Link Mining for Kernel-based Compound-Protein Interaction Predictions Using a Chemogenomics Approach

Virtual screening (VS) is widely used during computational drug discovery to reduce costs. Chemogenomics-based virtual screening (CGBVS) can be used to predict new compound-protein interactions (CPIs) from known CPI network data using several methods, including machine learning and data mining. Although CGBVS facilitates highly efficient and accurate CPI prediction, it has poor performance for prediction of new compounds for which CPIs are unknown. The pairwise kernel method (PKM) is a state-of-the-art CGBVS method and shows high accuracy for prediction of new compounds. In this study, on the basis of link mining, we improved the PKM by combining link indicator kernel (LIK) and chemical similarity and evaluated the accuracy of these methods. The proposed method obtained an average area under the precision-recall curve (AUPR) value of 0.562, which was higher than that achieved by the conventional Gaussian interaction profile (GIP) method (0.425), and the calculation time was only increased by a few percent

Statistical analysis of the features of diatonic music with jMusic

Much has been written about the rules of melody writing and this paper reports research that uses computer-based statistical analysis to test the efficacy of these rules. As a method to assist in the computer generation of melodies, we have devised computer software that analyses melodic features. This paper will outline the melodic features identified in melody-writing literature and the results of their fit with our statistical analysis of melodies from the western music repertoire. We will also present details of the computer-based analysis software and the jMusic software environment in which it was built. The software and jMusic environment are open source software projects that are freely available, and so opportunities to develop these tools to suit other music analysis tasks will be discussed.Hosted by the Scholarly Text and Imaging Service (SETIS), the University of Sydney Library, and the Research Institute for Humanities and Social Sciences (RIHSS), the University of Sydney

Applicative Bidirectional Programming with Lenses

A bidirectional transformation is a pair of mappings between source and view data objects, one in each direction. When the view is modified, the source is updated accordingly with respect to some laws. One way to reduce the development and maintenance effort of bidirectional transformations is to have specialized languages in which the resulting programs are bidirectional by construction---giving rise to the paradigm of bidirectional programming. In this paper, we develop a framework for applicative-style and higher-order bidirectional programming, in which we can write bidirectional transformations as unidirectional programs in standard functional languages, opening up access to the bundle of language features previously only available to conventional unidirectional languages. Our framework essentially bridges two very different approaches of bidirectional programming, namely the lens framework and Voigtlander’s semantic bidirectionalization, creating a new programming style that is able to bag benefits from both

Frontal plane pelvic motion during gait captures hip osteoarthritis related disability

Gait analysis has widely been accepted as an objective measure of function and clinical outcome. Ambulatory accelerometer-based gait analysis has emerged as a clinically more feasible alternative to optical motion capture systems but does not provide kinematic characterisation to identify disease dependent mechanisms causing walking disability. This study investigated the potential of a single inertial sensor to derive frontal plane motion of the pelvis (i.e. pelvic obliquity) and help identify hip osteoarthritis (OA) related gait alterations. Patients with advanced unilateral hip OA (n = 20) were compared to patients with advanced unilateral knee OA (n = 20) and to a healthy control group (n = 20). Kinematic characterisation of frontal plane pelvic motion during gait demonstrated decreased range of motion and increased asymmetry for hip OA patients specifically. </jats:p

Cost-effectiveness of laparoscopic versus open distal pancreatectomy for pancreatic cancer

BACKGROUND: A recent Cochrane review compared laparoscopic versus open distal pancreatectomy for people with for cancers of the body and tail of the pancreas and found that laparoscopic distal pancreatectomy may reduce the length of hospital stay. We compared the cost-effectiveness of laparoscopic distal pancreatectomy versus open distal pancreatectomy for pancreatic cancer. METHOD: Model based cost-utility analysis estimating mean costs and quality-adjusted life years (QALYs) per patient from the perspective of the UK National Health Service. A decision tree model was constructed using probabilities, outcomes and cost data from published sources. A time horizon of 5 years was used. One-way and probabilistic sensitivity analyses were undertaken. RESULTS: The probabilistic sensitivity analysis showed that the incremental net monetary benefit was positive (£3,708.58 (95% confidence intervals (CI) -£9,473.62 to £16,115.69) but the 95% CI includes zero, indicating that there is significant uncertainty about the cost-effectiveness of laparoscopic distal pancreatectomy versus open distal pancreatectomy. The probability laparoscopic distal pancreatectomy was cost-effective compared to open distal pancreatectomy for pancreatic cancer was between 70% and 80% at the willingness-to-pay thresholds generally used in England (£20,000 to £30,000 per QALY gained). Results were sensitive to the survival proportions and the operating time. CONCLUSIONS: There is considerable uncertainty about whether laparoscopic distal pancreatectomy is cost-effective compared to open distal pancreatectomy for pancreatic cancer in the NHS setting

