bluuebunny/crossref_metadata_2025 huggingface dataset:
Done in 100 ms: Path-dependent visuomotor transformation in the human upper limb
Authors: Gu Chao , Andrew Pruszynski J. , Gribble Paul L. , Corneil Brian D.
Published: September 2017

A core assumption underlying mental chronometry is that more complex tasks increase cortical processing, prolonging reaction times. Here we show that increases in task complexity alter the magnitude, rather than the latency, of the output for a circuit that rapidly transforms visual information into motor actions. We quantified visualstimulus-locked responses(SLRs), which are changes in upper limb muscle recruitment that evolve at a fixed latency ∼100 ms after novel visual stimulus onset. First, we studied the underlying reference frame of the SLR, by dissociating initial eye and hand position. Despite its quick latency, we found that the SLR was expressed in a hand-centric reference frame, suggesting that the circuit mediating the SLR integrated retinotopic visual information with body configuration. Next, we studied the influence of planned movement trajectory, requiring participants to prepare and generate curved or straight reaches in the presence of obstacles to attain the same visual stimulus. We found that SLR magnitude reflected the initial planned movement trajectory, regardless of the ensuing movement curvature. Based on these results, we suggest that the circuit mediating the SLR lies in parallel to other well-studied corticospinal pathways. Although the fixed latency of the SLR precludes extensive cortical processing, inputs conveying information relating to task complexity, such as body configuration and planned movement trajectory, can pre-set nodes within the circuit underlying to the SLR to modulate its magnitude.

SIGNIFICANCE STATEMENT

A core assumption underlying mental chronometry is that more complex tasks increase cortical processing, prolonging reaction times. Here, we showed that increases in task complexity altered the magnitude, rather than the latency, of a circuit that rapidly transforms visual information into motor actions. We focus onstimulus-locked responses(SLRs), which are changes in upper limb muscle recruitment that evolve at a fixed latency ∼100 ms after novel visual stimulus onset. We showed that despite is quick latency, the circuitry mediating the SLR transformed a retinotopic visual signal into a hand-centric motor command suitable to contribute to the initial movement trajectory. We suggest that this circuit lies in parallel to other well-studied corticospinal pathways.
UniProt Genomic Mapping for Deciphering Functional Effects of Missense Variants
Authors: McGarvey Peter B. , Nightingale Andrew , Luo Jie , Huang Hongzhan , Martin Maria J. , Wu Cathy ,   the UniProt Consortium
Published: September 2017

Understanding the association of genetic variation with its functional consequences in proteins is essential for the interpretation of genomic data and identifying causal variants in diseases. Integration of protein function knowledge with genome annotation can assist in rapidly comprehending genetic variation within complex biological processes. Here, we describe mapping UniProtKB human sequences and positional annotations such as active sites, binding sites, and variants to the human genome (GRCh38) and the release of a public genome track hub for genome browsers. To demonstrate the power of combining protein annotations with genome annotations for functional interpretation of variants, we present specific biological examples in disease-related genes and proteins. Computational comparisons of UniProtKB annotations and protein variants with ClinVar clinically annotated SNP data show that 32% of UniProtKB variants co-locate with 8% of ClinVar SNPs. The majority of co-located UniProtKB disease-associated variants (86%) map to ‘pathogenic’ ClinVar SNPs. UniProt and ClinVar are collaborating to provide a unified clinical variant annotation for genomic, protein and clinical researchers. The genome track hubs, and related UniProtKB files, are downloadable from the UniProt FTP site and discoverable as public track hubs at the UCSC and Ensembl genome browsers.
Chromatin accessibility profiling uncovers genetic- and T2D disease state-associated changes incis-regulatory element use in human islets
Authors: Khetan Shubham , Kursawe Romy , Youn Ahrim , Lawlor Nathan , Campos Eladio Marquez , Ucar Duygu , Stitzel Michael L.
Published: September 2017

