bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessment of biophysical properties of Royal Belum tropical forest, Malaysia
Authors: Kanniah Kasturi Devi , Tan Kian Pang , Cracknell Arthur P , Huete Alfredo R , Idris Nurul Hawani , Lau Alvin Meng Shin , Abd Rahman Muhammad Zulkarnain , Rasib Abd Wahid , Ahmad Anuar
Published: October 2017

The Royal Belum forest reserve is one of the oldest tropical rainforests in the world and it is one of the largest virgin forest reserves in Malaysia. However, not many studies have been conducted to understand the ecology of this forest. In this study we estimated the aboveground biomass (AGB) of the forest using diameter at breast height (DBH) and height of trees (h), tree species and hemispherical photographs of tree canopy. We estimated AGB using five allometric equations. Our results demonstrated that the AGB given by the one tree species specific allometric equation does not show any significant differences from the values given by the non‐tree species specific allometric equations at tree and plot levels. The AGB of Intsia bijuga species, Koompassia malaccensis species and Shorea genera were comparatively higher, owing to their greater wood density, DBH and h. This has added importance because some of these species are categorized as threatened species. Our results demonstrated that mean AGB values in this forest (293.16 t ha‐1) are the highest compared to some studies of other areas in Malaysia, tropical Africa and tropical Bazilian Amazonia, implying that the Royal Belum forest reserve, is an important carbon reservoir.
Feature analysis of ultrasound elastography image for quantitative assessment of cutaneous carcinoma
Authors: Morris M. A. , Ring C. M. , Managuli R. , Saboury B. , Mehregan D. , Siegel E. , Dasgeb B.
Published: October 2017

Background

To evaluate the feasibility of using quantitative texture features computed from high frequency ultrasound and ultrasound elastography (USE) images in the discrimination of benign from malignant skin lesions.

Methods

A commercial ultrasound system with a 14 MHz transducer was used to visualize skin lesions requiring biopsy on clinical evaluation. Patients were enrolled over a 6‐month period and imaged prospectively by operators blind to the histopathologic diagnosis. Anatomic ultrasound and USE imaging of the skin lesions was performed using a 2‐4 mm gel standoff pad before biopsy and histopathologic evaluation. The ElastoAnalysis software developed for the texture analysis of USE images was provided by Hitachi. The software computes thirteen texture features within a region of interest (ROI), which have demonstrated promise in diagnostic characterization of liver fibrosis staging and in quantitative elastography of breast cancer. This approach has not yet been studied in the quantitative assessment of skin cancer. Results were retrospectively compared to the histopathologic diagnosis and a diagnostic criteria with the goal of maximizing sensitivity was evaluated for each textural feature.

Results

Of the 37 lesions included, among 30 patients who participated, 12 lesions were malignant and 25 were benign. Eleven out of thirteen textural metrics computed by the software were useful in differentiating benign from malignant lesions with 100% sensitivity and specificities ranging from 28% to 85%.

Conclusions

This feasibility study demonstrated that feature analysis of USE may be useful in quantitatively differentiating cancerous from benign primary solitary skin lesions prior to biopsy.
Heterogeneous Space–Time Artificial Neural Networks for Space–Time Series Prediction
Authors: Deng Min , Yang Wentao , Liu Qiliang , Jin Rui , Xu Feng , Zhang Yunfei
Published: October 2017

Space–time series prediction plays a key role in the domain of geographic data mining and knowledge discovery. In general, the existing methods of space–time series prediction can be divided into two main categories: statistical machine learning methods. Comparatively, machine leaning methods have obvious advantages with respect to handling nonlinear problems. However, space–time dependence and the heterogeneity of space–time data are not well addressed by the existing machine learning methods. Because of this limitation, an accurate prediction of a space–time series is still a challenging problem. Therefore, in this study, both space–time dependence and heterogeneity are incorporated into the feedback artificial neural network, and heterogeneous space–time artificial neural networks (HSTANNs) are developed for space–time series prediction. First, to handle spatial heterogeneity, space–time series clustering is used to divide the study area into a set of homogeneous sub‐areas. Then, a space–time autocorrelation analysis is employed to explore the space–time dependence structure of the dataset. Finally, a HSTANN is established for each sub‐area. Further, HSTANNs are applied to predict the concentrations of fine particulate matter (PM2.5) in Beijing–Tianjin–Hebei. The experimental results show that when compared with other methods, the accuracy of the forecasting results is considerably improved by using HSTANNs.
The de minimis threshold in international trade: The costs of being too low
Authors: Latipov Olim , McDaniel Christine , Schropp Simon
Published: October 2017

With tariffs largely negotiated away, trade facilitation issues such as custom delays and border costs are one of the next key barriers for trade policymakers to address. One important trade facilitation issue is the de minimis threshold (DMT)—a valuation ceiling for imports below which no duty or tax is charged and the clearance procedures are minimal. Customs assessments are costly and low thresholds can hinder trade flows. We offer a detailed analytical approach to assess the direct economic effects of raising theDMT. We focus on Canada, which has one of the lowestDMTs among developed countries. We utilise a unique data set and find that raising Canada'sDMTwould have positive effects for consumers and businesses, particularly small businesses because the cost saving for smaller entities is disproportionately large. For the government, foregone duty and tax revenues are outweighed by the cost saving, resulting in a fiscally neutral or even positive effect for government revenues.
Symmetry solution on fractional equation
Authors: Iskandarova Gulistan , Kaya Dogan
Published: October 2017

