bluuebunny/crossref_metadata_2025 huggingface dataset:
Docking into Mycobacterium tuberculosis Thioredoxin Reductase Protein Yields Pyrazolone Lead Molecules for Methicillin-Resistant Staphylococcus aureus
Authors: Sweeney Noreena , Lipker Lauren , Hanson Alicia , Bohl Chris , Engel Katie , Kalous Kelsey , Stemper Mary , Sem Daniel , Schwan William
Published: January 2017

The thioredoxin/thioredoxin reductase system (Trx/TrxR) is an attractive drug target because of its involvement in a number of important physiological processes, from DNA synthesis to regulating signal transduction. This study describes the finding of pyrazolone compounds that are active against Staphylococcus aureus. Initially, the project was focused on discovering small molecules that may have antibacterial properties targeting the Mycobacterium tuberculosis thioredoxin reductase. This led to the discovery of a pyrazolone scaffold-containing compound series that showed bactericidal capability against S. aureus strains, including drug-resistant clinical isolates. The findings support continued development of the pyrazolone compounds as potential anti-S. aureus antibiotics.
Photocurable Bioink for the Inkjet 3D Pharming of Hydrophilic Drugs
Authors: Acosta-Vélez Giovanny , Linsley Chase , Craig Madison , Wu Benjamin
Published: January 2017

Novel strategies are required to manufacture customized oral solid dosage forms for personalized medicine applications. 3D Pharming, the direct printing of pharmaceutical tablets, is an attractive strategy, since it allows for the rapid production of solid dosage forms containing custom drug dosages. This study reports on the design and characterization of a biocompatible photocurable pharmaceutical polymer for inkjet 3D printing that is suitable for hydrophilic active pharmaceutical ingredients (API). Specifically, hyaluronic acid was functionalized with norbornene moieties that, in the presence of poly(ethylene) glycol dithiol, Eosin Y as a photoinitiator, and a visible light source, undergoes a rapid step-growth polymerization reaction through thiol-ene chemistry. The engineered bioink was loaded with Ropinirole HCL, dispensed through a piezoelectric nozzle onto a blank preform tablet, and polymerized. Drug release analysis of the tablet resulted in 60% release within 15 min of tablet dissolution. The study confirms the potential of inkjet printing for the rapid production of tablets through the deposition of a photocurable bioink designed for hydrophilic APIs.
Social Support Behaviors and Work Stressors among Nurses: A Comparative Study between Teaching and Non-Teaching Hospitals
Authors: Amarneh Basil
Published: January 2017

Purpose: The concept of “work stressors” has been well studied. However, in the field of nursing, studies concerning social support behaviors are limited. The aim of this study was to compare nurse work stressors, social support behaviors, and predictors of these variables among nurses in Jordanian teaching and non-teaching hospitals. Design: A convenience sampling technique and a comparative quantitative research design were used in the current study. Two hundred and ninety-one nurses were recruited from five teaching hospitals, and 172 were recruited from eight non-teaching hospitals in Jordan. Methods: The Nursing Stress Scale (NSS) and the Inventory of Social Supportive Behaviors (ISSB) were used to collect data. Results: The studied variables differed across hospitals. In some subscales, as well as in some individual items of the scales, nurse work stressors and social support behaviors differed between teaching and non-teaching hospitals. In teaching hospitals, the work shift was the only predictor of nurses’ work stressors, whereas the work shift and model of nursing care were predictors of social support behaviors. In non-teaching hospitals, the work shift, level of education, and model of nursing care were predictors of nurse work stressors. Predictors of social support behaviors were marital status, model of nursing, and organizational structure. Conclusions: Regardless of the type of hospital, nurse stressors should be assessed and, once identified, managed by providing various social support behaviors. Clinical relevance: By turning a work environment into a healthy workplace, researchers and nurse leaders believe that improvements can be realized in recruitment and patient safety and quality.
Engineering Surface Ligands of Noble Metal Nanocatalysts in Tuning the Product Selectivity
Authors: Jin Lei , Liu Ben , Duay Searle , He Jie
Published: January 2017

Nanosized noble metal catalysts supported on high-surface-area support are of great importance for numerous industrial chemical processes to mediate reaction pathways in heterogeneous catalysis. Control of surface area and surface energy of nanocatalysts is a key to achieving high activity and selectivity for desired products. In the past decade, new synthetic methodologies for noble metal nanocatalysts with well-defined nanostructures have been developed. Wet-chemical preparation of noble metal nanocatalysts usually involves the utilization of specific surfactants that can bind the surface of nanocatalysts as ligands to control the nanostructures and prevent the coalescence of nanocatalysts. Surface ligands that form a densely packed self-assembled monolayer offer a facile solution to tune the surface energy of nanocatalysts, and, therefore, the selectivity of products. In this minireview, we highlight the recent advances in understanding the role of surface ligands in control over the product selectivity in a multi-product reaction using noble metal nanocatalysts. The review is outlined according to the three possible roles of surface ligands, including steric effect, orientation effect and surface charge state, in varying the adsorption/binding of reactants/transition states.
Acceptance and Commitment Therapy for Pediatric Chronic Pain: Theory and Application
Authors: Pielech Melissa , Vowles Kevin , Wicksell Rikard
Published: January 2017

