bluuebunny/crossref_metadata_2025 huggingface dataset:
RNAi-Mediated Specific Gene Silencing as a Tool for the Discovery of New Drug Targets in Giardia lamblia; Evaluation Using the NADH Oxidase Gene
Authors: Marcial-Quino Jaime , Gómez-Manzo Saúl , Fierro Francisco , Rufino-González Yadira , Ortega-Cuellar Daniel , Sierra-Palacios Edgar , Vanoye-Carlo America , González-Valdez Abigail , Torres-Arroyo Angélica , Oria-Hernández Jesús , Reyes-Vivas Horacio
Published: November 2017

The microaerophilic protozoan Giardia lamblia is the agent causing giardiasis, an intestinal parasitosis of worldwide distribution. Different pharmacotherapies have been employed against giardiasis; however, side effects in the host and reports of drug resistant strains generate the need to develop new strategies that identify novel biological targets for drug design. To support this requirement, we have designed and evaluated a vector containing a cassette for the synthesis of double-stranded RNA (dsRNA), which can silence expression of a target gene through the RNA interference (RNAi) pathway. Small silencing RNAs were detected and quantified in transformants expressing dsRNA by a stem-loop RT-qPCR approach. The results showed that, in transformants expressing dsRNA of 100–200 base pairs, the level of NADHox mRNA was reduced by around 30%, concomitant with a decrease in enzyme activity and a reduction in the number of trophozoites with respect to the wild type strain, indicating that NADHox is indeed an important enzyme for Giardia viability. These results suggest that it is possible to induce the G. lamblia RNAi machinery for attenuating the expression of genes encoding proteins of interest. We propose that our silencing strategy can be used to identify new potential drug targets, knocking down genes encoding different structural proteins and enzymes from a wide variety of metabolic pathways.
Target 5000: Target Capture Sequencing for Inherited Retinal Degenerations
Authors: Dockery Adrian , Stephenson Kirk , Keegan David , Wynne Niamh , Silvestri Giuliana , Humphries Peter , Kenna Paul F. , Carrigan Matthew , Farrar G. Jane
Published: November 2017

There are an estimated 5000 people in Ireland who currently have an inherited retinal degeneration (IRD). It is the goal of this study, through genetic diagnosis, to better enable these 5000 individuals to obtain a clearer understanding of their condition and improved access to potentially applicable therapies. Here we show the current findings of a target capture next-generation sequencing study of over 750 patients from over 520 pedigrees currently situated in Ireland. We also demonstrate how processes can be implemented to retrospectively analyse patient datasets for the detection of structural variants in previously obtained sequencing reads. Pathogenic or likely pathogenic mutations were detected in 68% of pedigrees tested. We report nearly 30 novel mutations including three large structural variants. The population statistics related to our findings are presented by condition and credited to their respective candidate gene mutations. Rediagnosis rates of clinical phenotypes after genotyping are discussed. Possible causes of failure to detect a candidate mutation are evaluated. Future elements of this project, with a specific emphasis on structural variants and non-coding pathogenic variants, are expected to increase detection rates further and thereby produce an even more comprehensive representation of the genetic landscape of IRDs in Ireland.
The Tyrosyl-DNA Phosphodiesterase 1β (Tdp1β) Gene Discloses an Early Response to Abiotic Stresses
Authors: Sabatini Maria Elisa , Pagano Andrea , Araùjo Susana , Balestrazzi Alma , Macovei Anca
Published: November 2017

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is involved in DNA repair pathways as it mends the topoisomerase I—DNA covalent complexes. In plants, a small Tdp1 gene family, composed by Tdp1α and Tdp1β genes, was identified, but the roles of these genes in abiotic stress responses are not fully understood. To investigate their specific stress response patterns, the present study made use of bioinformatic and molecular tools to look into the Tdp1β gene function, so far described only in the plant kingdom, and compare it with Tdp1α gene coding for the canonical, highly conserved α isoform. The expression profiles of Tdp1α and Tdp1β genes were examined under abiotic stress conditions (cold, heat, high osmolarity, salt, and UV-B) in two model species, Arabidopsis thaliana and Medicago truncatula. The two isoforms of topoisomerase I (TOP1α and TOP1β) were also taken into consideration in view of their known roles in DNA metabolism and cell proliferation. Data relative to gene expression in Arabidopsis were retrieved from the AtGenExpress microarray dataset, while quantitative Real-Time PCR was carried out to evaluate the stress response in M. truncatula cell cultures. These analyses revealed that Tdp1β gene expression was enhanced during the first hour of treatment, whereas Tdp1α enhanced expression succeeded at subsequent timepoints. In agreement with the gene-specific responses to abiotic stress conditions, the promoter regions of Tdp1α and Tdp1β genes are well equipped with stress-related cis-elements. An in-depth bioinformatic characterization of the HIRAN motif, a distinctive feature of the Tdp1β protein, showed its wide distribution in chromatin remodeling and DNA repair proteins. The reported data suggests that Tdp1β functions in the early response to abiotic stresses.
The Role of Medication in Supporting Emotional Wellbeing in Young People with Long-Term Needs
Authors: Gray Nicola , Wood Damian
Published: November 2017

