bluuebunny/crossref_metadata_2025 huggingface dataset:
3D numerical simulation of laminar water hammer considering pipe wall viscoelasticity and the arbitrary Lagrangian-Eulerian method
Authors: Morvarid Masoud , Rezghi Ali , Riasi Alireza , Haghighi Yazdi Mojtaba
Published: February 2018

Purpose

Analysis of fast transient flow in water pipe systems is an important issue for the prevention of unfavorable pressure oscillations and severe damage to the pipelines. This paper aims to present the performance of three-dimensional (3D) simulation of laminar water hammer caused by fast closure of valve.

Design/methodology/approach

The viscoelastic behavior of pipe wall is mathematically modeled by using the rheological model of Maxwell. The arbitrary Lagrangian–Eulerian (ALE) method is also used to simulate fluid–structure interaction. In this method, unlike the classical water hammer theory, the acoustic wave velocity is calculated during the numerical simulations and therefore it is not predetermined.

Findings

Investigating the velocity profiles and the shear stress diagrams for transient flow in elastic pipe showed that the strong effect of viscous forces on the near wall region in conjunction with the influence of inertial forces in the central region of the pipe leads to creation of reverse flow near the pipe wall. Comparing the numerical results obtained for elastic pipe with those of viscoelastic pipe revealed that during transient condition, the viscoelastic wall absorbs the energy of fluid and therefore pressure fluctuations of viscoelastic pipe are damped more quickly. Moreover, the 3D simulation of water hammer confirmed the plane wave hypothesis of water hammer.

Originality/value

The 3D Navier–Stokes equations are solved considering the viscoelasticity of the pipe and the ALE method using the software package of COMSOL Multiphysics.
Impact of interpersonal relations on learning and development of professional identity: A study of residents’ perceptions
Authors: Blouin Danielle
Published: February 2018

Objectives

Informal learning includes all occurrences during one's life when learning is not deliberate. Prior research on informal learning in healthcare contexts examined learning happening outside of the formal curriculum, yet still in the workplace. This study explores residents’ perceptions about extracurricular factors outside of the workplace that contribute to their learning and development of professional identity, whether interpersonal relations are recognised as such factors, and positive and negative impacts of interpersonal relations.

Methods

In this qualitative study, all 21 residents in our Emergency Medicine programme were asked, in a web‐based survey with open‐ended questions, to identify extracurricular sources outside of the workplace perceived as contributing to their learning and professional identity development, and list positive and negative impacts of interpersonal relations outside of work on learning and identity development. Themes were extracted through content analysis of the narrative responses. Two reviewers coded all data.

Results

Thirteen (62%) residents identified 37 factors grouped under five themes: learning activity, role modelling, support, non‐clinical academic roles, and social interactions. Interpersonal relations were perceived as having positive and negative impacts, including creating support, positive role modelling and mentoring, increasing concrete learning, as well as lapses in teaching skills, deficits in professional role training, and loss of personal time.

Conclusions

Several extracurricular factors outside of the workplace contribute to resident learning and identity development, including interpersonal relations, which have positive and negative impacts. The most often noted negative impact of interpersonal relations outside of work between residents and faculty related to perceived lapses in teaching skills.
Insecticide toxicity associated with detoxification enzymes and genes related to transcription of cuticular melanization among color morphs of Asian citrus psyllid
Authors: Chen Xue Dong , Gill Torrence A. , Nguyen Chi D. , Killiny Nabil , Pelz‐Stelinski Kirsten S. , Stelinski Lukasz L.
Published: February 2018

The Asian citrus psyllid (Diaphorina citri Kuwayama) is known to exhibit abdominal color polymorphisms. In the current study, susceptibility to four insecticides was compared among orange/yellow, blue/green and gray/brown color morphs of field collected D. citri. The LD50 values and 95% fiducial limits were quantified for each insecticide and color morph combination and ranged between 0.10 ng/μL (0.06–0.10) and 6.16 ng/μL (3.30–12.50). Second, we measured the detoxification enzyme activity levels of orange/yellow, blue/green and gray/brown color morphs for cytochrome P450, glutathione S‐transferase, and general esterase. The mean P450 activity (equivalent units) was significantly lower in gray/brown (0.152 ± 0.006) and blue/green morphs (0.149 ± 0.005) than in the orange/yellow morphs (0.179 ± 0.008). GST activity (μmol/min/mg protein) was significantly lower in the orange/yellow morph (299.70 ±1.24) than gray/brown (350.86 ± 1.19) and blue/green (412.25 ± 1.37) morphs. The mean EST activity (μmol/min/mg protein) was significantly higher in blue/green (416.72 ± 5.12) and gray/brown morphs (362.19 ± 4.69) than in the orange/yellow morphs (282.56 ± 2.93). Additionally, we analyzed the relative expression of assortment genes involved in cuticular melanization and basal immunity. The transcripts of Dopa Decarboxylase and Tyrosine Hydroxylase were expressed higher in blue/green and gray/brown than orange/yellow morphs. The transcription results paralleled the susceptibility of D. citri to organophosphate, neonicotinoid and pyrethroid insecticides. GST and EST activity may also be correlated with low levels of insecticide susceptibility. Cuticular melanization could be a factor for the development of resistance to insecticides among different color morphs.
Timing of Metamorphism and Provenance of the Metamorphic Basement of the Xiangshan Uranium Orefield, Jiangxi Province, China
Authors: GUO Fusheng , SHI Guo , YANG Qingkun , ZHANG Wanliang , XIE Caifu , ZHOU Wanpeng , ZHANG Jiewei
Published: February 2018