As we know nearly all physical, chemical, and biological processes in nature can be described or modeled by dint of a differential equation or a system of differential equations, an integral equation or an integro-differential equation. The differential equations can be ordinary or partial, linear or nonlinear. So, we concentrate our attention in problem that can be presented in terms of a differential equation with fractional derivative. Our research in this work is to use symmetry transformation method and its analysis to search exact solutions to nonlinear fractional partial differential equations.
RNA editing with CRISPR-Cas13
Authors: Cox David B. T. , Gootenberg Jonathan S. , Abudayyeh Omar O. , Franklin Brian , Kellner Max J. , Joung Julia , Zhang Feng
Published: October 2017

Precise transcriptome engineering

Efficient and precise RNA editing to correct disease-relevant transcripts holds great promise for treating genetic disease. Cox
et al.
took advantage of the ability of Cas13b, an effector from a type VI CRISPR-Cas system, to target specific RNAs directly (see the Perspective by Yang and Chen). They fused Cas13b with the ADAR2 adenosine deaminase domain and used rational protein engineering to improve the resultant enzyme. These approaches yielded an RNA knockdown and editing platform that allowed efficient and specific RNA depletion and correction in mammalian cells.

Science
, this issue p.
1019
; see also p.
996
Infectious Laryngotracheitis Virus Viral Chemokine-Binding Protein Glycoprotein G Alters Transcription of Key Inflammatory Mediators
In Vitro
and
In Vivo
Authors: Coppo Mauricio J. C. , Devlin Joanne M. , Legione Alistair R. , Vaz Paola K. , Lee Sang-Won , Quinteros José A. , Gilkerson James R. , Ficorilli Nino , Reading Patrick C. , Noormohammadi Amir H. , Hartley Carol A.
Published: October 2017

Infectious laryngotracheitis virus (ILTV) is an alphaherpesvirus that infects chickens, causing upper respiratory tract disease and significant losses to poultry industries worldwide. Glycoprotein G (gG) is a broad-range viral chemokine-binding protein conserved among most alphaherpesviruses, including ILTV. A number of studies comparing the immunological parameters between infection with gG-expressing and gG-deficient ILTV strains have demonstrated that expression of gG is associated with increased virulence, modification of the amount and the composition of the inflammatory response, and modulation of the immune responses toward antibody production and away from cell-mediated immune responses. The aims of the current study were to examine the establishment of infection and inflammation by ILTV and determine how gG influences that response to infection.
In vitro
infection studies using tracheal organ tissue specimen cultures and blood-derived monocytes and
in vivo
infection studies in specific-pathogen-free chickens showed that leukocyte recruitment to the site of infection is an important component of the induced pathology and that this is influenced by the expression of ILTV gG and changes in the transcription of the chicken orthologues of mammalian CXC chemokine ligand 8 (CXCL8), chicken CXCLi1 and chicken CXCLi2, among other cytokines and chemokines. The results from this study demonstrate that ILTV gG interferes with chemokine and cytokine transcription at different steps of the inflammatory cascade, thus altering inflammation, virulence, and the balance of the immune response to infection.

IMPORTANCE
Infectious laryngotracheitis virus is an alphaherpesvirus that expresses gG, a conserved broad-range viral chemokine-binding protein known to interfere with host immune responses. However, little is known about how gG modifies virulence and influences the inflammatory signaling cascade associated with infection. Here, data from
in vitro
and
in vivo
infection studies are presented. These data show that gG has a direct impact on the transcription of cytokines and chemokine ligands
in vitro
(such as chicken CXCL8 orthologues, among others), which explains the altered balance of the inflammatory response that is associated with gG during ILTV infection of the upper respiratory tract of chickens. This is the first report to associate gG with the dysregulation of cytokine transcription at different stages of the inflammatory cascade triggered by ILTV infection of the natural host.
Selective Proteomic Analysis of Antibiotic-Tolerant Cellular Subpopulations inPseudomonas aeruginosaBiofilms
Authors: Babin Brett M. , Atangcho Lydia , van Eldijk Mark B. , Sweredoski Michael J. , Moradian Annie , Hess Sonja , Tolker-Nielsen Tim , Newman Dianne K. , Tirrell David A.
Published: October 2017

Biofilm infections exhibit high tolerance against antibiotic treatment. The study of biofilms is complicated by phenotypic heterogeneity; biofilm subpopulations differ in their metabolic activities and their responses to antibiotics. Here, we describe the use of the bio-orthogonal noncanonical amino acid tagging (BONCAT) method to enable selective proteomic analysis of aPseudomonas aeruginosabiofilm subpopulation. Through controlled expression of a mutant methionyl-tRNA synthetase, we targeted BONCAT labeling to cells in the regions of biofilm microcolonies that showed increased tolerance to antibiotics. We enriched and identified proteins synthesized by cells in these regions. Compared to the entire biofilm proteome, the labeled subpopulation was characterized by a lower abundance of ribosomal proteins and was enriched in proteins of unknown function. We performed a pulse-labeling experiment to determine the dynamic proteomic response of the tolerant subpopulation to supra-MIC treatment with the fluoroquinolone antibiotic ciprofloxacin. The adaptive response included the upregulation of proteins required for sensing and repairing DNA damage and substantial changes in the expression of enzymes involved in central carbon metabolism. We differentiated the immediate proteomic response, characterized by an increase in flagellar motility, from the long-term adaptive strategy, which included the upregulation of purine synthesis. This targeted, selective analysis of a bacterial subpopulation demonstrates how the study of proteome dynamics can enhance our understanding of biofilm heterogeneity and antibiotic tolerance.