Genetic and environmental factors both contribute to islet dysfunction and failure, resulting in type 2 diabetes (T2D). The islet epigenome integrates these cues and can be remodeled by genetic and environmental variation. However, our knowledge of how genetic variants and T2D disease state alter human islet chromatin landscape andcis-regulatory element (RE) use is lacking. To fill this gap, we profiled and analyzed human islet chromatin accessibility maps from 19 genotyped individuals (5 with T2D) using ATAC-seq technology. Chromatin accessibility quantitative trait locus (caQTL) analyses identified 3001 sequence variants (FDR<10%) altering putativecis-RE use/activity. Islet caQTL were significantly and specifically enriched in islet stretch enhancers and islet-specific transcription factor binding motifs, such as FOXA2, NKX6.1, RFX5/6 and PDX1. Importantly, these analyses identified putative functional single nucleotide variants (SNVs) in 13 T2D-associated GWAS loci, including those previously associated with alteredZMIZ1, MTNR1B, RNF6,andADCY5islet expression, and linked the risk alleles to increased (n=8) or decreased (n=5) islet chromatin accessibility. Luciferase reporter assays confirmed allelic differences incis-RE activity for 5/9 caQTL sequences tested, including a T2D-associated SNV in theIL20RAlocus. Comparison of T2D and non-diabetic islets revealed 1882 open chromatin sites exhibiting T2D-associated chromatin accessibility changes (FDR<10%). Together, this study provides new insights into genetic variant and T2D disease state effects on isletcis-RE use and serves as an important resource to identify putative functional variants in T2D-and islet dysfunction-associated GWAS loci and link their risk allele toin vivoloss or gain of chromatin accessibility.
Metabolic scaling of individuals vs. populations: Evidence for variation in scaling exponents at different hierarchical levels
Authors: Norin Tommy , Gamperl A. Kurt
Published: September 2017

The power scaling of metabolic rate with body mass is fundamental to animal biology, due to the profound influence that animal size has on ecology and physiology. Yet the value of the scaling exponent (b) is highly debated. This scaling exponent has been suggested to be fixed at 0.67 or 0.75, or to vary systematically with cell size or metabolic intensity between the boundaries of 0.67 and 1. Despite this tremendous interest in the value of scaling exponents, little is known about metabolic scaling within individual animals and how this relates to population‐level scaling.

Here, we conducted a long‐term study that repeatedly characterised the complete metabolic profile of a group of 68 individual fish (cunner, Tautogolabrus adspersus) by measuring their standard metabolic rate (SMR), routine metabolic rate (RMR), active metabolic rate (AMR) and aerobic scope (AS) in five separate trials over 10 months (fish mass range, 0.5–19.5 g).

At all levels of metabolic intensity, the mean exponents for the group of fish at any single point in time (i.e. within trials; bSMR = 0.89, bRMR = 0.89, bAMR = 0.94, bAS = 0.96) were higher than those characterising the group as it aged (i.e. across trials; bSMR = 0.82, bRMR = 0.84, bAMR = 0.90, bAS = 0.92), and both were higher than the mean exponents for individual fish as they grew (i.e. across trials but within individuals; bSMR = 0.74, bRMR = 0.79, bAMR = 0.83, bAS = 0.85).

This variation in scaling relationships, which occurred at different hierarchical levels and across time as the fish aged, may have implications for bioenergetics and ecosystem modelling and for individual ecological and physiological studies where body mass adjustments are made using specific scaling exponents to compare traits of interest between different‐sized individuals.

The findings suggest that studies on fish population dynamics should apply metabolic scaling exponents that are significantly higher than those used in studies on individuals. However, the generality of this assertion should be confirmed by future work, as a few existing studies on endotherms (mainly birds) have reported shallower scaling relationships for basal metabolic rate between individuals as compared to within individuals.

A plain language summary is available for this article.
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

Circadian 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

Background

Malondialdehyde (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.

Methods

Four 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).

Results

We 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.

Conclusions

MAA‐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

Background

There 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.

Methods

Standardized 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.

Results

Mean 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).

Conclusions

The 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

Allergic 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

Aims

Rivaroxaban, 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.

Methods

Cell 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.

Results

Rivaroxaban (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.

Conclusions

Rivaroxaban 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

Aims

Regional 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.

Methods

The 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.

Results

In 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.

Conclusion

The 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

Objectives

To assess the oucomes of penile prosthesis (PP) implantation after total phallic reconstruction secondary to gender dysphoria.