Young people frequently use and access prescribed medications for a range of health problems. Medications aimed at treating both common health problems and long-term physical and mental health needs in adolescence can have a significant effect on a young person’s emotional well-being. We use a series of case studies to illustrate the challenges for healthcare professionals supporting young people with medication use. The studies illustrate the efficacy and limitations of medication on improving emotional well-being by alleviating illness and distress, and how this efficacy must be balanced against both the adverse effects and the burden of treatment. There are specific challenges for medication management during adolescence including issues of adherence/concordance, facilitating autonomy and participation in decision making, and promoting independence.
Impact of Distance on Mode of Active Commuting in Chilean Children and Adolescents
Authors: Rodríguez-Rodríguez Fernando , Cristi-Montero Carlos , Celis-Morales Carlos , Escobar-Gómez Danica , Chillón Palma
Published: November 2017

Active commuting could contribute to increasing physical activity. The objective of this study was to characterise patterns of active commuting to and from schools in children and adolescents in Chile. A total of 453 Chilean children and adolescents aged between 10 and 18 years were included in this study. Data regarding modes of commuting and commuting distance was collected using a validated questionnaire. Commuting mode was classified as active commuting (walking and/or cycling) or non-active commuting (car, motorcycle and/or bus). Commuting distance expressed in kilometres was categorised into six subgroups (0 to 0.5, 0.6 to 1, 1.1 to 2, 2.1 to 3, 3.1 to 5 and >5 km). Car commuting was the main mode for children (to school 64.9%; from school 51.2%) and adolescents (to school 50.2%; from school 24.7%). Whereas public bus commuting was the main transport used by adolescents to return from school. Only 11.0% and 24.8% of children and adolescents, respectively, walk to school. The proportion of children and adolescents who engage in active commuting was lower in those covering longer distances compared to a short distance. Adolescents walked to and from school more frequently than children. These findings show that non-active commuting was the most common mode of transport and that journey distances may influence commuting modes in children and adolescents.
Plant Growth, Antibiotic Uptake, and Prevalence of Antibiotic Resistance in an Endophytic System of Pakchoi under Antibiotic Exposure
Authors: Zhang Hao , Li Xunan , Yang Qingxiang , Sun Linlin , Yang Xinxin , Zhou Mingming , Deng Rongzhen , Bi Linqian
Published: November 2017

Antibiotic contamination in agroecosystems may cause serious problems, such as the proliferation of various antibiotic resistant bacteria and the spreading of antibiotic resistance genes (ARGs) in the environment or even to human beings. However, it is unclear whether environmental antibiotics, antibiotic resistant bacteria, and ARGs can directly enter into, or occur in, the endophytic systems of plants exposed to pollutants. In this study, a hydroponic experiment exposing pakchoi (Brassica chinensis L.) to tetracycline, cephalexin, and sulfamethoxazole at 50% minimum inhibitory concentration (MIC) levels and MIC levels, respectively, was conducted to explore plant growth, antibiotic uptake, and the development of antibiotic resistance in endophytic systems. The three antibiotics promoted pakchoi growth at 50% MIC values. Target antibiotics at concentrations ranging from 6.9 to 48.1 µg·kg−1 were detected in the treated vegetables. Additionally, the rates of antibiotic-resistant endophytic bacteria to total cultivable endophytic bacteria significantly increased as the antibiotics accumulated in the plants. The detection and quantification of ARGs indicated that four types, tetX, blaCTX-M, and sul1 and sul2, which correspond to tetracycline, cephalexin, and sulfamethoxazole resistance, respectively, were present in the pakchoi endophytic system and increased with the antibiotic concentrations. The results highlight a potential risk of the development and spread of antibiotic resistance in vegetable endophytic systems.
Spatial Analysis of Linear Structures in the Exploration of Groundwater
Authors: Dembele Abdramane , Ye Xiufen
Published: November 2017

The analysis of linear structures on major geological formations plays a crucial role in resource exploration in the Inner Niger Delta. Highlighting and mapping of the large lithological units were carried out using image fusion, spectral bands (RGB coding), Principal Component Analysis (PCA), and band ratio methods. The automatic extraction method of linear structures has permitted the obtaining of a structural map with 82,659 linear structures, distributed on different stratigraphic stages. The intensity study shows an accentuation in density over 12.52% of the total area, containing 22.02% of the linear structures. The density and nodes (intersections of fractures) formed by the linear structures on the different lithologies allowed to observe the behavior of the region’s aquifers in the exploration of subsoil resources. The central density, in relation to the hydrographic network of the lowlands, shows the conditioning of the flow and retention of groundwater in the region, and in-depth fluids. The node areas and high-density linear structures, have shown an ability to have rejections in deep (pores) that favor the formation of structural traps for oil resources.
Mixture Statistical Distribution Based Multiple Component Model for Target Detection in High Resolution SAR Imagery
Authors: He Chu , Tu Mingxia , Liu Xinlong , Xiong Dehui , Liao Mingsheng
Published: November 2017

