Real-world evidence: Risdiplam in a patient with spinal muscular atrophy type I with a novel splicing mutation and one SMN2 copy.

Spinal muscular atrophy (SMA), which results from the deletion or/and mutation in the SMN1 gene, is an autosomal recessive neuromuscular disorder that leads to weakness and muscle atrophy. SMN2 is a paralogous gene of SMN1. SMN2 copy number affects the severity of SMA, but its role in patients treated with disease modifying therapies is unclear. The most appropriate individualized treatment for SMA has not yet been determined. Here, we reported a case of SMA type I with normal breathing and swallowing function. We genetically confirmed that this patient had a compound heterozygous variant: one deleted SMN1 allele and a novel splice mutation c.628-3T>G in the retained allele, with one SMN2 copy. Patient-derived sequencing of 4 SMN1 cDNA clones showed that this intronic single transversion mutation results in an alternative exon (e)5 3' splice site, which leads to an additional 2 nucleotides (AG) at the 5' end of e5, thereby explaining why the patient with only one copy of SMN2 had a mild clinical phenotype. Additionally, a minigene assay of wild type and mutant SMN1 in HEK293T cells also demonstrated that this transversion mutation induced e5 skipping. Considering treatment cost and goals of avoiding pain caused by injections and starting treatment as early as possible, risdiplam was prescribed for this patient. However, the patient showed remarkable clinical improvements after treatment with risdiplam for 7 months despite carrying only one copy of SMN2. This study is the first report on the treatment of risdiplam in a patient with one SMN2 copy in a real-world setting. These findings expand the mutation spectrum of SMA and provide accurate genetic counseling information, as well as clarify the molecular mechanism of careful genotype-phenotype correlation of the patient.

Sulphated Fucooligosaccharide from Sargassum Horneri: Structural Analysis and Anti-Alzheimer Activity.

In the present study, sulfated polysaccharides were obtained by digestion of Sargassum horneri and preparation with enzyme-assisted extraction using three food-grade enzymes, and their anti- Alzheimer's activities were investigated. The results demonstrated that the crude sulfated polysaccharides extracted using AMGSP, CSP and VSP dose-dependently (25-100 µg·mL- 1) raised the spontaneous alternating manner (%) in the Y maze experiment of mice and reduced the escape latency time in Morris maze test. AMGSP, CSP and VSP also exhibited good anti-AChE and moderate anti-BuChE activities. CSP displayed the best inhibitory efficacy against AChE. with IC50 values of 9.77 µM. And, CSP also exhibited good inhibitory selectivity of AChE over BuChE. Next, CSP of the best active crude extract was separated by the preparation type high performance liquid phase to obtain the sulphated fucooligosaccharide section: SFcup (→3-α-L-fucp(2-SO3-)-1→4-α-L-fucp(2,3-SO3-)-1→section), SFcup showed a best inhibitory efficacy against AChE with IC50 values of 4.03 µM. The kinetic research showed that SFcup inhibited AChE through dual binding sites. Moreover, the molecular docking of SFcup at the AChE active site was in accordance with the acquired pharmacological results.

Pose-based tremor type and level analysis for Parkinson's disease from video.

PURPOSE: Current methods for diagnosis of PD rely on clinical examination. The accuracy of diagnosis ranges between 73 and 84%, and is influenced by the experience of the clinical assessor. Hence, an automatic, effective and interpretable supporting system for PD symptom identification would support clinicians in making more robust PD diagnostic decisions. METHODS: We propose to analyze Parkinson's tremor (PT) to support the analysis of PD, since PT is one of the most typical symptoms of PD with broad generalizability. To realize the idea, we present SPA-PTA, a deep learning-based PT classification and severity estimation system that takes consumer-grade videos of front-facing humans as input. The core of the system is a novel attention module with a lightweight pyramidal channel-squeezing-fusion architecture that effectively extracts relevant PT information and filters noise. It enhances modeling performance while improving system interpretability. RESULTS: We validate our system via individual-based leave-one-out cross-validation on two tasks: the PT classification task and the tremor severity rating estimation task. Our system presents a 91.3% accuracy and 80.0% F1-score in classifying PT with non-PT class, while providing a 76.4% accuracy and 76.7% F1-score in more complex multiclass tremor rating classification task. CONCLUSION: Our system offers a cost-effective PT classification and tremor severity estimation results as warning signs of PD for undiagnosed patients with PT symptoms. In addition, it provides a potential solution for supporting PD diagnosis in regions with limited clinical resources.

