bluuebunny/crossref_metadata_2025_split huggingface dataset:
Daily expression of two circadian clock genes in compound eyes of Helicoverpa armigera: evidence for peripheral tissue circadian timing
Authors: Yan Shuo , Liu Yan‐Jun , Zhu Jia‐Lin , Cui Wei‐Na , Zhang Xin‐Fang , Yang Yu‐Hui , Liu Xiao‐Ming , Zhang Qing‐Wen , Liu Xiao‐Xia 
Published: September 2017

AbstractCircadian clock genes in peripheral tissues usually play an important role in regulating the circadian rhythms. Light is the most important environmental signal for synchronizing endogenous rhythms with the daily light‐dark cycle, and compound eyes are known as the principal circadian photoreceptor for photic entrainment in most moths. However, there is little evidence for circadian timing in compound eyes. In the current study, we isolated the timeless gene, designated Ha‐tim (GenBank accession number: KM233162), from the cotton bollworm Helicoverpa armigera. Ha‐tim and period (Ha‐per) showed low messenger RNA levels in the compound eyes compared to the other tested adult organs. Ha‐tim and Ha‐per transcript levels were dependent on an endogenous rhythm that fluctuated over a daily cycle in the compound eyes and heads. The cycles of Ha‐tim and Ha‐per transcript levels followed similar time courses, and identical expression patterns of the two genes were observed in the compound eyes and heads. Ha‐tim and Ha‐per were down‐regulated in the compound eyes after light exposure, copulation and starvation. These results indicated that Ha‐tim and Ha‐per transcript levels were regulated by endogenous and exogenous factors. Our study helped to improve our understanding of the circadian clock machinery in compound eyes and other peripheral tissues.
Malondialdehyde–Acetaldehyde (MAA) Protein Adducts Are Found Exclusively in the Lungs of Smokers with Alcohol Use Disorders and Are Associated with Systemic Anti‐MAA Antibodies
Authors: Sapkota Muna , Burnham Ellen L. , DeVasure Jane M. , Sweeter Jenea M. , Hunter Carlos D. , Duryee Michael J. , Klassen Lynell W. , Kharbanda Kusum K. , Sisson Joseph H. , Thiele Geoffrey M. , Wyatt Todd A. 
Published: September 2017

BackgroundMalondialdehyde (MDA) and acetaldehyde (AA) exist following ethanol metabolism and tobacco pyrolysis. As such, lungs of individuals with alcohol use disorders (AUDs) are a target for the effects of combined alcohol and cigarette smoke metabolites. MDA and AA form a stable protein adduct, malondialdehyde–acetaldehyde (MAA) adduct, known to be immunogenic, profibrotic, and proinflammatory. MAA adduct is the dominant epitope in anti‐MAA antibody formation. We hypothesized that MAA‐adducted protein forms in lungs of those who both abuse alcohol and smoke cigarettes, and that this would be associated with systemically elevated anti‐MAA antibodies.MethodsFour groups were established: AUD subjects who smoked cigarettes (+AUD/+smoke), smokers without AUD (−AUD/+smoke), AUD without smoke (+AUD/−smoke), and non‐AUD/nonsmokers (−AUD/−smoke).ResultsWe observed a significant increase in MAA adducts in lung cells of +AUD/+smoke versus −AUD/−smoke. No significant increase in MAA adducts was observed in −AUD/+smoke or in +AUD/−smoke compared to −AUD/−smoke. Serum from +AUD/+smoke had significantly increased levels of circulating anti‐MAA IgA antibodies. After 1 week of alcohol that MAA‐adducted protein is formed in the lungs of those who smoke cigarettes and abuse alcohol, leading to a subsequent increase in serum IgA antibodies.ConclusionsMAA‐adducted proteins could play a role in pneumonia and other diseases of the lung in the setting of AUD and smoking.
In vitro fracture strength and patterns in root‐filled teeth restored with different base materials
Authors: Chan T , Küçükkaya Eren S , Wong R , Parashos P 
Published: September 2017