Acceptance and Commitment Therapy (ACT) is a third wave behavior therapy approach which aims to increase engagement in activities that bring meaning, vitality, and value to the lives of individuals experiencing persistent pain, discomfort, or distress. This goal is particularly relevant when these aversive experiences cannot be effectively avoided or when avoidance efforts risk their exacerbation, all of which may be common experiences in children and adolescents with chronic pain conditions. The primary aim of the present paper is to review and summarize the extant literature on the application, utility, and evidence for using ACT with pediatric chronic pain populations by: (1) defining the theoretical assumptions of the ACT model; (2) summarizing research study findings and relevant measures from the published literature; and (3) critically discussing the strengths, limitations and areas in need of further development.
Excitons in Solids from Time-Dependent Density-Functional Theory: Assessing the Tamm-Dancoff Approximation
Authors: Byun Young-Moo , Ullrich Carsten
Published: January 2017

Excitonic effects in solids can be calculated using the Bethe-Salpeter equation (BSE) or the Casida equation of time-dependent density-functional theory (TDDFT). In both methods, the Tamm-Dancoff approximation (TDA), which decouples excitations and de-excitations, is widely used to reduce computational cost. Here, we study the effect of the TDA on exciton binding energies of solids obtained from the Casida equation using long-range-corrected (LRC) exchange-correlation kernels. We find that the TDA underestimates TDDFT-LRC exciton binding energies of semiconductors slightly, but those of insulators significantly (i.e., by more than 100%), and thus it is essential to solve the full Casida equation to describe strongly bound excitons. These findings are relevant in the ongoing search for accurate and efficient TDDFT approaches for excitons.
Grouped Bees Algorithm: A Grouped Version of the Bees Algorithm
Authors: Nasrinpour Hamid , Bavani Amir , Teshnehlab Mohammad
Published: January 2017

In many non-deterministic search algorithms, particularly those analogous to complex biological systems, there are a number of inherent difficulties, and the Bees Algorithm (BA) is no exception. The BA is a population-based metaheuristic search algorithm inspired by bees seeking nectar/pollen. Basic versions and variations of the BA have their own drawbacks. Some of these drawbacks are a large number of parameters to be set, lack of methodology for parameter setting and computational complexity. This paper describes a Grouped version of the Bees Algorithm (GBA) addressing these issues. Unlike its conventional version, in this algorithm bees are grouped to search different sites with different neighbourhood sizes rather than just discovering two types of sites, namely elite and selected. Following a description of the GBA, the results gained for 12 well-known benchmark functions are presented and compared with those of the basic BA, enhanced BA, standard BA and modified BA to demonstrate the efficacy of the proposed algorithm. Compared to the conventional implementations of the BA, the proposed version requires setting of fewer parameters, while producing the optimum solutions much more quickly.
The Association between Dietary Intake of Antioxidants and Ocular Disease
Authors: Braakhuis Andrea , Raman Ryan , Vaghefi Ehsan
Published: January 2017

To assess the association between dietary antioxidant intake and the incidence of the three major oxidative stress-related eye diseases, cataracts, glaucoma, and age-related macular degeneration, 78 cases from the University of Auckland Optometry and Vision Science clinic and 149 controls were recruited. Participants completed an antioxidant food-frequency questionnaire, analysed through multiple logistic regression. Protective associations were identified with higher consumption of fruit and vegetables (OR = 0.99; 95% CI: 0.98, 1.00; p = 0.004), vitamin C (OR = 0.63; 95% CI: 0.23, 1.03; p = 0.022), and β-carotene (OR = 0.56; 95% CI: 0.15, 0.98; p = 0.007). Meanwhile, harmful associations were observed with greater consumption of meat/nuts (OR = 1.03; 95% CI: 1.01, 1.05; p = 0.006) and cholesterol (OR = 1.09; 95% CI: 1.50, 2.46; p = 0.005). Diets rich in fruit and vegetables appear to be protective against cataracts, glaucoma, and age-related macular degeneration, while diets higher in meat and nuts may increase the risk of oxidative stress-related eye diseases. In addition, higher intakes of vitamin C and β-carotene from food, with reduction of dietary cholesterol intake, may be beneficial towards the outcome of oxidative stress-related eye diseases.
Bateman–Feshbach Tikochinsky and Caldirola–Kanai Oscillators with New Fractional Differentiation
Authors: Coronel-Escamilla Antonio , Gómez-Aguilar José , Baleanu Dumitru , Córdova-Fraga Teodoro , Escobar-Jiménez Ricardo , Olivares-Peregrino Victor , Qurashi Maysaa
Published: January 2017

In this work, the study of the fractional behavior of the Bateman–Feshbach–Tikochinsky and Caldirola–Kanai oscillators by using different fractional derivatives is presented. We obtained the Euler–Lagrange and the Hamiltonian formalisms in order to represent the dynamic models based on the Liouville–Caputo, Caputo–Fabrizio–Caputo and the new fractional derivative based on the Mittag–Leffler kernel with arbitrary order α. Simulation results are presented in order to show the fractional behavior of the oscillators, and the classical behavior is recovered when α is equal to 1.
Numerical Investigation of the Production Behavior of Methane Hydrates under Depressurization Conditions Combined with Well-Wall Heating
Authors: Ruan Xuke , Li Xiao-Sen , Xu Chun-Gang
Published: January 2017

