bluuebunny/crossref_metadata_2025 huggingface dataset:
Berry transcriptome: insights into a novel resource to understand development dependent secondary metabolism in Withania somnifera (Ashwagandha)
Authors: Tripathi Sandhya , Sangwan Rajender Singh , Mishra Bhawana , Jadaun Jyoti Singh , Sangwan Neelam Singh
Published: February 2019

Withania somnifera (Ashwagandha) is considered as Rasayana in Indian systems of medicine. This study reports a novel transcriptome of W. somnifera berries, with high depth, quality and coverage. Assembled and annotated transcripts for nearly all genes related with the withanolide biosynthetic pathway were obtained. Tissue‐wide gene expression analysis reflected almost similar definitions for the terpenoid pathway in leaf, root and berry tissues with relatively higher abundance of transcripts linked to steroid, phenylpropanoid metabolism as well as flavonoid metabolism in berries. The metabolome map generated from the data embodied transcripts from 143 metabolic pathways connected together and mediated collectively by about 1792 unique enzyme functions specific to berry, leaf and root tissues, respectively. Transcripts specific to cytochrome p450 (CYP450), methyltransferases and glycosyltransferases were distinctively located in a tissue specific manner and exhibited a complex network. Significant distribution of transcription factor genes such as MYB, early light inducible protein (ELI), minichromosome maintenance1, agamous, deficiens and serum response factor (MADS) and WRKY etc. was observed, as the major transcriptional regulators of secondary metabolism. Validation of the assembly was ascertained by cloning WsELI, which has a light dependent regulatory role in development. Quantitative expression of WsELI was observed to be considerably modulated upon exposure to abiotic stress and elicitors. Co‐relation of over‐expression of WsELI, may provide new aspects for the functional role of ELI proteins in plants linked to secondary metabolism. The study offers the first comprehensive and comparative evaluation of W. somnifera transcriptome data between the three tissues and across other members of Solanaceae (Nicotiana, Solanum and Capsicum) with respect to major pathways and their metabolome regulation.
Detection of an HLA‐C*03:04 variant, HLA‐C*03:04:71, in a Taiwanese individual
Authors: Yang Kuo‐Liang , Lin Py‐Yu
Published: February 2019

Nucleotide substitutions at residues 369 and 924 of HLA‐C*03:04:02 result in a novel allele, HLA‐C*03:04:71.
Nectin‐4 and p63 immunohistochemical expression in canine prostate tumourigenesis
Authors: Della Salda Leonardo , Massimini Marcella , Romanucci Mariarita , Palmieri Chiara , Perillo Antonella , Grieco Valeria , Malatesta Daniela , Spinillo Maria A. , Passantino Giuseppe , Dondi Francesco , Benazzi Cinzia
Published: February 2019

Nectin‐4 is an E‐cadherin‐based adherens junction protein of normal epithelial cells, as well as a potent mediator of anchorage‐independent cancer colony formation. It is considered a tumour‐associated histological and serological marker in various human cancers. The transcription factor p63 is a basal cell marker in the normal prostate, involved in cell adhesion, as well as in the formation and survival of circulating tumour cell clusters. The aim of this study was to evaluate Nectin‐4 and p63 immunohistochemical expression in 42 canine prostate tissues including 2 normal prostates, 10 benign prostatic hyperplasias (BPHs), 30 prostatic carcinomas (PCs), 1 pulmonary and 1 lymph node metastasis. From normal to neoplastic tissues, Nectin‐4 showed a progressive switching from membranous (m‐Nectin‐4) to cytoplasmic (c‐Nectin‐4), regardless of the histological subtypes, except for lack of expression in solid PCs. Metastatic cells exhibited both strong membranous and cytoplasmic positivity. c‐Nectin‐4 expression was significantly (P < 0.0001) increased in PCs/metastasis compared to BPHs cases and a decrease (P < 0.05) of nuclear p63 immunostaining was also detected in the two groups. Furthermore, data showed a significant association (P < 0.05) between p63 and m‐Nectin‐4 distribution, although their colocalization was detected only in scattered cells by double immunofluorescence. Our results suggest the involvement of m‐Nectin‐4 in canine prostate tumourigenesis and metastatic potential, while the exact role of c‐Nectin‐4 expression detectable in primary PCs requires further investigations.
Morphological and immunohistochemical characteristics of the equine corneal epithelium
Authors: Kammergruber Eva , Rahn Carolin , Nell Barbara , Gabner Simone , Egerbacher Monika
Published: February 2019

Objective

The morphology of the corneal epithelium in two age groups of horses is described. Distribution patterns of proliferation‐, differentiation‐, stem cell‐associated markers and cell junction proteins were assessed.

Methods

Corneal samples from 12 horses (six foals and six adult horses) were analyzed after H&E staining and immunohistochemistry using the following antibodies: E‐cadherin, β‐catenin, Connexin 43 (Cx43), tight junction protein 1 (TJP1), cytokeratin (CK) 14, CK 19, CK 3, CK 10, vimentin, Ki67, p63, nerve growth factor (NGF), ABCG2, and epithelial growth factor receptor. Semiquantitative analysis of crypt, limbal, peripheral, and central zone was performed. Semithin and ultrathin sections were used for ultrastructural evaluation of the epithelium.

Results

The height of the epithelium varied between age groups and crypts were consistently present. In the peripheral and central epithelium, three types of basal cells resembling a pseudostratified epithelium were characterized. Potential stem cell markers (CK 14, p63, NGF, and ABCG2) were present in all zones with decreasing frequency toward the center. Cornea‐specific differentiation marker CK 3 was not expressed in the most basal cell layer of the limbal epithelium. E‐cadherin, β‐catenin, and Cx43 revealed a similar apico‐lateral signal pattern throughout the entire epithelium; only TJP1 was additionally seen at the basal surface.