IMPORTANCEBacterial growth is frequently characterized by behavioral heterogeneity at the single-cell level. Heterogeneity is especially evident in the physiology of biofilms, in which distinct cellular subpopulations can respond differently to stresses, including subpopulations of pathogenic biofilms that are more tolerant to antibiotics. Global proteomic analysis affords insights into cellular physiology but cannot identify proteins expressed in a particular subpopulation of interest. Here, we report a chemical biology method to selectively label, enrich, and identify proteins expressed by cells within distinct regions of biofilm microcolonies. We used this approach to study changes in protein synthesis by the subpopulation of antibiotic-tolerant cells throughout a course of treatment. We found substantial differences between the initial response and the long-term adaptive strategy that biofilm cells use to cope with antibiotic stress. The method we describe is readily applicable to investigations of bacterial heterogeneity in diverse contexts.
An Important Role for Purifying Selection in Archaeal Genome Evolution
Authors: Lyu Zhe , Li Zhi-Gang , He Fei , Zhang Ziding
Published: October 2017

The evolution of genome complexities is a fundamental question in biology. A hallmark of eukaryotic genome complexity is that larger genomes tend to have more noncoding sequences, which are believed to be minimal in archaeal and bacterial genomes. However, we found that archaeal genomes also possessed this eukaryotic feature while bacterial genomes did not. This could be predicted from our analysis of genetic drift, which showed relaxed purifying selection in larger archaeal genomes, also a eukaryotic feature. In contrast, the opposite was evident in bacterial genomes.
Anti-MAG antibodies in 202 patients: clinicopathological and therapeutic features
Authors: Svahn Juliette , Petiot Philippe , Antoine Jean-Christophe , Vial Christophe , Delmont Emilien , Viala Karine , Steck Andreas J , Magot Armelle , Cauquil Cecile , Zarea Aline , Echaniz-Laguna Andoni , Iancu Ferfoglia Ruxandra , Gueguen Antoine , Magy Laurent , Léger Jean-Marc , Kuntzer Thierry , Ferraud Karine , Lacour Arnaud , Camdessanché Jean-Philippe
Published: October 2017

Objective

To assess the clinicopathological and therapeutic features of patients with low (≥1000 to <10 000 Bühlmann Titre Units) (BTU), medium (10 000–70 000) or high (≥70 000) anti-myelin-associated glycoprotein (anti-MAG) antibody titres.

Methods

We retrospectively and prospectively analysed standardised report forms and medical records of 202 patients from 14 neuromuscular centres.

Results

Mean age at onset and mean time between symptom onset to last follow-up were respectively 62.6 years (25–91.4) and 8.4 years (0.3–33.3). Anti-MAG antibody titres at diagnosis were low, medium or high in 11%, 51% and 38% of patients. Patients presented with monoclonal gammopathy of undetermined significance in 68% of cases. About 17% of patients presented with ‘atypical’ clinical phenotype independently of anti-MAG titres, including acute or chronic sensorimotor polyradiculoneuropathies (12.4%), and asymmetric or multifocal neuropathy (3%). At the most severe disease stage, 22.4% of patients were significantly disabled. Seventy-eight per cent of patients received immunotherapies. Transient clinical worsening was observed in 12% of patients treated with rituximab (11/92). Stabilisation after rituximab treatment during the 7–12-month follow-up period was observed in 29% of patients. Clinical response to rituximab during the 6-month and/or 7–12-month follow-up period was observed in 31.5% of patients and correlated with anti-MAG titre ≥10 000 BTU.

Conclusion

Our study highlights the extended clinical spectrum of patients with anti-MAG neuropathy, which appears unrelated to antibody titre. Besides, it may also suggest beneficial use of rituximab in the early phase of anti-MAG neuropathy.
Perceived intentional transmission of HIV infection, sustained viral suppression and psychosocial outcomes among men who have sex with men living with HIV: a cross-sectional assessment
Authors: Brown Monique J , Serovich Julianne M , Kimberly Judy A
Published: October 2017

Objective

HIV continues to be a global and national public health challenge, and men who have sex with men (MSM) are disproportionately affected in the USA. Transmission of HIV is intentional if the person living with HIV knows about his/her serostatus, acts with the intention to and actually transmits HIV. Research on intentional transmission of HIV infections is lacking, and the relationships between perceived intentional transmission, viral suppression and psychosocial outcomes have not been assessed. The objective of this study was to investigate the association between perceived intentional transmission of HIV, sustained viral suppression and psychosocial outcomes.

Methods

Data were obtained from 338 MSM living with HIV who participated in a disclosure intervention study. Logistic and linear regression models were used to assess the associations between perceived intentional transmission and viral suppression, condomless anal intercourse in the past 30 days, being at risk for clinical depression, substance use, self-efficacies for condom use, HIV disclosure and negotiation of safer sex practices, and sexual compulsivity.

Results

44% of the study population reported perceiving intentional HIV transmission. After adjusting for sociodemographic characteristics, men who thought that they were infected intentionally had 69% higher odds (adjusted OR: 1.69; 95% CI 1.01 to 2.83) of being at risk for clinical depression, and on average, scored approximately 3 points and 4 points higher on depressive symptoms and sexual compulsivity, respectively (adjusted β: 3.29; 95% CI 0.42 to 6.15; adjusted β: 3.74; 95% CI 1.32 to 6.17) compared with men who did not think that they were intentionally infected. After adjusting for confounders, there was no statistically significant association between perceived intentional transmission and viral suppression.