In this study, a 2D hydrate dissociation simulator has been improved and veriﬁed to be valid in numerical simulations of the gas production behavior using depressurization combined with a well-wall heating method. A series of numerical simulations were performed and the results showed that well-wall heating had an inﬂuence enhancing the depressurization-induced gas production, but the inﬂuence was limited, and it was even gradually weakened with the increase of well-wall heating temperature. Meanwhile, the results of the sensitivity analysis demonstrated the gas production depended on the initial hydrate saturation, initial pressure and the thermal boundary conditions. The supply of heat for hydrate dissociation mainly originates from the thermal boundaries,whichcontrolthehydratedissociationandgasproductionbydepressurizationcombined with well-wall heating. However, the effect of initial temperature on the gas production could be nearly negligible under depressurization conditions combined with well-wall heating.
Effect of Feed Protein:Lipid Ratio on Growth Parameters of African Catfish Clarias gariepinus after Fish Meal Substitution in the Diet with Bambaranut (Voandzeia subterranea) Meal and Soybean (Glycine max) Meal
Authors: Enyidi Uchechukwu , Pirhonen Juhani , Kettunen Juhani , Vielma Jouni
Published: January 2017

Fishmeal (FM) was substituted with soybean meal (Glycine max) (SBM) and bambaranut meal (Voandzeia subterranea) (BNM) in 10 experimental African catfish, Clarias gariepinus, diets. Feed formulation was designed using mixture model. The inclusion level of the three protein ingredients varied between 0% and 60%. Remaining 40% comprised of basal ingredients kept constant for all 10 feeds. African catfish of average initial weight 35.2 ± 0.9 g were fed with one of the treatment diets for 28 days. The protein:lipid ratios of the diets (range 1.5–3.4:1) were used in evaluating the feed utilization and growth of the fish. We found that catfish performances were mainly depending on ingredients and not the ratio itself. The protein:lipid ratios in the diets made of plant ingredients were high but SGR was low. Specific growth rate (SGR) increased with the increase of feed FM content, being ca. 5% day−1 with 60% FM diet but ca. 2% day−1 at both 60% BNM and 60% SBM diets. SGR was similar (3.5% day−1) with diets of 30% BNM or SBM inclusion with 30% FM. Feed conversion ratio increased from below 0.6 of the 60% FM diet up to 1.5 (60% SBM) and 1.7 (60% BNM). Protein efficiency ratio decreased linearly with increasing FM substitution, but protein productive value (PPV) was similar for catfish fed 60% FM diet and its 50% substitution with BNM or SBM. These results suggest that protein:lipid ratio cannot be used in assessing nutritional performance if the source of feed ingredient vary widely. However, these results suggest that BNM can partly substitute FM and completely replace SBM in the diets of African catfish.
A Reduced Model for Salt-Finger Convection in the Small Diffusivity Ratio Limit
Authors: Xie Jin-Han , Miquel Benjamin , Julien Keith , Knobloch Edgar
Published: January 2017

A simple model of nonlinear salt-ﬁnger convection in two dimensions is derived and studied. The model is valid in the limit of a small solute to heat diffusivity ratio and a large density ratio, which is relevant to both oceanographic and astrophysical applications. Two limits distinguished by the magnitude of the Schmidt number are found. For order one Schmidt numbers, appropriate for astrophysical applications, a modiﬁed Rayleigh–Bénard system with large-scale damping due to a stabilizing temperature is obtained. For large Schmidt numbers, appropriate for the oceanic setting, the model combines a prognostic equation for the solute ﬁeld and a diagnostic equation for inertia-free momentum dynamics. Two distinct saturation regimes are identiﬁed for the second model: the weakly driven regime is characterized by a large-scale ﬂow associated with a balance between advection and linear instability, while the strongly-driven regime produces multiscale structures, resulting in a balance between energy input through linear instability and energy transfer between scales. For both regimes, we analytically predict and numerically conﬁrm the dependence of the kinetic energy and salinity ﬂuxes on the ratio between solutal and thermal Rayleigh numbers. The spectra and probability density functions are also computed.
Brazilian Specialists’ Perspectives on the Patient Referral Process
Authors: Juliani Carmen , MacPhee Maura , Spiri Wilza
Published: January 2017

Since 1988, healthcare has been considered a citizen’s right in Brazil. The Sistema Único de Saúde (SUS), has undergone development and expansion to ensure universal health coverage for the Brazilian public, the world’s fifth largest population. The coordination of effective communications between primary care physicians, specialists and patients is a significant challenge, particularly the referral process. Our study objective was to understand the facilitators and barriers associated with referral process communications between primary care physicians and regional university hospital specialists in the State of Sao Paulo. This paper reports specialists’ perspectives of the referral process. This was a phenomenological study that employed a qualitative research method with three components (description, reduction and comprehension). We conducted focus groups with 54 hospital residents from different specialties (surgery, medicine, obstetrics/gynecology, pediatrics) from July to October 2014. The main results showed lack of an adequate referral-return referral process resulting in treatment delays and inappropriate use of emergency services. Communications were impeded by lack of integrated, computerized booking and standardized referral-return referral processes; underlying lack of trust in primary care physicians; and patients’ inappropriate use of healthcare services. Although computerized systems will facilitate communications between primary and specialty care, other strategies are needed to promote collaboration between services, and ensure appropriate utilization of them.
Effects of Gender on the Association of Urinary Phthalate Metabolites with Thyroid Hormones in Children: A Prospective Cohort Study in Taiwan
Authors: Weng Te-I , Chen Mei-Huei , Lien Guang-Wen , Chen Pai-Shan , Lin Jasper , Fang Cheng-Chung , Chen Pau-Chung
Published: January 2017

