Prediction of Ligand Activity at Subcellular Location

Understanding subcellular distribution and the mechanism of xenobiotics can help in modulating subcellular dysfunction mediated diseases. Therefore, with improved knowledge of how xenobiotics are distributed across subcellular locations and the mechanism for a specific molecule can play a crucial role in assessing drug efficacy and toxicity. Such knowledge would widen therapeutic windows by allowing specific receptors to be targeted efficiently. Based on datasets that provide information on the subcellular locations of proteins and their ligands, we developed machine learning models for 42 subcellular locations. Such models were trained and validated based on the grid search method and best models based on Cohen’s Kappa scores were selected. With the help of the state-of-the-art supercomputing facilities provided by the Texas Advanced Computing Center(TACC), we were able to develop a suite of more than 22300+ machine learning models. These machine learning models were built using 19 different fingerprints-based features for 42 different subcellular locations using 28 different ML classifiers. The web-application is available on an open portal and can be accessed at https://drugdiscovery.utep.edu/subcell/ by anyone in order to perform high-throughput cheminformatics simulations. All the data and models generated from the project are made available as open-source

A hard nut to crack : regulatory failure shows how rating really works

Credit rating agencies such as Moody’s and Standard & Poor’s are key players in the governance of global financial markets. Given the very strong criticism the rating agencies faced in the wake of the global financial crisis 2008, how can we explain the puzzle of their survival? Market and regulatory reliance on ratings continues, despite the shift from a light-touch to a mandatory system of agency regulation and supervision. Drawing on the analysis of rating agency regulation in the US and the EU before and after the financial crisis, we argue that a pervasive, persistent and, in our view, erroneous understanding of rating has supported the never-ending story of rating agency authority. We show how treating ratings as metrics, private goods, and independent and neutral third-party opinions contributes to the ineffectiveness of rating agency regulation and supports the continuing authoritative standing of the credit rating agencies in market and regulatory practices

Biofabrication of Anisotropic Gold Nanotriangles Using Extract of Endophytic Aspergillus clavatus as a Dual Functional Reductant and Stabilizer

Biosynthesis of metal and semiconductor nanoparticles using microorganisms has emerged as a more eco-friendly, simpler and reproducible alternative to the chemical synthesis, allowing the generation of rare forms such as nanotriangles and prisms. Here, we report the endophytic fungus Aspergillus clavatus, isolated from surface sterilized stem tissues of Azadirachta indica A. Juss., when incubated with an aqueous solution of chloroaurate ions produces a diverse mixture of intracellular gold nanoparticles (AuNPs), especially nanotriangles (GNT) in the size range from 20 to 35 nm. These structures (GNT) are of special interest since they possess distinct plasmonic features in the visible and IR regions, which equipped them with unique physical and optical properties exploitable in vital applications such as optics, electronics, catalysis and biomedicine. The reaction process was simple and convenient to handle and was monitored using ultraviolet–visible spectroscopy (UV–vis). The morphology and crystalline nature of the GNTs were determined from transmission electron microscopy (TEM), atomic force spectroscopy (AFM) and X-ray diffraction (XRD) spectroscopy. This proposed mechanistic principal might serve as a set of design rule for the synthesis of anisotropic nanostructures with desired architecture and can be amenable for the large scale commercial production and technical applications

Cost Efficient Scheduling of MapReduce Applications on Public Clouds

MapReduce framework has been one of the most prominent ways for efficient processing large amount of data requiring huge computational capacity. On-demand computing resources of Public Clouds have become a natural host for these MapReduce applications. However, the decision of what type and in what amount computing and storage resources should be rented is still a user’s responsibility. This is not a trivial task particularly when users may have performance constraints such as deadline and have several Cloud product types to choose with the intention of not spending much money. Even though there are several existing scheduling systems, however, most of them are not developed to manage the scheduling of MapReduce applications. That is, they do not consider things such as number of map and reduce tasks that are needed to be scheduled and heterogeneity of Virtual Machines (VMs) available. This paper proposes a novel greedy-based MapReduce application scheduling algorithm (MASA) that considers the user’s constraints in order to minimize cost of renting Cloud resources while considering Service Level Agreements (SLA) in terms of the user given budget and deadline constraints. The simulation results show that MASA can achieve 25-50% cost reduction in comparison to current SLA agnostic methods and there is only 10% performance disparity between MASA and an exhaustive search algorithm