This paper proposes an innovative Mixture Statistical Distribution Based Multiple Component (MSDMC) model for target detection in high spatial resolution Synthetic Aperture Radar (SAR) images. Traditional detection algorithms usually ignore the spatial relationship among the target’s components. In the presented method, however, both the structural information and the statistical distribution are considered to better recognize the target. Firstly, the method based on compressed sensing reconstruction is used to recover the SAR image. Then, the multiple component model composed of a root filter and some corresponding part filters is applied to describe the structural information of the target. In the following step, mixture statistical distributions are utilised to discriminate the target from the background, and the Method of Logarithmic Cumulants (MoLC) based Expectation Maximization (EM) approach is adopted to estimate the parameters of the mixture statistical distribution model, which will be finally merged into the proposed MSDMC framework together with the multiple component model. In the experiment, the aeroplanes and the electrical power towers in TerraSAR-X SAR images are detected at three spatial resolutions. The results indicate that the presented MSDMC Model has potential for improving the detection performance compared with the state-of-the-art SAR target detection methods.
Involvement of Opioid System, TRPM8, and ASIC Receptors in Antinociceptive Effect of Arrabidaea brachypoda (DC) Bureau
Authors: Rodrigues Vinícius , Rocha Cláudia , Périco Larissa , Santos Raquel , Ohara Rie , Nishijima Catarine , Ferreira Queiroz Emerson , Wolfender Jean-Luc , Rocha Lúcia , Santos Adair , Vilegas Wagner , Hiruma-Lima Clélia
Published: November 2017

Arrabidaea brachypoda (DC) Bureau is a medicinal plant found in Brazil. Known as “cipó-una”, it is popularly used as a natural therapeutic agent against pain and inflammation. This study evaluated the chemical composition and antinociceptive activity of the dichloromethane fraction from the roots of A. brachypoda (DEAB) and its mechanism of action. The chemical composition was characterized by high-performance liquid chromatography, and this fraction is composed only of dimeric flavonoids. The antinociceptive effect was evaluated in formalin and hot plate tests after oral administration (10–100 mg/kg) in male Swiss mice. We also investigated the involvement of TRPV1 (transient receptor potential vanilloid 1), TRPA1 (transient receptor potential ankyrin 1), TRPM8 (transient receptor potential melastatin 8), and ASIC (acid-sensing ion channel), as well as the opioidergic, glutamatergic, and supraspinal pathways. Moreover, the nociceptive response was reduced (30 mg/kg) in the early and late phase of the formalin test. DEAB activity appears to involve the opioid system, TRPM8, and ASIC receptors, clearly showing that the DEAB alleviates acute pain in mice and suggesting the involvement of the TRPM8 and ASIC receptors and the opioid system in acute pain relief.
Receptors for Insulin-Like Growth Factor-2 and Androgens as Therapeutic Targets in Triple-Negative Breast Cancer
Authors: Hamilton Nalo , Austin David , Márquez-Garbán Diana , Sanchez Rudy , Chau Brittney , Foos Kay , Wu Yanyuan , Vadgama Jaydutt , Pietras Richard
Published: November 2017

Triple-negative breast cancer (TNBC) occurs in 10–15% of all breast cancer patients, yet it accounts for about half of all breast cancer deaths. There is an urgent need to identify new antitumor targets to provide additional treatment options for patients afflicted with this aggressive disease. Preclinical evidence suggests a critical role for insulin-like growth factor-2 (IGF2) and androgen receptor (AR) in regulating TNBC progression. To advance this work, a panel of TNBC cell lines was investigated with all cell lines showing significant expression of IGF2. Treatment with IGF2 stimulated cell proliferation in vitro (p < 0.05). Importantly, combination treatments with IGF1R inhibitors BMS-754807 and NVP-AEW541 elicited significant inhibition of TNBC cell proliferation (p < 0.001). Based on Annexin-V binding assays, BMS-754807, NVP-AEW541 and enzalutamide induced TNBC cell death (p < 0.005). Additionally, combination of enzalutamide with BMS-754807 or NVP-AEW541 exerted significant reductions in TNBC proliferation even in cells with low AR expression (p < 0.001). Notably, NVP-AEW541 and BMS-754807 reduced AR levels in BT549 TNBC cells. These results provide evidence that IGF2 promotes TNBC cell viability and proliferation, while inhibition of IGF1R/IR and AR pathways contribute to blockade of TNBC proliferation and promotion of apoptosis in vitro.
Ammonia Reduces Intracellular Asymmetric Dimethylarginine in Cultured Astrocytes Stimulating Its y+LAT2 Carrier-Mediated Loss
Authors: Milewski Krzysztof , Bogacińska-Karaś Małgorzata , Fręśko Inez , Hilgier Wojciech , Jaźwiec Radosław , Albrecht Jan , Zielińska Magdalena
Published: November 2017

Previously we had shown that ammonia stimulates nitric oxide (NO) synthesis in astrocytes by increasing the uptake of the precursor amino acid, arginine via the heteromeric arginine/glutamine transporter y+LAT2. Ammonia also increases the concentration in the brain of the endogenous inhibitor of nitric oxide synthases (NOS), asymmetric dimethylarginine (ADMA), but distribution of ADMA surplus between the intraastrocytic and extracellular compartments of the brain has not been studied. Here we tested the hypothesis that ammonia modulates the distribution of ADMA and its analog symmetric dimethylarginine (SDMA) between the two compartments of the brain by competition with arginine for the y+LAT2 transporter. In extension of the hypothesis we analyzed the ADMA/Arg interaction in endothelial cells forming the blood-brain barrier. We measured by high-performance liquid chromatography (HPLC) and mass spectrometry (MS) technique the concentration of arginine, ADMA and SDMA in cultured cortical astrocytes and in a rat brain endothelial cell line (RBE-4) treated with ammonia and the effect of silencing the expression of a gene coding y+LAT2. We also tested the expression of ADMA metabolism enzymes: protein arginine methyltransferase (PRMT) and dimethylarginine dimethyl aminohydrolase (DDAH) and arginine uptake to astrocytes. Treatment for 48 h with 5 mM ammonia led to an almost 50% reduction of ADMA and SDMA concentration in both cell types, and the effect in astrocytes was substantially attenuated by silencing of the Slc7a6 gene. Moreover, the y+LAT2-dependent component of ammonia-evoked arginine uptake in astrocytes was reduced in the presence of ADMA in the medium. Our results suggest that increased ADMA efflux mediated by upregulated y+LAT2 may be a mechanism by which ammonia interferes with intra-astrocytic (and possibly intra-endothelial cell) ADMA content and subsequently, NO synthesis in both cell types.
Urinary Metabolomic Profiling to Identify Potential Biomarkers for the Diagnosis of Behcet’s Disease by Gas Chromatography/Time-of-Flight−Mass Spectrometry
Authors: Ahn Joong , Kim Jungyeon , Hwang Jiwon , Song Juhwan , Kim Kyoung , Cha Hoon-Suk
Published: November 2017