Conclusions

Intervention programmes for MSM living with HIV who thought they were infected intentionally are warranted and should aim to attenuate depressive symptoms and sexual compulsivity.
Treatment of chlamydia and gonorrhoea, compliance with treatment guidelines and factors associatedwith non-compliant prescribing: findings form a cross-sectional study
Authors: Tisler-Sala Anna , Ojavee Sven-Erik , Uusküla Anneli
Published: October 2017

Objectives

Proper antibiotic treatment of STI reduces transmission, antimicrobial resistance and serious disease complications. In this study, we assessed compliance with STI treatment guidelines for genital gonorrhoea and chlamydia infections in Estonia.

Methods

Prescription data from the Estonian Health Insurance Fund on 7556 treatment episodes of 6499 patients treated for gonorrhoea or chlamydia during 2012–2014 were analysed to assess compliance with the guidelines and factors associated with it.

Results

Between 1 January 2012 and 31 December 2014, a total of 6074 patients were treated for chlamydia and 425 for gonorrhoea in Estonia. Among all prescriptions, 48.6% were non-compliant with gonorrhoea treatment guidelines and 3.8% for chlamydia. Non-compliant antibiotic treatment for gonorrhoea was associated with patient gender (female (adjusted OR (AOR)) 3.0, 95% CI 1.6 to 5.9), region (east AOR 3.3, 95% CI 1.3 to 8.2; west AOR 6.5, 95% CI 2.2 to 19.7) and prescribing physician specialty (general healthcare doctors: AOR 5.6, 95% CI 2.3 to 13.8; gynaecologists: AOR 5.9, 95% CI 2.8 to 12.4). Non-compliant antibiotic treatment for chlamydia was associated with younger patient age (15–24 AOR 0.5, 95% CI 0.4 to 0.7), region (north AOR 1.9, 95% CI 1.4 to 2.6; west AOR 2.3, 95% CI 1.5 to 3.4) and multiple treatment episodes (AOR 2.7, 95% CI 2.1 to 3.9). Approximately 14% of prescriptions were multiple treatments for the same patient for the same infection over the 3-year period (6.1% for gonorrhoea and 14.5% for chlamydia).

Conclusion

There are significant differences in terms of compliance with treatment guidelines for gonorrhoea and chlamydia, and several factors associated with non-compliance that can potentially be targeted with interventions. Future research should explore reasons clinicians do not follow guidelines and examine ways to improve practice among doctors and patients and assess factors associated with multiple treatments, particularly multiple treatments for the same STI.
Mammary embryonal rhabdomyosarcoma with widespread metastasis in an adult dog
Authors: Dagher Lobna , Armién Anibal G , Dundas James , Dennis Michelle M
Published: October 2017

A 10‐year‐old female mixed‐breed dog presented for acute dyspnoea developing nine months after multiple mammary tumours were identified. The dog was euthanased and postmortem examination revealed widespread embryonal rhabdomyosarcoma of the myotubular variant involving the largest mammary tumour, the spleen, kidney, liver, lung and heart. The diagnosis was confirmed by immunohistochemical detection of desmin and the electron microscopic demonstration of cytoplasmic myofilaments with early sarcomere differentiation and rudimentary z‐lines within tumour cells. To the authors’ knowledge, this is the first comprehensive case description of the myotubular variant of embryonal rhabdomyosarcoma in the dog. This case is also unusual due to the involvement of mammary gland, the old age of the dog at the time of diagnosis and the confirmation of metastasis in a dog diagnosed after two years of age.
Matrix factorization method for actual atoms and molecules
Authors: Frolov Alexei M.
Published: October 2017

Matrix factorization method is developed to describe the bound state spectra in few- and many-electron atoms, ions, and molecules. Our method is based on the matrix factorization of many-electron (or many-particle) Coulomb Hamiltonians, which are written in hyperspherical coordinates. As follows from the results of our study, the bound state spectra of many-electron (or many-particle) Coulomb Hamiltonians always have the “ladder” structure and this fundamental fact can be used to determine and investigate the bound states in various few- and many-body Coulomb systems.
In VitroAntibacterial Activity of Pomegranate Juice and Peel Extracts on Cariogenic Bacteria
Authors: Ferrazzano Gianmaria Fabrizio , Scioscia Elisa , Sateriale Daniela , Pastore Gabiria , Colicchio Roberta , Pagliuca Chiara , Cantile Tiziana , Alcidi Brunella , Coda Marco , Ingenito Aniello , Scaglione Elena , Cicatiello Annunziata Gaetana , Volpe Maria Grazia , Di Stasio Michele , Salvatore Paola , Pagliarulo Caterina
Published: October 2017

Aim. To evaluate the antimicrobial activity of hydroalcoholic extracts of pomegranate (Punica granatumL.) peel and juice, against the microorganisms considered the main etiologic agents of dental caries.Methods. The values of the minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) were determined againstStreptococcus mutansClarke ATCC® 25175™ strain andRothia dentocariosaclinical isolate.Results. Peel extracts inhibit effectively the growth and survival ofS. mutansATCC 25175 strain andR. dentocariosaclinical isolate with MIC and MBC values of 10 μg/μl and 15 μg/μl, respectively. Furthermore, the pomegranate juice extract showed high inhibitory activity againstS. mutansATCC 25175 strain with a MIC value of 25 μg/μl and a MBC value of 40 μg/μl, whereas, againstR. dentocariosa, it has displayed a moderate inhibitory activity, with MIC and MBC values of 20 μg/μl and 140 μg/μl, respectively.Conclusions.In vitromicrobiological tests demonstrate that the hydroalcoholic extracts of pomegranate juice and peel are able to contrast the main cariogenic bacteria involved in tooth decay. Although being preliminary data, our results suggest that pomegranate polyphenolic compounds could represent a good adjuvant for the prevention and treatment of dental caries.
Mutual Information Based Analysis for the Distribution of Financial Contagion in Stock Markets
Authors: Wang Xudong , Hui Xiaofeng
Published: October 2017