AbstractBackgroundThere is little research on the effects of an intermediate base on the fracture strength of root‐filled teeth. This study compared the fracture strengths and patterns of root‐filled teeth restored with intermediate bases of glass‐ionomer cement (GIC), zinc polycarboxylate cement (ZPC), dual‐cured resin composite (DCRC) and Biodentine® under resin composite.MethodsStandardized cavities were prepared in 100 extracted human maxillary and mandibular premolars, and root canal treatment was performed. The teeth were stratified and randomly allocated to five groups (n = 20): (i) GIC; (ii) ZPC; (iii) DCRC; (iv) Biodentine; and (v) prepared but unrestored (control). The teeth were subjected to an oblique, ramped load until fracture. The fracture loads, level, mode and location were recorded.ResultsMean fracture strengths of all restored groups were not significantly different amongst the groups. There were significant overall effects on mean fracture strength for tooth type (P = 0.002) and buccolingual width of the crown (P = 0.001).ConclusionsThe four materials were appropriate intermediate bases. The laminate restorative technique promoted fracture strengths that are likely to withstand normal and maximum masticatory function. The base material can influence failure mode, which may have implications for the clinical presentation of fractures of root‐filled teeth.
EAACI Guidelines on Allergen Immunotherapy: Allergic rhinoconjunctivitis
Authors: Roberts G. , Pfaar O. , Akdis C. A. , Ansotegui I. J. , Durham S. R. , Gerth van Wijk R. , Halken S. , Larenas‐Linnemann D. , Pawankar R. , Pitsios C. , Sheikh A. , Worm M. , Arasi S. , Calderon M. A. , Cingi C. , Dhami S. , Fauquert J. L. , Hamelmann E. , Hellings P. , Jacobsen L. , Knol E. F. , Lin S. Y. , Maggina P. , Mösges R. , Oude Elberink J. N. G. , Pajno G. B. , Pastorello E. A. , Penagos M. , Rotiroti G. , Schmidt‐Weber C. B. , Timmermans F. , Tsilochristou O. , Varga E.‐M. , Wilkinson J. N. , Williams A. , Zhang L. , Agache I. , Angier E. , Fernandez‐Rivas M. , Jutel M. , Lau S. , van Ree R. , Ryan D. , Sturm G. J. , Muraro A. 
Published: September 2017

AbstractAllergic rhinoconjunctivitis (AR) is an allergic disorder of the nose and eyes affecting about a fifth of the general population. Symptoms of AR can be controlled with allergen avoidance measures and pharmacotherapy. However, many patients continue to have ongoing symptoms and an impaired quality of life; pharmacotherapy may also induce some side‐effects. Allergen immunotherapy (AIT) represents the only currently available treatment that targets the underlying pathophysiology, and it may have a disease‐modifying effect. Either the subcutaneous (SCIT) or sublingual (SLIT) routes may be used. This Guideline has been prepared by the European Academy of Allergy and Clinical Immunology's (EAACI) Taskforce on AIT for AR and is part of the EAACI presidential project “EAACI Guidelines on Allergen Immunotherapy.” It aims to provide evidence‐based clinical recommendations and has been informed by a formal systematic review and meta‐analysis. Its generation has followed the Appraisal of Guidelines for Research and Evaluation (AGREE II) approach. The process included involvement of the full range of stakeholders. In general, broad evidence for the clinical efficacy of AIT for AR exists but a product‐specific evaluation of evidence is recommended. In general, SCIT and SLIT are recommended for both seasonal and perennial AR for its short‐term benefit. The strongest evidence for long‐term benefit is documented for grass AIT (especially for the grass tablets) where long‐term benefit is seen. To achieve long‐term efficacy, it is recommended that a minimum of 3 years of therapy is used. Many gaps in the evidence base exist, particularly around long‐term benefit and use in children.
Protective, repairing and fibrinolytic effects of rivaroxaban on vascular endothelium
Authors: Álvarez Ezequiel , Paradela‐Dobarro Beatriz , Raposeiras‐Roubín Sergio , González‐Juanatey José Ramón 
Published: September 2017