Diagnosing Behcet’s disease (BD) is challenging because of the lack of a diagnostic biomarker. The purposes of this study were to investigate distinctive metabolic changes in urine samples of BD patients and to identify urinary metabolic biomarkers for diagnosis of BD using gas chromatography/time-of-flight–mass spectrometry (GC/TOF−MS). Metabolomic profiling of urine samples from 44 BD patients and 41 healthy controls (HC) were assessed using GC/TOF−MS, in conjunction with multivariate statistical analysis. A total of 110 urinary metabolites were identified. The urine metabolite profiles obtained from GC/TOF−MS analysis could distinguish BD patients from the HC group in the discovery set. The parameter values of the orthogonal partial least squared-discrimination analysis (OPLS-DA) model were R2X of 0.231, R2Y of 0.804, and Q2 of 0.598. A biomarker panel composed of guanine, pyrrole-2-carboxylate, 3-hydroxypyridine, mannose, l-citrulline, galactonate, isothreonate, sedoheptuloses, hypoxanthine, and gluconic acid lactone were selected and adequately validated as putative biomarkers of BD (sensitivity 96.7%, specificity 93.3%, area under the curve 0.974). OPLS-DA showed clear discrimination of BD and HC groups by a biomarker panel of ten metabolites in the independent set (accuracy 88%). We demonstrated characteristic urinary metabolic profiles and potential urinary metabolite biomarkers that have clinical value in the diagnosis of BD using GC/TOF−MS.
Diverse Effects of an Acetylcholinesterase Inhibitor, Donepezil, on Hippocampal Neuronal Death after Pilocarpine-Induced Seizure
Authors: Jeong Jeong Hyun , Choi Bo Young , Kho A Ra , Lee Song Hee , Hong Dae Ki , Lee Sang Hwon , Lee Sang Yup , Song Hong Ki , Choi Hui Chul , Suh Sang Won
Published: November 2017

Epileptic seizures are short episodes of abnormal brain electrical activity. Many survivors of severe epilepsy display delayed neuronal death and permanent cognitive impairment. Donepezil is an acetylcholinesterase inhibitor and is an effective treatment agent for Alzheimer’s disease. However, the role of donepezil in seizure-induced hippocampal injury remains untested. Temporal lobe epilepsy (TLE) was induced by intraperitoneal injection of pilocarpine (25 mg/kg). Donepezil (2.5 mg/kg/day) was administered by gavage in three different settings: (1) pretreatment for three days before the seizure; (2) for one week immediately after the seizure; and (3) for three weeks from three weeks after the seizure. We found that donepezil showed mixed effects on seizure-induced brain injury, which were dependent on the treatment schedule. Pretreatment with donepezil aggravated neuronal death, oxidative injury, and microglia activation. Early treatment with donepezil for one week showed neither adverse nor beneficial effects; however, a treatment duration of three weeks starting three weeks after the seizure showed a significant reduction in neuronal death, oxidative injury, and microglia activation. In conclusion, donepezil has therapeutic effects when injected for three weeks after seizure activity subsides. Therefore, the present study suggests that the therapeutic use of donepezil for epilepsy patients requires a well-conceived strategy for administration.
Actions of Brain-Derived Neurotrophic Factor and Glucocorticoid Stress in Neurogenesis
Authors: Numakawa Tadahiro , Odaka Haruki , Adachi Naoki
Published: November 2017

Altered neurogenesis is suggested to be involved in the onset of brain diseases, including mental disorders and neurodegenerative diseases. Neurotrophic factors are well known for their positive effects on the proliferation/differentiation of both embryonic and adult neural stem/progenitor cells (NSCs/NPCs). Especially, brain-derived neurotrophic factor (BDNF) has been extensively investigated because of its roles in the differentiation/maturation of NSCs/NPCs. On the other hand, recent evidence indicates a negative impact of the stress hormone glucocorticoids (GCs) on the cell fate of NSCs/NPCs, which is also related to the pathophysiology of brain diseases, such as depression and autism spectrum disorder. Furthermore, studies including ours have demonstrated functional interactions between neurotrophic factors and GCs in neural events, including neurogenesis. In this review, we show and discuss relationships among the behaviors of NSCs/NPCs, BDNF, and GCs.
Oxidative Stress in Human Atherothrombosis: Sources, Markers and Therapeutic Targets
Authors: Martin-Ventura Jose , Rodrigues-Diez Raquel , Martinez-Lopez Diego , Salaices Mercedes , Blanco-Colio Luis , Briones Ana
Published: November 2017

