Multiple Biolgical Sequence Alignment: Scoring Functions, Algorithms, and Evaluations

Aligning multiple biological sequences such as protein sequences or DNA/RNA sequences is a fundamental task in bioinformatics and sequence analysis. These alignments may contain invaluable information that scientists need to predict the sequences\u27 structures, determine the evolutionary relationships between them, or discover drug-like compounds that can bind to the sequences. Unfortunately, multiple sequence alignment (MSA) is NP-Complete. In addition, the lack of a reliable scoring method makes it very hard to align the sequences reliably and to evaluate the alignment outcomes. In this dissertation, we have designed a new scoring method for use in multiple sequence alignment. Our scoring method encapsulates stereo-chemical properties of sequence residues and their substitution probabilities into a tree-structure scoring scheme. This new technique provides a reliable scoring scheme with low computational complexity. In addition to the new scoring scheme, we have designed an overlapping sequence clustering algorithm to use in our new three multiple sequence alignment algorithms. One of our alignment algorithms uses a dynamic weighted guidance tree to perform multiple sequence alignment in progressive fashion. The use of dynamic weighted tree allows errors in the early alignment stages to be corrected in the subsequence stages. Other two algorithms utilize sequence knowledge-bases and sequence consistency to produce biological meaningful sequence alignments. To improve the speed of the multiple sequence alignment, we have developed a parallel algorithm that can be deployed on reconfigurable computer models. Analytically, our parallel algorithm is the fastest progressive multiple sequence alignment algorithm

Parallel progressive multiple sequence alignment on reconfigurable meshes

<p>Abstract</p> <p>Background</p> <p>One of the most fundamental and challenging tasks in bio-informatics is to identify related sequences and their hidden biological significance. The most popular and proven best practice method to accomplish this task is aligning multiple sequences together. However, multiple sequence alignment is a computing extensive task. In addition, the advancement in DNA/RNA and Protein sequencing techniques has created a vast amount of sequences to be analyzed that exceeding the capability of traditional computing models. Therefore, an effective parallel multiple sequence alignment model capable of resolving these issues is in a great demand.</p> <p>Results</p> <p>We design <it>O</it>(1) run-time solutions for both local and global dynamic programming pair-wise alignment algorithms on reconfigurable mesh computing model. To align <it>m </it>sequences with max length <it>n</it>, we combining the parallel pair-wise dynamic programming solutions with newly designed parallel components. We successfully reduce the progressive multiple sequence alignment algorithm's run-time complexity from <it>O</it>(<it>m </it>× <it>n</it>⁴) to <it>O</it>(<it>m</it>) using <it>O</it>(<it>m </it>× <it>n</it>³) processing units for scoring schemes that use three distinct values for match/mismatch/gap-extension. The general solution to multiple sequence alignment algorithm takes <it>O</it>(<it>m </it>× <it>n</it>⁴) processing units and completes in <it>O</it>(<it>m</it>) time.</p> <p>Conclusions</p> <p>To our knowledge, this is the first time the progressive multiple sequence alignment algorithm is completely parallelized with <it>O</it>(<it>m</it>) run-time. We also provide a new parallel algorithm for the Longest Common Subsequence (LCS) with <it>O</it>(1) run-time using <it>O</it>(<it>n</it>³) processing units. This is a big improvement over the current best constant-time algorithm that uses <it>O</it>(<it>n</it>⁴) processing units.</p

A Linux Implementation of Temporal Access Controls

Abstract — Control of access to information based upon temporal attributes can add another dimension to access control. To demonstrate the feasibility of operating system-level support for temporal access controls, the Time Interval File Protection System (TIFPS), a prototype of the Time In-terval Access Control (TIAC) model, has been implemented by modifying Linux extended attributes to include temporal metadata associated both with files and users. The Linux Security Module was used to provide hooks for temporal ac-cess control logic. In addition, a set of utilities was modified to be TIFPS-aware. These tools permit users to view and manage the temporal attributes associated with their files and directories. Functional, performance, and concurrency testing were conducted. The ability of TIFPS to grant or revoke access in the future, as well to limit access to specific time intervals enhances traditional information control and sharing. I