Phthalates are considered endocrine disruptors. Our study assessed the gender-specific effects of phthalate exposure on thyroid function in children. In total, 189 Taiwanese children were enrolled in the study. One-spot urine and blood samples were collected for analyzing 12 phthalate metabolites in urine and thyroid hormones. The association between urinary phthalate metabolites and serum thyroid hormones was determined using a generalized linear model with a log link function; the children were categorized into groups for analysis according to the 33rd and 66th percentiles. The data were stratified according to gender and adjusted for a priori defined covariates. In girls, a positive association existed between urinary di-2-ethylhexyl phthalate (DEHP) metabolites (mono-(2-ethylhexyl) phthalate, mono-(2-ethyl-5-oxohexyl) phthalate, and mono-(2-ethyl-5-hydroxyhexyl) phthalate) and free thyroxine (T4). In boys, urinary dibutyl phthalate (DBP) metabolites (mono-i-butyl phthalate and mono-n-butyl phthalate) were positively associated with free triiodothyronine (T3). After categorizing each exposure into three groups, urinary DEHP metabolites were positively associated with free T3 levels in boys. Our results suggested that DEHP is associated with free T4 in girls and that DBP is associated with free T3 in boys. Higher DEHP metabolite concentrations exerted larger effects on free T3 in boys. These results reveal the gender-specific relationships between phthalate metabolites and thyroid hormones.
Evaluation and Analysis of Eco-Security in Environmentally Sensitive Areas Using an Emergy Ecological Footprint
Authors: Chen Han-Shen
Published: January 2017

In this paper, the overall ecological and environmental sustainability in the Cing-Jing region in Taiwan is examined. As land use and cover change has been found to be an important analysis method, an emergy ecological footprint model was applied and the eco-security assessed to ensure authorities maintain a balance between ecological preservation and tourism development. While the ecological environment in the Cing-Jing region from 2008 to 2014 was found to be within safe levels, all related indices had increased considerably. A Grey model was used to predict the 2015–2024 ecological carrying capacities, from which it was found that there is expected to be a large increase in per capita ecological footprints (EFs), meaning that in the future there is going to be a larger ecological deficit and a higher ecological pressure index (EFI), with the eco-security predicted to reach a Grade 2 intermediate level in 2022. As the Cing-Jing region is predicted to become ecologically unsustainable, local, regional, and national governments need to implement regulations to strictly control the land use in the Cing-Jing region. This study demonstrated that emergy EF (EEF) theory application can give objective guidance to decision-makers to ensure that recreational non-urban eco-security can be maintained at a safe level.
Role of Antioxidants in Neonatal Hypoxic–Ischemic Brain Injury: New Therapeutic Approaches
Authors: Arteaga Olatz , Álvarez Antonia , Revuelta Miren , Santaolalla Francisco , Urtasun Andoni , Hilario Enrique
Published: January 2017

Hypoxic–ischemic brain damage is an alarming health and economic problem in spite of the advances in neonatal care. It can cause mortality or detrimental neurological disorders such as cerebral palsy, motor impairment and cognitive deficits in neonates. When hypoxia–ischemia occurs, a multi-faceted cascade of events starts out, which can eventually cause cell death. Lower levels of oxygen due to reduced blood supply increase the production of reactive oxygen species, which leads to oxidative stress, a higher concentration of free cytosolic calcium and impaired mitochondrial function, triggering the activation of apoptotic pathways, DNA fragmentation and cell death. The high incidence of this type of lesion in newborns can be partly attributed to the fact that the developing brain is particularly vulnerable to oxidative stress. Since antioxidants can safely interact with free radicals and terminate that chain reaction before vital molecules are damaged, exogenous antioxidant therapy may have the potential to diminish cellular damage caused by hypoxia–ischemia. In this review, we focus on the neuroprotective effects of antioxidant treatments against perinatal hypoxic–ischemic brain injury, in the light of the most recent advances.
Lannea coromandelica (Houtt.) Merr. Induces Heme Oxygenase 1 (HO-1) Expression and Reduces Oxidative Stress via the p38/c-Jun N-Terminal Kinase–Nuclear Factor Erythroid 2-Related Factor 2 (p38/JNK–NRF2)-Mediated Antioxidant Pathway
Authors: Alam Md , Kwon Kyoo-Ri , Lee Seok-Hyun , Lee Sang-Han
Published: January 2017

The leaves of Lannea coromandelica (Houtt.) Merr. are used in the Garo, Pahan, and Teli tribal communities of Bangladesh as a traditional medicinal plant to treat hepatitis, diabetes, ulcers, heart disease, and dysentery. However, there have been limited phytochemical and biological studies on the bark of L. coromandelica. This study aimed to investigate the antioxidant activities of L. coromandelica bark extract (LCBE) and the underlying mechanism using RAW 264.7 cells. The LCBE was analysed by high-pressure liquid chromatography (HPLC) to detect its key polyphenolic compounds. Various in vitro antioxidant assays were performed using RAW 264.7 cells to assess the antioxidant effects of the LCBE and to understand the underlying molecular mechanism. HPLC revealed the presence of gallic acid, (−)-epigallocatechin-3-gallate, catechin, chlorogenic acid, and caffeic acid in the LCBE. The extract showed a very potent capacity to scavenge numerous free radicals through hydrogen atom transfer and/or electron donation and also quenched cellular reactive oxygen species (ROS) generation without showing any toxicity. The LCBE was found to combat the oxidative stress by enhancing the expression, at both transcriptional and translational levels, of primary antioxidant enzymes as well as phase II detoxifying enzymes, especially heme oxygenase 1, through the upregulation of the nuclear factor erythroid 2-related factor 2 (NRF2)-mediated pathway in RAW 264.7 cells via the phosphorylation of p38 kinase and c-Jun N-terminal kinase (JNK). The LCBE exhibited strong antioxidant activities and mitigated the cellular ROS production. These results provide scientific evidence of its potential as an ideal applicant for a cost-effective, readily available, and natural phytochemical, as well as a strategy for preventing diseases associated with oxidative stress and attenuating disease progress.
Metabolomic Fingerprinting in the Comprehensive Study of Liver Changes Associated with Onion Supplementation in Hypercholesterolemic Wistar Rats
Authors: González-Peña Diana , Dudzik Danuta , García Antonia , Ancos Begoña , Barbas Coral , Sánchez-Moreno Concepción
Published: January 2017