Atherothrombosis remains one of the main causes of morbidity and mortality worldwide. The underlying pathology is a chronic pathological vascular remodeling of the arterial wall involving several pathways, including oxidative stress. Cellular and animal studies have provided compelling evidence of the direct role of oxidative stress in atherothrombosis, but such a relationship is not clearly established in humans and, to date, clinical trials on the possible beneficial effects of antioxidant therapy have provided equivocal results. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is one of the main sources of reactive oxygen species (ROS) in human atherothrombosis. Moreover, leukocyte-derived myeloperoxidase (MPO) and red blood cell-derived iron could be involved in the oxidative modification of lipids/lipoproteins (LDL/HDL) in the arterial wall. Interestingly, oxidized lipoproteins, and antioxidants, have been analyzed as potential markers of oxidative stress in the plasma of patients with atherothrombosis. In this review, we will revise sources of ROS, focusing on NADPH oxidase, but also on MPO and iron. We will also discuss the impact of these oxidative systems on LDL and HDL, as well as the value of these modified lipoproteins as circulating markers of oxidative stress in atherothrombosis. We will finish by reviewing some antioxidant systems and compounds as therapeutic strategies to prevent pathological vascular remodeling.
High Resolution Melting (HRM) for High-Throughput Genotyping—Limitations and Caveats in Practical Case Studies
Authors: Słomka Marcin , Sobalska-Kwapis Marta , Wachulec Monika , Bartosz Grzegorz , Strapagiel Dominik
Published: November 2017

High resolution melting (HRM) is a convenient method for gene scanning as well as genotyping of individual and multiple single nucleotide polymorphisms (SNPs). This rapid, simple, closed-tube, homogenous, and cost-efficient approach has the capacity for high specificity and sensitivity, while allowing easy transition to high-throughput scale. In this paper, we provide examples from our laboratory practice of some problematic issues which can affect the performance and data analysis of HRM results, especially with regard to reference curve-based targeted genotyping. We present those examples in order of the typical experimental workflow, and discuss the crucial significance of the respective experimental errors and limitations for the quality and analysis of results. The experimental details which have a decisive impact on correct execution of a HRM genotyping experiment include type and quality of DNA source material, reproducibility of isolation method and template DNA preparation, primer and amplicon design, automation-derived preparation and pipetting inconsistencies, as well as physical limitations in melting curve distinction for alternative variants and careful selection of samples for validation by sequencing. We provide a case-by-case analysis and discussion of actual problems we encountered and solutions that should be taken into account by researchers newly attempting HRM genotyping, especially in a high-throughput setup.
Recent Advances in Comprehending the Signaling Pathways Involved in the Progression of Breast Cancer
Authors: Nicolini Andrea , Ferrari Paola , Diodati Lucrezia , Carpi Angelo
Published: November 2017

This review describes recent advances in the comprehension of signaling pathways involved in breast cancer progression. Calcium sensing receptor (CaSR), caveolae signaling, signaling referred to hypoxia-inducing factors and disturbances in the apoptotic machinery are related to more general biological mechanisms and are considered first. The others refer to signaling pathways of more specific biological mechanisms, namely the heparin/heparin-sulfate interactome, over-expression of miRNA-378a-5p, restriction of luminal and basal epithelial cells, fatty-acid synthesis, molecular pathways related to epithelial to mesenchimal transition (EMT), HER-2/neu gene amplification and protein expression, and the expression of other members of the epithelial growth factor receptor family. This progress in basic research is fundamental to foster the ongoing efforts that use the new genotyping technologies, and aim at defining new prognostic and predictive biomarkers for a better personalized management of breast cancer disease.
The Hypothalamic–Pituitary Axis and Autoantibody Related Disorders
Authors: Cocco Cristina , Brancia Carla , Corda Giulia , Ferri Gian-Luca
Published: November 2017

This review summarized different studies reporting the presence of autoantibodies reacting against cells of the pituitary (APAs) and/or hypothalamus (AHAs). Both APAs and AHAs have been revealed through immunofluorescence using different kinds of substrates. Autoantibodies against gonadotropic cells were mainly found in patients affected by cryptorchidism and hypogonadotropic hypogonadism while those against prolactin cells were found in different kinds of patients, the majority without pituitary abnormalities. APAs to growth hormone (GH) cells have been associated with GH deficiency while those against the adrenocorticotropic cells have distinguished central Cushing’s disease patients at risk of incomplete cure after surgical adenoma removal. AHAs to vasopressin cells have identified patients at risk of developing diabetes insipidus. APAs have been also found together with AHAs in patients affected by idiopathic hypopituitarism, but both were also present in different kinds of patients without abnormalities of the hypothalamic–pituitary axis. Despite some data being promising, the clinical use of pituitary and hypothalamus autoantibodies is still limited by the low diagnostic sensitivity, irreproducibility of the results, and the absence of autoantigen/s able to discriminate the autoimmune reaction involving the pituitary or the hypothalamus from the other autoimmune states.
Divalent Cations Regulate the Ion Conductance Properties of Diverse Classes of Aquaporins
Authors: Kourghi Mohamad , Nourmohammadi Saeed , Pei Jinxin , Qiu Jiaen , McGaughey Samantha , Tyerman Stephen , Byrt Caitlin , Yool Andrea
Published: November 2017