This paper applies mutual information to research the distribution of financial contagion in global stock markets during the US subprime crisis. First, we symbolize the daily logarithmic stock returns based on their quantiles. Then, the mutual information of the stock indices is calculated and the block bootstrap approach is adopted to test the financial contagion. We analyze not only the contagion distribution during the entire crisis period but also its evolution over different stages by using the sliding window method. The empirical results prove the widespread existence of financial contagion and show that markets impacted by contagion tend to cluster geographically. The distribution of the contagion strength is positively skewed and leptokurtic. The average contagion strength is low at the beginning and then witnesses an uptrend. It has larger values in the middle stage and declines in the late phase of the crisis. Meanwhile, the cross-regional contagion between Europe and America is stronger than that between either America and Asia or Europe and Asia. Europe is found to be the region most deeply impacted by the contagion, whereas Asia is the least affected.
HIV as a Cause of Immune Activation and Immunosenescence
Authors: Sokoya T. , Steel H. C. , Nieuwoudt M. , Rossouw T. M.
Published: October 2017

Systemic immune activation has emerged as an essential component of the immunopathogenesis of HIV. It not only leads to faster disease progression, but also to accelerated decline of overall immune competence. HIV-associated immune activation is characterized by an increase in proinflammatory mediators, dysfunctional T regulatory cells, and a pattern of T-cell-senescent phenotypes similar to those seen in the elderly. These changes predispose HIV-infected persons to comorbid conditions that have been linked to immunosenescence and inflamm-ageing, such as atherosclerosis and cardiovascular disease, neurodegeneration, and cancer. In the antiretroviral treatment era, development of such non-AIDS-defining, age-related comorbidities is a major cause of morbidity and mortality. Treatment strategies aimed at curtailing persistent immune activation and inflammation may help prevent the development of these conditions. At present, the most effective strategy appears to be early antiretroviral treatment initiation. No other treatment interventions have been found effective in large-scale clinical trials, and no adjunctive treatment is currently recommended in international HIV treatment guidelines. This article reviews the role of systemic immune activation in the immunopathogenesis of HIV infection, its causes and the clinical implications linked to immunosenescence in adults, and the therapeutic interventions that have been investigated.
Barriers to Physical Activity in Low Back Pain Patients following Rehabilitation: A Secondary Analysis of a Randomized Controlled Trial
Authors: Schaller Andrea , Exner Anne-Kathrin , Schroeer Sarah , Kleineke Vera , Sauzet Odile
Published: October 2017

Background. Promoting health-enhancing physical activity following rehabilitation is a well-known challenge. This study analysed the barriers to leisure time activity among low back pain patients. Methods. A subset of 192 low back pain patients who participated in a randomized controlled trial promoting physical activity was analysed. Physical activity, barriers, and sociodemographic and indication-related variables were assessed by a questionnaire. Differences in barriers between active and inactive participants were tested by Pearson’s chi squared test. A logistic regression model was fitted to identify influencing factors on physical activity at six months following rehabilitation. Results. Inactive and active participants differed significantly in nine of the 19 barriers assessed. The adjusted regression model showed associations of level of education (OR = 5.366 [1.563; 18.425]; p value = 0.008) and fear of pain (OR = 0.612 [0.421; 0.889]; p value = 0.010) with physical activity. The barriers included in the model failed to show any statistically significant association after adjustment for sociodemographic factors. Conclusions. Low back pain patients especially with a low level of education and fear of pain seem to need tailored support in overcoming barriers to physical activity. This study is registered at German Clinical Trials Register (DRKS00004878).
Effects of NSAIDs on the Release of Calcitonin Gene-Related Peptide and Prostaglandin E2from Rat Trigeminal Ganglia
Authors: Vellani Vittorio , Moschetti Giorgia , Franchi Silvia , Giacomoni Chiara , Sacerdote Paola , Amodeo Giada
Published: October 2017

Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used to treat migraine, but the mechanisms of their effects in this pathology are not fully elucidated. The trigeminal ganglia and calcitonin gene-related peptide (CGRP) have been implicated in the pathophysiology of migraine. The release of CGRP and prostaglandin E2(PGE2) from freshly isolated rat trigeminal ganglia was evaluated after oral administration of nimesulide, etoricoxib, and ketoprofen, NSAIDs with different pharmacological features. Thirty minutes after oral administration, nimesulide, 10 mg/Kg, decreased the GCRP release induced by an inflammatory soup, while the other NSAIDs were ineffective at this point in time. Two hours after oral nimesulide (5 and 10 mg/Kg) and ketoprofen (10 mg/Kg), but not of etoricoxib, a significant decrease in the CGRP release was observed. All drugs reduced PGE2, although with some differences in timing and doses, and the action on CGRP does not seem to be related to PGE2inhibition. The reduction of CGRP release from rat trigeminal ganglia after nimesulide and ketoprofen may help to explain the mechanism of action of NSAIDs in migraine. Since at 30 minutes only nimesulide was effective in reducing CGRP release, these results suggest that this NSAID may exert a particularly rapid effect in patients with migraine.
PQR309 Is a Novel Dual PI3K/mTOR Inhibitor with Preclinical Antitumor Activity in Lymphomas as a Single Agent and in Combination Therapy
Authors: Tarantelli Chiara , Gaudio Eugenio , Arribas Alberto J. , Kwee Ivo , Hillmann Petra , Rinaldi Andrea , Cascione Luciano , Spriano Filippo , Bernasconi Elena , Guidetti Francesca , Carrassa Laura , Pittau Roberta Bordone , Beaufils Florent , Ritschard Reto , Rageot Denise , Sele Alexander , Dossena Barbara , Rossi Francesca Maria , Zucchetto Antonella , Taborelli Monica , Gattei Valter , Rossi Davide , Stathis Anastasios , Stussi Georg , Broggini Massimo , Wymann Matthias P. , Wicki Andreas , Zucca Emanuele , Cmiljanovic Vladimir , Fabbro Doriano , Bertoni Francesco
Published: October 2017