Conclusions

This study presents a systematic semiquantitative evaluation of the equine corneal epithelium, showing the presence of crypts as potential stem cell niche with CK 14, p63, NGF, and ABCG2 as relevant markers for cells with regenerative capacity. The pseudostratified arrangement of the basal layer was a unique finding.
Numerical Investigation of the Origin of Anomalous Tensile Twinning in Magnesium Alloys
Authors: Vaishakh K. V. , Subrahmanya Prasad N. , Narasimhan R.
Published: February 2019

It has been observed that tension twins (TTs) are triggered in rolled polycrystalline magnesium alloys under tensile loading applied along the rolling direction (RD) or the transverse direction. This is surprising because these alloys have a near-basal texture, and TTs would therefore cause extension (instead of contraction) along the normal direction. In this work, the origin of these anomalous TTs is first examined by performing crystal plasticity-based finite element simulations using model textures, wherein the c-axis in one grain is systematically tilted toward the loading direction (RD), with the other grains maintained in ideal basal orientation. It is shown that strong basal slip is triggered in the former, which through its effect on the local stress distribution plays a catalytic role in activating TTs. The above behavior is also observed in a simulation performed with an actual texture pertaining to a rolled AZ31 Mg alloy. Most importantly, when basal slip is suppressed, evolution of TTs is found to be very much retarded. The present results corroborate well with experimental observations.
The Precise Determination of the Johnson–Cook Material and Damage Model Parameters and Mechanical Properties of an Aluminum 7068-T651 Alloy
Authors: Bal B. , Karaveli K. K. , Cetin B. , Gumus B.
Published: February 2019

Al 7068-T651 alloy is one of the recently developed materials used mostly in the defense industry due to its high strength, toughness, and low weight compared to steels. The aim of this study is to identify the Johnson–Cook (J–C) material model parameters, the accurate Johnson–Cook (J–C) damage parameters, D1, D2, and D3 of the Al 7068-T651 alloy for finite element analysis-based simulation techniques, together with other damage parameters, D4 and D5. In order to determine D1, D2, and D3, tensile tests were conducted on notched and smooth specimens at medium strain rate, 100 s−1, and tests were repeated seven times to ensure the consistency of the results both in the rolling direction and perpendicular to the rolling direction. To determine D4 and D5 further, tensile tests were conducted on specimens at high strain rate (102 s−1) and temperature (300 °C) by means of the Gleeble thermal–mechanical physical simulation system. The final areas of fractured specimens were calculated through optical microscopy. The effects of stress triaxiality factor, rolling direction, strain rate, and temperature on the mechanical properties of the Al 7068-T651 alloy were also investigated. Damage parameters were calculated via the Levenberg–Marquardt optimization method. From all the aforementioned experimental work, J–C material model parameters were determined. In this article, J–C damage model constants, based on maximum and minimum equivalent strain values, were also reported which can be utilized for the simulation of different applications.
Tribological Properties of Nanoclay-Infused Banana Fiber Reinforced Epoxy Composites
Authors: Mohan T. P. , Kanny K.
Published: February 2019

The objective of this work is to study the tribological properties of natural fiber based composites using nanotechnology. The naturally available banana plant fibers were treated with nanoclay particles, and these treated fibers were then reinforced in an epoxy polymer to form composites. The friction and wear properties of nanoclay-treated banana fiber (NC-BF) reinforced composites were compared with untreated banana fiber (UT-BF) reinforced composites. Short NC-BF- and UT-BF-reinforced composites with fiber concentration ranging from 20 wt % to 60 wt % were prepared by the vacuum resin infusion processing method. The result indicates that the NC-BF-reinforced composites have shown improved friction and wear properties. Microscopy examination revealed that NC-BF-reinforced composites were able to form a transfer layer between the wear test specimen wear surface and counter face, resulting in improved wear properties. The nanoclay particles also induce increased hardness and friction to the composites and improve braking properties.
Segregation of voices with single or double fundamental frequencies
Authors: Deroche Mickael L. D. , Gracco Vincent L.
Published: February 2019

In cocktail-party situations, listeners can use the fundamental frequency (F0) of a voice to segregate it from competitors, but other cues in speech could help, such as co-modulation of envelopes across frequency or more complex cues related to the semantic/syntactic content of the utterances. For simplicity, this (non-pitch) form of grouping is referred to as “articulatory.” By creating a new type of speech with two steady F0s, it was examined how these two forms of segregation compete: articulatory grouping would bind the partials of a double-F0 source together, whereas harmonic segregation would tend to split them in two subsets. In experiment 1, maskers were two same-male sentences. Speech reception thresholds were high in this task (vicinity of 0 dB), and harmonic segregation behaved as though double-F0 stimuli were two independent sources. This was not the case in experiment 2, where maskers were speech-shaped complexes (buzzes). First, double-F0 targets were immune to the masking of a single-F0 buzz matching one of the two target F0s. Second, double-F0 buzzes were particularly effective at masking a single-F0 target matching one of the two buzz F0s. As a conclusion, the strength of F0-segregation appears to depend on whether the masker is speech or not.
Parallel adaptation of rabbit populations to myxoma virus
Authors: Alves Joel M. , Carneiro Miguel , Cheng Jade Y. , Lemos de Matos Ana , Rahman Masmudur M. , Loog Liisa , Campos Paula F. , Wales Nathan , Eriksson Anders , Manica Andrea , Strive Tanja , Graham Stephen C. , Afonso Sandra , Bell Diana J. , Belmont Laura , Day Jonathan P. , Fuller Susan J. , Marchandeau Stéphane , Palmer William J. , Queney Guillaume , Surridge Alison K. , Vieira Filipe G. , McFadden Grant , Nielsen Rasmus , Gilbert M. Thomas P. , Esteves Pedro J. , Ferrand Nuno , Jiggins Francis M.
Published: February 2019