The consumption of functional ingredients has been suggested to be a complementary tool for the prevention and management of liver disease. In this light, processed onion can be considered as a source of multiple bioactive compounds with hepatoprotective properties. The liver fingerprint of male Wistar rats (n = 24) fed with three experimental diets (control (C), high-cholesterol (HC), and high-cholesterol enriched with onion (HCO) diets) was obtained through a non-targeted, multiplatform metabolomics approach to produce broad metabolite coverage. LC-MS, CE-MS and GC-MS results were subjected to univariate and multivariate analyses, providing a list of significant metabolites. All data were merged in order to figure out the most relevant metabolites that were modified by the onion ingredient. Several relevant metabolic changes and related metabolic pathways were found to be impacted by both HC and HCO diet. The model highlighted several metabolites (such as hydroxybutyryl carnitine and palmitoyl carnitine) modified by the HCO diet. These findings could suggest potential impairments in the energy−lipid metabolism, perturbations in the tricarboxylic acid cycle (TCA) cycle and β-oxidation modulated by the onion supplementation in the core of hepatic dysfunction. Metabolomics shows to be a valuable tool to evaluate the effects of complementary dietetic approaches directed to hepatic damage amelioration or non-alcoholic fatty liver disease (NAFLD) prevention.
Integral Characterization of Defective BDNF/TrkB Signalling in Neurological and Psychiatric Disorders Leads the Way to New Therapies
Authors: Tejeda Gonzalo , Díaz-Guerra Margarita
Published: January 2017

Enhancement of brain-derived neurotrophic factor (BDNF) signalling has great potential in therapy for neurological and psychiatric disorders. This neurotrophin not only attenuates cell death but also promotes neuronal plasticity and function. However, an important challenge to this approach is the persistence of aberrant neurotrophic signalling due to a defective function of the BDNF high-affinity receptor, tropomyosin-related kinase B (TrkB), or downstream effectors. Such changes have been already described in several disorders, but their importance as pathological mechanisms has been frequently underestimated. This review highlights the relevance of an integrative characterization of aberrant BDNF/TrkB pathways for the rational design of therapies that by combining BDNF and TrkB targets could efficiently promote neurotrophic signalling.
Uridine Triphosphate Thio Analogues Inhibit Platelet P2Y12 Receptor and Aggregation
Authors: Gündüz Dursun , Tanislav Christian , Sedding Daniel , Parahuleva Mariana , Santoso Sentot , Troidl Christian , Hamm Christian , Aslam Muhammad
Published: January 2017

Platelet P2Y12 is an important adenosine diphosphate (ADP) receptor that is involved in agonist-induced platelet aggregation and is a valuable target for the development of anti-platelet drugs. Here we characterise the effects of thio analogues of uridine triphosphate (UTP) on ADP-induced platelet aggregation. Using human platelet-rich plasma, we demonstrate that UTP inhibits P2Y12 but not P2Y1 receptors and antagonises 10 µM ADP-induced platelet aggregation in a concentration-dependent manner with an IC50 value of ~250 °µM. An eight-fold higher platelet inhibitory activity was observed with a 2-thio analogue of UTP (2S-UTP), with an IC50 of 30 µM. The 4-thio analogue (4S-UTP) with an IC50 of 7.5 µM was 33-fold more effective. A three-fold decrease in inhibitory activity, however, was observed by introducing an isobutyl group at the 4S- position. A complete loss of inhibition was observed with thio-modification of the γ phosphate of the sugar moiety, which yields an enzymatically stable analogue. The interaction of UTP analogues with P2Y12 receptor was verified by P2Y12 receptor binding and cyclic AMP (cAMP) assays. These novel data demonstrate for the first time that 2- and 4-thio analogues of UTP are potent P2Y12 receptor antagonists that may be useful for therapeutic intervention.
High-Level γ-Glutamyl-Hydrolase (GGH) Expression is Linked to Poor Prognosis in ERG Negative Prostate Cancer
Authors: Melling Nathaniel , Rashed Masoud , Schroeder Cornelia , Hube-Magg Claudia , Kluth Martina , Lang Dagmar , Simon Ronald , Möller-Koop Christina , Steurer Stefan , Sauter Guido , Jacobsen Frank , Büscheck Franziska , Wittmer Corinna , Clauditz Till , Krech Till , Tsourlakis Maria , Minner Sarah , Huland Hartwig , Graefen Markus , Budäus Lars , Thederan Imke , Salomon Georg , Schlomm Thorsten , Wilczak Waldemar
Published: January 2017