Clinical feature and genetic mutation of KBG syndrome diagnosed in neonatal period: A case report.

RATIONALE: KBG syndrome (KBGS, OMIM: 148050), a rare genetic disorder, is clinically characterized by megalodontia, short stature, skeletal abnormalities, and nervous system manifestations. In the study, we explore the clinical and genetic characteristics of one neonate suffering KBGS caused by ANKRD11 gene mutation. PATIENT CONCERNS: The proband, a female, was born prematurely at 31 + 2 weeks. There were repeated infections and abdominal distension in the first month after birth, and the platelets could not rise to normal. Head ultrasound showed intracranial brain injury and intracranial hemorrhage. DIAGNOSES: Sequencing revealed that there was a heterozygous mutation in exon 9 of the ANKRD11 gene (NM_013275.5) for the child, c.1896_1897delTA (p.H632Qfs*30), which was a de novo mutation and has not been reported. Combining clinical features and genetic results, the proband was diagnosed as KBGS. INTERVENTIONS AND OUTCOMES: The brain sonography on day 4 after birth showed brain injury and intracranial hemorrhage. Therefore, 140 mg of bovine lung surfactant was administered through endotracheal intubation in addition to ventilator-assisted ventilation. Antibiotic treatment was also given till the inflammatory indicators of the infant returned to normal levels. The following-up of 1-year-6-month showed that the language, motion and height of development is slight falling behind the children of the same age. LESSONS: This is the first case of KBGS was diagnosed in the neonatal period, which provides a reference for the child to receive timely and correct treatment.

[Clinical and genetic analysis of a very early-onset inflammatory bowel disease type 28 child with atypical clinical manifestation].

OBJECTIVE: To explore the clinical and genetic characteristics of a very early-onset inflammatory bowel disease (VEO-IBD) type 28 child with atypical clinical manifestations. METHODS: A VEO-IBD type 28 child with atypical clinical manifestations admitted to the Department of Neonatology, Children's Hospital Affiliated to Shandong University on November 5, 2021 was selected as the study subject. Clinical data of the child was collected. Peripheral venous blood samples of the child and his parents were collected for high-throughput sequencing. Candidate variants were verified by Sanger sequencing and bioinformatic analysis. RESULTS: The child, a 50-day-old male, had manifested bronchitis, ulcerative stomatitis, eczema and slightly loose stool. High-throughput sequencing revealed that he has harbored compound heterozygous variants of the IL-10RA gene, namely c.299T>G (p.V100G) and c.301C>T (p.R101W), which were inherited from his father and mother, respectively. Bioinformatic analysis showed that both variants have been recorded in the HGMD database, though the c.299T>G variant has not been included in the gnomAD, 1000 Genomes, ExAC and ESP6500 databases, while the c.301C>T variant has a low population frequency. Both variants were predicted to be deleterious by the online software including SIFT, PolyPhen-2 and Mutation Taster. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were predicted to be pathogenic (PS3+PM2_Supporting+PP3). CONCLUSION: The c.299T>G and c.301C>T variants of the IL-10RA gene probably underlay the VEO-IBD type 28 in this child. Above finding has expanded the phenotypic spectrum of VEO-IBD type 28 due to variants of the IL-10RA gene and provided a reference for the clinical diagnosis of this disease.

Clinical and genetic features of luscan-lumish syndrome associated with a novel de novo variant of SETD2 gene: Case report and literature review.

