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Vissers-Bodmer Syndrome, an autosomal dominant disease, is a neurodevelopmental disorder characterized by global developmental delay, intellectual disability, hypotonia and autistic features with a highly variable phenotype. It is caused by variants in the CCR4-NOT transcription complex, subunit 1 gene (CNOT1). However, the pathophysiologic mechanism of the Vissers-Bodmer Syndrome remains unclear. Notably, this syndrome has not been previously reported in the Chinese. In this study, we utilized whole exome sequencing to identify three novel variants in the CNOT1 gene, encompassing one frameshift variant and two missense variants, in three Chinese patients mainly presenting with developmental delay, intellectual disability and/or autism. Interestingly, three patients exhibited novel manifestations including spina bifida occulta, horse-shoe kidney and café-au-lait spot. The frameshift variant, p.Gly172Alafs*5, occurring de novo, leading to a premature stop codon in the protein, was classified into pathogenic. Two missense variants c.3451A > G (p.Asn1151Asp) and c.557C > T (p.Ser186Phe) were predicted to be deleterious by multiple prediction algorithms with high conservation among a variety of species. Additionally, three-dimensional structure modeling and predicting indicated the substitution of the mutated amino acids would decrease the stability of CNOT1 protein. Given that CNOT1 is a relatively novel disease gene, we evaluated the gene-disease validity following ClinGen Standard Operating Procedure. The existing evidence substantiates a “Definitive” level of gene-disease relationship. The genetic findings provide a reliable basis for the genetic counseling of the family reproduction. Moreover, our results expand the genetic and phenotypic spectrum of CNOT1-related Vissers-Bodmer Syndrome.

Objective: To investigate the differences between meditation and resting states using infrared thermal imaging (IRTI) to determine facial temperature distribution features during meditation and annotate the patterns of facial temperature changes during meditation from the perspective of traditional Chinese medicine facial diagnosis. Methods: Each participant performed 10 min meditation and 10 min resting but in different sequences. A concentration test was set as the task load, followed by a meditation/resting or resting/meditation session, during which the participants' facial temperatures were observed using IRTI. Participants were scored on the Big Five Inventory (BFI) and Mindful Attention Awareness Scale (MAAS). Results: Forehead temperatures decreased more during meditation than during the resting state. The chin temperature increased only during meditation (P

Introduction: Clinical precision oncology increasingly relies on accurate genome-wide profiling using large panel next generation sequencing; however, difficulties in accurate and consistent detection of somatic mutation from individual platforms and pipelines remain an open question. Objectives: To obtain paired tumor–normal reference materials that can be effectively constructed and interchangeable with clinical samples, and evaluate the performance of 56 panels under routine testing conditions based on the reference samples. Methods: Genes involved in mismatch repair and DNA proofreading were knocked down using the CRISPR-Cas9 technology to accumulate somatic mutations in a defined GM12878 cell line. They were used as reference materials to comprehensively evaluate the reproducibility and accuracy of detection results of oncopanels and explore the potential influencing factors. Results: In total, 14 paired tumor–normal reference DNA samples from engineered cell lines were prepared, and a reference dataset comprising 168 somatic mutations in a high-confidence region of 1.8 Mb were generated. For mutations with an allele frequency (AF) of more than 5% in reference samples, 56 panels collectively reported 1306 errors, including 729 false negatives (FNs), 179 false positives (FPs) and 398 reproducibility errors. The performance metric varied among panels with precision and recall ranging from 0.773 to 1 and 0.683 to 1, respectively. Incorrect and inadequate filtering accounted for a large proportion of false discovery (including FNs and FPs), while low-quality detection, cross-contamination and other sequencing errors during the wet bench process were other sources of FNs and FPs. In addition, low AF (

Objective: The purpose of this study was to construct a 3D and 2D contrast-enhanced computed tomography (CECT) radiomics model to predict CGB3 levels and assess its prognostic abilities in bladder cancer (Bca) patients. Methods: Transcriptome data and CECT images of Bca patients were downloaded from The Cancer Imaging Archive (TCIA) and The Cancer Genome Atlas (TCGA) database. Clinical data of 43 cases from TCGA and TCIA were used for radiomics model evaluation. The Volume of interest (VOI) (3D) and region of interest (ROI) (2D) radiomics features were extracted. For the construction of predicting radiomics models, least absolute shrinkage and selection operator regression were used, and the filtered radiomics features were fitted using the logistic regression algorithm (LR). The model's effectiveness was measured using 10-fold cross-validation and the area under the receiver operating characteristic curve (AUC of ROC). Result: CGB3 was a differential expressed prognosis-related gene and involved in the immune response process of plasma cells and T cell gamma delta. The high levels of CGB3 are a risk element for overall survival (OS). The AUCs of VOI and ROI radiomics models in the training set were 0.841 and 0.776, while in the validation set were 0.815 and 0.754, respectively. The Delong test revealed that the AUCs of the two models were not statistically different, and both models had good predictive performance. Conclusion: The CGB3 expression level is an important prognosis factor for Bca patients. Both 3D and 2D CECT radiomics are effective in predicting CGB3 expression levels.