Locating myxomatosis resistance

Myxomatosis is a viral infection that was deliberately introduced from American cottontail rabbits into European rabbit populations to control their population. Over the past 60 years or so, similar resistance variants have emerged in parallel in the United Kingdom, France, and Australia. Alves
et al.
discovered that the basis for this resistance is polygenic, with selection converging on several host immunity and proviral alleles (see the Perspective by Miller and Metcalf). Interestingly, it now seems that the virus is counterevolving immune suppressive traits.

Science
, this issue p.
1319
; see also p.
1277
BCR-dependent lineage plasticity in mature B cells
Authors: Graf Robin , Seagal Jane , Otipoby Kevin L. , Lam Kong-Peng , Ayoub Salah , Zhang Baochun , Sander Sandrine , Chu Van Trung , Rajewsky Klaus
Published: February 2019

B1 or B2? The BCR decides

Immunological B cells are generally divided into two major subsets. B2 cells generate specific antibodies against foreign antigens in secondary lymphoid organs. B1 cells, found predominantly in the peritoneal and pleural cavities, instead produce “natural” antibodies as part of the innate immune system. Two models to explain this split exist: the “lineage model,” wherein both subsets have distinct progenitors, and the “selection model,” in which fates are directed by different B cell antigen receptors (BCRs). Graf
et al.
provide support for the selection model using a transgenic system in which BCR specificities can be changed. Mature B2 cells differentiated into functional B1 cells when a self-reactive B1 BCR was swapped in, in the absence of B1 lineage precommitment.

Science
, this issue p.
748
Inferring Earth’s discontinuous chemical layering from the 660-kilometer boundary topography
Authors: Wu Wenbo , Ni Sidao , Irving Jessica C. E.
Published: February 2019

Inferring blocked mantle convection

The boundaries between rocks with different physical properties in Earth's interior come from either a change in crystal structure or a change in chemical composition. Wu
et al.
examined the roughness of the boundary between Earth's upper and lower mantle, thought to form from a change in mineral structure (see the Perspective by Houser). To their surprise, in some locations, the boundary has small-scale roughness that requires some chemical difference above and below the boundary. This observation provides evidence of partially blocked mantle circulation that leads to some chemical differences between the upper and lower mantle.

Science
, this issue p.
736
; see also p.
696
Photoelectrical imaging and coherent spin-state readout of single nitrogen-vacancy centers in diamond
Authors: Siyushev Petr , Nesladek Milos , Bourgeois Emilie , Gulka Michal , Hruby Jaroslav , Yamamoto Takashi , Trupke Michael , Teraji Tokuyuki , Isoya Junichi , Jelezko Fedor
Published: February 2019

An integrated route to quantum detection

The quantum properties of the nitrogen-vacancy (NV) center defect in diamond are being pursued as building blocks for quantum-enhanced technologies. Addressing and manipulating the defects, however, typically requires bulk optics, which could limit scalability. Siyushev
et al.
developed an on-chip technique in which the NV center is detected optoelectronically. Such a detection and manipulation method offers a route to develop an integrated platform for scalable quantum-based sensing technologies.

Science
, this issue p.
728
Long delays in banning trade in threatened species
Authors: Frank Eyal G. , Wilcove David S.
Published: February 2019

Scientific knowledge should be applied with more urgency
How a circularized tmRNA moves through the ribosome
Authors: Rae Christopher D. , Gordiyenko Yuliya , Ramakrishnan V.
Published: February 2019

Mechanism of ribosome rescue

Bacterial ribosomes that stall on truncated or cleaved messenger RNA (mRNA) are rescued by trans-translation. Two factors, transfer-messenger RNA (tmRNA) and small protein B (SmpB), resolve the stalled complex by tagging the nascent polypeptide for degradation and facilitating release of the ribosome. Rae
et al.
determined structures of key trans-translation intermediates. The structures reveal how SmpB identifies stalled ribosomes; how the large, circularized tmRNA molecule moves through the ribosome; and how translation is shifted from the truncated mRNA to tmRNA.

Science
, this issue p.
740
Molecular basis for pore blockade of human Na
+
channel Na
v
1.2 by the μ-conotoxin KIIIA
Authors: Pan Xiaojing , Li Zhangqiang , Huang Xiaoshuang , Huang Gaoxingyu , Gao Shuai , Shen Huaizong , Liu Lei , Lei Jianlin , Yan Nieng
Published: February 2019

Targeting sodium channels

Voltage-gated sodium (Na
v
) channels have been implicated in cardiac and neurological disorders. There are many subtypes of these channels, making it challenging to develop specific therapeutics. A core α subunit is sufficient for voltage sensing and ion conductance, but function is modulated by β subunits and by natural toxins that can either act as pore blockers or gating modifiers (see the Perspective by Chowdhury and Chanda). Shen
et al.
present the structures of Na
v
1.7 in complex with both β1 and β2 subunits and with animal toxins. Pan
et al.
present the structure of Na
v
1.2 bound to β2 and a toxic peptide, the µ-conotoxin KIIIA. The structure shows why KIIIA is specific for Na
v
1.2. These and other recently determined Na
v
structures provide a framework for targeted drug development.

