A simultaneous bus route design and frequency setting problem for Tin Shui Wai, Hong Kong

A bus network design problem for Tin Shui Wai, a suburban residential area in Hong Kong, is investigated, which considers the bus services from the origins inside this suburban area to the destinations in the urban areas. The problem aims to improve the existing bus services by reducing the number of transfers and the total travel time of the users. This has been achieved by the proposed integrated solution method which can solve the route design and frequency setting problems simultaneously. In the proposed solution method, a genetic algorithm, which tackles the route design problem, is hybridized with a neighborhood search heuristic, which tackles the frequency setting problem. A new solution representation scheme and specific genetic operators are developed so that the genetic algorithm can search all possible route structures, rather than selecting routes from the predefined set. To avoid premature convergence, a diversity control mechanism is incorporated in the solution method based on a new definition of hamming distance. To illustrate the robustness and quality of solutions obtained, computational experiments are performed based on 1000 perturbed demand matrices. The t-test results show that the design obtained by the proposed solution method is robust under demand uncertainty, and the design is better than both the current design and the design obtained by solving the route design problem and the frequency setting problem sequentially. Compared with the current bus network design, the proposed method can generate a design which can simultaneously reduce the number of transfers and total travel time at least by 20.9% and 22.7% respectively. Numerical studies are also performed to illustrate the effectiveness of the diversity control mechanism introduced and the effects of weights on the two objective values. © 2010 Elsevier B.V. All rights reserved.postprin

An artificial bee colony algorithm for the capacitated vehicle routing problem

This paper introduces an artificial bee colony heuristic for solving the capacitated vehicle routing problem. The artificial bee colony heuristic is a swarm-based heuristic, which mimics the foraging behavior of a honey bee swarm. An enhanced version of the artificial bee colony heuristic is also proposed to improve the solution quality of the original version. The performance of the enhanced heuristic is evaluated on two sets of standard benchmark instances, and compared with the original artificial bee colony heuristic. The computational results show that the enhanced heuristic outperforms the original one, and can produce good solutions when compared with the existing heuristics. These results seem to indicate that the enhanced heuristic is an alternative to solve the capacitated vehicle routing problem. © 2011 Elsevier B.V. All rights reserved.postprin

Diagnostic Value of Methylated Human Telomerase Reverse Transcriptase in Human Cancers: A Meta-Analysis

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Data-Driven Optimization of Public Transit Schedule

Bus transit systems are the backbone of public transportation in the United States. An important indicator of the quality of service in such infrastructures is on-time performance at stops, with published transit schedules playing an integral role governing the level of success of the service. However there are relatively few optimization architectures leveraging stochastic search that focus on optimizing bus timetables with the objective of maximizing probability of bus arrivals at timepoints with delays within desired on-time ranges. In addition to this, there is a lack of substantial research considering monthly and seasonal variations of delay patterns integrated with such optimization strategies. To address these,this paper makes the following contributions to the corpus of studies on transit on-time performance optimization: (a) an unsupervised clustering mechanism is presented which groups months with similar seasonal delay patterns, (b) the problem is formulated as a single-objective optimization task and a greedy algorithm, a genetic algorithm (GA) as well as a particle swarm optimization (PSO) algorithm are employed to solve it, (c) a detailed discussion on empirical results comparing the algorithms are provided and sensitivity analysis on hyper-parameters of the heuristics are presented along with execution times, which will help practitioners looking at similar problems. The analyses conducted are insightful in the local context of improving public transit scheduling in the Nashville metro region as well as informative from a global perspective as an elaborate case study which builds upon the growing corpus of empirical studies using nature-inspired approaches to transit schedule optimization.Comment: 20 pages, 6 figures, 2 table