Electromagnetic form factor of pion from N_f=2+1 dynamical flavor QCD

We present a calculation of the electromagnetic form factor of the pion in $N_f=2+1$ flavor lattice QCD. Calculations are made on the PACS-CS gauge field configurations generated using Iwasaki gauge action and Wilson-clover quark action on a $32^3\times64$ lattice volume with the lattice spacing estimated as $a=0.0907(13)$ fm at the physical point. Measurements of the form factor are made using the technique of partially twisted boundary condition to reach small momentum transfer as well as periodic boundary condition with integer momenta. Additional improvements including random wall source techniques and a judicious choice of momenta carried by the incoming and outgoing quarks are employed for error reduction. Analyzing the form factor data for the pion mass at $M_\pi \approx 411$ MeV and 296 MeV, we find that the NNLO SU(2) chiral perturbation theory fit yields $=0.441 \pm 0.046 {\rm fm}^2$ for the pion charge radius at the physical pion mass. Albeit the error is quite large, this is consistent with the experimental value of $0.452\pm 0.011 {\rm fm}^2$. Below $M_\pi\approx 300$ MeV, we find that statistical fluctuations in the pion two- and three-point functions become too large to extract statistically meaningful averages on a $32^3$ spatial volume. We carry out a sample calculation on a $64^4$ lattice with the quark masses close to the physical point, which suggests that form factor calculations at the physical point become feasible by enlarging lattice sizes to $M_\pi L\approx 4$.Comment: 28 pages, 14 figure

Distorted wave impulse approximation analysis for spin observables in nucleon quasi-elastic scattering and enhancement of the spin-longitudinal response

We present a formalism of distorted wave impulse approximation (DWIA) for analyzing spin observables in nucleon inelastic and charge exchange reactions leading to the continuum. It utilizes response functions calculated by the continuum random phase approximation (RPA), which include the effective mass, the spreading widths and the \Delta degrees of freedom. The Fermi motion is treated by the optimal factorization, and the non-locality of the nucleon-nucleon t-matrix by an averaged reaction plane approximation. By using the formalism we calculated the spin-longitudinal and the spin-transverse cross sections, ID_q and ID_p, of 12C, 40Ca (\vec{p},\vec{n}) at 494 and 346 MeV. The calculation reasonably reproduced the observed ID_q, which is consistent with the predicted enhancement of the spin-longitudinal response function R_L. However, the observed ID_p is much larger than the calculated one, which was consistent with neither the predicted quenching nor the spin-transverse response function R_T obtained by the (e,e') scattering. The Landau-Migdal parameter g'_N\Delta for the N\Delta transition interaction and the effective mass at the nuclear center m^*(r=0) are treated as adjustable parameters. The present analysis indicates that the smaller g'_{N\Delta}(\approx 0.3) and m^*(0) \approx 0.7 m are preferable. We also investigate the validity of the plane wave impulse approximation (PWIA) with the effective nucleon number approximation for the absorption, by means of which R_L and R_T have conventionally been extracted.Comment: RevTex 3, 29 pages, 2 tables, 8 figure

Dysfunctional BMPR2 signaling drives an abnormal endothelial requirement for glutamine in pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is increasingly recognized as a systemic disease driven by alteration in the normal functioning of multiple metabolic pathways affecting all of the major carbon substrates, including amino acids. We found that human pulmonary hypertension patients (WHO Group I, PAH) exhibit systemic and pulmonary-specific alterations in glutamine metabolism, with the diseased pulmonary vasculature taking up significantly more glutamine than that of controls. Using cell culture models and transgenic mice expressing PAH-causing BMPR2 mutations, we found that the pulmonary endothelium in PAH shunts significantly more glutamine carbon into the tricarboxylic acid (TCA) cycle than wild-type endothelium. Increased glutamine metabolism through the TCA cycle is required by the endothelium in PAH to survive, to sustain normal energetics, and to manifest the hyperproliferative phenotype characteristic of disease. The strict requirement for glutamine is driven by loss of sirtuin-3 (SIRT3) activity through covalent modification by reactive products of lipid peroxidation. Using 2-hydroxybenzylamine, a scavenger of reactive lipid peroxidation products, we were able to preserve SIRT3 function, to normalize glutamine metabolism, and to prevent the development of PAH in BMPR2 mutant mice. In PAH, targeting glutamine metabolism and the mechanisms that underlie glutamine-driven metabolic reprogramming represent a viable novel avenue for the development of potentially disease-modifying therapeutics that could be rapidly translated to human studies

Cerebral oximetry during cardiac arrest : a multicenter study of neurologic outcomes and survival