Purpose: Activation of the PI3K/mTOR signaling pathway is recurrent in different lymphoma types, and pharmacologic inhibition of the PI3K/mTOR pathway has shown activity in lymphoma patients. Here, we extensively characterized the in vitro and in vivo activity and the mechanism of action of PQR309 (bimiralisib), a novel oral selective dual PI3K/mTOR inhibitor under clinical evaluation, in preclinical lymphoma models.

Experimental Design: This study included preclinical in vitro activity screening on a large panel of cell lines, both as single agent and in combination, validation experiments on in vivo models and primary cells, proteomics and gene-expression profiling, and comparison with other signaling inhibitors.

Results: PQR309 had in vitro antilymphoma activity as single agent and in combination with venetoclax, panobinostat, ibrutinib, lenalidomide, ARV-825, marizomib, and rituximab. Sensitivity to PQR309 was associated with specific baseline gene-expression features, such as high expression of transcripts coding for the BCR pathway. Combining proteomics and RNA profiling, we identified the different contribution of PQR309-induced protein phosphorylation and gene expression changes to the drug mechanism of action. Gene-expression signatures induced by PQR309 and by other signaling inhibitors largely overlapped. PQR309 showed activity in cells with primary or secondary resistance to idelalisib.

Conclusions: On the basis of these results, PQR309 appeared as a novel and promising compound that is worth developing in the lymphoma setting. Clin Cancer Res; 24(1); 120–9. ©2017 AACR.
The Intracranial Aneurysm Gene THSD1 Connects Endosome Dynamics to Nascent Focal Adhesion Assembly
Authors: Rui Yan-Ning , Xu Zhen , Fang Xiaoqian , Menezes Miriam R. , Balzeau Julien , Niu Airu , Hagan John P. , Kim Dong H.
Published: October 2017

Background/Aims: We recently discovered that harmful variants in THSD1 (Thrombospondin type-1 domain-containing protein 1) likely cause intracranial aneurysm and subarachnoid hemorrhage in a subset of both familial and sporadic patients with supporting evidence from two vertebrate models. The current study seeks to elucidate how THSD1 and patient-identified variants function molecularly in focal adhesions. Methods: Co-immunostaining and co-immunoprecipitation were performed to define THSD1 subcellular localization and interacting partners. Transient expression of patient-identified THSD1 protein variants and siRNA-mediated loss-of-function THSD1 were used to interrogate gene function in focal adhesion and cell attachment to collagen I in comparison to controls. Results: THSD1 is a novel nascent adhesion protein that co-localizes with several known markers such as FAK, talin, and vinculin, but not with mature adhesion marker zyxin. Furthermore, THSD1 forms a multimeric protein complex with FAK/talin/vinculin, wherein THSD1 promotes talin binding to FAK but not to vinculin, a key step in nascent adhesion assembly. Accordingly, THSD1 promotes mature adhesion formation and cell attachment, while its rare variants identified in aneurysm patients show compromised ability. Interestingly, THSD1 also localizes at different stages of endosomes. Clathrin-mediated but not caveolae-mediated endocytosis pathway is involved in THSD1 intracellular trafficking, which positively regulates THSD1-induced focal adhesion assembly, in contrast to the traditional role of endosomes in termination of integrin signals. Conclusions: The data suggest that THSD1 functions at the interface between endosome dynamics and nascent focal adhesion assembly that is impaired by THSD1 rare variants identified from intracranial aneurysm patients.
СТРАТЕГІЯ ВПРОВАДЖЕННЯ КУРСІВ ЗА ВИБОРОМ НА БАЗІ ТЕХНОЛОГІЇ ОНЛАЙН-КУРСІВ НА ПЛАТФОРМІ edX
Authors: Kolesnyk Yu. M. , Avramenko M. O. , Morhuntsova S. A. , Ryzhov O. A.
Published: October 2017

У статті розкрита послідовна стратегія впровадження в медичному університеті курсів за вибором на базі технології дистанційного навчання у вигляді онлайн-курсів. Показано, що успішне впровадження онлайн-курсів можливо при наявності таких складових, як: готовність викладацького складу до опанування нових технологій навчання та зміни своєї ролі в навчальному процесі; готовність студентів до використання дистанційних технологій навчання; наявність інфраструктури в університеті, яка забезпечує сервіси дистанційного навчання; наявність системи перевірки якості контенту онлайн-курсів, які розробляються. Особлива увага звертається на необхідність зміни структури навчального процесу та ролі викладачів при впровадженні онлайн-курсів. Авторами обґрунтовано вибір платформи для розробки онлайн-курсів Open edX за критеріями.
Inflammatory Biomarkers Interleukin‐6 and C‐Reactive Protein and Outcomes in Stable Coronary Heart Disease: Experiences From the STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) Trial
Authors: Held Claes , White Harvey D. , Stewart Ralph A. H. , Budaj Andrzej , Cannon Christopher P. , Hochman Judith S. , Koenig Wolfgang , Siegbahn Agneta , Steg Philippe Gabriel , Soffer Joseph , Weaver W. Douglas , Östlund Ollie , Wallentin Lars ,   on behalf of the STABILITY Investigators
Published: October 2017

Background

Evaluation of cardiovascular prognosis in patients with stable coronary heart disease is based on clinical characteristics and biomarkers indicating dysglycemia, dyslipidemia, renal dysfunction, and possibly cardiac dysfunction. Inflammation plays a key role in atherosclerosis, but the association between inflammatory biomarkers and clinical outcomes is less studied in this population.