Introduction: Luscan-Lumish syndrome (LLS) is currently recognized as a rarely-observed condition featured with overgrowth, macrocephaly, obesity, type I Chiari malformation, and linguistic retardation. So far, there have been only a few LLS cases registered worldwide, but with none of them reported from China. To acquire a deeper understanding on the clinical and genetic features of this disease, a Chinese boy with LLS caused by a heterozygous variant in SETD2 gene was investigated in the present study. Methods: The patient was clinically examined and the medical history of his family was collected. Genetic testing was performed to determine the genetic etiology. Results: The proband was a boy aged 5-year-7-month-old, who was referred to our hospital due to "being a slow learner in kindergarten". The child had a history of delayed motor and language development in comparison to his peers. After admission, physical examination revealed tall stature and macrocephaly as the major manifestation, in addition to a relatively lower rating in intelligence assessment as well as abnormal MRI images showing a slightly shorter corpus callosum accompanied by a mildly thinner corpus callosum body. Whole exome sequencing (WES) revealed a heterozygous c.2514_2516delTAG (p.Ser838del) variant in SETD2 gene, which was subsequently identified as a novel de novo variant. According to the standardized genetic variant classification published by the American College of Medical Genetics and Genomics (ACMG), the variant, with a pathogenicity analysis result indicating PS2 + PM2_Supporting + PM4, was determined to be likely pathogenic. Through literature review, the clinical phenotypes of the 15 LLS cases were summarized, including 8 cases of overgrowth (53%), 13 cases of macrocephaly (87%), 11 cases of developmental delay (73%), 8 cases of autism (53%), and 7 cases of special facial features (47%). Besides, abnormal craniocerebral MRI findings were noticed in 7 cases. Despite that the mutation sites of the 15 patients varied from case to case, they showed a uniformly distributed pattern throughout the whole SETD2 gene, including 5 missense mutations, 5 frameshift mutations and 5 non-sense mutations. Conclusion: LLS, not having been recognized till recent years, is identified as an autosomal dominant syndrome triggered by SETD2 gene mutation. As the first report of LLS in China, the case in our study was proved to be associated with a unique type of SETD2 gene mutation that has never been reported previously, which is believed to enrich the mutation spectrum of SETD2 gene and also, deepening the clinicians' understanding on the disease.

Vishniacozyma victoriae: An endophytic antagonist yeast of kiwifruit with biocontrol effect to Botrytis cinerea.

Botrytis cinerea is a pathogenic fungus to fruit, biocontrol is a promising approach to relieve this issue. In this study, Vishniacozyma victoriae is an endophytic yeast extracted from kiwifruit, was used to enhance the resistance of host to B. cinerea. The results showed that lesion diameter of the kiwifruit inoculated with B. cinerea was 55.16 %, 50.57 %, and 48.07 % lower than that of inoculated with V. victoriae + B. cinerea on 4th, 8th, and 12th day, respectively. On 12th day, the total organic acid content and energy charge of kiwifruit inoculated with B. cinerea were 19.25 % and 7.95 % lower than those inoculated with V. victoriae + B. cinerea. These indicated that V. victoriae used the organic acids and energy of host to colonize in the wound, which prevented B. cinerea from contacting the host. Accordingly, V. victoriae is a promising biocontrol yeast to inhibit the infection of B. cinerea on kiwifruit.

A synonymous mutation in PI4KA impacts the transcription and translation process of gene expression.

Phosphatidylinositol-4-kinase alpha (PI4KIIIα), encoded by the PI4KA gene, can synthesize phosphatidylinositol-4-phosphate (PI-4-P), which serves as a specific membrane marker and is instrumental in signal transduction. PI4KA mutations can cause autosomal recessive diseases involving neurological, intestinal, and immunological conditions (OMIM:619621, 616531, 619708). We detected sepsis, severe diarrhea, and decreased immunoglobulin levels in one neonate. Two novel compound heterozygous mutations, c.5846T>C (p.Leu1949Pro) and c.3453C>T (p.Gly1151=), were identified in the neonate from the father and the mother, respectively. Sanger sequencing and reverse transcription polymerase chain reaction (RT-PCR) for peripheral blood and minigene splicing assays showed a deletion of five bases (GTGAG) with the c.3453C>T variant at the mRNA level, which could result in a truncated protein (p.Gly1151GlyfsTer17). The missense mutation c.5846T>C (p.Leu1949Pro) kinase activity was measured, and little or no catalytic activity was detected. According to the clinical characteristics and gene mutations with functional verification, our pediatricians diagnosed the child with a combined immunodeficiency and intestinal disorder close to gastrointestinal defects and immunodeficiency syndrome 2 (GIDID2; OMIM: 619708). Medicines such as immunomodulators are prescribed to balance immune dysregulation. This study is the first report of a synonymous mutation in the PI4KA gene that influences alternative splicing. Our findings expand the mutation spectrum leading to PI4KIIIa deficiency-related diseases and provide exact information for genetic counseling.

