Machine Learning and Integrative Analysis of Biomedical Big Data.

Recent developments in high-throughput technologies have accelerated the accumulation of massive amounts of omics data from multiple sources: genome, epigenome, transcriptome, proteome, metabolome, etc. Traditionally, data from each source (e.g., genome) is analyzed in isolation using statistical and machine learning (ML) methods. Integrative analysis of multi-omics and clinical data is key to new biomedical discoveries and advancements in precision medicine. However, data integration poses new computational challenges as well as exacerbates the ones associated with single-omics studies. Specialized computational approaches are required to effectively and efficiently perform integrative analysis of biomedical data acquired from diverse modalities. In this review, we discuss state-of-the-art ML-based approaches for tackling five specific computational challenges associated with integrative analysis: curse of dimensionality, data heterogeneity, missing data, class imbalance and scalability issues

The contribution of Alu exons to the human proteome.

BackgroundAlu elements are major contributors to lineage-specific new exons in primate and human genomes. Recent studies indicate that some Alu exons have high transcript inclusion levels or tissue-specific splicing profiles, and may play important regulatory roles in modulating mRNA degradation or translational efficiency. However, the contribution of Alu exons to the human proteome remains unclear and controversial. The prevailing view is that exons derived from young repetitive elements, such as Alu elements, are restricted to regulatory functions and have not had adequate evolutionary time to be incorporated into stable, functional proteins.ResultsWe adopt a proteotranscriptomics approach to systematically assess the contribution of Alu exons to the human proteome. Using RNA sequencing, ribosome profiling, and proteomics data from human tissues and cell lines, we provide evidence for the translational activities of Alu exons and the presence of Alu exon derived peptides in human proteins. These Alu exon peptides represent species-specific protein differences between primates and other mammals, and in certain instances between humans and closely related primates. In the case of the RNA editing enzyme ADARB1, which contains an Alu exon peptide in its catalytic domain, RNA sequencing analyses of A-to-I editing demonstrate that both the Alu exon skipping and inclusion isoforms encode active enzymes. The Alu exon derived peptide may fine tune the overall editing activity and, in limited cases, the site selectivity of ADARB1 protein products.ConclusionsOur data indicate that Alu elements have contributed to the acquisition of novel protein sequences during primate and human evolution

Continuous Femoral Nerve Block versus Intravenous Patient Controlled Analgesia for Knee Mobility and Long-Term Pain in Patients Receiving Total Knee Replacement: A Randomized Controlled Trial

Objectives. To evaluate the comparative analgesia effectiveness and safety of postoperative continuous femoral nerve block (CFNB) with patient controlled intravenous analgesia (PCIA) and their impact on knee function and chronic postoperative pain. Methods. Participants were randomly allocated to receive postoperative continuous femoral nerve block (group CFNB) or intravenous patient controlled analgesia (group PCIA). Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores for knee and incidence of chronic postoperative pain at 3, 6, and 12 months postoperatively were compared. postoperative pain and salvage medication at rest or during mobilization 24 hours, 48 hours, and 7 days postoperatively were also recorded. Results. After discharge from the hospital and rehabilitation of joint function, patients in group CFNB reported significantly improved knee flexion and less incidence of chronic postoperative pain at 3 months and 6 months postoperatively (P<0.05). Analgesic rescue medications were significantly reduced in patients receiving CFNB (P<0.001 and P=0.031, resp.). Conclusion. With standardized rehabilitation therapy, continuous femoral nerve block analgesia reduced the incidence of chronic postoperative pain, improved motility of replaced joints, and reduced the dosages of rescue analgesic medications, suggesting a recovery-enhancing effect of peripheral nerve block analgesia

The Evaluation of the Oxidative Stress Parameters in Patients with Primary Angle-Closure Glaucoma

