Video question answering (Video-QA) is a subject undergoing intense study in Artificial Intelligence, which is one of the tasks which can evaluate such AI abilities. In this paper, we propose a ...Modality Attention Fusion framework with Hybrid Multi-head Self-attention (MAF-HMS). MAF-HMS focuses on the task of answering multiple-choice questions regarding a video-subtitle-QA representation by fusion of attention and self-attention between each modality. We use BERT to extract text features, and use Faster R-CNN to ex-tract visual features to provide a useful input representation for our model to answer questions. In addition, we have constructed a Modality Attention Fusion (MAF) framework for the attention fusion matrix from different modalities (video, subtitles, QA), and use a Hybrid Multi-headed Self-attention (HMS) to further determine the correct answer. Experiments on three separate scene datasets show our overall model outperforms the baseline methods by a large margin. Finally, we conducted extensive ablation studies to verify the various components of the network and demonstrate the effectiveness and advantages of our method over existing methods through question type and required modality experimental results.
Video question answering (Video-QA) is a subject undergoing intense study in Artificial Intelligence, which is one of the tasks which can evaluate such AI abilities. In this paper, we propose a ...Modality Attention Fusion framework with Hybrid Multi-head Self-attention (MAF-HMS). MAF-HMS focuses on the task of answering multiple-choice questions regarding a video-subtitle-QA representation by fusion of attention and self-attention between each modality. We use BERT to extract text features, and use Faster R-CNN to ex-tract visual features to provide a useful input representation for our model to answer questions. In addition, we have constructed a Modality Attention Fusion (MAF) framework for the attention fusion matrix from different modalities (video, subtitles, QA), and use a Hybrid Multi-headed Self-attention (HMS) to further determine the correct answer. Experiments on three separate scene datasets show our overall model outperforms the baseline methods by a large margin. Finally, we conducted extensive ablation studies to verify the various components of the network and demonstrate the effectiveness and advantages of our method over existing methods through question type and required modality experimental results.
The prokaryotic type II CRISPR/Cas9 system has been adapted to perform targeted genome editing in cells and model organisms. Here, we describe targeted gene deletion and replacement in human cells ...via the CRISPR/Cas9 system using two guide RNAs. The system effectively generated targeted deletions of varied length, regardless of the transcriptional status of the target gene. It is notable that targeted gene deletions generated via CRISPR/Cas9 and two guide RNAs resulted in the formation of correct junctions at high efficiency. Moreover, in the presence of a homology repair donor, the CRISPR/Cas9 system could guide precise gene replacement. Our results illustrate that the CRISPR/Cas9 system can be used to precisely and effectively generate targeted deletions or gene replacement in human cells, which will facilitate characterization of functional domains in protein-coding genes as well as noncoding regulatory sequences in animal genomes.
We investigated changes in plasma transfer RNA related fragments (tRF) in children with obstructive sleep apnea-hypopnea syndrome (OSAHS) and the potential value as a disease marker.
Firstly, we ...randomly selected five plasma samples from the case group and the control group for high-throughput RNA sequencing. Secondly, we screened one tRF with different expression between the two groups, amplified it by quantitative reverse transcription-PCR (qRT-PCR) and sequenced the amplified product. After confirming that the qRT-PCR results were consistent with the sequencing results and the sequence of the amplified product contained the original sequence of the tRF, we performed qRT-PCR on all samples. Then we analyzed the diagnostic value of the tRF and its correlation with some clinical data.
A total of 50 OSAHS children and 38 control children were included in this study. There were significant differences in height, serum creatinine (SCR) and total cholesterol (TC) between the two groups. The plasma expression levels of tRF-21-U0EZY9X1B (tRF-21) were significantly different between the two groups. Receiver operating characteristic curve (ROC) showed that it had valuable diagnostic index, with area under the curve (AUC) of 0.773, 86.71% and 63.16% sensitivity and specificity.
