatment of CRC via disruption of gastrointestinal flora remains less explored. Aiming at the up-regulated activity of nitroreductase in F. nucleatum-infected tumors, here, we developed the nitroreductase-instructed supramolecular self-assembly. The designed assembly precursors underwent enzymatic transformation to form assemblies, which agglutinated F. nucleatum and eradicated the targeted bacteria. These assemblies with anti-F. nucleatum activity could further alleviate the bacteria-induced drug resistance effect, thus sensitizing CRC cells against chemo-drugs. Eventually, in mice bearing F. nucleatum-infected CRC, the local introduction of nitroreductase-instructed assemblies could efficiently inhibit the tumor growth. Overall, this study incorporated nitroreductase to broaden the toolbox of enzyme-instructed supramolecular self-assembly. The local introduction of nitroreductase-instructed assemblies could target F. nucleatum to eliminate its contribution to CRC drug resistance and ameliorate chemotherapy outcomes.

Nanocrystalline Cellulose Cures Constipation via Gut Microbiota Metabolism.

Constipation can seriously affect the quality of life and increase the risk of colorectal cancer. The present strategies for constipation therapy have adverse effects, such as causing irreversible intestinal damage and affecting the absorption of nutrients. Nanocrystalline cellulose (NCC), which is from natural plants, has good biocompatibility and high safety. Herein, we used NCC to treat constipation assessed by the black stool, intestinal tissue sections, and serum biomarkers. We studied the effect of NCC on gut microbiota and discussed the correlation of gut microbiota and metabolites. We evaluated the long-term biosafety of NCC. NCC could effectively treat constipation through gut microbiota metabolism, which required a small dosage and did not affect the organs and intestines. NCC could be used as an alternative to medications and dietary fiber for constipation therapy.

Development of antimicrobial oxidized cellulose film for active food packaging.

Foodborne diseases caused by bacteria have aroused ongoing concerns for food safety. Most existing packaging plastics bring pollution and potential toxicity. Here antimicrobial dialdehyde cellophane (DACP) was developed by periodate oxidation. The structure, mechanical properties, optical properties, and barrier properties of DACP were characterized. The antimicrobial activity of DACP against four Gram-positive bacteria was studied. The packaging effect of DACP for food with high water content was evaluated, including strawberry and tofu. The antimicrobial activity of DACP improved with increased aldehyde content. Compared with the polyethylene film and cellophane, our DACP exhibited excellent antimicrobial effect and extended the shelf life of food significantly, which shows promising prospects in food packaging.

Trans-eQTLs of the CYP3A4 and CYP3A5 associated with tacrolimus trough blood concentration in Chinese renal transplant patients.

This study aimed to systematically investigate trans-eQTLs of CYP3A4 and CYP3A5 affecting tacrolimus trough blood concentrations in Chinese renal transplant patients. We used Plink v1.90 to perform data quality control and linear regression analysis on GTEx v8 data. SNPs with p-value < 0.05 were selected and the GTEx eQTL Calculator was used to further prioritize the eQTLs of CYP3A4 and CYP3A5 in the liver and small intestine. The eQTLs with a p-value < 5 × 10-5 and MAF≥ 0.05 in the CHB population were selected as candidate eQTLs. The genotyping of candidate eQTLs was performed using high-resolution melting (HRM) assays and Sanger DNA sequencing. This study included 845 Chinese renal transplant patients who received tacrolimus as an immunosuppressive agent. Association between 103 candidate eQTLs and log-transformed tacrolimus concentration/dose ratio (log (C0/D)) in this cohort was conducted using the SNPassoc package of R software. In the end, a total of 75,632 liver eQTLs of CYP3A4, 69,558 liver eQTLs of CYP3A5, 48,596 small intestine eQTLs of CYP3A4 and 28,616 small intestine eQTLs of CYP3A5 were obtained using the GTEx v8 eQTL Calculator. Of the 103 candidate eQTLs, rs75727207, rs181294422 and rs28522676 were significantly associated with tacrolimus log(C0/D) in different genetic models. We discovered a substantial number of novel eQTLs of CYP3A4 and CYP3A5 in liver and small intestine, also found that rs75727207, rs181294422 and rs28522676 may affect tacrolimus trough blood concentrations in Chinese renal transplant patients.