Science
, this issue p.
1303
, p.
1309
; see also p.
1278
Hyperbolic 3D architectures with 2D ceramics
Authors: Chhowalla Manish , Jariwala Deep
Published: February 2019

A hexagonal boron nitride aerogel has high resistance to thermal and mechanical shock
Cigarette pricing 1 year after new restrictions on tobacco industry retailer programmes in Quebec, Canada
Authors: Callard Cynthia D , Collishaw Neil
Published: February 2019

Objectives

Over the past 15 years, tobacco companies operating in Canada abandoned their long-standing unitary price model in favour of price differentiation. Concerns about low cigarette prices were identified by the Quebec government in 2015 when it introduced restrictions on the types of incentives that tobacco manufacturers may offer to retailers. This study sought to explore cigarette prices in Quebec 1 year after these restrictions came into effect.

Methods

Details on cigarette trading terms and programmes were obtained from websites maintained by retailer groups. Visits were made to tobacco retailers in four Quebec municipalities in the autumn of 2017. The price displayed for cigarettes was observed and recorded in 273 convenience stores.

Results

Two forms of price differentiation were observed. The first was price-segmentation between brands, reflected in a difference of $3 or more in the average displayed price between premium and discount brands of each manufacturer (ie, $10.48 vs $7.43 for a package of 20 cigarettes of the most and least expensive brands sold by Philip Morris International). Price localisation was also observed, reflected in a $2 range of prices between retail outlets for the same package of cigarettes. Even among outlets of a given chain of convenience stores, the price of the least expensive brands varied by more than $1 per package. The size of the variance in prices rivals or exceeds the size of tobacco tax increases in Quebec over the past decade.

Conclusions

Recent restrictions on tobacco industry incentive programmes for retailers have not ended price differentiation. Tobacco manufacturers’ and retailers’ pricing policies continue to provide price-sensitive smokers with ways to avoid the impact of tobacco tax increases.
‘Both Sides of the Argument’? A critical review of existing evidence on the illicit trade in tobacco products in Canada
Authors: Smith Julia , Thompson Sheryl , Lee Kelley
Published: February 2019

Introduction

The illicit trade in tobacco products (ITTP) is widely recognised as a substantial and complex problem in Canada. However, the independence of available data and quality of analyses remains unknown. Reliable and accurate data on the scale and causes of the problem are needed to inform effective policy responses.

Methods

We searched the scholarly and grey literature using keywords related to ITTP in Canada. We identified 26 studies published in English since 2008 that present original research drawing on primary data. We analysed these studies for their independence from the tobacco industry, methodology, findings and gaps in knowledge.

Results

The study finds 42% of the literature reviewed has links to the tobacco industry. These studies provide insufficient methodological detail, present higher estimates of the volume of ITTP and attribute the causes to higher rates of tobacco taxation. The classification of all indigenous tobacco sales as illicit, by both industry linked and independent studies, contributes to overestimates and serves the interests of transnational tobacco companies. There is need for independent and comprehensive data on the ITTP in Canada over time, across population groups and geographies.

Conclusion

While there is evidence that the ITTP in Canada is a major and complex issue that requires effective tobacco control policies, there is a limited evidence base on which to develop such responses. This review finds industry-linked studies lack independence, employ biased methodologies and serve tobacco industry interests. Independent studies present more rigorous approaches, but primarily focus on youth and the province of Ontario.
Randomised controlled trial of real-time feedback and brief coaching to reduce indoor smoking
Authors: Hovell Melbourne F , Bellettiere John , Liles Sandy , Nguyen Benjamin , Berardi Vincent , Johnson Christine , Matt Georg E , Malone John , Boman-Davis Marie C , Quintana Penelope J E , Obayashi Saori , Chatfield Dale , Robinson Robert , Blumberg Elaine J , Ongkeko Weg M , Klepeis Neil E , Hughes Suzanne C
Published: February 2019

Background

Previous secondhand smoke (SHS) reduction interventions have provided only delayed feedback on reported smoking behaviour, such as coaching, or presenting results from child cotinine assays or air particle counters.

Design

This SHS reduction trial assigned families at random to brief coaching and continuous real-time feedback (intervention) or measurement-only (control) groups.

Participants

We enrolled 298 families with a resident tobacco smoker and a child under age 14.

Intervention

We installed air particle monitors in all homes. For the intervention homes, immediate light and sound feedback was contingent on elevated indoor particle levels, and up to four coaching sessions used prompts and praise contingent on smoking outdoors. Mean intervention duration was 64 days.

Measures

The primary outcome was ‘particle events’ (PEs) which were patterns of air particle concentrations indicative of the occurrence of particle-generating behaviours such as smoking cigarettes or burning candles. Other measures included indoor air nicotine concentrations and participant reports of particle-generating behaviour.

Results

PEs were significantly correlated with air nicotine levels (r=0.60) and reported indoor cigarette smoking (r=0.51). Interrupted time-series analyses showed an immediate intervention effect, with reduced PEs the day following intervention initiation. The trajectory of daily PEs over the intervention period declined significantly faster in intervention homes than in control homes. Pretest to post-test, air nicotine levels, cigarette smoking and e-cigarette use decreased more in intervention homes than in control homes.

Conclusions

Results suggest that real-time particle feedback and coaching contingencies reduced PEs generated by cigarette smoking and other sources.