The origin, age and evolution of the Precambrian metamorphic basement of southern China provide useful insights into early crustal development. Here, we present new laser ablation–inductively coupled plasma–mass spectrometry (LA–ICP–MS) U–Pb age data for detrital zircons from five samples of the Precambrian metamorphic basement of the Xiangshan uranium orefield. Two of these samples, from the northern Xiangshan volcanic basin, yielded a total of 140 U–Pb ages that cluster within the Neoproterozoic (773–963 Ma; 79.3% of data points), with the rest being scattered through the Paleoproterozoic and Mesoproterozoic, along with a single Archean age. These ages indicate that this basement material is associated with the Cathaysia Block. In comparison, the 172 concordant ages from the other three samples from the southern part of the Xiangshan volcanic basin cluster within the Neoproterozoic (767–944 Ma; 59.8%) as well as the Proterozoic (37.8%) and the Archean (2502–2712 Ma; 14.5%). These samples are also free of zircons with Grenvillian ages, indicating that these units are associated with the southeastern Yangtze Block. Combining these data with the geochemistry of these units, which suggests that the metamorphosed sedimentary rocks within the northern and southern parts of the Xiangshan basin have a common component from a magmatic island arc that formed during the early Neoproterozoic, we infer that the basin was located along the boundary between the Cathaysian and Yangtze blocks. In addition, the zircons within the samples from the southern and northern parts of the Xiangshan basin show different pre‐Neoproterozoic (963 Ma) age populations but similar post‐Neoproterozoic zircon populations, indicating that the amalgamation of the Cathaysian and Yangtze blocks occurred after the Neoproterozoic (960 Ma), with magmatism peaking at 830 Ma and rifting starting at ∼770 Ma, leading to the subsequent deposition (from bottom to top) of the Shenshan, Kuli, and Shangshi formations.
The Dihedral Angle and Intersection Processes of a Conjugate Strike‐Slip Fault System in the Tarim Basin, NW China
Authors: WU Guanghui , YUAN Yajuan , HUANG Shaoying , Vandyk Thomas Matthew , XIAO Yang , CAI Quan , LUO Bingxu
Published: February 2018

Recent studies, focused on dihedral angles and intersection processes, have increased understandings of conjugate fault mechanisms. We present new 3‐D seismic data and microstructural core analysis in a case study of a large conjugate strike‐slip fault system from the intracratonic Tarim Basin, NW China. Within our study area, “X” type NE and NW trending faults occur within Cambrian‐Ordovician carbonates. The dihedral angles of these conjugate faults have narrow ranges, 19° to 62° in the Cambrian and 26° to 51° in the Ordovician, and their modes are 42° and 44° respectively. These data are significantly different from the ∼60° predicted by the Coulomb fracture criterion. It is concluded that: (1) The dihedral angles of the conjugate faults were not controlled by confining pressure, which was low and associated with shallow burial; (2) As dihedral angles were not controlled by pressure they can be used to determine the shortening direction during faulting; (3) Sequential slip may have played an important role in forming conjugate fault intersections; (4) The conjugate fault system of the Tarim basin initiated as rhombic joints; these subsequently developed into sequentially active “X” type conjugate faults; followed by preferential development of the NW‐trending faults; then reactivation of the NE trending faults. This intact rhombic conjugate fault system presents new insights into mechanisms of dihedral angle development, with particular relevance to intracratonic basins.
Geology and Mineral Chemistry of Gold Mineralization in Mirge‐Naqshineh Occurrence (Saqez, NW Iran): Implications for Transportation and Precipitation of Gold
Authors: ASGHARI Golale , ALIPOUR Samad , AZIZI Hossein , MIRNEJAD Hassan
Published: February 2018

The Mirge‐Naqshineh gold district is situated at northwest of Iran with a NW‐trending brittle‐ductile shear zone. It is hosted by Precambrian meta‐sedimentary and meta‐volcanic units traversed by mineralized quartz veins. In terms of cross‐cutting relationships and sulfide content three types of quartz veins are identified in the region. Among those, parallel to bedding quartz vein (type I) is the main host for gold mineralization. Gold is found in three different forms: 1) submicrometer‐size inclusions of gold in arsenian pyrite, 2) as electrum and 3) in the crystal lattice of sulfides (pyrite, galena and chalcopyrite). Six types of pyrite (Py1‐Py6) were identified in this ore reserve. Py3 coexists with arsenopyrite and contains the greatest As‐Au concentrations. There is a negative correlation between the As and S contents in Py2 and Py3, implying the substitution of sulfur by arsenic. Pyrites and mineralized quartz veins were formed via metamorphic‐hydrothermal fluid and reflect the gold‐transportation as Au(HS)−2 under reducing and acidic conditions. The gold precipitation mainly controlled by crystallization of arsenian pyrite during fluid/rock interactions and variation of fO2. The volcanic host rock has played an important role in gold concentration, as Py3 in this rock contains inclusion of gold particles, but gold is within the lattice of pyrite in phyllite or other units.
Changes at the nuclear lamina alter binding of pioneer factor Foxa2 in aged liver
Authors: Whitton Holly , Singh Larry N. , Patrick Marissa A. , Price Andrew J. , Osorio Fernando G. , López‐Otín Carlos , Bochkis Irina M.
Published: February 2018