Epilepsy of infancy with migrating focal seizures (EIMFS) is a kind of epileptic encephalopathy with high genetic heterogeneity. The most common pathogenic gene for EIMFS is potassium sodium-activated channel subfamily T member 1 (KCNT1). Using Sendai virus-mediated reprogramming, we established an induced pluripotent stem cell (iPSC) line from the peripheral blood mononuclear cells (PBMCs) of a five-month-old Chinese girl with heterozygous missense mutation (c.2800 G>A) in the KCNT1 gene. The iPSCs were stable during amplification, expressed pluripotent genes, maintained a normal karyotype, and showed characteristics of the three germs layers in an in vitro differentiation assay.

Aristaless-related homeobox (ARX)-related disorders are recessive X-linked intellectual disability disorders. We encountered a patient with a hemizygous mutation (c.1507_1508del) showing intellectual disability, early-onset epileptic encephalopathy and Ohtahara syndrome. The patient had female genitals, but an XY karyotype. We established an induced pluripotent stem cell (iPSC) line from the peripheral blood mononuclear cells (PBMCs) of a six-month Chinese child with a hemizygous mutation (c.1507_1508del) in ARX. The PBMCs were reprogrammed with Sendai viral vectors. The iPSCs showed stable amplification, pluripotency-related gene expression, and trilineage differentiation potential. Karyotype analysis of the iPSCs showed 23 pairs of chromosomes with normal structure and sex chromosome is XY.

Refractory/relapsed B cell lymphoma patients who received the available anti-CD19 chimeric antigen receptor (CAR) T cells may still experience a short duration of remission. Here in this study, we evaluated the safety and efficacy of a novel dominant-negative programmed cell death-1 (PD-1) armored anti-CD19 CAR T cells. A total of 9 patients (including 4 diffuse large B cell lymphomas, DLBCL, 2 transformed follicular lymphomas, TFL, and 3 follicular lymphomas, FL) received the novel CAR T cells infusion at a dose of more than 1 × 106/kg. Grade ≥ 3 cytokine release syndrome (CRS) and neurotoxicity were observed in 11.1% (n = 1/9) and 11.1% (n = 1/9) of patients, respectively. The overall response rate (ORR) was 77.8% (n = 7/9) and complete response (CR) rate was 55.6% (n = 5/9). Two patients have ongoing CR (all at 20+ months). CAR T cells expanded after infusion and continued to be detectable at 12+ months in patients with ongoing CR. This novel CD19-CAR T cell was safe and effective with durable remissions in patients with refractory/relapsed B cell lymphoma.

Mental retardation, X-linked 21/34 (MRX21/34), is a rare intellectual disability disease caused by mutations in the IL1RAPL1 (Interleukin-1 Receptor Accessory Protein-Like 1) gene. Using Sendai virus-mediated reprogramming, we established an induced pluripotent stem cell (iPSC) line from PBMCs collected from a ten-year-old boy with MRX21/34. The iPSCs showed stable amplification, expressed pluripotent genes, displayed a normal karyotype, and had characteristics of trilineage differentiation potential in an in vitro differentiation assay.

Allan–Herndon–Dudley syndrome (AHDS) is a rare, X-chromosome-linked inherited disorder that affects brain development and is caused by a mutation in SLC16A2. Herein, we generated an induced pluripotent stem cell (iPSC) line from the peripheral blood mononuclear cells of a one-year-old male infant with AHDS using Sendai-virus-mediated reprogramming. These iPSCs exhibited stable amplification, expressed pluripotent markers, and differentiated spontaneously into three germ layers in vitro. Additionally, this iPSC line was found to maintain a normal karyotype and retain the pathogenic mutation in SLC16A2, facilitating the study of disease mechanisms and development of new therapies of AHDS.