Viral integration drives multifocal HCC during the occult HBV infection

© 2019 The Author(s). Background & Aims: Although the prognosis of patients with occult hepatitis B virus (HBV) infection (OBI) is usually benign, a small portion may undergo cirrhosis and subsequently hepatocellular carcinoma (HCC). We studied the mechanism of life-long Integration of virus DNA into OBI host's genome, of which may induce hepatocyte transformation. Methods: We applied HBV capture sequencing on single cells from an OBI patient who, developed multiple HCC tumors and underwent liver resection in May 2013 at Tongji Hospital in China. Despite with the undetectable virus DNA in serum, we determined the pattern of viral integration in tumor cells and adjacent non-tumor cells and obtained the details of the viral arrangement in host genome, and furthermore the HBV integrated region in cancer genome. Results: HBV captured sequencing of tissues and individual cells revealed that samples from multiple tumors shared two viral integration sites that could affect three host genes, including CSMD2 on chr1 and MED30/EXT1 on chr8. Whole genome sequencing further indicated one hybrid chromosome formed by HBV integrations between chr1 and chr8 that was shared by multiple tumors. Additional 50 poorly differentiated liver tumors and the paired adjacent non-tumors were evaluated and functional studies suggested up-regulated EXT1 expression promoted HCC growth. We further observed that the most somatic mutations within the tumor cell genome were common among the multiple tumors, suggesting that HBV associated, multifocal HCC is monoclonal in origin. Conclusion: Through analyzing the HBV integration sites in multifocal HCC, our data suggested that the tumor cells were monoclonal in origin and formed in the absence of active viral replication, whereas the affected host genes may subsequently contribute to carcinogenesis

The Complexity of Vascular and Non-Vascular Complications of Diabetes: The Hong Kong Diabetes Registry

Diabetes is a complex disease characterized by chronic hyperglycemia and multiple phenotypes. In 1995, we used a doctor-nurse-clerk team and structured protocol to establish the Hong Kong Diabetes Registry in a quality improvement program. By 2009, we had accrued 2616 clinical events in 9588 Chinese type 2 diabetic patients with a follow-up duration of 6 years. The detailed phenotypes at enrollment and follow-up medications have allowed us to develop a series of risk equations to predict multiple endpoints with high sensitivity and specificity. In this prospective database, we were able to validate findings from clinical trials in real practice, confirm close links between cardiovascular and renal disease, and demonstrate the emerging importance of cancer as a leading cause of death. In addition to serving as a tool for risk stratification and quality assurance, ongoing data analysis of the registry also reveals secular changes in disease patterns and identifies unmet needs

Entomopathogenic Fungi on Hemiberlesia pitysophila

Hemiberlesia pitysophila Takagi is an extremely harmful exotic insect in forest to Pinus species, including Pinus massoniana. Using both morphological taxonomy and molecular phylogenetics, we identified 15 strains of entomogenous fungi, which belong to 9 genera with high diversities. Surprisingly, we found that five strains that were classified as species of Pestalotiopsis, which has been considered plant pathogens and endophytes, were the dominant entomopathogenic fungus of H. pitysophila. Molecular phylogenetic tree established by analyzing sequences of ribosomal DNA internal transcribed spacer showed that entomopathogenic Pestalotiopsis spp. were similar to plant Pestalotiopsis, but not to other pathogens and endophytes of its host plant P. massoniana. We were the first to isolate entomopathogenic Pestalotiopsis spp. from H. pitysophila. Our findings suggest a potential and promising method of H. pitysophila bio-control

Assessment of the EarlyCDT-Lung test as an early biomarker of lung cancer in ever-smokers - A retrospective nested case-control study in two prospective cohorts

The EarlyCDT-Lung test is a blood-based autoantibody assay intended to identify high-risk individuals for low-dose computed tomography lung cancer screening. However, there is a paucity of evidence on the performance of the EarlyCDT-Lung test in ever-smokers. We conducted a nested case-control study within two prospective cohorts to evaluate the risk-discriminatory performance of the EarlyCDT-Lung test using pre-diagnostic blood samples from 154 future lung cancer cases and 154 matched controls. Cases were selected from those who had ever smoked and had a pre-diagnostic blood samples less than 3 years prior to diagnosis. Conditional logistic regression was used to estimate the association between EarlyCDT-Lung test results and lung cancer risk. Sensitivity and specificity of the EarlyCDT-Lung test were calculated in all subjects and subgroups based on age, smoking history, lung cancer stage, sample collection time before diagnosis and year of sample collection. The overall lung cancer odds ratios were 0.89 (95% CI, 0.34-2.30) for a moderate risk EarlyCDT-Lung test result and 1.09 (95% CI, 0.48-2.47) for a high-risk test result compared to no significant test result. The overall sensitivity was 8.4% (95% CI, 4.6-14) and overall specificity was 92% (95% CI, 87-96) when considering a high-risk result as positive. Stratified analysis indicated higher sensitivity (17%, 95% CI, 7.2-32.1) in subjects with blood drawn up to 1 year prior to diagnosis. In conclusion, our study does not support a role of the EarlyCDT-Lung test in identifying the high-risk subjects in ever-smokers for lung cancer screening in the EPIC and NSHDS cohorts