Increasing evidence suggests that regulation of heterochromatin at the nuclear envelope underlies metabolic disease susceptibility and age‐dependent metabolic changes, but the mechanism is unknown. Here, we profile lamina‐associated domains (LADs) using lamin B1 ChIP‐Seq in young and old hepatocytes and find that, although lamin B1 resides at a large fraction of domains at both ages, a third of lamin B1‐associated regions are bound exclusively at each age in vivo. Regions occupied by lamin B1 solely in young livers are enriched for the forkhead motif, bound by Foxa pioneer factors. We also show that Foxa2 binds more sites in Zmpste24 mutant mice, a progeroid laminopathy model, similar to increased Foxa2 occupancy in old livers. Aged and Zmpste24‐deficient livers share several features, including nuclear lamina abnormalities, increased Foxa2 binding, de‐repression of PPAR‐ and LXR‐dependent gene expression, and fatty liver. In old livers, additional Foxa2 binding is correlated to loss of lamin B1 and heterochromatin (H3K9me3 occupancy) at these loci. Our observations suggest that changes at the nuclear lamina are linked to altered Foxa2 binding, enabling opening of chromatin and de‐repression of genes encoding lipid synthesis and storage targets that contribute to etiology of hepatic steatosis.
A Randomized Trial of a Personalized Feedback Intervention for Nonstudent Emerging Adult At‐Risk Drinkers
Authors: Lau‐Barraco Cathy , Braitman Abby L. , Stamates Amy L.
Published: February 2018

Background

Emerging adulthood is a period of heightened vulnerability for problematic alcohol use. Considerable research has been devoted to reducing alcohol risks in college student populations, although far less effort has focused on their noncollege‐attending peers. Research targeting nonstudent emerging adults is critical as this group is at risk of experiencing alcohol‐related harms. Consequently, the main objective of the present randomized study was to examine the preliminary efficacy of a brief personalized feedback intervention (PFI) tailored for nonstudent at‐risk drinkers. We also examined the influence of gender on intervention outcomes. Finally, we explored participant acceptability of the intervention.

Methods

Participants were 164 (65.9% men) emerging adults (M age = 21.98, SD = 2.02) recruited from the community. They were randomly assigned to either a 50‐minute, in‐person PFI or an assessment‐only control group and were assessed over 9 months postintervention.

Results

Results showed that for short‐term change (1 month), the PFI condition reduced drinking significantly more than controls. For longer‐term change (1 to 9 months), both conditions continued to show gradual decline in consumption. The groups did not differ in alcohol‐related problems, and the intervention was equally effective for both women and men. Regarding acceptability, participants were extremely satisfied with the intervention, perceived the information to be personally relevant, and thought it provided them a new way of looking at their own drinking.

Conclusions

Overall, the present research advanced knowledge regarding an understudied and at‐risk group of drinkers. This is among one of the first randomized studies to evaluate a brief intervention tailored to the needs of nonstudent emerging adults based on prior formative research with this group. Our data support PFI as a promising intervention approach for nonstudent drinkers in the community. Ultimately, this line of research aims to reduce alcohol‐related health disparities associated with inequities in education.
Trabecular and subchondral bone development of the talus and distal tibia from foal to adult in the warmblood horse
Authors: Gorissen B. M. C. , Wolschrijn C. F. , van Rietbergen B. , Rieppo L. , Saarakkala S. , van Weeren P. R.
Published: February 2018

Horses are precocial animals and able to stand and walk within hours after birth. To cope with associated loading, intrauterine bone development has shown to be anticipative. This study provides further insight into the post‐natal development of structurally important features of trabecular and subchondral bone of the talus and sagittal ridge of the tibia of warm‐blooded horses. In all areas studied, the average bone volume fraction showed a gradual increase over time, which was the result of a significant increase in trabecular thickness, without significant changes in the degree of anisotropy. Similar to the mineralised part of the bone, collagen content, measured as average retardation using polarised light microscopy, increased significantly, but the degree of anisotropy of the collagen type I network did not. At birth, the subchondral bone layer had a more trabecular aspect, gradually changing to an even surface with only a few vascular canals at an age of 2 months. Presented results indicate the necessity for a stronger structure, but not for a different structural design after birth, providing further evidence for anticipatory bone development in the horse. More knowledge about the strategies used to cope with mechanical loading after birth might be helpful in understanding the developmental bone and joint diseases.
Prognostic value of T‐wave morphology parameters in coronary artery disease in current treatment era
Authors: Pirkola Joni M. , Konttinen Maija , Kenttä Tuomas V. , Holmström Lauri T. A. , Junttila M. Juhani , Ukkola Olavi H. , Huikuri Heikki V. , Perkiömäki Juha S.
Published: February 2018

Background

The prognostic value of T‐wave morphology parameters in coronary artery disease in the current treatment era is not well established.