Cerebral Palsy Prediction with Frequency Attention Informed Graph Convolutional Networks.

Early diagnosis and intervention are clinically con-sidered the paramount part of treating cerebral palsy (CP), so it is essential to design an efficient and interpretable automatic prediction system for CP. We highlight a significant difference between CP infants' frequency of human movement and that of the healthy group, which improves prediction performance. However, the existing deep learning-based methods did not use the frequency information of infants' movement for CP prediction. This paper proposes a frequency attention informed graph convolutional network and validates it on two consumer-grade RGB video datasets, namely MINI-RGBD and RVI-38 datasets. Our proposed frequency attention module aids in improving both classification performance and system interpretability. In addition, we design a frequency-binning method that retains the critical frequency of the human joint position data while filtering the noise. Our prediction performance achieves state-of-the-art research on both datasets. Our work demonstrates the effectiveness of frequency information in supporting the prediction of CP non-intrusively and provides a way for supporting the early diagnosis of CP in the resource-limited regions where the clinical resources are not abundant.

Pregnancy Outcome Difference between Fresh and Frozen Embryos in Women without Polycystic Ovary Syndrome: a Systematic Review and Meta-Analysis.

The purpose of this study is to identify that the advantages of frozen embryos are not evident in ovulatory women or women with non-polycystic ovary syndrome (non-PCOS) by meta-analysis. An exhaustive literature search of PubMed (MEDLINE), Embase, and Cochrane Library databases was performed until March 20, 2020 (limited to articles published in English). We included randomized clinical trials comparing the results of frozen and fresh embryo transfers. The primary outcomes were live birth rate and birth weight. The fixed effect model was used when a significant heterogeneity was observed. Otherwise, a random effect model was used. In 511 identified studies, 4 were eligible and were included in this review. There was no difference in live birth rate, singleton birth weight, clinical pregnancy, ongoing pregnancy, gestational diabetes, and gestational hypertension between frozen and fresh embryos. In frozen embryos, the relative risk of moderate or severe ovarian hyperstimulation syndrome (OHSS) was lower, the incidence rate of pre-eclampsia higher, and the standardized mean difference of twin birth weight higher than in fresh embryos. There is no significant difference between frozen embryo transfer (FET) and fresh embryo transfer in ovulatory women or women with non-PCOS. We recommend that the transfer depends on the actual situation in the patient in clinical practice, rather than the "freeze all" policy and thawing FET.

Six-transmembrane epithelial antigen of the prostate 1 expression promotes ovarian cancer metastasis by aiding progression of epithelial-to-mesenchymal transition.

Ovarian cancer is a severe malignant tumour of the female genital organs. Six-transmembrane epithelial antigen of the prostate 1 (STEAP1) expression is correlated with the occurrence and progression of multiple cancers. Here, we assessed STEAP1 expression in ovarian cancer and explored the relationship between STEAP1 and ovarian cancer progression. We used immunohistochemistry and public databases to test STEAP1 expression in normal human ovarian tissues, benign ovarian tumours, and ovarian cancer. The expression of STEAP1 and epithelial-to-mesenchymal transition (EMT)-related genes was analysed using immunocytochemistry, quantitative reverse transcription polymerase chain reaction, and western blotting in ovarian cancer cell lines. Lentivirus was used to knockdown and overexpress STEAP1. Invasion, migration, growth, clonogenicity, and apoptosis were assessed using transwell assay, growth curve, plate clone formation assay, and flow cytometry. We used a tumour xenograft to verify the relationship between STEAP1 and in vivo ovarian cancer cell growth. Matrix metalloproteinase-2 (MMP2) and matrix metalloproteinase-9 (MMP9) activities were examined using Matrix metalloproteinase zymography assay. STEAP1 was highly expressed in the human ovarian cancer tissues and a highly invasive ovarian cancer cell line. Overexpression of STEAP1 was related to poor prognosis in ovarian cancer patients. Down-regulation of STEAP1 suppressed the invasion, migration, proliferation, clonogenicity, EMT progression in human ovarian cancer cells and xenograft tumour growth in vivo, but it enhanced apoptosis. In human ovarian cancer, the STEAP1 gene is highly expressed, and its function is correlated with human ovarian cancer cell metastasis and growth. STEAP1 may be a possible target for suppressing ovarian cancer metastasis.