Functional Diversity and Structural Disorder in the Human Ubiquitination Pathway

The ubiquitin-proteasome system plays a central role in cellular regulation and protein quality control (PQC). The system is built as a pyramid of increasing complexity, with two E1 (ubiquitin activating), few dozen E2 (ubiquitin conjugating) and several hundred E3 (ubiquitin ligase) enzymes. By collecting and analyzing E3 sequences from the KEGG BRITE database and literature, we assembled a coherent dataset of 563 human E3s and analyzed their various physical features. We found an increase in structural disorder of the system with multiple disorder predictors (IUPred - E1: 5.97%, E2: 17.74%, E3: 20.03%). E3s that can bind E2 and substrate simultaneously (single subunit E3, ssE3) have significantly higher disorder (22.98%) than E3s in which E2 binding (multi RING-finger, mRF, 0.62%), scaffolding (6.01%) and substrate binding (adaptor/substrate recognition subunits, 17.33%) functions are separated. In ssE3s, the disorder was localized in the substrate/adaptor binding domains, whereas the E2-binding RING/HECT-domains were structured. To demonstrate the involvement of disorder in E3 function, we applied normal modes and molecular dynamics analyses to show how a disordered and highly flexible linker in human CBL (an E3 that acts as a regulator of several tyrosine kinase-mediated signalling pathways) facilitates long-range conformational changes bringing substrate and E2-binding domains towards each other and thus assisting in ubiquitin transfer. E3s with multiple interaction partners (as evidenced by data in STRING) also possess elevated levels of disorder (hubs, 22.90% vs. non-hubs, 18.36%). Furthermore, a search in PDB uncovered 21 distinct human E3 interactions, in 7 of which the disordered region of E3s undergoes induced folding (or mutual induced folding) in the presence of the partner. In conclusion, our data highlights the primary role of structural disorder in the functions of E3 ligases that manifests itself in the substrate/adaptor binding functions as well as the mechanism of ubiquitin transfer by long-range conformational transitions. © 2013 Bhowmick et al

Hyperlipidemia and Atherosclerotic Lesion Development in Ldlr-Deficient Mice on a Long-Term High-Fat Diet

BACKGROUND: Mice deficient in the LDL receptor (Ldlr(-/-) mice) have been widely used as a model to mimic human atherosclerosis. However, the time-course of atherosclerotic lesion development and distribution of lesions at specific time-points are yet to be established. The current study sought to determine the progression and distribution of lesions in Ldlr(-/-) mice. METHODOLOGY/PRINCIPAL FINDINGS: Ldlr-deficient mice fed regular chow or a high-fat (HF) diet for 0.5 to 12 months were analyzed for atherosclerotic lesions with en face and cross-sectional imaging. Mice displayed significant individual differences in lesion development when fed a chow diet, whereas those on a HF diet developed lesions in a time-dependent and site-selective manner. Specifically, mice subjected to the HF diet showed slight atherosclerotic lesions distributed exclusively in the aortic roots or innominate artery before 3 months. Lesions extended to the thoracic aorta at 6 months and abdominal aorta at 9 months. Cross-sectional analysis revealed the presence of advanced lesions in the aortic sinus after 3 months in the group on the HF diet and in the innominate artery at 6 to 9 months. The HF diet additionally resulted in increased total cholesterol, LDL, glucose, and HBA1c levels, along with the complication of obesity. CONCLUSIONS/SIGNIFICANCE: Ldlr-deficient mice on the HF diet tend to develop site-selective and size-specific atherosclerotic lesions over time. The current study should provide information on diet induction or drug intervention times and facilitate estimation of the appropriate locations of atherosclerotic lesions in Ldlr(-/-) mice