Methods

The Innovation to reduce Cardiovascular Complications of Diabetes at the Intersection (ARTEMIS) study included 1,946 patients with angiographically verified coronary artery disease (CAD). The study patients underwent thorough examinations including 12‐lead digital electrocardiogram (ECG) at baseline.

Results

During a follow‐up period of 73 ± 22 months, a total of 201 (10.3%) patients died. Of the study patients, 95 (4.9%) experienced cardiac death (CD) consisting of 44 (2.3%) sudden cardiac deaths (SCD) and 51 (2.6%) nonsudden cardiac deaths (NSCD), and 106 (5.4%) patients experienced noncardiac death (NCD). T‐wave morphology dispersion (TMD), T‐wave area dispersion (TWAD), and total cosine R‐to‐T (TCRT) had a significant association with CD even after adjustment with relevant clinical risk markers in the Cox regression analysis (multivariate HRs: 1.015, 95% CI 1.007–1.023, p = .0003; 0.474, 95% CI 0.305–0.737, p = .0009; 0.598, 95% CI 0.412–0.866, p = .006, respectively). When including these parameters to the clinical risk model for CD, the C‐index increased from 0.810 to 0.823 improving the discrimination significantly (integrated discrimination index [IDI] = 0.0118, 95% CI 0.0028–0.0208, p = .01). These parameters were more closely associated with NSCD (multivariate p‐values from .016 to .001) than with SCD (univariate/multivariate p‐values for TMD .015/.197 and for TCRT .012/.43).

Conclusion

T‐wave morphology parameters describing repolarization heterogeneity improve the predictive power of the clinical risk model for CD in patients with CAD in the current treatment era.
Combining Rome III criteria with alarm symptoms provides high specificity but low sensitivity for functional gastrointestinal disorders in children
Authors: Uusijärvi Agneta , Olén Ola , Malmborg Petter , Eriksson Martina , Grimheden Peter , Arnell Henrik
Published: February 2018

Aim

This study aimed to validate the Rome III criteria and alarm symptoms with regard to their ability to discriminate between organic and functional diagnoses in children with gastrointestinal complaints.

Methods

We recruited 258 children aged four years to 17 years who consulted a paediatrician in secondary or tertiary care in Stockholm from January 2013 to May 2014 due to gastrointestinal complaints. A symptom questionnaire based on the official Questionnaire on Pediatric Gastrointestinal Symptoms Rome III, including questions on alarm symptoms, was used. A diagnostic review of their medical records was also carried out.

Results

The reference diagnoses were organic (16%), pain‐predominant functional gastrointestinal disorders (54%) and other functional diseases (30%). When the reported symptoms that fulfilled the Rome III criteria for pain‐predominant functional gastrointestinal disorders were combined with an absence of alarm symptoms, they had a high specificity (0.90) for a functional diagnosis, but a low sensitivity (0.15). Alarm symptoms were equally common in patients with organic (83%) and functional diseases (80%, p = 0.66).

Conclusions

Combining the Rome III criteria and an absence of alarm symptoms from patient questionnaires had high specificity but low sensitivity when diagnosing pain‐predominant functional gastrointestinal disorders in children seeking medical care for gastrointestinal complaints.
rpoBgene mutations amongMycobacterium tuberculosisisolates from extrapulmonary sites
Authors: Khosravi Azar Dokht , Meghdadi Hossein , Ghadiri Ata A. , Alami Ameneh , Sina Amir Hossein , Mirsaeidi Mehdi
Published: February 2018

The aim of this study was to analyze mutations occurring in therpoBgene ofMycobacterium tuberculosis(MTB) isolates from clinical samples of extrapulmonary tuberculosis (EPTB). Seventy formalin‐fixed, paraffin‐embedded samples and fresh tissue samples from confirmed EPTB cases were analyzed. Nested PCR based on therpoBgene was performed on the extracted DNAs, combined with cloning and subsequent sequencing. Sixty‐seven (95.7%) samples were positive for nester PCR. Sequence analysis of the 81 bp region of therpoBgene demonstrated mutations in 41 (61.2%) of 67 sequenced samples. Several point mutations including deletion mutations at codons 510, 512, 513 and 515, with 45% and 51% of the mutations in codons 512 and 513 respectively were seen, along with 26% replacement mutations at codons 509, 513, 514, 518, 520, 524 and 531. The most common alteration was Gln → His, at codon 513, presented in 30 (75.6%) isolates. This study demonstrated sequence alterations in codon 513 of the 81 bp region of therpoBgene as the most common mutation occurred in 75.6% of molecularly confirmed rifampin‐resistant strains. In addition, simultaneous mutation at codons 512 and 513 was demonstrated in 34.3% of the isolates.
Strategies of salvation: Evangelical Christian praxis and sites of degradation in Sri Lanka
Authors: Woods Orlando
Published: February 2018