γ-glutamyl-hydrolase (GGH) is a ubiquitously-expressed enzyme that regulates intracellular folate metabolism for cell proliferation, DNA synthesis, and repair. Employing GGH immunohistochemistry on a tissue microarray with 12,427 prostate cancers, we found that GGH expression was negative to low in normal prostate epithelium, whereas 88.3% of our 10,562 interpretable cancers showed GGH expression. GGH staining was considered as low intensity in 49.6% and as high intensity in 38.6% of cancers. High GGH expression was linked to the TMPRSS2:ERG-fusion positive subset of cancers (p < 0.0001), advanced pathological tumor stage, and high Gleason grade (p < 0.0001 each). Further analysis revealed that these associations were merely driven by the subset of ERG-negative cancers, High GGH expression was weakly linked to early biochemical recurrence in ERG negative cancers (p < 0.0001) and independent from established histo-pathological parameters. Moreover, GGH expression was linked to features of genetic instability, including presence of recurrent deletions at 3p, 5q, 6q, and 10q (PTEN, p ≤ 0.01 each), as well as to accelerated cell proliferation as measured by Ki67 immunohistochemistry (p < 0.0001). In conclusion, the results of our study identify GGH as an ERG subtype specific molecular marker with modest prognostic relevance, which may have clinical relevance if analyzed in combination with other molecular markers.
Decreased Expression of Vitamin D Receptor Affects an Immune Response in Primary Biliary Cholangitis via the VDR-miRNA155-SOCS1 Pathway
Authors: Kempinska-Podhorodecka Agnieszka , Milkiewicz Malgorzata , Wasik Urszula , Ligocka Joanna , Zawadzki Michał , Krawczyk Marek , Milkiewicz Piotr
Published: January 2017

Primary biliary cholangitis (PBC) is an immune-mediated cholestatic disease. Vitamin D receptor (VDR)-dependent signaling constrains an inflammatory response by targeting the miRNA155-SOCS1 (suppressor of cytokine signaling 1) axis. The VDR-miRNA155-SOCS1 pathway was investigated in the context of the autoimmune response associated with PBC. Human liver tissues from non-cirrhotic PBC (n = 22), cirrhotic PBC (n = 22), cirrhotic primary sclerosing cholangitis (PSC, n=13), controls (n = 23), and peripheral blood mononuclear cells (PBMC) obtained from PBC (n = 16) and PSC (n = 10) patients and healthy subjects (n = 11) were used for molecular analyses. VDR mRNA and protein expressions were substantially reduced in PBC livers (51% and 59%, respectively). Correspondingly, the decrease of SOCS1 protein expression in PBC livers, after normalization to a marker of lymphocytes and forkhead family transcriptional regulator box P3 (FOXP3, marker of Treg), was observed, and this phenomenon was accompanied by enhanced miRNA155 expression. In PSC livers, protein expressions of VDR and SOCS1 were comparable to the controls. However, in PBM cells, protein expressions of VDR and SOCS1 were considerably decreased in both PBC and PSC. We demonstrated that VDR/miRNA155-modulated SOCS1 expression is decreased in PBC which may lead to insufficient negative regulation of cytokine signaling. These findings suggest that the decreased VDR signaling in PBC could be of importance in the pathogenesis of PBC.
A Mixture of Persistent Organic Pollutants and Perfluorooctanesulfonic Acid Induces Similar Behavioural Responses, but Different Gene Expression Profiles in Zebrafish Larvae
Authors: Khezri Abdolrahman , Fraser Thomas , Nourizadeh-Lillabadi Rasoul , Kamstra Jorke , Berg Vidar , Zimmer Karin , Ropstad Erik
Published: January 2017

Persistent organic pollutants (POPs) are widespread in the environment and some may be neurotoxic. As we are exposed to complex mixtures of POPs, we aimed to investigate how a POP mixture based on Scandinavian human blood data affects behaviour and neurodevelopment during early life in zebrafish. Embryos/larvae were exposed to a series of sub-lethal doses and behaviour was examined at 96 h post fertilization (hpf). In order to determine the sensitivity window to the POP mixture, exposure models of 6 to 48 and 48 to 96 hpf were used. The expression of genes related to neurological development was also assessed. Results indicate that the POP mixture increases the swimming speed of larval zebrafish following exposure between 48 to 96 hpf. This behavioural effect was associated with the perfluorinated compounds, and more specifically with perfluorooctanesulfonic acid (PFOS). The expression of genes related to the stress response, GABAergic, dopaminergic, histaminergic, serotoninergic, cholinergic systems and neuronal maintenance, were altered. However, there was little overlap in those genes that were significantly altered by the POP mixture and PFOS. Our findings show that the POP mixture and PFOS can have a similar effect on behaviour, yet alter the expression of genes relevant to neurological development differently.
Antioxidant and Cytoprotective Activities of Fucus spiralis Seaweed on a Human Cell in Vitro Model
Authors: Pinteus Susete , Silva Joana , Alves Celso , Horta André , Thomas Olivier , Pedrosa Rui
Published: January 2017