Aquaporins (AQPs) are known to facilitate water and solute fluxes across barrier membranes. An increasing number of AQPs are being found to serve as ion channels. Ion and water permeability of selected plant and animal AQPs (plant Arabidopsis thaliana AtPIP2;1, AtPIP2;2, AtPIP2;7, human Homo sapiens HsAQP1, rat Rattus norvegicus RnAQP4, RnAQP5, and fly Drosophila melanogaster DmBIB) were expressed in Xenopus oocytes and examined in chelator-buffered salines to evaluate the effects of divalent cations (Ca2+, Mg2+, Ba2+ and Cd2+) on ionic conductances. AtPIP2;1, AtPIP2;2, HsAQP1 and DmBIB expressing oocytes had ionic conductances, and showed differential sensitivity to block by external Ca2+. The order of potency of inhibition by Ca2+ was AtPIP2;2 > AtPIP2;1 > DmBIB > HsAQP1. Blockage of the AQP cation channels by Ba2+ and Cd2+ caused voltage-sensitive outward rectification. The channels with the highest sensitivity to Ca2+ (AtPIP2;1 and AtPIP2;2) showed a distinctive relief of the Ca2+ block by co-application of excess Ba2+, suggesting that divalent ions act at the same site. Recognizing the regulatory role of divalent cations may enable the discovery of other classes of AQP ion channels, and facilitate the development of tools for modulating AQP ion channels. Modulators of AQPs have potential value for diverse applications including improving salinity tolerance in plants, controlling vector-borne diseases, and intervening in serious clinical conditions involving AQPs, such as cancer metastasis, cardiovascular or renal dysfunction.
Estrogen Effects on Wound Healing
Authors: Horng Huann-Cheng , Chang Wen-Hsun , Yeh Chang-Ching , Huang Ben-Shian , Chang Chia-Pei , Chen Yi-Jen , Tsui Kuan-Hao , Wang Peng-Hui
Published: November 2017

Wound healing is a physiological process, involving three successive and overlapping phases—hemostasis/inflammation, proliferation, and remodeling—to maintain the integrity of skin after trauma, either by accident or by procedure. Any disruption or unbalanced distribution of these processes might result in abnormal wound healing. Many molecular and clinical data support the effects of estrogen on normal skin homeostasis and wound healing. Estrogen deficiency, for example in postmenopausal women, is detrimental to wound healing processes, notably inflammation and re-granulation, while exogenous estrogen treatment may reverse these effects. Understanding the role of estrogen on skin might provide further opportunities to develop estrogen-related therapy for assistance in wound healing.
Whole Blood mRNA Expression-Based Prognosis of Metastatic Renal Cell Carcinoma
Authors: Giridhar Karthik , Sosa Carlos , Hillman David , Sanhueza Cristobal , Dalpiaz Candace , Costello Brian , Quevedo Fernando , Pitot Henry , Dronca Roxana , Ertz Donna , Cheville John , Donkena Krishna , Kohli Manish
Published: November 2017

The Memorial Sloan Kettering Cancer Center (MSKCC) prognostic score is based on clinical parameters. We analyzed whole blood mRNA expression in metastatic clear cell renal cell carcinoma (mCCRCC) patients and compared it to the MSKCC score for predicting overall survival. In a discovery set of 19 patients with mRCC, we performed whole transcriptome RNA sequencing and selected eighteen candidate genes for further evaluation based on associations with overall survival and statistical significance. In an independent validation of set of 47 patients with mCCRCC, transcript expression of the 18 candidate genes were quantified using a customized NanoString probeset. Cox regression multivariate analysis confirmed that two of the candidate genes were significantly associated with overall survival. Higher expression of BAG1 [hazard ratio (HR) of 0.14, p < 0.0001, 95% confidence interval (CI) 0.04–0.36] and NOP56 (HR 0.13, p < 0.0001, 95% CI 0.05–0.34) were associated with better prognosis. A prognostic model incorporating expression of BAG1 and NOP56 into the MSKCC score improved prognostication significantly over a model using the MSKCC prognostic score only (p < 0.0001). Prognostic value of using whole blood mRNA gene profiling in mCCRCC is feasible and should be prospectively confirmed in larger studies.
Genome Analysis and Genetic Stability of the Cryptophlebia leucotreta Granulovirus (CrleGV-SA) after 15 Years of Commercial Use as a Biopesticide
Authors: Van der Merwe Marcel , Jukes Michael , Rabalski Lukasz , Knox Caroline , Opoku-Debrah John , Moore Sean , Krejmer-Rabalska Martyna , Szewczyk Boguslaw , Hill Martin
Published: November 2017