Patients and Methods

We 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.

Results

The 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).

Conclusions

Implantation 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 Purpose

Ethanol 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 Approach

We used protein biochemistry, patch‐clamp on engineered channel subunits, reversible cDNA permeabilization of KCNMB1 K/O mouse arteries and artery in vitro pressurization.

Key Results

Ethanol 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 Implications

BK 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 Purpose

We evaluated the concordance of results from two sets of nonclinical cardiovascular safety studies on pitolisant.

Experimental Approach

Nonclinical 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 Results

Both 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 Implications

Our 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 Articles

This 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
Antifibrotic effects of pentoxifylline improve the efficacy of gemcitabine in human pancreatic tumor xenografts
Authors: Kim Jung Ho , Shin Byung Cheol , Park Won Sang , Lee Jaehwi , Kuh Hyo‐Jeong
Published: September 2017

We investigated the combinatorial effects of pentoxifylline (PTX) on the efficacy of gemcitabine (GEM) in a human pancreatic tumor xenograft model. PTX significantly improved the efficacy of GEM, as shown by a 50% reduction in tumor growth rate at 4 weeks of treatment compared with that in animals given GEM alone. The fluorescent drug doxorubicin (DOX) was used to test whether drug delivery was improved by PTX, contributing to the improved efficacy of GEM. PTX given for 2 weeks prior to giving DOX improved drug distribution by 1.8‐ to 2.2‐fold with no changes in vessel density, suggesting that improvement in drug delivery was not related to the vascular mechanism. Instead, collagen I content in tumor stroma was significantly reduced, as was the expression of alpha‐smooth muscle actin of cancer‐associated fibroblasts and connective tissue growth factor (CTGF) by PTX pretreatment. Overall, our data demonstrated that increased efficacy of GEM by PTX was associated with improved drug delivery to tumor tissue, which may be attributed to decreased expression of CTGF and subsequent reduction in the stromal collagen matrix in the pancreatic ductal adenocarcinoma tumor. These results support the usefulness of PTX in combination with chemotherapy for targeting drug delivery barriers associated with the stromal matrix, which should be further evaluated for clinical development.
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

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

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 < 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.
Weekly oral bisphosphonates over 2 years prevent bone loss in cardiac transplant patients
Authors: Lange Uwe , Classen Katharina , Müller‐Ladner Ulf , Richter Manfred
Published: September 2017

Background

Heart transplantation (HTX) is an established therapy for end‐stage heart disease. The aim of this study was to determine whether application of oral bisphosphonates is effective in preventing osseous complications after HTX.

Methods

Thirty‐three cardiac transplant recipients were treated with alendronate 70 mg/wk or risedronate 35 mg/wk in combination with 1000 mg calcium and 800 IU vitamin D. Markers of bone metabolism and dual‐energy X‐ray absorptiometry (DXA) were determined directly after HTX and 2 years later. Primary endpoints were changes in bone mineral density (BMD), markers of bone metabolism (osteocalcin, crosslaps), serum levels of the cytokines osteoprotegerin (OPG), receptor activator of NF kappa‐B ligand (RANKL), and incidence of fractures.

Results

Eight patients presented with osteoporosis, and 16 patients with osteopenia by DXA without prevalent fractures. Over 2 years, the BMD improved in 2 patients from osteoporosis to osteopenia, and overall BMD remained stable, and fractures did not occur. In addition, the serum levels of OPG increased (P < .0005), and the RANKL levels (P < .001) as well as the RANKL/OPG‐ratio decreased significantly (P < .0005). The serum crosslaps showed no significant changes. The BMD showed a significant association with the increased 25‐vitamin D levels only in females (P < .001).

Conclusions

In heart transplanted patients, weekly oral bisphosphonates in combination with calcium and vitamin D supplementation preserved bone mass, prevented uncoupling of bone resorption/formation and fractures. Bone density should be measured and adequately treated, that is, with regular bisphosphonates.
Semaglutide improves postprandial glucose and lipid metabolism, and delays first‐hour gastric emptying in subjects with obesity
Authors: Hjerpsted Julie B. , Flint Anne , Brooks Ashley , Axelsen Mads B. , Kvist Trine , Blundell John
Published: September 2017

Aim

To investigate the effects of semaglutide on fasting and postprandial glucose and lipid responses, and on gastric emptying.