Antioxidants play an important role as Reactive Oxygen Species (ROS) chelating agents and, therefore, the screening for potent antioxidants from natural sources as potential protective agents is of great relevance. The main aim of this study was to obtain antioxidant-enriched fractions from the common seaweed Fucus spiralis and evaluate their activity and efficiency in protecting human cells (MCF-7 cells) on an oxidative stress condition induced by H2O2. Five fractions, F1–F5, were obtained by reversed-phase vacuum liquid chromatography. F3, F4 and F5 revealed the highest phlorotannin content, also showing the strongest antioxidant effects. The cell death induced by H2O2 was reduced by all fractions following the potency order F4 > F2 > F3 > F5 > F1. Only fraction F4 completely inhibited the H2O2 effect. To understand the possible mechanisms of action of these fractions, the cellular production of H2O2, the mitochondrial membrane potential and the caspase 9 activity were studied. Fractions F3 and F4 presented the highest reduction on H2O2 cell production. All fractions decreased both caspase-9 activity and cell membrane depolarization (except F1). Taken all together, the edible F. spiralis reveal that they provide protection against oxidative stress induced by H2O2 on the human MCF-7 cellular model, probably acting as upstream blockers of apoptosis.
Lung Infections in Systemic Rheumatic Disease: Focus on Opportunistic Infections
Authors: Di Franco Manuela , Lucchino Bruno , Spaziante Martina , Iannuccelli Cristina , Valesini Guido , Iaiani Giancarlo
Published: January 2017

Systemic rheumatic diseases have significant morbidity and mortality, due in large part to concurrent infections. The lung has been reported among the most frequent sites of infection in patients with rheumatic disease, who are susceptible to developing pneumonia sustained both by common pathogens and by opportunistic microorganisms. Patients with rheumatic disease show a peculiar vulnerability to infectious complications. This is due in part to intrinsic disease-related immune dysregulation and in part to the immunosuppressive treatments. Several therapeutic agents have been associated to a wide spectrum of infections, complicating the management of rheumatic diseases. This review discusses the most frequent pulmonary infections encountered in rheumatic diseases, focusing on opportunistic agents, consequent diagnostic challenges and appropriate therapeutic strategies.
Metabolomic Biomarkers in Urine of Cushing’s Syndrome Patients
Authors: Kotłowska Alicja , Puzyn Tomasz , Sworczak Krzysztof , Stepnowski Piotr , Szefer Piotr
Published: January 2017

Cushing’s syndrome (CS) is a disease which results from excessive levels of cortisol in the human body. The disorder is associated with various signs and symptoms which are also common for the general population not suffering from compound hypersecretion. Thus, more sensitive and selective methods are required for the diagnosis of CS. This follow-up study was conducted to determine which steroid metabolites could serve as potential indicators of CS and possible subclinical hypercortisolism in patients diagnosed with so called non-functioning adrenal incidentalomas (AIs). Urine samples from negative controls (n = 37), patients with CS characterized by hypercortisolism and excluding iatrogenic CS (n = 16), and patients with non-functioning AIs with possible subclinical Cushing’s syndrome (n = 25) were analyzed using gas chromatography-mass spectrometry (GC/MS) and gas chromatograph equipped with flame ionization detector (GC/FID). Statistical and multivariate methods were applied to investigate the profile differences between examined individuals. The analyses revealed hormonal differences between patients with CS and the rest of examined individuals. The concentrations of selected metabolites of cortisol, androgens, and pregnenetriol were elevated whereas the levels of tetrahydrocortisone were decreased for CS when opposed to the rest of the study population. Moreover, after analysis of potential confounding factors, it was also possible to distinguish six steroid hormones which discriminated CS patients from other study subjects. The obtained discriminant functions enabled classification of CS patients and AI group characterized by mild hypersecretion of cortisol metabolites. It can be concluded that steroid hormones selected by applying urinary profiling may serve the role of potential biomarkers of CS and can aid in its early diagnosis.
Role of Aquaporin 1 Signalling in Cancer Development and Progression
Authors: Tomita Yoko , Dorward Hilary , Yool Andrea , Smith Eric , Townsend Amanda , Price Timothy , Hardingham Jennifer
Published: January 2017

Cancer is a major health burden worldwide. Despite the advances in our understanding of its pathogenesis and continued improvement in cancer management and outcomes, there remains a strong clinical demand for more accurate and reliable biomarkers of metastatic progression and novel therapeutic targets to abrogate angiogenesis and tumour progression. Aquaporin 1 (AQP1) is a small hydrophobic integral transmembrane protein with a predominant role in trans-cellular water transport. Recently, over-expression of AQP1 has been associated with many types of cancer as a distinctive clinical prognostic factor. This has prompted researchers to evaluate the link between AQP1 and cancer biological functions. Available literature implicates the role of AQP1 in tumour cell migration, invasion and angiogenesis. This article reviews the current understanding of AQP1-facilitated tumour development and progression with a focus on regulatory mechanisms and downstream signalling pathways.
Comparisons of Transcriptional Profiles of Gut Genes between Cry1Ab-Resistant and Susceptible Strains of Ostrinia nubilalis Revealed Genes Possibly Related to the Adaptation of Resistant Larvae to Transgenic Cry1Ab Corn
Authors: Yao Jianxiu , Zhu Yu-Cheng , Lu Nanyan , Buschman Lawrent , Zhu Kun
Published: January 2017

A microarray developed on the basis of 2895 unique transcripts from larval gut was used to compare gut gene expression profiles between a laboratory-selected Cry1Ab-resistant (R) strain and its isoline susceptible (S) strain of the European corn borer (Ostrinia nubilalis) after the larvae were fed the leaves of transgenic corn (MON810) expressing Cry1Ab or its non-transgenic isoline for 6 h. We revealed 398 gut genes differentially expressed (i.e., either up- or down-regulated genes with expression ratio ≥2.0) in S-strain, but only 264 gut genes differentially expressed in R-strain after being fed transgenic corn leaves. Although the percentages of down-regulated genes among the total number of differentially expressed genes (50% in S-strain and 45% in R-strain) were similar between the R- and S-strains, the expression ratios of down-regulated genes were much higher in S-strain than in R-strain. We revealed that 17 and 9 significantly up- or down-regulated gut genes from S and R-strain, respectively, including serine proteases and aminopeptidases. These genes may be associated with Cry1Ab toxicity by degradation, binding, and cellular defense. Overall, our study suggests enhanced adaptation of Cry1Ab-resistant larvae on transgenic Cry1Ab corn as revealed by lower number and lower ratios of differentially expressed genes in R-strain than in S-strain of O. nubilalis.
Gene–Environment Interactions in Preventive Medicine: Current Status and Expectations for the Future
Authors: Narimatsu Hiroto
Published: January 2017