The Role of the p14ARF Tumour Suppressor in Promoting Apoptosis

The incidence of melanoma has risen dramatically during the past three decades, yet there has been little improvement in effective treatments for this intractable and aggressive disease. Melanoma tumours are notoriously resistant to apoptosis, a cell suicide program that is activated by most cancer therapies. This thesis explores the role of the melanoma susceptibility gene product p14ARF in promoting cell cycle arrest and apoptosis, in order to resolve the impact of this tumour suppressor in melanomagenesis and melanoma susceptibility. The p14ARF tumour suppressor gene is mutated in almost half of all cancers, and germline mutations in p14ARF confer a greatly increased risk of developing melanoma. The primary function of p14ARF is to relay oncogenic signals to p53, a central regulator of cellular response to stress. There is conflicting evidence regarding the role of p14ARF in promoting apoptosis. Much of the current evidence is based on murine studies, which may not translate accurately to humans due to important differences in animal physiology and the primary sequence and functions of the mouse and human ARF proteins. Furthermore, results from previous studies are often compounded by supra-physiological expression of p14ARF, and are complicated by the fact that p14ARF shares its genomic sequence with the p16INK4a tumour suppressor gene. This study demonstrates that p14ARF expression in human cancer and primary cell lines promotes rapid p53-dependent cell cycle arrest, rather than apoptosis. As p14ARF expression did not induce apoptosis, we investigated if p14ARF could modulate the sensitivity of a cell to apoptosis induced by cytotoxic agents. Using a p14ARF-inducible U2OS osteosarcoma cell line model, we examined the impact of p14ARF expression on the apoptotic response of the cell to a panel of thirteen cytotoxic agents. p14ARF expression increased apoptosis caused by a sub-set of agents, including trichostatin A, sodium butyrate, DRB, Adriamycin and UVB radiation. p14ARF-mediated chemosensitivity was p53- and caspase-dependent, and involved the loss of mitochondrial potential. While loss of mitochondrial potential was dependent on p53, it was not blocked by caspase inhibition, demonstrating that caspases play a role downstream of mitochondrial depolarisation. Inhibition of individual components of the apoptotic program showed that p14ARF-mediated chemosensitivity was not strictly dependent on the pro-apoptotic Bax or Fas proteins. We also investigated whether p14ARF could sensitise melanoma to chemotherapeutics in vivo. We investigated the expression level of p14ARF, p16INK4a and MITFm and mutation status of B-RAF, N-RAS and PTEN in melanomas from 30 patients that had undergone isolated limb infusion - a palliative therapeutic strategy that results in much higher response rates than systemic treatment. Expression of p14ARF did not predict response to the drugs actinomycin D and melphalan . Instead, high expression of p16INK4a and presence of activating N-RAS mutation were independent predictors of response to high doses of these chemotherapeutic drugs. This work suggests that p14ARF analogues may be beneficial adjuncts in cancer therapy, but are unlikely to be effective as single agents. Additionally, p14ARF mimetics will only be effective in tumours with intact p53 signalling. Melanomas frequently carry functional p53, and may be susceptible to this mode of treatment providing the apoptotic pathway downstream of p53 is intact or can be restored

Electrical Characterization of 1.8 MeV Proton-Bombarded ZnO

We report on the electrical characterization of single-crystal ZnO and Au Schottky contacts formed thereon before and after bombarding them with 1.8 MeV protons. From capacitance–voltage measurements, we found that ZnO is remarkably resistant to high-energy proton bombardment and that each incident proton removes about two orders of magnitude less carriers than in GaN. Deep level transient spectroscopy indicates a similar effect: the two electron traps detected are introduced in extremely low rates. One possible interpretation of these results is that the primary radiation-induced defects in ZnO may be unstable at room temperature and anneal out without leaving harmful defects that are responsible for carrier compensation

The transrectus sheath preperitoneal mesh repair for inguinal hernia: technique, rationale, and results of the first 50 cases

Item does not contain fulltextINTRODUCTION: Laparoscopic and endoscopic hernia repair popularized the preperitoneal mesh position due to promising results concerning less chronic pain. However, considerable proportions of severe adverse events, learning curves, or added costs have to be taken into account. Therefore, open preperitoneal mesh techniques may have more advantages. The open approach to the preperitoneal space (PPS) according to transrectus sheath preperitoneal (TREPP) mesh repair is through the sheath of the rectus abdominus muscle. This technique provides an excellent view of the PPS and facilitates elective or acute hernia reduction and mesh positioning under direct vision. In concordance with the promising transinguinal preperitoneal inguinal hernia repair experiences in the literature, we investigated the feasibility of TREPP. METHODS: A rationale description of the surgical technique, available level of evidence for thoughts behind technical considerations. Furthermore, a descriptive report of the clinical outcomes of our pilot case series including 50 patients undergoing the TREPP mesh repair. RESULTS: A consecutive group of our first 50 patients were operated with the TREPP technique. No technical problems were experienced during the development of this technique. No conversions to Lichtenstein repair were necessary. No recurrences and no chronic pain after a mean follow-up of 2 years were notable findings. CONCLUSION: This description of the technique shows that the TREPP mesh repair might be a promising method because of the complete preperitoneal view, the short learning curve, and the stay-away-from-the-nerves principle. The rationale of the TREPP repair is discussed in detail.1 juni 201