AimsRivaroxaban, a direct inhibitor of activated factor X (FXa), is the only new oral anticoagulant approved for secondary prevention after acute coronary syndrome. Our objective was to identify the possible molecular mechanisms of rivaroxaban that contribute to endothelial function.MethodsCell viability and growth of human umbilical vein endothelial cells (HUVEC) were registered. Gene expression studies comparing the effects of rivaroxaban and FXa were conducted by a selective RNA array and confirmed by protein quantification. Wound‐healing experiments on HUVEC, platelet adhesion, enzymatic activity, and cell‐based assays for fibrin formation were performed with rivaroxaban.ResultsRivaroxaban (50 nM) only altered (>2 fold change) the expression of matrix metallopeptidase 2 and urokinase plasminogen activator (u‐PA), but counteracted the FXa (9 nM)‐induced upregulation of several pro‐inflammatory genes (P < 0.05) and FXa‐enhanced platelet adhesion over HUVEC. Rivaroxaban increased u‐PA protein expression in HUVEC supernatants and enhanced u‐PA activity (up to 4 IU ng−1 of u‐PA). Rivaroxaban (1 nM–1 μM) showed a significant and dose‐dependent positive effect on HUVEC growth that was inhibited by BC‐11‐hydroxibromide, an inhibitor of u‐PA. Healing properties after a wound on HUVEC cultures, and fibrinolytic properties were also shown by rivaroxaban. Both effects were reversed by BC‐11‐hydroxibromide.ConclusionsRivaroxaban enhanced viability, growth and migration of HUVEC, mainly by u‐PA activation and upregulation, which also participate in the rivaroxaban‐induced fibrinolytic activity at endothelial level. Rivaroxaban also protected from the pro‐inflammatory effects of FXa on HUVEC. Altogether may improve endothelial functionality and could contribute to the cardiovascular benefits of rivaroxaban.
Quantitative analysis of the effect of end‐tidal carbon dioxide on regional cerebral oxygen saturation in patients undergoing carotid endarterectomy under general anaesthesia
Authors: Ki Seung‐Hee , Rhim Jin‐Ho , Park Jae‐Hong , Han Young‐Jin , Cho Yong‐Pil , Kwon Tae‐Won , Choi Byung‐Moon , Noh Gyu‐Jeong 
Published: September 2017

AimsRegional cerebral oxygen saturation (rSO2) is currently the most used measure in clinical practice to monitor cerebral ischaemia in patients undergoing carotid endarterectomy (CEA). Although end‐tidal carbon dioxide (PETCO2) is known as a factor that influences rSO2, the relationship between PETCO2 and rSO2 has not been quantitatively evaluated in patients with severe arteriosclerosis. This study aimed to evaluate the effect of PETCO2 on rSO2 in patients undergoing CEA under general anaesthesia.MethodsThe intervention to change PETCO2 was conducted between skin incision and clamping of the carotid artery. The rSO2 values were observed by changing PETCO2 in the range of 25–45 mmHg. The PETCO2–rSO2 relationship was characterized by population analysis using a turnover model.ResultsIn total, 1651 rSO2 data points from 30 patients were used to determine the pharmacodynamic characteristics. Hypertension (HTN) and systolic blood pressure (SBP) were significant covariates on the slope factor in the stimulatory effect of PETCO2 on rSO2 and fractional turnover rate constant (kout), respectively. The estimates of the parameters were kout(min−1): 3.59 for SBP <90 mmHg and 0.491 for SBP ≥90 mmHg, slope: 0.00321 for patients with HTN and 0.00664 for patients without HTN.ConclusionThe presence of HTNattenuates the response of rSO2 after a change in PETCO2. When cerebral blood flow is in a state of decline caused by a decrease in SBP to <90 mmHg, the response of rSO2 to PETCO2 is increased. It is advisable to maintain SBP >90 mmHg in patients with HTNduring CEA.
Outcomes of inflatable penile prosthesis insertion in 247 patients completing female to male gender reassignment surgery
Authors: Falcone Marco , Garaffa Giulio , Gillo Arianna , Dente Dino , Christopher Andrew N. , Ralph David J. 
Published: September 2017

ObjectivesTo assess the oucomes of penile prosthesis (PP) implantation after total phallic reconstruction secondary to gender dysphoria.Patients and MethodsWe conducted a retrospective single‐centre analysis of 247 consecutive patients. The recruitment period was January 2001 to October 2015. A total of 328 inflatable PPs were implanted. A two‐staged inflatable PP implantation was carried out. As a first step, an extraperitoneal reservoir placement was performed simultaneously with the glans sculpture and the insertion of a single large testicular prosthesis into the labia majora. Subsequently, cylinder(s) and pump placement was performed. A Dacron envelope was fitted around the proximal and distal aspect of the cylinder(s) to anchor the device to the pubic bone and to prevent apical protrusion. The outcomes measured were postoperative complications, eventual need for revision surgery, and long‐term survival of the implants. Patient and partner satisfaction rates were extrapolated from the administered non‐validated questionnaires. The data were analysed using non‐parametric tests, multivariate logistic regression analysis, and a Kaplan–Meier survival curve.ResultsThe mean follow‐up was 20 months. In all, 88% of patients were satisfied with the result, although only 77% used their device for sexual intercourse. The overall 5‐year device survival was 78%, with no one device being superior. Device infection occurred in 8.5% of patients with an overall revision rate of 43%. According to the multivariate logistic regression analysis, only type of phalloplasty significantly affected the infection risk (P = 0.013).ConclusionsImplantation of a PP into a neophallus is a complex procedure but yields high satisfaction rates. Nevertheless, complication rates are high and patients must be warned that multiple revisions will be necessary throughout their lifetime.
BK β1 subunit‐dependent facilitation of ethanol inhibition of BK current and cerebral artery constriction is mediated by the β1 transmembrane domain 2
Authors: Kuntamallappanavar Guruprasad , Dopico Alex M 
Published: September 2017