The expression levels of tRF-21 in the plasma of OSAHS children decreased significantly which were closely related to hemoglobin, mean corpuscular hemoglobin, triglyceride and creatine kinase-MB, may become novel biomarkers for the diagnosis of pediatric OSAHS.
The prognostic value of epidermal growth factor receptor (EGFR) mutations in resected non-small cell lung cancer (NSCLC) remains controversial. We performed a systematic review with meta-analysis to ...assess its role.
Studies were identified via an electronic search on PubMed, Embase and Cochrane Library databases. Pooled hazard ratio (HR) for disease-free survival (DFS) and overall survival (OS) were calculated for meta-analysis.
There were 16 evaluated studies (n = 3337) in the meta-analysis. The combined HR evaluating EGFR mutations on disease free survival was 0.96 (95% CI 0.79-1.16 P = 0.65). The combined HR evaluating EGFR mutations on overall survival was 0.86 (95% CI 0.72-1.04 P = 0.12). The subgroup analysis based on univariate and multivariate analyses in DFS and OS showed no statistically significant difference. There was also no statistically significant difference in DFS and OS of stage I NSCLC patients.
The systematic review with meta-analysis showed that EGFR mutations were not a prognostic factor in patients with surgically resected non-small cell lung cancer. Well designed prospective study is needed to confirm the result.
Background
Identifying genetic variants of the ABO gene may reveal new biologic mechanisms underlying variant phenotypes of the ABO blood group. We report the molecular genetic analysis of 322 ...apparently unrelated ABO subgroup individuals in an estimated 2.1 million donors.
Study Design and Methods
We performed phenotype investigations by serology studies, analyzed the DNA sequence of the ABO gene by direct sequencing or sequencing after cloning, and evaluated promoter activity by reporter assays.
Results
In 62 rare ABO alleles, we identified 29 novel ABO subgroup alleles in 43 apparently unrelated subgroup individuals and their four available pedigrees. Of these alleles, one was a deletion‐mutation allele, four were hybrid alleles, and 24 were point‐mutation alleles. Most of the point mutations were detected in Exons 6 to 7, while several others were also detected in Exons 1 to 5 or splicing regions. One ABO promoter mutation, −35 to −18 del, was found and verified to reduce promoter activity, as determined by dual luciferase assays. Two mutations, 7G>T and 52C>T, carrying the premature terminal codons E3X and R18X in the 5′‐region, were found to be associated with the very weak ABO subgroups “Ael” and “Bel.”
Conclusion
Twenty‐nine ABO subgroup alleles were newly linked to different kinds of ABO variations. We provide the first evidence that promoter abnormality is involved in the formation of weak ABO phenotypes. We also described the first naturally occurring ABO alleles with premature terminal codons in the 5′‐region that led to Ael and Bel phenotypes.
Obstructive sleep apnea-hypopnea syndrome (OSAHS), typically characterized by chronic intermittent hypoxia (CIH), is associated with neurocognitive dysfunction in children. Sulforaphane (SFN), an ...activator of nuclear factor E2-related factor 2 (Nrf2), has been demonstrated to protect against oxidative stress in various diseases. However, the effect of SFN on OSAHS remains elusive. In this research, we investigated the neuroprotective role of SFN in CIH-induced cognitive dysfunction and underlying mechanisms of regulation of Nrf2 signaling pathway and autophagy. CIH exposures for 4 weeks in mice, modeling OSAHS, contributed to neurocognitive dysfunction, manifested as increased working memory errors (WMEs), reference memory errors (RMEs) and total memory errors (TEs) in the 8-arm radial maze test. The mice were intraperitoneally injected with SFN (0.5 mg/kg) 30 min before CIH exposure everyday. SFN treatment ameliorated neurocognitive dysfunction in CIH mice, which demonstrates less RME, WME, and TE. Also, SFN effectively alleviated apoptosis of hippocampal neurons following CIH by decreased TUNEL-positive cells, downregulated cleaved PARP, cleaved caspase 3, and upregulated Bcl-2. SFN protects hippocampal tissue from CIH-induced oxidative stress as evidenced by elevated superoxide dismutase (SOD) activities and reduced malondialdehyde (MDA). In addition, we found that SFN enhanced Nrf2 nuclear translocation to hold an antioxidative function on CIH-induced neuronal apoptosis in hippocampus. Meanwhile, SFN promoted autophagy activation, as shown by increased Beclin1, ATG5, and LC3II/LC3I. Overall, our findings indicated that SFN reduced the apoptosis of hippocampal neurons through antioxidant effect of Nrf2 and autophagy in CIH-induced brain damage, which highlights the potential of SFN as a novel therapy for OSAHS-related neurocognitive dysfunction.