This paper demonstrates how disasters create sites of degradation – potent spaces of upheaval and engagement – that are readily filled and exploited by evangelical Christian groups. In doing so, it explores how disasters provide opportunities for evangelical groups to gain a foothold in localities where Christian presence, and evangelical praxis, may otherwise be restricted. Drawing on qualitative data collected in Sri Lanka throughout 2010–2011, two comparative case studies are presented that reveal the strategies of evangelical Christian praxis in and through sites of environmental and political degradation. Specifically, the case studies reveal how evangelical groups pursue ‘outside‐in’ and ‘inside‐out’ strategies of salvation, which, by blurring the boundaries of religion and relief, can lead to the formation of new hierarchies of power.
Tying modified clinch knots during single‐incision laparoscopic surgery
Authors: Fujioka Shuichi , Misawa Takeyuki , Kitamura Hiroaki , Kumagai Yu , Akiba Tadashi , Yanaga Katsuhiko
Published: February 2018

Introduction

Recent advances in single‐incision laparoscopic surgery (SILS) have caused increased difficulties when tying knots because of the limited working space. Although extracorporeal knot‐tying techniques may be a practical alternative choice in SILS, it is not always appropriate. For example, sliding resistance may be encountered when tying knots for a Z‐shaped suture, and it could damage the sutured tissue.

Materials and Surgical Technique

The clinch knot is a kind of slipknot that has been historically used by fishermen. We modified it for SILS so that it has a locking mechanism caused by knot deformation. We apply pre‐tied modified clinch (MC) knots in the peritoneal cavity with a needle driver. After the suture, the needle is pulled through the knot and exits out the trocar. After the MC knot has been tightened, locking is achieved by pulling the other end of the axial thread and folding the thread in an acute angle. Because both ends of the suture thread leave the trocar together, every step can be carried out quickly through a single trocar. The MC knot can also be used to tie knots for Z‐shaped sutures because of its short sliding distance. Twelve simple interrupted sutures and 55 Z‐shaped sutures were tied by MC knot in SILS. All knots were successfully tied, and the mean required time to tie a knot was 27 s.

Discussion

The MC knot is feasible knot‐tying procedure especially for a Z‐shaped suture during SILS.
Antinociceptive effect of two novel transient receptor potential melastatin 8 antagonists in acute and chronic pain models in rat
Authors: De Caro Carmen , Russo Roberto , Avagliano Carmen , Cristiano Claudia , Calignano Antonio , Aramini Andrea , Bianchini Gianluca , Allegretti Marcello , Brandolini Laura
Published: February 2018

Background and Purpose

Transient receptor potential (TRP) channels are a superfamily of non‐selective cation permeable channels involved in peripheral sensory signalling. Animal studies have shown that several TRPs are important players in pain modulation. Among them, the TRP melastatin 8 (TRPM8) has elicited more interest for its controversial role in nociception. This channel, expressed by a subpopulation of sensory neurons in dorsal root ganglia (DRG) and trigeminal ganglia (TG), is activated by cold temperatures and cooling agents. In experimental neuropathic pain models, an up‐regulation of this receptor in DRG and TG has been observed, suggesting a key role for TRPM8 in the development and maintenance of pain. Consistent with this hypothesis, TRPM8 knockout mice are less responsive to pain stimuli.

Experimental Approach

In this study, the therapeutic potential and efficacy of two novel TRPM8 antagonists, DFL23693 and DFL23448, were tested.

Key Results

Two potent and selective TRPM8 antagonists with distinct pharmacokinetic profiles, DFL23693 and DFL23448, have been fully characterized in vitro. In vivo studies in well‐established models, namely, the wet‐dog shaking test and changes in body temperature, confirmed their ability to block the TRPM8 channel. Finally, TRPM8 blockage resulted in a significant antinociceptive effect in formalin‐induced orofacial pain and in chronic constriction injury‐induced neuropathic pain, confirming an important role for this channel in pain perception.

Conclusion and Implications

Our findings, in agreement with previous literature, encourage further studies for a better comprehension of the therapeutic potential of TRPM8 blockers as novel agents for pain management.
Eicosanoids in the gastrointestinal tract
Authors: Wallace John L
Published: February 2018

Eicosanoids play important roles in modulating inflammation throughout the body. The gastrointestinal (GI) tract, in part because of its intimate relationship with the gut microbiota, is in a constant state of low‐grade inflammation. Eicosanoids like PGs, lipoxins and leukotrienes play essential roles in maintenance of mucosal integrity. On the other hand, in some circumstances, these mediators can become major drivers of inflammatory processes when the lining of the GI tract is breached. Drugs such as nonsteroidal anti‐inflammatories, by altering the production of various eicosanoids, can dramatically impact the ability of the GI tract to respond appropriately to injury. Disorders such as inflammatory bowel disease appear to be driven in part by altered production of eicosanoids. Several classes of drugs have been developed that target eicosanoids.

Linked Articles

This article is part of a themed section on Eicosanoids 35 years from the 1982 Nobel: where are we now? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.8/issuetoc
A two‐state model for the kinetics of competitive radioligand binding
Authors: Guo Dong , Peletier Lambertus A , Bridge Lloyd , Keur Wesley , de Vries Henk , Zweemer Annelien , Heitman Laura H , IJzerman Adriaan P
Published: February 2018

Background and Purpose

Ligand–receptor binding kinetics is receiving increasing attention in the drug research community. The Motulsky and Mahan model, a one‐state model, offers a method for measuring the binding kinetics of an unlabelled ligand, with the assumption that the labelled ligand has no preference while binding to distinct states or conformations of a drug target. As such, the one‐state model is not applicable if the radioligand displays biphasic binding kinetics to the receptor.