Trial registration number

NCT01634334; Post-results.
A NOVEL APPROACH FOR EPILEPSY DETECTION USING TIME–FREQUENCY LOCALIZED BI-ORTHOGONAL WAVELET FILTER
Authors: SHARMA MANISH , SHAH SUNNY , ACHUTH P. V.
Published: February 2019

Identification of seizure using electroencephalogram (EEG) signal is crucial to detect diseases like epilepsy. Manual epilepsy detection is time consuming and prone to errors. Various techniques have been developed to get quick and accurate results for epilepsy detection. We propose a novel approach to detect epileptic seizure using bi-orthogonal wavelet filters. The bi-orthogonal wavelet filters divide the EEG signal into different sub-bands. Then different features, i.e., Shannon entropy (ShEn), Renyi entropy (RenEn), fractal dimension (FD), energy and fuzzy entropy (FE) are extracted from the sub-bands. The [Formula: see text]-values of the features are used to evaluate the discriminating ability of the features. These features are given as input to the support vector machine (SVM). The EEG signals are then classified into the following classes: (i) normal versus seizure, (ii) seizure-free versus seizure, (iii) normal versus seizure-free versus seizure, and (iv) normal versus seizure-free. We have used two independent datasets: a public dataset for training and validation of the model, and a private dataset for evaluating the model’s performance. The ten-fold cross-validation method is used here to reduce the chances of over fitting. The SVM classifier yielded 100% accuracy in discriminating both seizure-free and normal patients for public dataset, and inter-ictal and ictal for private dataset. It also gave very good classification accuracies for the other classification problems for both the datasets. The proposed method is ready for the clinical trial to be tested with huge databases before the actual practical usage.
An analysis of the photophysical and optical limiting properties of a novel 1,3,5-tristyrylBODIPY dye
Authors: Harris Jessica , May Aviwe K. , Ngoy Bokolombe P. , Mack John , Nyokong Tebello
Published: February 2019

The synthesis and characterization of a novel dibrominated 1,3,5-tristyrylBODIPY dye is reported, and its potential utility as a singlet oxygen photosensitizer and optical limiting material is assessed. The main spectral band lies in the therapeutic window, and there is a moderately high singlet oxygen quantum yield making the dye potentially suitable for use in biomedical applications and as an optical limiting dye at 532 nm. The optical limiting parameters are comparable to those reported previously for 3,5-distyrylBODIPYs, which suggests that mixtures of 3,5-distyryl and 1,3,5-tristyryl compounds that are formed in Knoevenagel condensation reactions could be used for this application. Theoretical calculations are used to assess the effect of 1,3,5-tristyryl substitution. A smaller red shift of the main spectral band is observed upon styrylation at the 1-position than is the case with the 3,5-positions due to there being smaller MO coefficients at this position, limiting the utility of this structural modification method for shifting the main BODIPY spectral band further into the therapeutic window.
Bile acids drive colonic secretion of glucagon-like-peptide 1 and peptide-YY in rodents
Authors: Christiansen Charlotte Bayer , Trammell Samuel Addison Jack , Wewer Albrechtsen Nicolai Jacob , Schoonjans Kristina , Albrechtsen Reidar , Gillum Matthew Paul , Kuhre Rune Ehrenreich , Holst Jens Juul
Published: February 2019

A large number of glucagon-like-peptide-1 (GLP-1)- and peptide-YY (PYY)-producing L cells are located in the colon, but little is known about their contribution to whole body metabolism. Since bile acids (BAs) increase GLP-1 and PYY release, and since BAs spill over from the ileum to the colon, we decided to investigate the ability of BAs to stimulate colonic GLP-1 and PYY secretion. Using isolated perfused rat/mouse colon as well as stimulation of the rat colon in vivo, we demonstrate that BAs significantly enhance secretion of GLP-1 and PYY from the colon with average increases of 3.5- and 2.9-fold, respectively. Furthermore, we find that responses depend on BA absorption followed by basolateral activation of the BA-receptor Takeda-G protein-coupled-receptor 5. Surprisingly, the apical sodium-dependent BA transporter, which serves to absorb conjugated BAs, was not required for colonic conjugated BA absorption or conjugated BA-induced peptide secretion. In conclusion, we demonstrate that BAs represent a major physiological stimulus for colonic L-cell secretion.

NEW & NOTEWORTHY By the use of isolated perfused rodent colon preparations we show that bile acids are potent and direct promoters of colonic glucagon-like-peptide 1 and peptide-YY secretion. The study provides convincing evidence that basolateral Takeda-G protein-coupled-receptor 5 activation is mediating the effects of bile acids in the colon and thus add to the existing literature described for L cells in the ileum.
Pulmonary vascular mechanical consequences of ischemic heart failure and implications for right ventricular function
Authors: Philip Jennifer L. , Murphy Thomas M. , Schreier David A. , Stevens Sydney , Tabima Diana M. , Albrecht Margie , Frump Andrea L. , Hacker Timothy A. , Lahm Tim , Chesler Naomi C.
Published: February 2019

Left heart failure (LHF) is the most common cause of pulmonary hypertension, which confers an increase in morbidity and mortality in this context. Pulmonary vascular resistance has prognostic value in LHF, but otherwise the mechanical consequences of LHF for the pulmonary vasculature and right ventricle (RV) remain unknown. We sought to investigate mechanical mechanisms of pulmonary vascular and RV dysfunction in a rodent model of LHF to address the knowledge gaps in understanding disease pathophysiology. LHF was created using a left anterior descending artery ligation to cause myocardial infarction (MI) in mice. Sham animals underwent thoracotomy alone. Echocardiography demonstrated increased left ventricle (LV) volumes and decreased ejection fraction at 4 wk post-MI that did not normalize by 12 wk post-MI. Elevation of LV diastolic pressure and RV systolic pressure at 12 wk post-MI demonstrated pulmonary hypertension (PH) due to LHF. There was increased pulmonary arterial elastance and pulmonary vascular resistance associated with perivascular fibrosis without other remodeling. There was also RV contractile dysfunction with a 35% decrease in RV end-systolic elastance and 66% decrease in ventricular-vascular coupling. In this model of PH due to LHF with reduced ejection fraction, pulmonary fibrosis contributes to increased RV afterload, and loss of RV contractility contributes to RV dysfunction. These are key pathologic features of human PH secondary to LHF. In the future, novel therapeutic strategies aimed at preventing pulmonary vascular mechanical changes and RV dysfunction in the context of LHF can be tested using this model.