Assessment of endothelial function by brachial artery flow mediated dilatation in microvascular disease

<p>Abstract</p> <p>Background</p> <p>Cardiac syndrome X is an important therapeutic and diagnostic challenge to physician. Study of Csx patients may help to understand the pathophysiology of coronary microcirculation and to gain an insight on the management of these group patients.</p> <p>Methods</p> <p>We measured the flow mediated dilation of the brachial artery both endothelium dependent and independent vasodilatation by high resolution ultrasound in 30 cardiac syndrome X patients and matched with 30 healthy control subjects.</p> <p>Results</p> <p>Significantly decreased flow mediated dilatation was observed in patients when compared to control (9.42 ± 7.20 vs 21.11 ± 9.16 p < 0.01) but no significant difference was observed between groups in response to nitroglycerin (25.39 ± 6.82 vs 28.87 ± 8.69). Receiver operator characteristic analysis showed that value of < 11.11 had sensitivity of 80%, specificity 86.67%, positive predictive value 76.66%, negative predictive value 83.33%. In total, 46% of subjects had endothelial dysfunction and of them, CSX subjects had higher prevalence (76% vs 16% p < 0.01) than control subjects. Higher mean values of body mass index, systolic blood pressure and diastolic blood pressure was observed in subjects with FMD < 11.11 than > 11.11(p < 0.01). In logistic regression analysis, FMD was significantly associated with systolic blood pressure (Odds ratio 1.122 95% CI 1.053-1.196 p < 0.01) and body mass index (Odds 1.248 95%CI 0.995-1.56 p < 0.05).</p> <p>Conclusions</p> <p>The study suggests impairment of endothelial function in cardiac syndrome X patients. Increased Systolic blood pressure and body mass index may increase the risk of impairment of endothelial function in this group of patients.</p

Aβ efflux impairment and inflammation linked to cerebrovascular accumulation of amyloid-forming amylin secreted from pancreas

Impairment of vascular pathways of cerebral β-amyloid (Aβ) elimination contributes to Alzheimer disease (AD). Vascular damage is commonly associated with diabetes. Here we show in human tissues and AD-model rats that bloodborne islet amyloid polypeptide (amylin) secreted from the pancreas perturbs cerebral Aβ clearance. Blood amylin concentrations are higher in AD than in cognitively unaffected persons. Amyloid-forming amylin accumulates in circulating monocytes and co-deposits with Aβ within the brain microvasculature, possibly involving inflammation. In rats, pancreatic expression of amyloid-forming human amylin indeed induces cerebrovascular inflammation and amylin-Aβ co-deposits. LRP1-mediated Aβ transport across the blood-brain barrier and Aβ clearance through interstitial fluid drainage along vascular walls are impaired, as indicated by Aβ deposition in perivascular spaces. At the molecular level, cerebrovascular amylin deposits alter immune and hypoxia-related brain gene expression. These converging data from humans and laboratory animals suggest that altering bloodborne amylin could potentially reduce cerebrovascular amylin deposits and Aβ pathology

Altered Neurocircuitry in the Dopamine Transporter Knockout Mouse Brain

The plasma membrane transporters for the monoamine neurotransmitters dopamine, serotonin, and norepinephrine modulate the dynamics of these monoamine neurotransmitters. Thus, activity of these transporters has significant consequences for monoamine activity throughout the brain and for a number of neurological and psychiatric disorders. Gene knockout (KO) mice that reduce or eliminate expression of each of these monoamine transporters have provided a wealth of new information about the function of these proteins at molecular, physiological and behavioral levels. In the present work we use the unique properties of magnetic resonance imaging (MRI) to probe the effects of altered dopaminergic dynamics on meso-scale neuronal circuitry and overall brain morphology, since changes at these levels of organization might help to account for some of the extensive pharmacological and behavioral differences observed in dopamine transporter (DAT) KO mice. Despite the smaller size of these animals, voxel-wise statistical comparison of high resolution structural MR images indicated little morphological change as a consequence of DAT KO. Likewise, proton magnetic resonance spectra recorded in the striatum indicated no significant changes in detectable metabolite concentrations between DAT KO and wild-type (WT) mice. In contrast, alterations in the circuitry from the prefrontal cortex to the mesocortical limbic system, an important brain component intimately tied to function of mesolimbic/mesocortical dopamine reward pathways, were revealed by manganese-enhanced MRI (MEMRI). Analysis of co-registered MEMRI images taken over the 26 hours after introduction of Mn^(2+) into the prefrontal cortex indicated that DAT KO mice have a truncated Mn^(2+) distribution within this circuitry with little accumulation beyond the thalamus or contralateral to the injection site. By contrast, WT littermates exhibit Mn^(2+) transport into more posterior midbrain nuclei and contralateral mesolimbic structures at 26 hr post-injection. Thus, DAT KO mice appear, at this level of anatomic resolution, to have preserved cortico-striatal-thalamic connectivity but diminished robustness of reward-modulating circuitry distal to the thalamus. This is in contradistinction to the state of this circuitry in serotonin transporter KO mice where we observed more robust connectivity in more posterior brain regions using methods identical to those employed here