Experimental Approach

We extended the Motulsky and Mahan model to a two‐state model, in which the kinetics of the unlabelled competitor binding to different receptor states (R1 and R2) can be measured. With this extended model, we determined the binding kinetics of unlabelled N‐5′‐ethylcarboxamidoadenosine (NECA), a representative agonist for the adenosine A1 receptor. Subsequently, an application of the model was exemplified by measuring the binding kinetics of other A1 receptor ligands. In addition, limitations of the model were investigated as well.

Key Results

The kinetic rate constants of unlabelled NECA were comparable with the results of kinetic radioligand binding assays in which [3H]‐NECA was used. The model was further validated by good correlation between simulated results and the experimental data.

Conclusion

The two‐state model is sufficient to analyse the binding kinetics of an unlabelled ligand, when a radioligand shows biphasic association characteristics. We expect this two‐state model to have general applicability for other targets as well.
Review of parental activation interventions for parents of children with special health care needs
Authors: Mirza M. , Krischer A. , Stolley M. , Magaña S. , Martin M.
Published: February 2018

Background

A large number of U.S. children are identified as having special health care needs (CSHCN). Despite parents' central role in managing their child's needs, many parents report difficulties in navigating service systems, finding information about their child's condition, and accessing health care and community resources. Therefore, there is a need for interventions that “activate” parents of children with special health care needs to increase their knowledge, skills, and confidence in managing, coordinating, and advocating for their child's needs. This study sought to review the existing literature and examine the effects of parent support interventions that focus on parental activation either in part or whole, on child, parent, or family outcomes. Specific aims included (a) summarizing the nature and content of interventions; (b) describing changes in relevant outcomes; (c) identifying limitations and making recommendations for future research.

Methods

Following electronic databases were searched: MEDLINE, EMBASE, PsycINFO via ProQuest, PubMed, Cumulative Index to Nursing and Allied Health via EBSCO, Education Resources Information Center (ERIC) via ProQuest, The Cochrane Library (Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Cochrane Methodology Register), and Google Scholar. Twenty‐two studies were selected, data were extracted, and quality was assessed using standardized procedures.

Results

Five intervention categories were identified: parent‐to‐parent supports, psycho‐educational groups, content‐specific groups, community health worker model, and self‐management‐based interventions. Although most studies showed positive effects of the intervention, evidence was inconsistent for parental outcomes such as self‐efficacy, confidence, strain, depression, and perceived social support. Evidence was more consistent in showing improvement in parent coping and in use of community‐based services and resources.

Conclusions

There is a need to boost active ingredients of interventions that specifically target enhancing parent skill sets relevant to areas of self‐efficacy, confidence, and empowerment. Future studies must also adapt intervention and study design to recruit socioeconomically vulnerable families.
More Similar Than Different: Gender Differences in Children's Basic Numerical Skills Are the Exception Not the Rule
Authors: Hutchison Jane E. , Lyons Ian M. , Ansari Daniel
Published: February 2018

This study investigates gender differences in basic numerical skills that are predictive of math achievement. Previous research in this area is inconsistent and has relied upon traditional hypothesis testing, which does not allow for assertive conclusions to be made regarding nonsignificant findings. This study is the first to compare male and female performance (N = 1,391; ages 6–13) on many basic numerical tasks using both Bayesian and frequentist analyses. The results provide strong evidence of gender similarities on the majority of basic numerical tasks measured, suggesting that a male advantage in foundational numerical skills is the exception rather than the rule.
Pharmacological or transcriptional inhibition of both HDAC1 and 2 leads to cell cycle blockage and apoptosis via p21Waf1/Cip1 and p19INK4d upregulation in hepatocellular carcinoma
Authors: Zhou Hengyu , Cai Ying , Liu Dina , Li Menghui , Sha Yu , Zhang Wenlu , Wang Kai , Gong Jianping , Tang Ni , Huang Ailong , Xia Jie
Published: February 2018

Objectives

Histone deacetylases (HDACs) are commonly dysregulated in cancer and represent promising therapeutic targets. However, global HDAC inhibitors have shown limited efficacy in the treatment of solid tumours, including hepatocellular carcinoma (HCC). In this study, we investigated the therapeutic effect of selectively inhibiting HDAC1 and 2 in HCC.

Methods

HDAC1 inhibitor Tacedinaline (CI994), HDAC2 inhibitor Santacruzamate A (CAY10683), HDAC1/2 common inhibitor Romidepsin (FK228) and global HDAC inhibitor Vorinostat (SAHA) were used to treat HCC cells. Cell cycle, apoptosis and the protein levels of CDKs and CDKNs were performed to evaluate HCC cell growth. Inhibition of HDAC1/2 by RNAi was further investigated.