NEW & NOTEWORTHY In this study, we investigate the mechanical consequences of left heart failure with reduced ejection fraction for the pulmonary vasculature and right ventricle. Using comprehensive functional analyses of the cardiopulmonary system in vivo and ex vivo, we demonstrate that pulmonary fibrosis contributes to increased RV afterload and loss of RV contractility contributes to RV dysfunction. Thus this model recapitulates key pathologic features of human pulmonary hypertension-left heart failure and offers a robust platform for future investigations.
Bacillus anthracis lethal toxin, but not edema toxin, increases pulmonary artery pressure and permeability in isolated perfused rat lungs
Authors: Cui Xizhong , Xu Wanying , Neupane Pranita , Weiser-Schlesinger Andie , Weng Ray , Pockros Benjamin , Li Yan , Moayeri Mahtab , Leppla Stephen H. , Fitz Yvonne , Eichacker Peter Q.
Published: February 2019

Although lethal toxin (LT) and edema toxin (ET) contribute to lethality during Bacillus anthracis infection, whether they increase vascular permeability and the extravascular fluid accumulation characterizing this infection is unclear. We employed an isolated perfused Sprague-Dawley rat lung model to investigate LT and ET effects on pulmonary vascular permeability. Lungs ( n ≥ 6 per experimental group) were isolated, ventilated, suspended from a force transducer, and perfused. Lung weight and pulmonary artery (Ppa) and left atrial pressures were measured over 4 h, after which pulmonary capillary filtration coefficients (Kf.c) and lung wet-to-dry weight ratios (W/D) were determined. When compared with controls, LT increased Ppa over 4 h and Kf.c and W/D at 4 h ( P < 0.0001). ET decreased Ppa in a significant trend ( P = 0.09) but did not significantly alter Kf.c or W/D ( P ≥ 0.29). Edema toxin actually blocked LT increases in Ppa but not LT increases in Kf.c and W/D. When Ppa was maintained at control levels, LT still increased Kf.c and W/D ( P ≤ 0.004). Increasing the dose of each toxin five times significantly increased and a toxin-directed monoclonal antibody decreased the effects of each toxin ( P ≤ 0.05). Two rho-kinase inhibitors (GSK269962 and Y27632) decreased LT increases in Ppa ( P ≤ 0.02) but actually increased Kf.c and W/D in LT and control lungs ( P ≤ 0.05). A vascular endothelial growth factor receptor inhibitor (ZM323881) had no significant effect ( P ≥ 0.63) with LT. Thus, LT but not ET can increase pulmonary vascular permeability independent of increased Ppa and could contribute to pulmonary fluid accumulation during anthrax infection. However, pulmonary vascular dilation with ET could disrupt protective hypoxic vasoconstriction.

NEW & NOTEWORTHY The most important findings from the present study are that Bacillus anthracis lethal toxin increases pulmonary artery pressure and pulmonary permeability independently in the isolated rat lung, whereas edema toxin decreases the former and does not increase permeability. Each effect could be a basis for organ dysfunction in patients with this lethal infection. These findings further support the need for adjunctive therapies that limit the effects of both toxins during infection.
NRP1 regulates HMGB1 in vascular endothelial cells under high homocysteine condition
Authors: Ma Yeshuo , Zhang Zhen , Chen Runtai , Shi Rui , Zeng Pingyu , Chen Ruifang , Leng Yiping , Chen Alex F.
Published: February 2019

Endothelial inflammation plays an important role in hyperhomocysteinemia (HHcy)-associated vascular diseases. High mobility group box 1 (HMGB1) is a pro-inflammatory danger molecule produced by endothelial cells. However, whether HMGB1 is involved in vascular endothelial inflammation of HHcy is poorly understood. Neuropilin-1 (NRP1) mediates inflammatory response and activates mitogen-activated protein kinases (MAPKs) pathway that has been reported to be involved in regulation of HMGB1. The aim of this study was to determine the alteration of HMGB1 in HHcy, and the role of NRP1 in regulation of endothelial HMGB1 under high homocysteine (Hcy) condition. In the present study, we first observed that the plasma level of HMGB1 was elevated in HHcy patients and an experimental rat model, and increased HMGB1 was also observed in the thoracic aorta of an HHcy rat model. HMGB1 was induced by Hcy accompanied with upregulated NRP1 in vascular endothelial cells. Overexpression of NRP1 promoted expression and secretion of HMGB1 and endothelial inflammation; knockdown of NRP1 inhibited HMGB1 and endothelial inflammation induced by Hcy, which partially regulated through p38 MAPK pathway. Furthermore, NRP1 inhibitor ATWLPPR reduced plasma HMGB1 level and expression of HMGB1 in the thoracic aorta of HHcy rats. In conclusion, our data suggested that Hcy requires NRP1 to regulate expression and secretion of HMGB1. The present study provides the evidence for inhibition of NRP1 and HMGB1 to be the novel therapeutic targets of vascular endothelial inflammation in HHcy in the future.

