Prioritizing de novo potential non-canonical splicing variants in neurodevelopmental disorders.

BACKGROUND: Genomic variants outside of the canonical splicing site (±2) may generate abnormal mRNA splicing, which are defined as non-canonical splicing variants (NCSVs). However, the clinical interpretation of NCSVs in neurodevelopmental disorders (NDDs) is largely unknown. METHODS: We investigated the contribution of NCSVs to NDDs from 345,787 de novo variants (DNVs) in 47,574 patients with NDDs. We performed functional enrichment and protein-protein interaction analysis to assess the association between genes carrying prioritised NCSVs and NDDs. Minigene was used to validate the impact of NCSVs on mRNA splicing. FINDINGS: We observed significantly more NCSVs (p = 0.02, odds ratio [OR] = 2.05) among patients with NDD than in controls. Both canonical splicing variants (CSVs) and NCSVs contributed to an equal proportion of patients with NDD (0.76% vs. 0.82%). The candidate genes carrying NCSVs were associated with glutamatergic synapse and chromatin remodelling. Minigene successfully validated 59 of 79 (74.68%) NCSVs that led to abnormal splicing in 40 candidate genes, and 9 of the genes (ARID1B, KAT6B, TCF4, SMARCA2, SHANK3, PDHA1, WDR45, SCN2A, SYNGAP1) harboured recurrent NCSVs with the same variant present in more than two unrelated patients with NDD. Moreover, 36 of 59 (61.02%) NCSVs are novel clinically relevant variants, including 34 unreported and 2 clinically conflicting interpretations or of uncertain significance NCSVs in the ClinVar database. INTERPRETATION: This study highlights the common pathology and clinical importance of NCSVs in unsolved patients with NDD. FUNDING: The present study was funded by grants from the National Natural Science Foundation of China, China Postdoctoral Science Foundation, the Hunan Youth Science and Technology Innovation Talent Project, the Provincial Natural Science Foundation of Hunan, The Scientific Research Program of FuRong laboratory, and the Natural Science Project of the University of Anhui Province.

Multimodal feature learning and fusion on B-mode ultrasonography and sonoelastography using point-wise gated deep networks for prostate cancer diagnosis.

B-mode ultrasonography and sonoelastography are used in the clinical diagnosis of prostate cancer (PCa). A combination of the two ultrasound (US) modalities using computer aid may be helpful for improving the diagnostic performance. A technique for computer-aided diagnosis (CAD) of PCa is presented based on multimodal US. Firstly, quantitative features are extracted from both B-mode US images and sonoelastograms, including intensity statistics, regional percentile features, gray-level co-occurrence matrix (GLCM) texture features and binary texture features. Secondly, a deep network named PGBM-RBM2 is proposed to learn and fuse multimodal features, which is composed of the point-wise gated Boltzmann machine (PGBM) and two layers of the restricted Boltzmann machines (RBMs). Finally, the support vector machine (SVM) is used for prostatic disease classification. Experimental evaluation was conducted on 313 multimodal US images of the prostate from 103 patients with prostatic diseases (47 malignant and 56 benign). Under five-fold cross-validation, the classification sensitivity, specificity, accuracy, Youden's index and area under the receiver operating characteristic (ROC) curve with the PGBM-RBM2 were 87.0%, 88.8%, 87.9%, 75.8% and 0.851, respectively. The results demonstrate that multimodal feature learning and fusion using the PGBM-RBM2 can assist in the diagnosis of PCa. This deep network is expected to be useful in the clinical diagnosis of PCa.

Elevated hardness of peripheral gland on real-time elastography is an independent marker for high-risk prostate cancers.

OBJECTIVES: To examine the role of quantitative real-time elastography (RTE) features on differentiation between high-risk prostate cancer (PCA) and non-high-risk prostatic diseases in the initial transperineal biopsy setting. METHODS: We retrospectively included 103 patients with suspicious PCA who underwent both RTE and initial transperineal prostate biopsy. Patients were grouped into high-risk and non-high-risk categories according to the D'Amico's risk stratification. With computer assistance based on MATLAB programming, three features were extracted from RTE, i.e., the median hardness within peripheral gland (PG) (H med), the ratio of the median hardness within PG to that outside PG (H ratio), and the ratio of the hard area within PG to the total PG area (H ar). A multiple regression model incorporating an RTE feature, age, transrectal ultrasound finding, and prostate volume was used to identify markers for high-risk PCA. RESULTS: Forty-seven patients (45.6%) were diagnosed with PCA and 34 (33.0%) were diagnosed with high-risk PCA. Three RTE features were all statistically higher in high-risk PCA than in non-high-risk diseases (p < 0.001), indicating that the PGs in high-risk PCA patients were harder than those in non-high-risk patients. A high H ratio, high age, and low prostate volume were found to be independent markers for PCAs (p < 0.05), among which the high H ratio was the only independent marker for high-risk PCAs (p = 0.012). When predicting high-risk PCAs, the multiple regression achieved an area under receiver operating characteristic curve of 0.755, sensitivity of 73.5%, and specificity of 71.0%. CONCLUSIONS: The elevated hardness of PG identified high-risk PCA and served as an independent marker of high-risk PCA. As a non-invasive imaging modality, the RTE could be potentially used in routine clinical practice for the detection of high-risk PCA to decrease unnecessary biopsies and reduce overtreatment.

[Chemical constituents contained in ethanol extracts from Acorus tatarinowii and their anti-fatigue activity].

Chemical constituents in ethyl acetate and butanol fractions of ethanol extracts from Acorus tatarinowii were separated by column chromatography. Bufo skeletal muscle fatigue model was established to study the anti-fatigue activity of separated compounds. Five compounds were separated and identified by spectroscopic analysis as acoramone(1),cycloartenone(2),2,4,5-trimethoxyl-2'-butoxy-1,2-phenyl propandiol(3),5-hydroxymethyl furfural(4), and 5-butoxymethyl furfural(5). Compound 3 was a new compound, and compounds 2 and 5 were separated from this plant for the first time. Compound 4 exhibited a notable anti-fatigue activity.

Simultaneous determination of chlorogenic acid, forsythin and arctiin in Chinese traditional medicines preparation by reversed phase-HPLC.

A reversed phase (RP)-HPLC method was established for simultaneous determination of chlorogenic acid, arctiin and forsythin in Yinqiao Jiedu Granules, which was a commonly used Chinese herbal medical preparation for treatment of rheum ailments. The determination was based on a gradient elution (A: 1% acetic acid, pH=3.0, B: methanol) on a C18 column and an automatic wavelength switching program, where 325 nm was used for chlorogenic acid and 280 nm for arctiin and forsythin, respectively. Good linearities were obtained over the range of 2-200 mg.l(-1) for the 3 objective compounds. The spike recoveries were within 96.0-97.9%.