Thaumatotibia leucotreta Meyrick (Lepidoptera: Tortricidae) is an indigenous pest in southern Africa which attacks citrus fruits and other crops. To control T. leucotreta in South Africa, an integrated pest management (IPM) programme incorporating the baculovirus Cryptophlebia leucotreta granulovirus (CrleGV-SA) as a biopesticide has been implemented. This study investigated the genetic stability of a commercially produced CrleGV-SA product that has been applied in the field since 2000. Seven representative full-genome sequences of the CrleGV-SA isolate spanning a 15-year period were generated and compared with one another. Several open reading frames (ORFs) were identified to have acquired single nucleotide polymorphisms (SNPs) during the 15-year period, with three patterns observed and referred to as “stable”, “reversion”, and “unstable switching”. Three insertion events were also identified, two of which occurred within ORFs. Pairwise multiple alignments of these sequences showed an identity ranging from 99.98% to 99.99%. Concentration-response bioassays comparing samples of CrleGV-SA from 2000 and 2015 showed an increase in virulence toward neonate T. leucotreta larvae. The CrleGV-SA genome sequence generated from the 2015 sample was compared to the Cape Verde reference genome, CrleGV-CV3. Several fusion events were identified between ORFs within these genomes. These sequences shared 96.7% pairwise identity, confirming that CrleGV-SA is a genetically distinct isolate. The results of this study indicate that the genome of CrleGV-SA has remained stable over many years, with implications for its continued use as a biopesticide in the field. Furthermore, the study describes the first complete baculovirus genome to be sequenced with the MinION (Oxford Nanopore, Oxford, UK) platform and the first complete genome sequence of the South African CrleGV isolate.
Case Study of a Nearly Zero Energy Building in Italian Climatic Conditions
Authors: Khan Hassan , Asif Muhammad , Mohammed Mohammed
Published: November 2017

The building sector is an important stakeholder in the energy and environmental scenario of any country. It continues to grow across the world due to factors such as population growth, and economic and infrastructure development. Within the European Union, buildings account for 40% of the total energy requirements and 30% of carbon dioxide emissions. The building sector is keen to improve its sustainability standards and also to help achieve the 20-20-20 targets set by the European Union. The present work aims to design a nearly zero energy sports gymnasium building in Calolziocorte, Italy. Various sustainability techniques are applied in an integrated design project approach using ECOTECT software to undertake the energy modelling exercise. Firstly, the base-case is modelled with conventional building materials and the total energy demand is calculated. Duly considering the local climatic conditions, sustainable materials are chosen for walls, the floor, the roof, and windows and a 38% reduction is noted in the total energy demand of the building compared to the base-case. The impact of louvers as a passive design technique has also been examined on the total energy demand of the building. The monthly load/discomfort analysis is undertaken for various individual functions inside the building to identify the critical areas that consume more energy. The monthly load/discomfort analysis is performed with the proposed materials and the air infiltration rate is improved through the building envelope and 63% reduction is noted in the total energy demand of the building compared to the base-case. A solar access analysis is conducted to understand the on-site energy production and then the building net energy demand is calculated, which is reduced to 90% compared to the base-case.
Adenosine A2B Receptors: An Optional Target for the Management of Irritable Bowel Syndrome with Diarrhea?
Authors: Asano Teita , Takenaga Mitsuko
Published: November 2017

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder, with the characteristic symptoms of chronic abdominal pain and altered bowel habits (diarrhea, constipation, or both). IBS is a highly prevalent condition, which negatively affects quality of life and is a significant burden on global healthcare costs. Although many pharmacological medicines have been proposed to treat IBS, including those targeting receptors, channels, and chemical mediators related to visceral hypersensitivity, successful pharmacotherapy for the disease has not been established. Visceral hypersensitivity plays an important role in IBS pathogenesis. Immune activation is observed in diarrhea-predominant patients with IBS and contributes to the development of visceral hypersensitivity. Adenosine is a chemical mediator that regulates many physiological processes, including inflammation and nociception. Among its receptors, the adenosine A2B receptor regulates intestinal secretion, motor function, and the immune response. We recently demonstrated that the adenosine A2B receptor is involved in visceral hypersensitivity in animal models of IBS. In this review, we discuss the possibility of the adenosine A2B receptor as a novel therapeutic target for IBS.
Effect of Laser Remelting and Simultaneous Application of Ultrasonic Vibrations during Laser Melting on the Microstructural and Tribological Properties of Laser Clad Al-SiC Composites
Authors: Biswas Sourabh , Alavi S. , Harimkar Sandip
Published: November 2017

Laser composite surfacing of aluminum alloys with ceramic particles has been extensively investigated for improving tribological properties. However, the process often results in incomplete penetration of ceramic particles in the melt pool and undesirable interfacial reactions. In this paper, laser composite surfacing of 2024 aluminum alloy with SiC particles is investigated using two distinct approaches: laser remelting and laser melting under the influence of ultrasonic vibrations of preplaced powder mixture. Detailed analysis of variation of clad layer thickness, microstructure in the composite clad layer, phase/texture development, surface roughness, and sliding wear performance with laser processing conditions is presented. The analysis showed that remelting and ultrasonic vibration assist results in significant improvement in clad layer thickness and microstructure (reduction in needle-like α-Si phase). While the laser remelting resulted in significant reduction in wear rate, the specimens processed with ultrasonic vibration-assisted laser melting showed variable wear rate, likely due to complex effects of microstructural modification and enhanced surface roughness.
Insights into the Performance of Magnetoelectric Ceramic Layered Composites
Authors: Ramos Pablo , Amorin Harvey , Ricote Jesus , Castro Alicia , Alguero Miguel
Published: November 2017

Finite element analysis is used to simulate the magnetoelectric response of magnetostrictive-piezoelectric NiFe2O4-Bi0.36Pb0.64Sc0.36Ti0.64O3 ceramic two-layer, three-layer, and multilayer structures considering finite geometry and introducing the conductivity of the magnetic component. Results are compared with those obtained with existing approximate analytical solutions, and with the experimental data available for high-quality layered composites. Limitations of the widely used analytical solution for a bilayer are revealed, and the reported good agreement with experimental coefficients is shown to be coincidental. Magnetoelectric coefficients obtained by simulation using realistic material parameters are systematically above the experimental values for three-layer and multilayer composites. Possible mechanisms for the reduction in response are analyzed. Strain relaxation across the piezoelectric layer, strongly associated with its mechanical performance, is shown to be the most feasible cause.
Comparative Analysis of Coastal Flooding Vulnerability and Hazard Assessment at National Scale
Authors: Di Risio Marcello , Bruschi Antonello , Lisi Iolanda , Pesarino Valeria , Pasquali Davide
Published: November 2017