NEW & NOTEWORTHY This study shows for the first time to our knowledge that the plasma level of high mobility group box 1 (HMGB1) is elevated in hyperhomocysteinemia (HHcy) patients, and homocysteine promotes expression and secretion of HMGB1 partially regulated by neuropilin-1 in endothelial cells, which is involved in endothelial inflammation. Most importantly, these new findings will provide a potential therapeutic strategy for vascular endothelial inflammation in HHcy.
(Not Giving Up) The Marathon Race of MET Targeting Therapy: Are We There Yet?
Authors: Ma Patrick C.
Published: February 2019

Among the various MET aberrations, MET amplification and METex14 have emerged as valid predictive biomarkers for MET inhibition. Despite challenges that have limited the development of MET inhibitors, we can learn from the latest efforts in biomarker-based therapy to better identify the patients who will benefit from treatment with these agents.

See related articles by Hong et al., p. 2403 and Van Cutsem et al., p. 2414
Primary CNS Lymphoma in the Elderly: The Challenge
Authors: Siegal Tali , Bairey Osnat
Published: February 2019

Primary central nervous system (CNS) lymphoma is an aggressive brain tumor sensitive to chemotherapy and radiotherapy. Its incidence has increased in the elderly, and they account for the majority of patients. The median survival of patients older than 70 years did not change over the last 40 years and remained in the range of 6–7 months. The definition of elderly is nonuniform, and chronological age is not the best marker of treatment tolerability or a predictor of treatment-related toxicity. Some patients who are fit can tolerate induction, consolidation, and even high-dose chemotherapy with autologous stem cell transplantation, whereas others who have multiple comorbidities with reduced renal and bone marrow function can tolerate only intermediate doses of methotrexate. The latter may benefit from maintenance treatment. The “elderly” are also susceptible to the accelerated and detrimental cognitive side effects of whole-brain irradiation which is an alternative consolidation to high-dose chemotherapy. The optimal treatment remains an unresolved matter. A comprehensive comorbidity and geriatric assessment is imperative for appraisal of treatment-induced risks for CNS and systemic toxicity. An individualized approach is required aiming to prolong survival while minimizing toxicity. Future studies should assess the potential of new agents for improving outcome and maintaining quality of life.
Multiple Neurenteric Cysts along the Spinal Axis of an Infant: A Rare Entity
Authors: Vasani Viral , Konar Subhas , Nandeesh Bevinahalli Nanjegowda , Praharaj Shanti Sankar
Published: February 2019

A spinal neurenteric cyst is a rare entity. It commonly presents already at 5 weeks of age up to the 6th decade of life. The most common location is the cervical region followed by thoracic and lumbosacral regions. We report a 9-month-old male infant with sudden onset of weakness in both lower limbs. MRI revealed 2 cystic lesions at cervical and thoracic level with spinal cord compression. He underwent laminectomy and excision of the cervical lesion. The child improved significantly. The postoperative MRI shows complete excision of a dorsal lesion and presence of a cervical lesion. Later, he underwent cervical laminotomy and partial wall excision followed by shunt placement. The histopathological report revealed a neurenteric cyst. Two neurenteric cysts presented in the neuroaxis of the same patient: one was located ventral (thoracic) and the other dorsal (cervical). At the 2-year follow-up, the child was active and walking without support. Multiple cystic lesions in the neuroaxis can be neurenteric cysts.
Head or Neck First? Speed and Rates of Reperfusion in Thrombectomy for Tandem Large Vessel Occlusion Strokes
Authors: Haussen Diogo C. , Turjman Francis , Piotin Michel , Labreuche Julien , Steglich-Arnholm Henrik , Holtmannspötter Markus , Taschner Christian , Eiden Sebastian , Nogueira Raul G. , Papanagiotou Panagiotis , Boutchakova Maria , Siddiqui Adnan H. , Lapergue Bertrand , Dorn Franziska , Cognard Christophe , Killer Monika , Mangiafico Salvatore , Ribo Marc , Psychogios Marios N. , Spiotta Alejandro M. , Labeyrie Marc-Antoine  , Mazighi Mikael , Biondi Alessandra , Richard Sébastien , Grossberg Jonathan A. , Anxionnat René , Bracard Serge , Gory Benjamin ,   on behalf of the TITAN (Thrombectomy In TANdem Lesions) Investigators
Published: February 2019

Background: We aim to evaluate the speed and rates of reperfusion in tandem large vessel occlusion acute stroke patients undergoing upfront cervical lesion treatment (Neck-First: angioplasty and/or stent before thrombectomy) as compared to direct intracranial occlusion therapy (Head-First) in a large international multicenter cohort. Methods: The Thrombectomy In TANdem Lesions (TITAN) collaboration pooled individual data of prospectively collected thrombectomy international databases for all consecutive anterior circulation tandem patients who underwent emergent thrombectomy. The co-primary outcome measures were rates of successful reperfusion (modified Thrombolysis in Cerebral Infarction 2b/3) and time from groin puncture to successful reperfusion. Results: In total, 289 patients with tandem atherosclerotic etiology were included in the analysis (182 Neck-First and 107 Head-First patients). Except for differences in the Alberta Stroke Program Early CT Score (ASPECTS; median 8 [range 7–10] Neck-First vs. 7 [range 6–8] Head-First; p < 0.001) and cervical internal carotid artery (ICA) lesion severity (complete occlusion in 35% of the Neck-First vs. 57% of the Head-First patients; p < 0.001), patient characteristics were well balanced. After adjustments, there was no difference in successful reperfusion rates between the study groups (odds ratio associated with Neck-First: 1.18 [95% confidence interval, 0.60–2.17]). The time to successful reperfusion from groin puncture was significantly shorter in the Head-First group after adjustments (median 56 min [range 39–90] vs. 70 [range 50–102]; p = 0.001). No significant differences in the rates of full reperfusion, symptomatic hemorrhage, 90-day independence, or mortality were observed. Sensitivity analysis excluding patients with complete cervical ICA occlusion yielded similar results. Conclusions: The upfront approach of the intracranial lesion in patients with tandem large vessel occlusion strokes leads to similar reperfusion rates but faster reperfusion as compared to initial cervical revascularization followed by mechanical thrombectomy. Controlled studies are warranted.
Telemedicine in General Neurology: Interrater Reliability of Clinical Neurological Examination Via Audio-Visual Telemedicine
Authors: Awadallah Mohamed , Janssen Frank , Körber Barbara , Breuer Lorenz , Scibor Mateusz , Handschu René
Published: February 2019