Results

Combined inhibition of HDAC1/2 led to HCC cell morphology changes, growth inhibition, cell cycle blockage and apoptosis in vitro and suppressed the growth of subcutaneous HCC xenograft tumours in vivo. p21Waf1/Cip1 and p19INK4d, which play roles in cell cycle blockage and apoptosis induction, were upregulated. Inhibition of HDAC1/2 by siRNA further demonstrated that HDAC1 and 2 cooperate in blocking the cell cycle and inducing apoptosis via p19INK4d and p21Waf1/Cip1 upregulation. Finally, H3K18, H3K56 and H4K12 in the p19INK4d and p21Waf1/Cip1 promoter regions were found to be targets of HDAC1/2.

Conclusions

Pharmacological or transcriptional inhibition of HDAC1/2 increases p19INK4d and p21Waf1/Cip1 expression, decreases CDK expression and arrests HCC growth. These results indicated a potential pharmacological mechanism of selective HDAC1/2 inhibitors in HCC therapy.
Intravesicular taxane‐induced dermatotoxicity in a 78‐year‐old man with urothelial carcinoma and primary cutaneous anaplastic large cell lymphoma
Authors: J Pelletier Daniel , O'Donnell Michael , Stone Mary Seabury , Liu Vincent
Published: February 2018

Patients treated with intravesical bacillus Calmette‐Guérin therapy for urothelial carcinoma often become refractory and experience recurrent disease, thus necessitating alternative intravesical treatment modalities if the patient is to be spared the morbidities associated with radical cystectomy. Intravesical treatment with taxane‐based chemotherapy, such as docetaxel, has gained traction in urologic oncology, proving to be an effective salvage therapy in such patients. Systemic taxane‐based chemotherapeutic regimens have long been used in several advanced malignancies, and their systemic side‐effects and associated histologic correlates have been extensively documented. In contrast to adverse effects associated with systemic administration, intravesical taxane administration has thus far proven to be well‐tolerated, with little to no systemic absorption. To our knowledge, features of taxane‐induced systemic effects have not been reported in this setting. Herein, we report a case of a patient with recurrent urothelial carcinoma treated with intravesical docetaxel, along with primary cutaneous anaplastic large cell lymphoma, who developed characteristic dermatotoxic histologic findings associated with intravenous taxane administration. As such histopathologic findings often represent close mimickers of neoplastic and infectious etiologies, knowledge of the potential for systemic manifestations of taxane therapy in patients treated topically may prevent potentially costly diagnostic pitfalls.
Physical appearance concerns are uniquely associated with the severity of steroid dependence and depression in anabolic–androgenic steroid users
Authors: Griffiths Scott , Jacka Brendan , Degenhardt Louisa , Murray Stuart B. , Larance Briony
Published: February 2018

Introduction and Aims

Emerging research suggests that the sub‐population of anabolic–androgenic steroid (AAS) users who experience physical appearance concerns may suffer greater psychological dysfunction than other sub‐populations, including users with athletic or occupational concerns. Thus, among current AAS users, we sought to determine whether, and to what extent, social physique anxiety—an established measure of appearance concern—was associated with psychological dysfunction.

Design and Methods

Interviews were conducted with a sample of 74 male AAS users living in Australia. Users completed self‐report instruments of the severity of AAS dependence, depression, hazardous and risky drinking, use of non‐AAS illicit drugs, psychological side‐effects due to AAS use and abnormal test results due to AAS use.

Results

Multivariate analyses revealed that greater social physique anxiety was uniquely associated with more severe symptoms of both AAS dependence and depression. Moreover, the effect size of these relationships was large. Social physique anxiety was not associated with hazardous or risky drinking, non‐AAS illicit drug use, psychological side‐effects or abnormal test results.

Discussion and Conclusions

Limitations notwithstanding, the study is consistent with the notion that AAS users who experience appearance concerns are at heightened risk of co‐morbid psychological dysfunction. Given trends indicating an increase in the prevalence of AAS use in Australia and elsewhere, the findings suggest that health‐care systems may need to consider prioritising the sub‐population of AAS users who experience appearance concerns. Further investigation of the clinical syndrome of AAS dependence is required, including its relation to body image and eating disorders.
Assessing habitat loss and fragmentation and their effects on population viability of forest specialist birds: Linking biogeographical and population approaches
Authors: Carvajal Mario A. , Alaniz Alberto J. , Smith‐Ramírez Cecilia , Sieving Kathryn E.
Published: February 2018

Aim

Biogeographic approaches usually have been developed apart from population ecology, resulting in predictive models without key parameters needed to account for reproductive and behavioural limitations on dispersal. Our aim was to incorporate fully spatially explicit population traits into a classic species distribution model (SDM) using Geographic Information Systems (GIS), aiming at conservation purposes.

Location

Southern South America.

Methods

Our analysis incorporates the effects of habitat loss and fragmentation on population viability and therefore provides insights into how much spatially explicit population traits can improve the SDM prediction of habitable habitat. We utilized a well‐studied focal endemic bird of South American temperate rainforests (Scelorchilus rubecula). First, at a large scale, we assessed the historical extent habitat based on climate envelopes in an SDM. Second, we used a land cover change analysis at a regional scale to account for recent habitat loss and fragmentation. Third, we used empirically derived criteria to predict population responses to fragmented forest landscapes to identify actual losses of habitat and population. Then we selected three sites of high conservation value in southern Chile and applied our population model. Finally, we discuss the degree to which spatially explicit population traits can improve the SDM output without intervening in the modelling process itself.