Objective: To clarify the presence of oxidative stress in patients with primary angle-closure glaucoma (PACG) and to investigate the relationship between oxidative stress and PACG. Methods: Fifty patients with primary angle-closure glaucoma and fifty healthy controls of matched age and gender were included in the study prospectively. Serum samples were obtained to detect the oxidation degradation products malondialdehyde (MDA), conjugated diene (CD), 4-hydroxynonenal (4-HNE), advanced oxidation protein products (AOPP), protein carbonyl (PC), ischemia-modified albumin (IMA) and 8-hydroxydeoxyguanosin (8-OHdG). Results: The concentration of MDA and CD in PACG patients was significantly higher than those of the control subjects (P,0.05, P,0.01). The serum 4-HNE concentrations were increased in PACG patients, but the differences with those of the healthy controls were not statistically significant. Compared to normal subjects, there was significant higher in serum AOPP and PC in PACG patients (P,0.01). PACG patients had higher levels of 8-OHdG in serum with respect to the comparative group of normal subjects (P,0.01). When plasma IMA levels in the PACG group were compared with those in the control group, significant increases in IMA were observed in the former (P,0.05). Conclusions: Our study demonstrated that IMA is a new biomarker available for assessing oxidative stress in PCAG. Oxidative stress is an important risk factor in the development of primary angle-closure glaucoma. Increased levels o

Clinical Temporal Relation Extraction with Probabilistic Soft Logic Regularization and Global Inference

There has been a steady need in the medical community to precisely extract the temporal relations between clinical events. In particular, temporal information can facilitate a variety of downstream applications such as case report retrieval and medical question answering. Existing methods either require expensive feature engineering or are incapable of modeling the global relational dependencies among the events. In this paper, we propose a novel method, Clinical Temporal ReLation Exaction with Probabilistic Soft Logic Regularization and Global Inference (CTRL-PG) to tackle the problem at the document level. Extensive experiments on two benchmark datasets, I2B2-2012 and TB-Dense, demonstrate that CTRL-PG significantly outperforms baseline methods for temporal relation extraction.Comment: 10 pages, 4 figures, 7 tables, accepted by AAAI 202

Flow-Responsive Vascular Endothelial Growth Factor Receptor-Protein Kinase C Isoform Epsilon Signaling Mediates Glycolytic Metabolites for Vascular Repair

Aims: Hemodynamic shear stress participates in maintaining vascular redox status. Elucidating flow-mediated endothelial metabolites enables us to discover metabolic biomarkers and therapeutic targets. We posited that flow-responsive vascular endothelial growth factor receptor (VEGFR)-protein kinase C isoform epsilon (PKCɛ)-6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) signaling modulates glycolytic metabolites for vascular repair. Results: Bidirectional oscillatory flow (oscillatory shear stress [OSS]: 0.1 ± 3 dyne·cm^(−2) at 1 Hz) upregulated VEGFR-dependent PKCɛ expression to a greater degree than did unidirectional pulsatile flow (pulsatile shear stress [PSS]: 23 ± 8 dyne·cm^(−2) at 1 Hz) in human aortic endothelial cells (p < 0.05, n = 3). PSS and OSS further upregulated PKCɛ-dependent PFKFB3 expression for glycolysis (p < 0.05, n = 4). Constitutively active PKCɛ increased, whereas dominant-negative PKCɛ reduced both basal and maximal extracellular acidification rates for glycolytic flux (p < 0.01, n = 4). Metabolomic analysis demonstrated an increase in PKCɛ-dependent glycolytic metabolite, dihydroxyacetone (DHA), but a decrease in gluconeogenic metabolite, aspartic acid (p < 0.05 vs. control, n = 6). In a New Zealand White rabbit model, both PKCɛ and PFKFB3 immunostaining was prominent in the PSS- and OSS-exposed aortic arch and descending aorta. In a transgenic Tg(flk-1:EGFP) zebrafish model, GATA-1a morpholino oligonucleotide injection (to reduce viscosity-dependent shear stress) impaired vascular regeneration after tail amputation (p < 0.01, n = 20), which was restored with PKCɛ messenger RNA (mRNA) rescue (p < 0.05, n = 5). As a corollary, siPKCɛ inhibited tube formation and vascular repair, which were restored by DHA treatment in our Matrigel and zebrafish models. Innovation and Conclusion: Flow-sensitive VEGFR-PKCɛ-PFKFB3 signaling increases the glycolytic metabolite, dihydroxyacetone, to promote vascular repair