On Prediction Using Variable Order Markov Models

This paper is concerned with algorithms for prediction of discrete sequences over a finite alphabet, using variable order Markov models. The class of such algorithms is large and in principle includes any lossless compression algorithm. We focus on six prominent prediction algorithms, including Context Tree Weighting (CTW), Prediction by Partial Match (PPM) and Probabilistic Suffix Trees (PSTs). We discuss the properties of these algorithms and compare their performance using real life sequences from three domains: proteins, English text and music pieces. The comparison is made with respect to prediction quality as measured by the average log-loss. We also compare classification algorithms based on these predictors with respect to a number of large protein classification tasks. Our results indicate that a "decomposed" CTW (a variant of the CTW algorithm) and PPM outperform all other algorithms in sequence prediction tasks. Somewhat surprisingly, a different algorithm, which is a modification of the Lempel-Ziv compression algorithm, significantly outperforms all algorithms on the protein classification problems

A GAIN in understanding autoproteolytic G protein‐coupled receptors and polycystic kidney disease proteins

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102153/1/embj201251.pd

Perspective of mesenchymal transformation in glioblastoma.

Despite aggressive multimodal treatment, glioblastoma (GBM), a grade IV primary brain tumor, still portends a poor prognosis with a median overall survival of 12-16 months. The complexity of GBM treatment mainly lies in the inter- and intra-tumoral heterogeneity, which largely contributes to the treatment-refractory and recurrent nature of GBM. By paving the road towards the development of personalized medicine for GBM patients, the cancer genome atlas classification scheme of GBM into distinct transcriptional subtypes has been considered an invaluable approach to overcoming this heterogeneity. Among the identified transcriptional subtypes, the mesenchymal subtype has been found associated with more aggressive, invasive, angiogenic, hypoxic, necrotic, inflammatory, and multitherapy-resistant features than other transcriptional subtypes. Accordingly, mesenchymal GBM patients were found to exhibit worse prognosis than other subtypes when patients with high transcriptional heterogeneity were excluded. Furthermore, identification of the master mesenchymal regulators and their downstream signaling pathways has not only increased our understanding of the complex regulatory transcriptional networks of mesenchymal GBM, but also has generated a list of potent inhibitors for clinical trials. Importantly, the mesenchymal transition of GBM has been found to be tightly associated with treatment-induced phenotypic changes in recurrence. Together, these findings indicate that elucidating the governing and plastic transcriptomic natures of mesenchymal GBM is critical in order to develop novel and selective therapeutic strategies that can improve both patient care and clinical outcomes. Thus, the focus of our review will be on the recent advances in the understanding of the transcriptome of mesenchymal GBM and discuss microenvironmental, metabolic, and treatment-related factors as critical components through which the mesenchymal signature may be acquired. We also take into consideration the transcriptomic plasticity of GBM to discuss the future perspectives in employing selective therapeutic strategies against mesenchymal GBM

Initial Safety and Tumor Control Results From a "First-in-Human" Multicenter Prospective Trial Evaluating a Novel Alpha-Emitting Radionuclide for the Treatment of Locally Advanced Recurrent Squamous Cell Carcinomas of the Skin and Head and Neck.

Purpose Our purpose was to report the feasibility and safety of diffusing alpha-emitter radiation therapy (DaRT), which entails the interstitial implantation of a novel alpha-emitting brachytherapy source, for the treatment of locally advanced and recurrent squamous cancers of the skin and head and neck. Methods and Materials This prospective first-in-human, multicenter clinical study evaluated 31 lesions in 28 patients. The primary objective was to determine the feasibility and safety of this approach, and the secondary objectives were to evaluate the initial tumor response and local progression-free survival. Eligibility criteria included all patients with biopsy-proven squamous cancers of the skin and head and neck with either primary tumors or recurrent/previously treated disease by either surgery or prior external beam radiation therapy; 13 of 31 lesions (42%) had received prior radiation therapy. Toxicity was evaluated according to the Common Terminology Criteria for Adverse Events version 4.03. Tumor response was assessed at 30 to 45 days at a follow-up visit using the Response Evaluation Criteria in Solid Tumors, version 1.1. Median follow-up time was 6.7 months. Results Acute toxicity included mostly local pain and erythema at the implantation site followed by swelling and mild skin ulceration. For pain and grade 2 skin ulcerations, 90% of patients had resolution within 3 to 5 weeks. Complete response to the Ra-224 DaRT treatment was observed in 22 lesions (22/28; 78.6%); 6 lesions (6/28, 21.4%) manifested a partial response (>30% tumor reduction). Among the 22 lesions with a complete response, 5 (22%) developed a subsequent local relapse at the site of DaRT implantation at a median time of 4.9 months (range, 2.43-5.52 months). The 1-year local progression-free survival probability at the implanted site was 44% overall (confidence interval [CI], 20.3%-64.3%) and 60% (95% CI, 28.61%-81.35%) for complete responders. Overall survival rates at 12 months post-DaRT implantation were 75% (95% CI, 46.14%-89.99%) among all patients and 93% (95% CI, 59.08%-98.96%) among complete responders. Conclusions Alpha-emitter brachytherapy using DaRT achieved significant tumor responses without grade 3 or higher toxicities observed. Longer follow-up observations and larger studies are underway to validate these findings

Discrete profile comparison using information bottleneck

Sequence homologs are an important source of information about proteins. Amino acid profiles, representing the position-specific mutation probabilities found in profiles, are a richer encoding of biological sequences than the individual sequences themselves. However, profile comparisons are an order of magnitude slower than sequence comparisons, making profiles impractical for large datasets. Also, because they are such a rich representation, profiles are difficult to visualize. To address these problems, we describe a method to map probabilistic profiles to a discrete alphabet while preserving most of the information in the profiles. We find an informationally optimal discretization using the Information Bottleneck approach (IB). We observe that an 80-character IB alphabet captures nearly 90% of the amino acid occurrence information found in profiles, compared to the consensus sequence's 78%. Distant homolog search with IB sequences is 88% as sensitive as with profiles compared to 61% with consensus sequences (AUC scores 0.73, 0.83, and 0.51, respectively), but like simple sequence comparison, is 30 times faster. Discrete IB encoding can therefore expand the range of sequence problems to which profile information can be applied to include batch queries over large databases like SwissProt, which were previously computationally infeasible

Comparative studies on the structure of an upland African stream ecosystem

Upland stream systems have been extensively investigated in Europe, North America and Australasia and many of the central ideas concerning their function are based on these systems. One central paradigm, the river continuum concept is ultimately derived from those North American streams whose catchments remain forested with native vegetation. Streams of the tropics may or may not fit the model. They have been little studied. The Amani Nature Reserve in the East Usambara Mountains of north-eastern Tanzania offers an opportunity to bring these naturally forested systems to the attention of the ecological community. This article describes a comparison made between two lengths of the River Dodwe in this area. The work was carried out by a group of postgraduate students from eighteen European and African countries with advice from five staff members, as part of a course organised by the Tropical Biology Association. Rigorous efforts were made to standardise techniques, in a situation where equipment and laboratory facilities were very basic, through a management structure and deliberate allocation of work to specialists in each area.The article offers a summary of invertebrate communities found in the stream and its biomass. Crabs seem to be the key organism in both sections of the streams