Materials and methods

This was a randomized, double‐blind, placebo‐controlled, 2‐period, crossover trial. Subjects with obesity (N = 30) received once‐weekly subcutaneous semaglutide, dose‐escalated to 1.0 mg, or placebo. After each 12‐week treatment period, glucose and lipid metabolism were assessed before and after standardized meals. Gastric emptying (paracetamol absorption test) and peptide YY (PYY) response were also assessed.

Results

Semaglutide treatment significantly lowered fasting concentrations of glucose and glucagon, and increased insulin vs placebo (estimated treatment ratio: 0.95 [95% confidence interval: 0.91, 0.98]; 0.86 [0.75, 0.98]; 1.45 [1.20, 1.75], respectively). Postprandial glucose metabolism significantly improved with semaglutide vs placebo (incremental area under the curve 0 to 5 hours [iAUC0‐5h]; estimated treatment difference: glucose −1.34 mmol h/L [−2.42, −0.27]; insulin −921 pmol h/L [−1461, −381]; C‐peptide −1.42 nmol h/L [−2.33, −0.51]). Fasting and postprandial lipid metabolism improved with semaglutide vs placebo. First‐hour gastric emptying after the meal was delayed with semaglutide vs placebo (AUC0‐1h; estimated treatment ratio: 0.73 [0.61, 0.87]); this may have contributed to the lower postprandial glucose increase in semaglutide‐treated subjects. Overall gastric emptying (AUC0‐5h) was not statistically different between treatments. Fasting and postprandial PYY responses were significantly lower with semaglutide vs placebo (P = .0397 and P = .0097, respectively).

Conclusion

Semaglutide improved fasting and postprandial glucose and lipid metabolism. Overall gastric emptying was similar to that with placebo; however, the observed first‐hour delay with semaglutide may contribute to a slower entry of glucose into the circulation.
Different intervention strategies for preventing type 2 diabetes mellitus in China: A systematic review and network meta‐analysis of randomized controlled trials
Authors: Pang Bing , Zhao Lin‐hua , Li Xin‐long , Song Jun , Li Qing‐wei , Liao Xing , Feng Shuo , Zhao Xi‐yan , Zheng Yu‐jiao , Gou Xiao‐wen , Ni Qing , Tong Xiao‐lin
Published: September 2017

Different strategies are increasingly used for early intervention in prediabetes in China, but the effects of these strategies on incident diabetes have not yet been confirmed. The aim of the present study was to assess systematically the effects of different strategies for preventing diabetes, aimed at Chinese people with prediabetes. Seven electronic databases were searched to identify eligible trials published from inception to September 20, 2016. Randomized controlled trials with a minimum follow‐up duration of 6 months were included. Standard pairwise meta‐analysis with a random‐effects model and network meta‐analysis with a frequentist framework were performed. A total of 63 studies, including 11 intervention strategies, were included. Compared with placebo, all strategies, except for lipid‐affecting drugs and sitagliptin, reduced the rate of incident diabetes with different levels of effectiveness, ranging from 0.18 (95% confidence interval [CI] 0.12, 0.27) to 0.39 (95% CI 0.20, 0.75). Ranking probability analysis indicated that metformin and β‐cell‐stimulating drugs reduced the risk of diabetes most, with probabilities of 87.4% and 81%, respectively. Ethnicity and cultural factors should be considered for diabetes prevention. Most of the included trials were of poor methodological quality, however, and the results should be interpreted with caution.
Mycobacterial infections in equids: Clinical characteristics and diagnostic techniques
Authors: Sutton D. G. M. , Michel A. L.
Published: September 2017