Background and PurposeEthanol at concentrations obtained in the circulation during moderate‐heavy episodic drinking (30–60 mM) causes cerebral artery constriction in several species, including humans. In rodents, ethanol‐induced cerebral artery constriction results from ethanol inhibition of large conductance voltage/Ca2+i‐gated K+ (BK) channels in cerebral artery myocytes. Moreover, the smooth muscle‐abundant BK β1 accessory subunit is required for ethanol to inhibit cerebral artery myocyte BK channels under physiological Ca2+i and voltages and thus constrict cerebral arteries. The molecular bases of these ethanol actions remain unknown. Here, we set to identify the BK β1 region(s) that mediates ethanol‐induced inhibition of cerebral artery myocyte BK channels and eventual arterial constriction.Experimental ApproachWe used protein biochemistry, patch‐clamp on engineered channel subunits, reversible cDNA permeabilization of KCNMB1 K/O mouse arteries and artery in vitro pressurization.Key ResultsEthanol inhibition of BK current was facilitated by β1 but not β4 subunits. Furthermore, only BK complexes containing β chimeras with β1 transmembrane (TM) domains on a β4 background or with a β1 TM2 domain on a β4 background displayed ethanol responses identical to those of BK complexes including wild‐type β1. Moreover, β1 TM2 itself but not other β regions were necessary for ethanol‐induced cerebral artery constriction.Conclusions and ImplicationsBK β1 TM2 is necessary for this subunit to enable ethanol‐induced inhibition of myocyte BK channels and cerebral artery constriction at physiological Ca2+ and voltages. Thus, novel agents that target β1 TM2 may be considered to counteract ethanol‐induced cerebral artery constriction and associated cerebrovascular conditions.
Nonclinical cardiovascular safety of pitolisant: comparing International Conference on Harmonization S7B and Comprehensive in vitro Pro‐arrhythmia Assay initiative studies
Authors: Ligneau Xavier , Shah Rashmi R , Berrebi‐Bertrand Isabelle , Mirams Gary R , Robert Philippe , Landais Laurent , Maison‐Blanche Pierre , Faivre Jean‐François , Lecomte Jeanne‐Marie , Schwartz Jean‐Charles 
Published: September 2017

Background and PurposeWe evaluated the concordance of results from two sets of nonclinical cardiovascular safety studies on pitolisant.Experimental ApproachNonclinical studies envisaged both in the International Conference on Harmonization (ICH) S7B guideline and Comprehensive in vitro Pro‐arrhythmia Assay (CiPA) initiative were undertaken. The CiPA initiative included in vitro ion channels, stem cell‐derived human ventricular myocytes, and in silico modelling to simulate human ventricular electrophysiology. ICH S7B‐recommended assays included in vitro hERG (KV11.1) channels, in vivo dog studies with follow‐up investigations in rabbit Purkinje fibres and the in vivo Carlsson rabbit pro‐arrhythmia model.Key ResultsBoth sets of nonclinical data consistently excluded pitolisant from having clinically relevant QT‐liability or pro‐arrhythmic potential. CiPA studies revealed pitolisant to have modest calcium channel blocking and late INa reducing activities at high concentrations, which resulted in pitolisant reducing dofetilide‐induced early after‐depolarizations (EADs) in the ICH S7B studies. Studies in stem cell‐derived human cardiomyocytes with dofetilide or E‐4031 given alone and in combination with pitolisant confirmed these properties. In silico modelling confirmed that the ion channel effects measured are consistent with results from both the stem cell‐derived cardiomyocytes and rabbit Purkinje fibres and categorized pitolisant as a drug with low torsadogenic potential. Results from the two sets of nonclinical studies correlated well with those from two clinical QT studies.Conclusions and ImplicationsOur findings support the CiPA initiative but suggest that sponsors should consider investigating drug effects on EADs and the use of pro‐arrhythmia models when the results from CiPA studies are ambiguous.
Assembly and architecture of the Wnt/β‐catenin signalosome at the membrane
Authors: DeBruine Zachary J , Xu H E , Melcher Karsten 
Published: September 2017