Development of a biosensor for urea assay based on amidase inhibition, using an ion-selective electrode

A biosensor for urea has been developed based on the observation that urea is a powerful active-site inhibitor of amidase, which catalyzes the hydrolysis of amides such as acetamide to produce ammonia and the corresponding organic acid. Cell-free extract from Pseudomonas aeruginosa was the source of amidase (acylamide hydrolase, EC 3.5.1.4) which was immobilized on a polyethersulfone membrane in the presence of glutaraldehyde; anion-selective electrode for ammonium ions was used for biosensor development. Analysis of variance was used for optimization of the biosensorresponse and showed that 30 mu L of cell-free extract containing 7.47 mg protein mL(-1), 2 mu L of glutaraldehyde (5%, v/v) and 10 mu L of gelatin (15%, w/v) exhibited the highest response. Optimization of other parameters showed that pH 7.2 and 30 min incubation time were optimum for incubation ofmembranes in urea. The biosensor exhibited a linear response in the range of 4.0-10.0 mu M urea, a detection limit of 2.0 mu M for urea, a response timeof 20 s, a sensitivity of 58.245 % per mu M urea and a storage stability of over 4 months. It was successfully used for quantification of urea in samples such as wine and milk; recovery experiments were carried out which revealed an average substrate recovery of 94.9%. The urea analogs hydroxyurea, methylurea and thiourea inhibited amidase activity by about 90%, 10% and 0%, respectively, compared with urea inhibition

Self medication with antibiotics in Yogyakarta City Indonesia: a cross sectional population-based survey

Extent: 8p.Background: Self medication with antibiotics has become an important factor driving antibiotic resistance. This study investigated the period prevalence, patterns of use, and socio-demographic factors associated with self medication with antibiotics in Yogyakarta City Indonesia. This cross-sectional population-based survey used a pre-tested questionnaire which was self-administered to randomly selected respondents (over 18 years old) in Yogyakarta City Indonesia in 2010 (N = 625). Descriptive statistics, chi-square and logistic regression were applied. Results: A total of 559 questionnaires were analyzed (response rate = 90%). The period prevalence of self medication with antibiotics during the month prior to the study was 7.3%. Amoxicillin was the most popular (77%) antibiotic for self medication besides ampicilline, fradiomisin-gramisidin, tetracycline, and ciprofloxacin to treat the following symptoms: the common-cold including cough and sore throat, headache, and other minor symptoms; with the length of use was mostly less than five days. Doctors or pharmacists were the most common source of information about antibiotics for self medication (52%). Antibiotics were usually purchased without prescription in pharmacies (64%) and the cost of the purchases was commonly less than US $1 (30%). Previous experience was reported to be the main reason for using non-prescribed antibiotics (54%). There were no socio-demographic variables significantly associated with the actual practice of using non-prescribed antibiotics. However, gender, health insurance, and marital status were significantly associated with the intent to self medicate with antibiotics (P < 0.05). Being male (Odds Ratio = 1.7 (1.2 - 2.6)) and having no health insurance (Odds Ratio = 1.5 (1.0 -2.3)) is associated with the intent to self medicate with antibiotics. Conclusions: This study is the first population-based study of self-medication with antibiotics among the Indonesian population. Usage of non-prescribed antibiotics as well as intent of doing so is common across socio-demographic categories. Given the findings, factors influencing people's intentions to self medicate with antibiotics are required to be investigated to better understand such behavior. Impact of health insurance coverage on self medication with antibiotics should also be further investigated.Aris Widayati, Sri Suryawati, Charlotte de Crespigny and Janet E Hille