Mediator complex subunit 12 (MED12)-related disorders are recessive-X-linked intellectual disabilities present primarily in male patients. We came across a female patient with a heterozygous mutation (c.1249-1G > C) related to MED12-related syndrome. MED12 expression was significantly lower than that in her parents, and another X chromosome was inactive. We established an induced pluripotent stem cell (iPSC) line from peripheral blood mononuclear cells (PBMCs) of a 1-year old Chinese girl with a heterozygous mutation (c.1249-1G > C) in MED12. PBMCs were reprogrammed using nonintegrative Sendai viral vectors. The iPSCs showed stable amplification, pluripotency-related gene expression, trilineage differentiation potential, and a normal karyotype.

Mitochondrial DNA depletion syndrome-13 (MTDPS13) is a rare autosomal recessive mitochondrial disease caused by mutations in the FBXL4 (F-box and leucine-rich repeat protein 4) gene. Using Sendai virus-mediated reprogramming, we established an induced pluripotent stem cell (iPSC) line from PBMCs collected from a one-year-old female patient with MTDPS13. The iPSCs were stable during amplification, expressed pluripotent genes, maintained a normal karyotype, and showed characteristics of the three germs layers in an in vitro differentiation assay.

Summary: DExD/H-box helicase members are key receptors for recognizing viral nucleic acids, and they regulate retinoic acid-inducible gene I (RIG-I)-like receptor (RLR)-mediated type I interferon (IFN) production. Here, we report that the DExD/H-box helicase family member DExD/H-box RNA helicase 19 (DDX19) is a negative regulator of type I IFN production. Ectopic expression of DDX19 suppressed poly(I:C) (polyinosinic-polycytidylic acid)- and Sendai-virus-induced type I IFN production, whereas knockdown of DDX19 expression enhanced type I IFN production. Mechanistically, DDX19 inhibited TANK-binds kinase 1 (TBK1)- and inhibitor-κb kinase ε (IKKε)-mediated phosphorylation of interferon regulatory factor 3 (IRF3) by disrupting the interaction between TBK1 or IKKε and IRF3. Additionally, DDX19 recruited Lamtor2 and then formed the TBK1-IKKε-Lamtor2-DDX19-IRF3 complex to suppress IFN production by promoting TBK1 and IKKε degradation. We generated Ddx19 knockout mice using transcription activator-like effector nucleases (TALENs) and found that Ddx19 deficiency in vivo augmented type I IFN production, resulting in suppression of encephalomyocarditis virus replication. These data show that DDX19 is an important negative regulator of RLR-mediated type I IFN production. : DExD/H-box helicase members are key receptors for recognizing viral nucleic acids and participate in regulating RLR-mediated type I IFN production. Zhang et al. show that DDX19 acts as a critical negative regulator of type I IFN production by disrupting TBK1-IKKε-IRF3 complex formation and recruiting Lamtor2 to degrade TBK1 and IKKε. Keywords: DDX19, IRF3, IKKε, Lamtor2, negative regulatory, type I IFN, TBK1

Objective: To establish a rat model of type 2 diabetes (T2DM) manifesting the Chinese medicine syndrome pattern of both qi and yin deficiency for evaluating the efficacy of a Chinese herbal formula (CHF), integrative medicine (IM), and pioglitazone (PIO) on T2DM indicators in the animal model. Methods: The rat model was induced by a high-fat diet (HFD) and streptozotocin (STZ, 30 mg/kg). CHF (3.4 g/kg), PIO (2.7 mg/kg), and IM (3.4 g CHF + 2.7 mg PIO) were administered to rats once daily for 14 days. Related laboratory parameters were observed. Results: Diabetic rats showed unsmooth fur, alopecia, reduced activity, huddling, somnolence, depression, pale or reddened tongue, damp/dark red tail, and high levels of water and food intake, urine volume, and stool weight, but weakened grip strength. Low levels of serum SOD, Na+-K+-ATPase, cAMP/cGMP, and a high level of iNOS were observed. Hyperglycemia, hyperinsulinemia, insulin resistance, high levels of serum glucagon/IDE and pancreatic amylin, and low serum and pancreatic SS levels were evident as well. Conclusions: A rat model of T2DM with both qi and yin deficiency was successfully replicated. CHF appeared to be more efficacious than IM and PIO in the rat model of qi and yin deficiency pattern of T2DM, though IM and PIO were each found to have their merits and drawbacks in attenuating T2DM indicators in the rat model.