The progression of many common disorders involves a complex interplay of multiple factors, including numerous different genes and environmental factors. Gene–environmental cohort studies focus on the identification of risk factors that cannot be discovered by conventional epidemiological methodologies. Such epidemiological methodologies preclude precise predictions, because the exact risk factors can be revealed only after detailed analyses of the interactions among multiple factors, that is, between genes and environmental factors. To date, these cohort studies have reported some promising results. However, the findings do not yet have sufficient clinical significance for the development of precise, personalized preventive medicine. Especially, some promising preliminary studies have been conducted in terms of the prevention of obesity. Large-scale validation studies of those preliminary studies, using a prospective cohort design and long follow-ups, will produce useful and practical evidence for the development of preventive medicine in the future.
Photocatalytic Degradation of Organic Dye under UV‐A Irradiation Using TiO2‐Vetiver Multifunctional Nano Particles
Authors: Thao Le , Dang Trinh , Khanitchaidecha Wilawan , Channei Duangdao , Nakaruk Auppatham
Published: January 2017

The properties and photocatalytic performance of anatase nanoparticles of pure TiO2 and a core–shell structure of TiO2 on calcined vetiver grass leaves have been compared. Samples were fabricated by sol‐gel and heating at 450 °C for 5h.The comparison was based on data for X‐ray diffraction(XRD), UV‐Vis spectrophotometry, photoluminescence, transmission electron microscopy, specific surface area measurement, pore volume assessment, and methylene blue degradation testing. The results showed that the pure TiO2 consisted of agglomerated equiaxed nanoparticles of individual grain sizes in the range 10–20 nm. In contrast, the TiO2‐vetiver composite exhibited a core–shell structure consisting of a carbonaceous core and TiO2 shell of thickness 10–15nm. These features influenced the photocatalytic performance in such a way that the lower crosssectional area, greater surface area, and higher pore volume of the TiO2 shell increased the number of active sites, reduced the charge carrier diffusion distance, and reduced the recombination rate, thereby improving the photocatalytic activity. This improvement derived from morphological characteristics rather than crystallographic, semiconducting, or optical properties. The improved performance of the TiO2‐vetiver core–shell was unexpected since the X‐ray diffraction data showed that the crystallinity of the TiO2 was lower than that of the pure TiO2. These outcomes are attributed to the reducing effect of the carbon on the TiO2 during heating, thereby facilitating the formation of oxygen vacancies, which enhance charge separation and hence photocatalysis by TiO2.
Influence of Cryogenic Temperatures on the Microstructure and Mechanical Properties of Magnesium Alloys: A Review
Authors: Dieringa Hajo
Published: January 2017

Magnesium alloys have been used in the automotive industry and 3C (computer, communication, and consumer electronics) for many years. Their room temperature properties combined with their low density offer a wide range of applications, especially when processed by High Pressure Die Casting (HPDC). The use of magnesium alloys at higher temperatures is well-studied; special creep resistant alloys containing the rare earth elements silver or yttrium are needed. However, when it comes to very low temperatures, only a few studies have been performed to determine the property-microstructure relationship. The possible fields of application at low temperatures are aerospace and satellite parts and tanks for liquefied gases. This review shall not only examine mechanical properties at low temperatures, but also the permanent effects of cyclic or long-lasting cryogenic treatment on the microstructure and mechanical properties. It was found that cryogenic treatment is able to influence the precipitate concentration and grain orientation in some magnesium alloys. Reduction in the number of brittle phases is improving ductility in some cases. It is well-known that high speed tool steels, in particular, can be influenced by cryogenic treatment. Whether this is possible with magnesium alloys and what the mechanisms are shall be reviewed.
Metal Fluorides, Metal Chlorides and Halogenated Metal Oxides as Lewis Acidic Heterogeneous Catalysts. Providing Some Context for Nanostructured Metal Fluorides
Authors: Lennon David , Winfield John
Published: January 2017

Aspects of the chemistry of selected metal fluorides, which are pertinent to their real or potential use as Lewis acidic, heterogeneous catalysts, are reviewed. Particular attention is paid to β-aluminum trifluoride, aluminum chlorofluoride and aluminas γ and η, whose surfaces become partially fluorinated or chlorinated, through pre-treatment with halogenating reagents or during a catalytic reaction. In these cases, direct comparisons with nanostructured metal fluorides are possible. In the second part of the review, attention is directed to iron(III) and copper(II) metal chlorides, whose Lewis acidity and potential redox function have had important catalytic implications in large-scale chlorohydrocarbons chemistry. Recent work, which highlights the complexity of reactions that can occur in the presence of supported copper(II) chloride as an oxychlorination catalyst, is featured. Although direct comparisons with nanostructured fluorides are not currently possible, the work could be relevant to possible future catalytic developments in nanostructured materials.