The evaluation of the coastal hazard and vulnerability caused by storm conditions is an important issue related to coastal flooding and erosion. Although these topics have been widely tackled by past research, they cannot be avoided, but need to be carefully managed by local authorities in order to limit damage to coastal infrastructure, to protect human life, habitats and sensitive species. Usually, this issue is tackled through common approaches at the regional scale. This paper illustrates the first steps of a research project aimed at assessing coastal hazard and vulnerability to wave-induced flooding at the national scale. In order to apply the method to the national scale, it is necessary to select a suitable dataset. This has to be consistent with the whole application area, concerning its spatial distribution, reliability and availability. Thus, one of the aims of this project is to perform a comparative analysis using data available at the national and local scale. The analysis was performed for the area of Montalto di Castro (Tyrrhenian Sea) by using datasets with different spatial resolutions. The results revealed that the use of low resolution data does not significantly affect the estimated nearshore wave features, while the wave runup in underestimated by about 25%. This underestimation influences also the vulnerability and hazard assessments. In particular, the vulnerability is conservatively assessed if low resolution data are used. On the other hand, the hazard is conservatively assessed when low resolution data are used only if the wave runup is amplified by considering the 25% underestimation. The results presented herein can be extended to other sites with the same general features (i.e., microtidal and dissipative coastal stretches).
Water Rights on Community Lands: LandMark’s Findings from 100 Countries
Authors: Alden Wily Liz , Dubertret Fabrice , Veit Peter , Reytar Katie , Tagliarino Nicholas
Published: November 2017

This paper analyzes whether national laws acknowledge indigenous peoples and other rural communities in 100 countries as owners of waters that arise within their lands. Results derive from information collected by LandMark to score the legal status of community land tenure. Findings are positive; half of all countries recognize communities as lawful possessors of water on their lands. Three quarters permit communities to manage the distribution and use of water on their lands. While 71 percent of countries declare water to be a public resource, this belies the substantial existence of privately owned water. In 29 percent of countries, private water is an identified legal category, and in many other countries obtainable rights to water are sufficiently substantial to imply lawful possession. Communities are beneficiaries mainly where customary rights are accorded status as property rights, or where ownership of public lands and water are devolved to rural collectives. However, opposite trends of nationalization and regulation of water suggest that while legal recognition of community land ownership may rise in the future, this will not necessarily include waters on the land. Irrespective of tenure, rural communities in 72 of 77 countries (93.5 percent) are legally assured access to water for domestic purposes. This is consistent with the rising definition of safe drinking water as a human right, although access does not necessarily come free of cost.
Development of a Model for Dynamic Recrystallization Consistent with the Second Derivative Criterion
Authors: Imran Muhammad , Kühbach Markus , Roters Franz , Bambach Markus
Published: November 2017

Dynamic recrystallization (DRX) processes are widely used in industrial hot working operations, not only to keep the forming forces low but also to control the microstructure and final properties of the workpiece. According to the second derivative criterion (SDC) by Poliak and Jonas, the onset of DRX can be detected from an inflection point in the strain-hardening rate as a function of flow stress. Various models are available that can predict the evolution of flow stress from incipient plastic flow up to steady-state deformation in the presence of DRX. Some of these models have been implemented into finite element codes and are widely used for the design of metal forming processes, but their consistency with the SDC has not been investigated. This work identifies three sources of inconsistencies that models for DRX may exhibit. For a consistent modeling of the DRX kinetics, a new strain-hardening model for the hardening stages III to IV is proposed and combined with consistent recrystallization kinetics. The model is devised in the Kocks-Mecking space based on characteristic transition in the strain-hardening rate. A linear variation of the transition and inflection points is observed for alloy 800H at all tested temperatures and strain rates. The comparison of experimental and model results shows that the model is able to follow the course of the strain-hardening rate very precisely, such that highly accurate flow stress predictions are obtained.
Mineral Trioxide Aggregate—A Review of Properties and Testing Methodologies
Authors: Ha William N. , Nicholson Timothy , Kahler Bill , Walsh Laurence J.
Published: November 2017

Mineral trioxide aggregate (MTA) restoratives and MTA sealers are commonly used in endodontics. Commonly referenced standards for testing of MTA are ISO 6876, 9917-1 and 10993. A PubMed search was performed relating to the relevant tests within each ISO and “mineral trioxide aggregate”. MTA restoratives are typically tested with a mixture of tests from multiple standards. As the setting of MTA is dependent upon hydration, the results of various MTA restoratives and sealers are dependent upon the curing methodology. This includes physical properties after mixing, physical properties after setting and biocompatibility. The tests of flow, film thickness, working time and setting time can be superseded by rheology as it details how MTA hydrates. Physical property tests should replicate physiological conditions, i.e. 37 °C and submerged in physiological solution. Biocompatibility tests should involve immediate placement of samples immediately after mixing rather than being cured prior to placement as this does not replicate clinical usage. Biocompatibility tests should seek to replicate physiological conditions with MTA tested immediately after mixing.