Methods and Results

Overall, 15 828 patients with coronary heart disease in the
STABILITY
(Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) trial were randomized to treatment with darapladib or placebo and observed for a median of 3.7 years. In 14 611 patients, levels of interleukin‐6 (
IL
‐6) and high‐sensitivity C‐reactive protein were measured in plasma samples: median levels were 2.1 (interquartile range, 1.4–3.2) ng/L and 1.3 (interquartile range, 0.6–3.1) mg/L, respectively. Associations between continuous levels or quartile groups and adjudicated outcomes were evaluated by spline graphs and Cox regression adjusted for clinical factors and cardiovascular biomarkers.
IL
‐6 was associated with increased risk of major adverse cardiovascular events (quartile 4 versus quartile 1 hazard ratio [
HR
], 1.60; 95% confidence interval [CI], 1.30–1.97;
P
<0.0001); cardiovascular death (
HR
, 2.15; 95% CI, 1.53–3.04;
P
<0.0001); myocardial infarction (
HR
, 1.53; 95% CI, 1.14–2.04;
P
<0.05); all‐cause mortality (
HR
, 2.11; 95% CI, 1.62–2.76;
P
<0.0001); and risk of hospitalization for heart failure (
HR
, 2.28; 95% CI, 1.34–3.89;
P
<0.001). Cancer death was doubled in the highest
IL
‐6 quartile group (
HR
, 2.34; 95% CI, 1.20–4.53;
P
<0.05). High‐sensitivity C‐reactive protein was associated with both cardiovascular and non‐cardiovascular events in the unadjusted model, but these did not remain after multivariable adjustments.

Conclusions

IL
‐6, an upstream inflammatory marker, was independently associated with the risk of major adverse cardiovascular events, cardiovascular and all‐cause mortality, myocardial infarction, heart failure, and cancer mortality in patients with stable coronary heart disease. IL‐6 might reflect a pathophysiological process involved in the development of these events.

Clinical Trial Registration

URL
:
http://www.clinicaltrials.gov
. Unique identifier:
NCT
00799903.
Cumulative Exposure to High‐Sensitivity C‐Reactive Protein Predicts the Risk of Cardiovascular Disease
Authors: Wang Aitian , Liu Jie , Li Chunguang , Gao Jingli , Li Xiaolan , Chen Shuohua , Wu Shouling , Ding Hui , Fan Haojun , Hou Shike
Published: October 2017

Background

One measurement of hs‐CRP (high‐sensitivity C‐reactive protein) is associated with increased risk of cardiovascular disease (
CVD
). The objective of this study was to characterize the association of cumulative exposure to increased hs‐
CRP
with incident cardiovascular events.

Methods and Results

We included 53 065 participants with hs‐
CRP
measured at 3 examinations in 2006, 2008, and 2010. Cumulative exposure to hs‐
CRP
was calculated as the weighted sum of the average hs‐
CRP
level for each time interval (level×time). Participants were classified into nonexposed group (hs‐
CRP
<3.0 mg/L in all 3 examinations), 1‐exposed group (hs‐
CRP
≥3.0 mg/L in 1 of the 3 examinations), 2‐exposed group (hs‐
CRP
≥3.0 mg/L in 2 of the 3 examinations), and 3‐exposed group (hs‐
CRP
≥3.0 mg/L in 3 examinations). Cox proportional hazards models were used to assess the association of cumulative hs‐
CRP
with incident
CVD
. The study showed a dose‐response pattern with risk of
CVD
and myocardial infarction as the number of years of exposure to hs‐
CRP
increases. Participants in the 3‐exposed group had significantly increased
CVD
risk with hazard ratio (95% confidence interval) of 1.38 (1.11–1.72), in comparison with 1.28 (1.07–1.52) for participants in the 2‐exposed group and 1.13 (0.97–1.31) for those in the 1‐exposed group (
P
<0.05); meanwhile, the similar and significant associations were also observed for myocardial infarction with respective hazard ratio (95% confidence interval) of 2.13 (1.42–3.18), 1.60 (1.12–2.27), and 1.57 (1.17–2.10). The associations between stroke and cumulative hs‐
CRP
were not statistically significant (
P
=0.360).

Conclusions

Cumulative exposure to hs‐
CRP
was dose dependently associated with a subsequent increased risk of
CVD
and myocardial infarction.

Clinical Trial Registration

URL
:
https://www.clinicaltrials.gov/
. Unique identifier: ChiCTR‐TNC‐11001489.
Collecting Duct Nitric Oxide Synthase 1ß Activation Maintains Sodium Homeostasis During High Sodium Intake Through Suppression of Aldosterone and Renal Angiotensin II Pathways
Authors: Hyndman Kelly A. , Mironova Elena V. , Giani Jorge F. , Dugas Courtney , Collins Jessika , McDonough Alicia A. , Stockand James D. , Pollock Jennifer S.
Published: October 2017

Background

During high sodium intake, the renin‐angiotensin‐aldosterone system is downregulated and nitric oxide signaling is upregulated in order to remain in sodium balance. Recently, we showed that collecting duct nitric oxide synthase 1β is critical for fluid‐electrolyte balance and subsequently blood pressure regulation during high sodium feeding. The current study tested the hypothesis that high sodium activation of the collecting duct nitric oxide synthase 1β pathway is critical for maintaining sodium homeostasis and for the downregulation of the renin‐angiotensin‐aldosterone system–epithelial sodium channel axis.