Impact of nanomaterials on the intestinal mucosal barrier and its application in treating intestinal diseases.

The intestinal mucosal barrier (IMB) is one of the important barriers to prevent harmful substances and pathogens from entering the body environment and to maintain intestinal homeostasis. The dysfunction of the IMB is associated with intestinal diseases and disorders. Nanomaterials have been widely used in medicine and as drug carriers due to their large specific surface area, strong adsorbability, and good biocompatibility. In this review, we comprehensively discuss the impact of typical nanomaterials on the IMB and summarize the treatment of intestinal diseases by using nanomaterials. The effects of nanomaterials on the IMB are mainly influenced by factors such as the dosage, size, morphology, and surface functional groups of nanomaterials. There is huge potential and a broad prospect for the application of nanomaterials in regulating the IMB for achieving an optimal therapeutic effect for antibiotics, oral vaccines, drug carriers, and so on.

Dialdehyde Nanocrystalline Cellulose as Antibiotic Substitutes against Multidrug-Resistant Bacteria.

Antibiotic abuse resulted in the emergence of multidrug-resistant Gram-positive pathogens, which pose a severe threat to public health. It is urgent to develop antibiotic substitutes to kill multidrug-resistant Gram-positive pathogens effectively. Herein, the antibacterial dialdehyde nanocrystalline cellulose (DNC) was prepared and characterized. The antibacterial activity and biosafety of DNC were studied. With the increasing content of aldehyde groups, DNC exhibited high antibacterial activity against Gram-positive pathogens in vitro. DNC3 significantly reduced the amounts of methicillin-resistant Staphylococcus aureus (MRSA) on the skin of infected mice models, which showed low cytotoxicity, excellent skin compatibility, and no acute oral toxicity. DNC exhibited potentials as antibiotic substitutes to fight against multidrug-resistant bacteria, such as ingredients in salves to treat skin infection and other on-skin applications.

Hot-starting software containers for STAR aligner.

Background: Using software containers has become standard practice to reproducibly deploy and execute biomedical workflows on the cloud. However, some applications that contain time-consuming initialization steps will produce unnecessary costs for repeated executions. Findings: We demonstrate that hot-starting from containers that have been frozen after the application has already begun execution can speed up bioinformatics workflows by avoiding repetitive initialization steps. We use an open-source tool called Checkpoint and Restore in Userspace (CRIU) to save the state of the containers as a collection of checkpoint files on disk after it has read in the indices. The resulting checkpoint files are migrated to the host, and CRIU is used to regenerate the containers in that ready-to-run hot-start state. As a proof-of-concept example, we create a hot-start container for the spliced transcripts alignment to a reference (STAR) aligner and deploy this container to align RNA sequencing data. We compare the performance of the alignment step with and without checkpoints on cloud platforms using local and network disks. Conclusions: We demonstrate that hot-starting Docker containers from snapshots taken after repetitive initialization steps are completed significantly speeds up the execution of the STAR aligner on all experimental platforms, including Amazon Web Services, Microsoft Azure, and local virtual machines. Our method can be potentially employed in other bioinformatics applications in which a checkpoint can be inserted after a repetitive initialization phase.

Surface modification of PS microtiter plate with chitosan oligosaccharides by 60Co irradiation.

By 60Co-γ irradiation method, the Chitosan-oligosaccharide (COS) was grafted onto the inner surface of the polystyrene (PS) microtiter, which was soaked with COS solution before the irradiation. To evaluated the effect of COS concentration on the properties of the PS microtiter, FTIR, XPS, AFM, Contact angle tester and enzyme-linked analyser was used to measure the surface properties and BSA adsorption of PS-COS plates. The results shows that, with the increase of COS concentration, the contact angle clearly decreased at the dose of 12kGy. The absorbance variances of the COS modified plate is less than 5% while the BSA adsorption is higher than the PS plates. The COS-modified microtiter has the potential applications in biochemical analysis.