Six-transmembrane epithelial antigen of the prostate 1 is associated with tumor invasion and migration in endometrial carcinomas.

Six-transmembrane epithelial antigen of the prostate 1 (STEAP1), a member of the STEAP family, is a general tumor antigen. However, no information has been available to date regarding the function of STEAP1 in the progression of endometrial carcinoma. In this study, we used in vitro and in vivo strategies to prove that STEAP1 plays an important role in the progression of endometrial carcinoma. Immunohistochemistry, immunocytochemistry, quantitative reverse transcription polymerase chain reaction (RT-qPCR), and Western blot analysis were used to detect the expression of STEAP1 in normal endometrial cells and endometrial cancer cell lines. The progression of the cell cycle, plate clone formation assay, and transwell migration and invasion assays were performed to examine the effects of STEAP1 on cell proliferation, clonogenicity, migration, and their invasive capacity. In addition, we confirmed that STEAP1 was tightly correlated with the development of tumor in vivo. The relationship between epithelial to mesenchymal transition (EMT) and STEAP1 expression was evaluated by RT-qPCR and Western blot analysis. Matrix metalloproteinase (MMP) zymography assay was used to detect the activities of MMP2 and MMP9. STEAP1 was restrictively expressed in endometrial carcinoma and downregulation of the STEAP1 gene increased proliferation and clonogenicity, as well as promoted cell migration, invasion, and the progress of EMT. STEAP1 is downregulated in endometrial carcinoma and can restrict migration and invasion of endometrial carcinoma cells. Overall, STEAP1 may be an ideal target for tumor therapy and diagnosis in the future.

STEAP1 Inhibits Breast Cancer Metastasis and Is Associated With Epithelial-Mesenchymal Transition Procession.

PURPOSE: Six-transmembrane epithelial antigen of prostate 1 (STEAP1) is a cell surface antigen overexpressed in multiple cancers and is associated with malignancy and disease prognosis. The aims of this study were to evaluate STEAP1 expression in breast cancer and to determine the mechanisms involved. METHODS: STEAP1 expression was compared in normal breast tissue (n = 40), benign fibroadenoma (n = 52), and primary breast cancer (n = 211) using immunohistochemistry. Quantitative real-time polymerase chain reaction, Western blot analysis, and immunocytochemistry were used to evaluate STEAP1 expression in 3 breast cancer cell lines and in a normal mammary epithelial cell line. STEAP1 expression and its prognostic value in breast cancer were verified using the Oncomine and Kaplan-Meier Plotter databases. Transfection of cells to up-regulate or knock down STEAP1 expression was used to determine the effect of STEAP1 on cell invasion and proliferation, and to evaluate its relationship to epithelial-mesenchymal transition (EMT) progression. RESULTS: STEAP1 expression was lower in breast cancers cells, and low expression was associated with a malignant phenotype and poor prognosis. Analysis of public databases supported our conclusions. Knockdown of STEAP1 expression enhanced cellular invasion and migration abilities, increased expression of EMT-related genes MMP2, MMP9, MMP13, VIM, and CDH2, and decreased CDH1 expression. Enhanced STEAP1 expression significantly inhibited cellular invasion and migration abilities, decreased expression of the EMT-related genes, and increased CDH1 expression. Up-regulation or knockdown of STEAP1 had little effect on cellular proliferation. CONCLUSION: STEAP1 was down-regulated in breast cancer, inhibited metastasis of breast cancer, and hampered the levels of EMT markers, which thus implicated STEAP1 in the suppression of EMT.