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

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

Hypoxia-inducible factor-1α gene polymorphisms and cancer risk: a meta-analysis

<p>Abstract</p> <p>Background</p> <p>The results from the published studies on the association between <it>hypoxia-inducible factor -1α </it>(HIF-1α) polymorphisms and cancer risk are conflicting. In this meta-analysis, we aimed to investigate the association between <it>HIF-1α </it>1772 C/T and 1790 G/A polymorphisms and cancer.</p> <p>Methods</p> <p>The meta-analysis for 1772 C/T polymorphism included 4131 cancer cases and 5387 controls, and for 1790 G/A polymorphism included 2058 cancer cases and 3026 controls. Allelic and genotypic comparisons between cases and controls were evaluated. Subgroup analyses by cancer types, ethnicity, and gender were also performed. We included prostate cancer in male subgroup, and female specific cancers in female subgroup.</p> <p>Results</p> <p>For the 1772 C/T polymorphism, the analysis showed that the T allele and genotype TT were significantly associated with higher cancer risk: odds ratio (OR) = 1.29 [95% confidence interval (CI, 1.01, 1.65)], P = 0.04, P_{heterogeneity}< 0.00001, and OR = 2.18 [95% CI (1.32, 3.62)], P = 0.003, P_{heterogeneity}= 0.02, respectively. The effect of the genotype TT on cancer especially exists in Caucasians and female subjects: OR = 2.40 [95% CI (1.26, 4.59)], P = 0.008, P_{heterogeneity}= 0.02, and OR = 3.60 [95% CI (1.17, 11.11)], P = 0.03, P_{heterogeneity}= 0.02, respectively. For the 1790 G/A polymorphism, the pooled ORs for allelic frequency comparison and dominant model comparison suggested a significant association of 1790 G/A polymorphism with a decreased breast cancer risk: OR = 0.28 [95% CI (0.08, 0.90)], P = 0.03, P_{heterogeneity}= 0.45, and OR = 0.29 [95% CI (0.09, 0.97)], P = 0.04, P_{heterogeneity}= 0.41, respectively. The frequency of the <it>HIF-1α </it>1790 A allele was very low and only two studies were included in the breast cancer subgroup.</p> <p>Conclusions</p> <p>Our meta-analysis suggests that the <it>HIF-1α </it>1772 C/T polymorphism is significantly associated with higher cancer risk, and 1790 G/A polymorphism is significantly associated with decreased breast cancer risk. The effect of the 1772 C/T polymorphism on cancer especially exists in Caucasians and female subjects. Only female specific cancers were included in female subgroup, which indicates that the 1772 C/T polymorphism is significantly associated with an increased risk for female specific cancers. The association between the 1790 G/A polymorphism and lower breast cancer risk could be due to chance.</p

Quantitative Proteomics Reveals Myosin and Actin as Promising Saliva Biomarkers for Distinguishing Pre-Malignant and Malignant Oral Lesions

Oral cancer survival rates increase significantly when it is detected and treated early. Unfortunately, clinicians now lack tests which easily and reliably distinguish pre-malignant oral lesions from those already transitioned to malignancy. A test for proteins, ones found in non-invasively-collected whole saliva and whose abundances distinguish these lesion types, would meet this critical need.To discover such proteins, in a first-of-its-kind study we used advanced mass spectrometry-based quantitative proteomics analysis of the pooled soluble fraction of whole saliva from four subjects with pre-malignant lesions and four with malignant lesions. We prioritized candidate biomarkers via bioinformatics and validated selected proteins by western blotting. Bioinformatic analysis of differentially abundant proteins and initial western blotting revealed increased abundance of myosin and actin in patients with malignant lesions. We validated those results by additional western blotting of individual whole saliva samples from twelve other subjects with pre-malignant oral lesions and twelve with malignant oral lesions. Sensitivity/specificity values for distinguishing between different lesion types were 100%/75% (p = 0.002) for actin, and 67%/83% (p<0.00001) for myosin in soluble saliva. Exfoliated epithelial cells from subjects' saliva also showed increased myosin and actin abundance in those with malignant lesions, linking our observations in soluble saliva to abundance differences between pre-malignant and malignant cells.Salivary actin and myosin abundances distinguish oral lesion types with sensitivity and specificity rivaling other non-invasive oral cancer tests. Our findings provide a promising starting point for the development of non-invasive and inexpensive salivary tests to reliably detect oral cancer early

Why the South Pacific Convergence Zone is diagonal

During austral summer, the majority of precipitation over the Pacific Ocean is concentrated in the South Pacific Convergence Zone (SPCZ). The surface boundary conditions required to support the diagonally (northwest-southeast) oriented SPCZ are determined through a series of experiments with an atmospheric general circulation model. Continental configuration and orography do not have a significant influence on SPCZ orientation and strength. The key necessary boundary condition is the zonally asymmetric component of the sea surface temperature (SST) distribution. This leads to a strong subtropical anticyclone over the southeast Pacific that, on its western flank, transports warm moist air from the equator into the SPCZ region. This moisture then intensifies (diagonal) bands of convection that are initiated by regions of ascent and reduced static stability ahead of the cyclonic vorticity in Rossby waves that are refracted toward the westerly duct over the equatorial Pacific. The climatological SPCZ is comprised of the superposition of these diagonal bands of convection. When the zonally asymmetric SST component is reduced or removed, the subtropical anticyclone and its associated moisture source is weakened. Despite the presence of Rossby waves, significant moist convection is no longer triggered; the SPCZ disappears. The diagonal SPCZ is robust to large changes (up to +/-6 degC) in absolute SST (i.e. where the SST asymmetry is preserved). Extreme cooling (change less than -6 degC) results in a weaker and more zonal SPCZ, due to decreasing atmospheric temperature, moisture content and convective available potential energy