Colorectal cancer (CRC) is the third most prevalent cancer in China but few large-scale studies were conducted to understand CRC patients. The current study is aimed to gain a real-world perspectives ...of CRC patients in China.
Using electronic medical records of sampled patients between 2011 and 2016 from 12 hospitals in China, a retrospective cohort study was conducted to describe demographics and disease prognosis of CRC patients, and examine treatment sequences among metastatic CRC (mCRC) patients. Descriptive, comparative and survival analyses were conducted.
Among mCRC patients (3878/8136, 48%), the fluorouracil, leucovorin, and oxaliplatin (FOLFOX) and other oxaliplatin-based regimens were the most widely-used first-line treatment (42%). Fluorouracil, leucovorin, irinotecan (FOLFIRI) and other irinotecan-based regimens dominated the second-line (40%). There was no a dominated regimen for the third-line. The proportion of patients receiving chemotherapy with targeted biologics increased from less than 20% for the first- and second- lines to 34% for the third-line (p < 0.001). The most common sequence from first- to second-line was from FOLFOX and other oxaliplatin-based regimens to FOLFIRI and other irinotecan-based regimens (286/1200, 24%).
Our findings reflected a lack of consensus on the choice of third-line therapy and limited available options in China. It is evident o continue promoting early CRC diagnosis and to increase the accessibility of treatment options for mCRC patients. As the only nationwide large-scale study among CRC and mCRC patients before more biologics became available in China, our results can also be used as the baseline to assess treatment pattern changes before and after more third-line treatment were approved and covered into the National Health Insurance Plan in China between 2017 and 2018.
TH-302 is a 2-nitroimidazole triggered hypoxia-activated prodrug (HAP) of bromo-isophosphoramide mustard currently undergoing clinical evaluation. Here, we describe broad-spectrum activity, ...hypoxia-selective activation, and mechanism of action of TH-302. The concentration and time dependence of TH-302 activation was examined as a function of oxygen concentration, with reference to the prototypic HAP tirapazamine, and showed superior oxygen inhibition of cytotoxicity and much improved dose potency relative to tirapazamine. Enhanced TH-302 cytotoxicity under hypoxia was observed across 32 human cancer cell lines. One-electron reductive enzyme dependence was confirmed using cells overexpressing human NADPH:cytochrome P450 oxidoreductase and radiolytic reduction established the single-electron stoichiometry of TH-302 fragmentation (activation). Examining downstream effects of TH-302 activity, we observed hypoxia-dependent induction of γH2AX phosphorylation, DNA cross-linking, and cell-cycle arrest. We used Chinese hamster ovary cell-based DNA repair mutant cell lines and established that lines deficient in homology-dependent repair, but not lines deficient in base excision, nucleotide excision, or nonhomologous end-joining repair, exhibited marked sensitivity to TH-302 under hypoxia. Consistent with this finding, enhanced sensitivity to TH-302 was also observed in lines deficient in BRCA1, BRCA2, and FANCA. Finally, we characterized TH-302 activity in the three-dimensional tumor spheroid and multicellular layer models. TH-302 showed much enhanced potency in H460 spheroids compared with H460 monolayer cells under normoxia. Multicellular layers composed of mixtures of parental HCT116 cells and HCT116 cells engineered to express an oxygen-insensitive bacterial nitroreductase showed that TH-302 exhibits a significant bystander effect.
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