OBJECTIVES Cardiac arrest is associated with morbidity and mortality because of cerebral ischemia. Therefore, we tested the hypothesis that higher regional cerebral oxygenation during resuscitation is associated with improved return of spontaneous circulation, survival, and neurologic outcomes at hospital discharge. We further examined the validity of regional cerebral oxygenation as a test to predict these outcomes. DESIGN Multicenter prospective study of in-hospital cardiac arrest. SETTING Five medical centers in the United States and the United Kingdom. PATIENTS Inclusion criteria are as follows: in-hospital cardiac arrest, age 18 years old or older, and prolonged cardiopulmonary resuscitation greater than or equal to 5 minutes. Patients were recruited consecutively during working hours between August 2011 and September 2014. Survival with a favorable neurologic outcome was defined as a cerebral performance category 1-2. INTERVENTIONS Cerebral oximetry monitoring. MEASUREMENTS AND MAIN RESULTS Among 504 in-hospital cardiac arrest events, 183 (36%) met inclusion criteria. Overall, 62 of 183 (33.9%) achieved return of spontaneous circulation, whereas 13 of 183 (7.1%) achieved cerebral performance category 1-2 at discharge. Higher mean ± SD regional cerebral oxygenation was associated with return of spontaneous circulation versus no return of spontaneous circulation (51.8% ± 11.2% vs 40.9% ± 12.3%) and cerebral performance category 1-2 versus cerebral performance category 3-5 (56.1% ± 10.0% vs 43.8% ± 12.8%) (both p < 0.001). Mean regional cerebral oxygenation during the last 5 minutes of cardiopulmonary resuscitation best predicted the return of spontaneous circulation (area under the curve, 0.76; 95% CI, 0.69-0.83); regional cerebral oxygenation greater than or equal to 25% provided 100% sensitivity (95% CI, 94-100) and 100% negative predictive value (95% CI, 79-100); regional cerebral oxygenation greater than or equal to 65% provided 99% specificity (95% CI, 95-100) and 93% positive predictive value (95% CI, 66-100) for return of spontaneous circulation. Time with regional cerebral oxygenation greater than 50% during cardiopulmonary resuscitation best predicted cerebral performance category 1-2 (area under the curve, 0.79; 95% CI, 0.70-0.88). Specifically, greater than or equal to 60% cardiopulmonary resuscitation time with regional cerebral oxygenation greater than 50% provided 77% sensitivity (95% CI,:46-95), 72% specificity (95% CI, 65-79), and 98% negative predictive value (95% CI, 93-100) for cerebral performance category 1-2. CONCLUSIONS Cerebral oximetry allows real-time, noninvasive cerebral oxygenation monitoring during cardiopulmonary resuscitation. Higher cerebral oxygenation during cardiopulmonary resuscitation is associated with return of spontaneous circulation and neurologically favorable survival to hospital discharge. Achieving higher regional cerebral oxygenation during resuscitation may optimize the chances of cardiac arrest favorable outcomes

Novel biomaterials: plasma-enabled nanostructures and functions

Material processing techniques utilizing low-temperature plasmas as the main process tool feature many unique capabilities for the fabrication of various nanostructured materials. As compared with the neutral-gas based techniques and methods, the plasma-based approaches offer higher levels of energy and flux controllability, often leading to higher quality of the fabricated nanomaterials and sometimes to the synthesis of the hierarchical materials with interesting properties. Among others, nanoscale biomaterials attract significant attention due to their special properties towards the biological materials (proteins, enzymes), living cells and tissues. This review briefly examines various approaches based on the use of low-temperature plasma environments to fabricate nanoscale biomaterials exhibiting high biological activity, biological inertness for drug delivery system, and other features of the biomaterials make them highly attractive. In particular, we briefly discuss the plasma-assisted fabrication of gold and silicon nanoparticles for bio-applications; carbon nanoparticles for bioimaging and cancer therapy; carbon nanotube-based platforms for enzyme production and bacteria growth control, and other applications of low-temperature plasmas in the production of biologically-active materials

Lenalidomide Promotes the Development of TP53-Mutated Therapy-Related Myeloid Neoplasms

There is a growing body of evidence that therapy-related myeloid neoplasms (t-MNs) with driver gene mutations arise in the background of clonal hematopoiesis (CH) under the positive selective pressure of chemo- and radiation therapies. Uncovering the exposure relationships that provide selective advantage to specific CH mutations is critical to understanding the pathogenesis and etiology of t-MNs. In a systematic analysis of 416 patients with t-MN and detailed prior exposure history, we found that TP53 mutations were significantly associated with prior treatment with thalidomide analogs, specifically lenalidomide. We demonstrated experimentally that lenalidomide treatment provides a selective advantage to Trp53-mutant hematopoietic stem and progenitor cells (HSPCs) in vitro and in vivo, the effect of which was specific to Trp53-mutant HSPCs and was not observed in HSPCs with other CH mutations. Because of the differences in CK1α degradation, pomalidomide treatment did not provide an equivalent level of selective advantage to Trp53-mutant HSPCs, providing a biological rationale for its use in patients at high risk for t-MN. These findings highlight the role of lenalidomide treatment in promoting TP53-mutated t-MNs and offer a potential alternative strategy to mitigate the risk of t-MN development

Introductory programming: a systematic literature review

As computing becomes a mainstream discipline embedded in the school curriculum and acts as an enabler for an increasing range of academic disciplines in higher education, the literature on introductory programming is growing. Although there have been several reviews that focus on specific aspects of introductory programming, there has been no broad overview of the literature exploring recent trends across the breadth of introductory programming. This paper is the report of an ITiCSE working group that conducted a systematic review in order to gain an overview of the introductory programming literature. Partitioning the literature into papers addressing the student, teaching, the curriculum, and assessment, we explore trends, highlight advances in knowledge over the past 15 years, and indicate possible directions for future research