Methods and Results

Male control and collecting duct nitric oxide synthase 1β knockout (
CDNOS
1
KO
) mice were placed on low, normal, and high sodium diets for 1 week. In response to the high sodium diet, plasma sodium was significantly increased in control mice and to a significantly greater level in
CDNOS
1
KO
mice.
CDNOS
1
KO
mice did not suppress plasma aldosterone in response to the high sodium diet, which may be partially explained by increased adrenal

AT
1R

expression. Plasma renin concentration was appropriately suppressed in both genotypes. Furthermore,
CDNOS
1
KO
mice had significantly higher intrarenal angiotensin
II
with high sodium diet, although intrarenal angiotensinogen levels and angiotensin‐converting enzyme activity were similar between knockout mice and controls. In agreement with inappropriate renin‐angiotensin‐aldosterone system activation in the
CDNOS
1
KO
mice on a high sodium diet, epithelial sodium channel activity and sodium transporter abundance were significantly higher compared with controls.

Conclusions

These data demonstrate that high sodium activation of collecting duct nitric oxide synthase 1β signaling induces suppression of systemic and intrarenal renin‐angiotensin‐aldosterone system, thereby modulating epithelial sodium channel and other sodium transporter abundance and activity to maintain sodium homeostasis.
Social Cohesion, Religious Beliefs, and the Effect of Protestantism on Suicide
Authors: Becker Sascha O. , Woessmann Ludger
Published: October 2017

In an economic theory of suicide, we model social cohesion of the religious community and religious beliefs about afterlife as two mechanisms by which Protestantism increases suicide propensity. We build a unique microregional data set of 452 Prussian counties for 1816 to 1821 and 1869 to 1871, when religiousness was still pervasive. Exploiting the concentric dispersion of Protestantism around Wittenberg, our instrumental variable model finds that Protestantism had a substantial positive effect on suicide. Results are corroborated in first-difference models. Tests relating to the two mechanisms based on historical church attendance data and modern suicide data suggest that the sociological channel plays the more important role.
Performance in Mixed-Sex and Single-Sex Competitions: What We Can Learn from Speedboat Races in Japan
Authors: Booth Alison , Yamamura Eiji
Published: October 2017

In speedboat racing in Japan, men and women compete under the same conditions and are randomly assigned to mixed-sex or single-sex groups for each race. We use a sample of over 140,000 individual-level records to examine how male-dominated circumstances affect women’s racing performance. Our fixed-effects estimates reveal that women’s race time is slower in mixed-sex than all-women races, whereas men’s race time is faster in mixed-sex than men-only races. The same result is found for place in race. Moreover, in mixed-sex races, men are more aggressive, as proxied by lane changing, than women in spite of the risk of being penalized for rule infringement.
First description of the last instar larva and pupa of the aquatic crane fly Limnorimarga limonioides (Alexander, 1945) (Diptera: Limoniidae)
Authors: PODENIENE VIRGINIJA , SEO HONG-YUL , KIM TAE-WOO , BYUN HYE-WOO
Published: October 2017

Descriptions, illustrations and habitat characteristics are given for the previously unknown larvae and pupae of the East Palaearctic monotypic aquatic crane fly genus Limnorimarga Alexander, 1945 collected from Korea in hygropetric habitats. Diagnostic features and phylogenetic relationships are discussed.
Coupling of Stratospheric Warmings with Mesospheric Coolings in Observations and Simulations
Authors: Zülicke Christoph , Becker Erich , Matthias Vivien , Peters Dieter H. W. , Schmidt Hauke , Liu Han-Li , Ramos Laura de la Torre , Mitchell Daniel M.
Published: October 2017

The vertical coupling between the stratosphere and the mesosphere is diagnosed from polar cap temperatures averaged over 60°–90°N with a new method: the joint occurrence of a warm stratosphere at 10 hPa and a cold mesosphere at 0.01 hPa. The investigation of an 11-yr-long dataset (2004–15) from Aura-MLS observations shows that such mesospheric coupling days appear in 7% of the winter. During major sudden stratospheric warming events mesospheric couplings are present with an enhanced average daily frequency of 22%. This daily frequency changes from event to event but broadly results in five of seven major warmings being classified as mesospheric couplings (2006, 2008, 2009, 2010, and 2013). The observed fraction of mesospheric coupling events (71%) is compared with simulations of the Kühlungsborn Mechanistic Circulation Model (KMCM), the Hamburg Model of the Neutral and Ionized Atmosphere (HAMMONIA), and the Whole Atmosphere Community Climate Model (WACCM). The simulated fraction of mesospheric coupling events ranges between 57% and 94%, which fits the observations. In searching for causal relations weak evidence is found that major warming events with strong intensity or split vortices favor their coupling with the upper mesosphere. More evidence is found with a conceptual model: an effective vertical coupling between 10 and 0.01 hPa is provided by deep zonal-mean easterlies at 60°N, which are acting as a gravity-wave guide. The explained variance is above 40% in the four datasets, which indicates a near-realistic simulation of this process.