Wnt/β‐catenin signalling is initiated by a ternary Wnt‐Frizzled (FZD)‐LDL receptor‐related protein (LRP) 5/6 binding event. The resulting conformational changes in the FZD and LRP5/6 receptors promote the assembly of an intracellular signalosome driven by Dishevelled and Axin co‐polymerization. Recent evidence suggests that the FZD receptor and LRP5/6 participate in the assembly of this signalosome by forming regulatory scaffolds for stabilizing Dishevelled and Axin adapters. In this review, we focus on the contributions of Wnts and their receptors in the assembly of the signalosome. We present an emerging model, which unifies Wnt receptor oligomerization with intracellular signalosome formation, and then discuss how FZD receptors might be targeted to either disrupt or enhance their capacity as a dynamic sensor of Wnt binding.Linked ArticlesThis article is part of a themed section on WNT Signalling: Mechanisms and Therapeutic Opportunities. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.24/issuetoc
Lys63-polyubiquitination by the E3 ligase casitas B-lineage lymphoma-b (Cbl-b) modulates peripheral regulatory T cell tolerance in patients with systemic lupus erythematosus
Authors: Romo-Tena J , Rajme-López S , Aparicio-Vera L , Alcocer-Varela J , Gómez-Martín D 
Published: September 2017

Summary
T cells from systemic lupus erythematosus (SLE) patients display a wide array of anomalies in peripheral immune tolerance mechanisms. The role of ubiquitin ligases such as Cbl-b has been described recently in these phenomena. However, its role in resistance to suppression phenotype in SLE has not been characterized, which was the aim of the present study. Thirty SLE patients (20 with active disease and 10 with complete remission) and 30 age- and sex-matched healthy controls were recruited. Effector (CD4+CD25–) and regulatory (CD4+CD25+) T cells (Tregs) were purified from peripheral blood mononuclear cells (PBMCs) by magnetic selection. Suppression assays were performed in autologous and allogeneic co-cultures and analysed by a flow cytometry assay. Cbl-b expression and lysine-63 (K63)-specific polyubiquitination profile were assessed by Western blotting. We found a defective Cbl-b expression in Tregs from lupus patients in contrast to healthy controls (1·1 ± 0·9 versus 2·5 ± 1·8, P = 0·003), which was related with resistance to suppression (r = 0·633, P = 0·039). Moreover, this feature was associated with deficient K63 polyubiquitination substrates and enhanced expression of phosphorylated signal transducer and activation of transcription 3 (pSTAT-3) in Tregs from lupus patients. Our findings support that Cbl-b modulates resistance to suppression by regulating the K63 polyubiquitination profile in lupus Tregs. In addition, defective K63 polyubiquitination of STAT-3 is related to increased pSTAT-3 expression, and might promote the loss of suppressive capacity of Tregs in lupus patients.
Immunoproteasome in the blood plasma of children with acute appendicitis, and its correlation with proteasome and UCHL1 measured by SPR imaging biosensors
Authors: Matuszczak E , Sankiewicz A , Debek W , Gorodkiewicz E , Milewski R , Hermanowicz A 
Published: September 2017

Summary
The aim of this study was to determinate the immunoproteasome concentration in the blood plasma of children with appendicitis, and its correlation with circulating proteasome and ubiquitin carboxyl-terminal hydrolase L1 (UCHL1). Twenty-seven children with acute appendicitis, managed at the Paediatric Surgery Department, were included randomly into the study (age 2 years 9 months up to 14 years, mean age 9·5 ± 1 years). There were 10 girls and 17 boys; 18 healthy, age-matched subjects, admitted for planned surgeries served as controls. Mean concentrations of immunoproteasome, 20S proteasome and UCHL1 in the blood plasma of children with appendicitis before surgery 24 h and 72 h after the appendectomy were higher than in the control group. The immunoproteasome, 20S proteasome and UCHL1 concentrations in the blood plasma of patients with acute appendicitis were highest before surgery. The immunoproteasome, 20S proteasome and UCHL1 concentration measured 24 and 72 h after the operation decreased slowly over time and still did not reach the normal range (P &lt; 0·05). There was no statistical difference between immunoproteasome, 20S proteasome and UCHL1 concentrations in children operated on laparoscopically and children after classic appendectomy. The immunoproteasome concentration may reflect the metabolic response to acute state inflammation, and the process of gradual ebbing of the inflammation may thus be helpful in the assessment of the efficacy of treatment. The method of operation – classic open appendectomy or laparoscopic appendectomy – does not influence the general trend in immunoproteasome concentration in children with appendicitis.