Mycobacterial infections in equids are relatively rare but the case report (Charlesworth 2017) detailed in this issue highlights that Mycobacterium bovis infections may still result in clinical signs in this incidental host and have zoonotic potential. Most reported cases of M. bovis in horses have a protracted disease course, with features including pyrexia, weight loss and oedema with a nonspecific inflammatory profile. As such, the clinical features of disease overlap with conditions such as neoplasia, peritonitis, protein‐losing enteropathies and bacterial infections including Rhodococcus equi and Lawsonia intracellularis. In this clinical satellite article, mycobacterial infections in equids are considered in terms of incidence and mode of transmission, key clinical features and perhaps most importantly, in terms of the diagnostic techniques that can be used in order to reach a definitive (ante mortem) diagnosis. The major zoonotic risk to veterinary personnel is likely to occur at the time of post‐mortem examination of infected horses, and awareness of these potential risks remains of the utmost importance.
Exosomes from human adipose‐derived stem cells promote proliferation and migration of skin fibroblasts
Authors: Choi Eun Wook , Seo Min Koo , Woo Eun Young , Kim Suk Hyung , Park Eun Joo , Kim Sue
Published: September 2017

This study was undertaken to evaluate whether exosomes from human adipose‐derived stem cells (ASC‐exo) can stimulate the regeneration of human dermal fibroblasts (HDFs). Immunoblotting and FACS analyses showed that ASC‐exo was positive for exosome markers. Fluorescence tracking revealed that the contents of ASC‐exo were transferred into the HDFs. ASC‐exo treatment also stimulated the proliferation and migration of HDFs in a dose‐dependent manner. Similarly, the expression levels of genes involved in skin cell proliferation were increased by ASC‐exo. Microarray analysis showed an enrichment of microRNAs that have regenerative function. We suggest that the ASC‐exo can stimulate skin cell proliferation.
The Diamantina Monazite: A New Low‐Th Reference Material for Microanalysis
Authors: Gonçalves Guilherme O. , Lana Cristiano , Scholz Ricardo , Buick Ian S. , Gerdes Axel , Kamo Sandra L. , Corfu Fernando , Rubatto Daniela , Wiedenbeck Michael , Nalini Hermínio A. , Oliveira Luiz Carlos A.
Published: September 2017

Most monazite reference materials (RMs) for in situ U‐Pb geochronology are rich in Th; however, many hydrothermal ore deposits contain monazite that is low in trace element contents, including Th, U and Pb. Because of potential problems with matrix effects and the lack of appropriate matrix‐matched RMs, such variations can bias dating of hydrothermal deposits. In this paper, we describe a polycrystalline low‐U and low‐Th Diamantina monazite from the Espinhaço Range, SE Brazil. It has a U‐Pb ID‐TIMS weighted mean 207Pb*/235U ratio of 0.62913 ± 0.00079, 206Pb*/238U of 0.079861 ± 0.000088 and 207Pb*/206Pb* of 0.057130 ± 0.000031, yielding a weighted mean 206Pb*/238U date of 495.26 ± 0.54 Ma (95% c.l.). In situ dates acquired with different methods (LA‐(Q, SF, MC)‐ICP‐MS and SIMS) are within uncertainty of the ID‐TIMS data. U‐Pb LA‐(Q, MC)‐ICP‐MS runs, using Diamantina as a primary RM, reproduced the ages of other established RMs within < 1% deviation. The LA‐MC‐ICP‐MS analyses yielded homogeneous Sm‐Nd isotopic compositions (143Nd/144Nd = 0.511427 ± 23, 2s; 147Sm/144Nd = 0.1177 ± 13, 2s) and εNd(495 Ma) of −18.7 ± 0.5 (2s). SIMS oxygen isotope determinations showed measurement reproducibility better than ± 0.3‰ (2s), confirming Diamantina's relative homogeneity at test portion masses below 1 ng.
Thermal effects of Er3+/Yb3+‐doped NaYF4 phosphor induced by 980/1510 nm laser diode irradiation
Authors: Wang Hong , Yin Xiumei , Xing Mingming , Fu Yao , Tian Ying , Feng Xin , Jiang Tao , Luo Xixian
Published: September 2017