Results

We found a historical habitat loss of 39.12% and an additional forest cover loss of 3.03% during 2000–2014; the latter occurred with a high degree of fragmentation, reducing the overall estimation of (1) carrying capacity by −82.4%, −33.1% and −45.1% and (2) estimated number of pairs on viable populations by −84.1%, −33.0% and −54.6% on the three selected sites.

Main conclusion

We conclude that our approach sharpened the SDM prediction on environmental suitability by 54.4%, adjusting the habitable area by adding population parameters through GIS, and allowing to incorporate other phenomena as fragmentation and habitat loss.
“That is just what they want you to believe”: A modest defence of Marxist paranoia
Authors: Olsson Yaouzis Nicolas
Published: February 2018

This essay defends a rational reconstruction of a genealogical debunking argument that begins with the premise “that's just what the economic elite want you to believe” and ends in the conclusion “you should lower your confidence in your belief.” The argument is genealogical because it includes a causal explanation of your beliefs; it is debunking because it claims that the contingencies uncovered by the genealogy undermine your beliefs. The essay begins by defending a plausible causal explanation of your belief in terms of the wants of the elite. Then a number of recent objections to genealogical debunking arguments are considered. It is argued that the genealogy offered in the first part constitutes evidence that a testimony‐based belief is not safe and therefore does not constitute knowledge if the economic elite wants you to believe it.
Mutational analysis of TAF6 revealed the essential requirement of the histone‐fold domain and the HEAT repeat domain for transcriptional activation
Authors: Dahiya Rashmi , Natarajan Krishnamurthy
Published: February 2018

TAF6, bearing the histone H4‐like histone‐fold domain (HFD), is a subunit of the core TAF module in TFIID and SAGA transcriptional regulatory complexes. We isolated and characterized several yeast TAF6 mutants bearing amino acid substitutions in the HFD, the middle region or the HEAT repeat domain. The TAF6 mutants were highly defective for transcriptional activation by the Gcn4 and Gal4 activators. CHIP assays showed that the TAF6‐HFD and the TAF6‐HEAT domain mutations independently abrogated the promoter occupancy of TFIID and SAGA complex in vivo. We employed genetic and biochemical assays to identify the relative contributions of the TAF6 HFD and HEAT domains. First, the temperature‐sensitive phenotype of the HEAT domain mutant was suppressed by overexpression of the core TAF subunits TAF9 and TAF12, as well as TBP. The HFD mutant defect, however, was suppressed by TAF5 but not by TAF9, TAF12 or TBP. Second, the HEAT mutant but not the HFD mutant was defective for growth in the presence of transcription elongation inhibitors. Third, coimmunoprecipitation assays using yeast cell extracts indicated that the specific TAF6 HEAT domain residues are critical for the interaction of core TAF subunits with the SAGA complex but not with TFIID. The specific HFD residues in TAF6, although required for heterodimerization between TAF6 and TAF9 recombinant proteins, were dispensable for association of the core TAF subunits with TFIID and SAGA in yeast cell extracts. Taken together, the results of our studies have uncovered the non‐overlapping requirement of the evolutionarily conserved HEAT domain and the HFD in TAF6 for transcriptional activation.
A morphogram for silica‐witherite biomorphs and its application to microfossil identification in the early earth rock record
Authors: Rouillard J. , García‐Ruiz J.‐M. , Gong J. , van Zuilen M. A.
Published: February 2018

Archean hydrothermal environments formed a likely site for the origin and early evolution of life. These are also the settings, however, were complex abiologic structures can form. Low‐temperature serpentinization of ultramafic crust can generate alkaline, silica‐saturated fluids in which carbonate–silica crystalline aggregates with life‐like morphologies can self‐assemble. These “biomorphs” could have adsorbed hydrocarbons from Fischer–Tropsch type synthesis processes, leading to metamorphosed structures that resemble carbonaceous microfossils. Although this abiogenic process has been extensively cited in the literature and has generated important controversy, so far only one specific biomorph type with a filamentous shape has been discussed for the interpretation of Archean microfossils. It is therefore critical to precisely determine the full distribution in morphology and size of these biomorphs, and to study the range of plausible geochemical conditions under which these microstructures can form. Here, a set of witherite‐silica biomorph synthesis experiments in silica‐saturated solutions is presented, for a range of pH values (from 9 to 11.5) and barium ion concentrations (from 0.6 to 40 mmol/L BaCl2). Under these varying conditions, a wide range of life‐like structures is found, from fractal dendrites to complex shapes with continuous curvature. The size, spatial concentration, and morphology of the biomorphs are strongly controlled by environmental parameters, among which pH is the most important. This potentially limits the diversity of environments in which the growth of biomorphs could have occurred on Early Earth. Given the variety of the observed biomorph morphologies, our results show that the morphology of an individual microstructure is a poor criterion for biogenicity. However, biomorphs may be distinguished from actual populations of cellular microfossils by their wide, unimodal size distribution. Biomorphs grown by diffusion in silica gel can be differentiated by their continuous gradient in size, spatial density, and morphology along the direction of diffusion.