The thermal effects of Er/Yb‐doped NaYF4 phosphor induced by 980/1510 nm laser diode irradiation were intuitively and contrastively investigated using an infrared thermal imaging technology with real‐time online monitoring. The Yb3+/Er3+ codoped materials have strong thermal effects and high‐temperature elevation under 980 nm irradiation. However, the severe thermal effects of materials with higher Er3+ ion doping concentration are remarkably attributed to the cross relaxation between the Er3+ ions under 980 nm irradiation. The energy transfer between Er3+ and Yb3+ ions in Er3+/Yb3+‐codoped materials also contributes to the thermal effects under 1510 nm laser diode irradiation. Under the same testing conditions, the temperature elevation ∆T of samples induced by 1510 nm laser diode irradiation is lower than that induced by 980 nm laser diode irradiation. The temperature rising rate and elevation ∆T value of samples depend on the ion doping concentration and power density of the laser diode excitation. The internal temperature of the samples exhibits deep temperature gradient under 980/1510 nm laser diode irradiation. By comparing the two kinds of thermometry methods, the temperature value calculated by fluorescence intensity ratio is almost similar to that obtained through infrared thermal imaging technology under higher excitation power pumping.
Facile synthesis of nanocrystalline hexagonal tungsten trioxide from metallic tungsten powder and hydrogen peroxide
Authors: Tsuyumoto Isao
Published: September 2017

A hexagonal form of tungsten trioxide (h‐WO3, particle size: 15.9‐57.1 nm) was found to be formed by a direct reaction between metallic tungsten powder (W, particle size: 0.45‐0.59 μm) and 15%‐30% hydrogen peroxide (H2O2) aq solution. Oxide film on the powder surface having the similar crystal structure as h‐WO3 was essential for the formation, and the surface oxide film was formed by aging the powder in air at 45°C, a relative humidity of 100% (PH2O 96 hPa) for 3‐28 days or in ambient atmosphere at room temperature for 12 years. The Rietveld analysis performed in the space group P63/mcm (Z = 6) indicated the crystal structures were the same as those of the reported h‐WO3 and that the crystallographic characteristic was as follows: a = 0.74219 nm, c = 0.77198 nm for h‐WO3 from the 28‐day aged powder, and a = 0.74538 nm, c = 0.77194 nm for h‐WO3 from the 12‐year aged powder.
Deoxycholic acid promotes development of gastroesophageal reflux disease and Barrett's oesophagus by modulating integrin‐αv trafficking
Authors: Prichard David O. , Byrne Anne Marie , Murphy James O. , Reynolds John V. , O'Sullivan Jacintha , Feighery Ronan , Doyle Brendan , Eldin Osama Sharaf , Finn Stephen P. , Maguire Aoife , Duff Deirdre , Kelleher Dermot P. , Long Aideen
Published: September 2017

The fundamental mechanisms underlying erosive oesophagitis and subsequent development of Barrett's oesophagus (BO) are poorly understood. Here, we investigated the contribution of specific components of the gastric refluxate on adhesion molecules involved in epithelial barrier maintenance. Cell line models of squamous epithelium (HET‐1A) and BO (QH) were used to examine the effects of bile acids on cell adhesion to extracellular matrix proteins (Collagen, laminin, vitronectin, fibronectin) and expression of integrin ligands (α3, α4, α5, α6 and αν). Experimental findings were validated in human explant oesophageal biopsies, a rat model of gastroesophageal reflux disease (GORD) and in patient tissue microarrays. The bile acid deoxycholic acid (DCA) specifically reduced adhesion of HET‐1A cells to vitronectin and reduced cell‐surface expression of integrin‐αν via effects on endocytic recycling processes. Increased expression of integrin‐αv was observed in ulcerated tissue in a rat model of GORD and in oesophagitis and Barrett's intestinal metaplasia patient tissue compared to normal squamous epithelium. Increased expression of integrin‐αν was observed in QH BO cells compared to HET‐1A cells. QH cells were resistant to DCA‐mediated loss of adhesion and reduction in cell‐surface expression of integrin‐αν. We demonstrated that a specific component of the gastric refluxate, DCA, affects the epithelial barrier through modulation of integrin αν expression, providing a novel mechanism for bile acid‐mediated erosion of oesophageal squamous epithelium and promotion of BO. Strategies aimed at preventing bile acid‐mediated erosion should be considered in the clinical management of patients with GORD.