Introduction: While there are several studies on reliability of telemedicine in assessing stroke scales, little is known about the validity of a general neurological examination performed via telemedicine. Therefore, we sought to test the agreement between bedside and remote examination in acute patients of the emergency room. Methods: Acute patients at the emergency room of a 450-bed academic teaching hospital were included in this study. A clinical neurological examination consisting of 22 items was performed at bedside and also remotely via an audio-visual link by a different neurologist; both were experienced clinicians at the consultant level. Kappa statistics were calculated for each item of the examination. Results: Forty three patients completed both examinations (mean age 58.3 years, 56% female). Patients were seen between 8 and 72 min after admission (mean 36.3 min). Total time for remote examination was 12.6 min (8–21 min) and 8.9 min (5–18 min) for bedside examination. K-coefficients ranged from 0.32 (muscle tone) – 0.82 (language) indicating a fair to excellent agreement in most items. Conclusions: Remote examination via an audio-visual link produces comparable results to bedside performance even in acute patients of the emergency room. Compared to the scarce data available, inter-observer agreement is about the same as that between 2 examiners at bedside. However, more studies on reliability and validity of clinical neurological examination are required.
Desenvolvimento e avaliação de vídeo educativo em dermatite atópica como ferramenta no ensino médico
Authors: Choinski Adriane Gonçalves Menezes , Spagnol Caroline , Ribas Caroline Rakoski , Kutzke Ana Luiza Reichmann Moreira Pinto , Purim Kátia Sheylla Malta
Published: February 2019

Introdução. A tecnologia reorganizou a forma como se vive nos últimos anos, bem como a forma de se comunicar e aprender. As Tecnologias da Informação e Comunicação (TICs), como filmes e vídeos, apresentam uma proposta dinâmica de exposição e debate de conteúdo e são cada vez mais empregadas como recursos didáticos na educação médica. Objetivo. O presente trabalho teve como objetivo desenvolver e avaliar o impacto de um vídeo educativo no aprendizado de alunos de graduação do curso de medicina. Materiais e Métodos. Para tanto, foi realizada uma pesquisa descritiva transversal com estudantes de medicina do 1º ao 4º ano de uma universidade privada em Curitiba-PR. Foi desenvolvido um vídeo educativo sobre dermatite atópica com posterior exibição aos participantes. Houve aplicação de questionário estruturado com questões objetivas sobre o conteúdo do vídeo (Questionário Dermatite Atópica) antes e após o vídeo e um segundo questionário sobre a satisfação com o uso do vídeo como recurso didático (Questionário Avaliação do Vídeo Educativo) após a exibição do vídeo. As análises foram feitas através do Teste de Homogeneidade Marginal, Teste Não Paramétrico de Fisher e Qui-Quadrado (nível de significância de 5%). Resultados. No total, 215 alunos participaram do estudo. A análise do Questionário Dermatite Atópica pré e pós exibição do vídeo mostrou aumento de acerto em cinco das sete questões de maneira global, sendo três delas com significância (p< 0,05). O aumento da taxa de acerto geral foi constatado também no grupo dos alunos que já haviam tido aula expositiva curricular sobre dermatite atópica. Quanto ao Questionário Avaliação do Vídeo Educativo, 93,55% considerou o vídeo satisfatório ou totalmente satisfatório quanto a qualidade científica, 79,36% teve suas expectativas de ensino atendidas e 89,45% acreditou que o uso dessa ferramenta facilita a aprendizagem. A respeito da utilização de vídeos educativos na graduação, 73,85% recomenda o uso como recurso pedagógico. Conclusão. A avaliação do uso de vídeo educativo no ensino médico demonstrou taxas significativas de satisfação com o recurso e de contribuição para a aprendizagem, sendo recomendado como ferramenta de ensino pela maioria dos alunos. As TICs podem, portanto, atuar como facilitadoras na correlação teórico-prática, além de terem um potencial de auxílio na retenção do conteúdo e no aprendizado.
Relato de caso de hidradenocarcinoma nodular
Authors: Dias Tiago Miranda , Dias Junior Leonidas Leonidas Braga , Santos Bruno de Oliveira , Neder Antuan Assad Iwasaka , Costa Simone Beverly Nascimento da , Guedes Juan Andrade , Miranda Claudia do Socorro Carvalho , Sousa Júnior Alcinês da Silva , Gonçalves Nelson Veiga , Palacios Vera Regina da Cunha Menezes
Published: February 2019

Relato de caso de hidradenocarcinoma nodular, neoplasia rara e pouco descrita na literatura, em paciente masculino, 78 anos, branco, procedente de área rural, atendido no SUS em julho de 2013, em Belém, Pará, Brasil. Foi observada lesão eritematonodular, com três meses de evolução, infiltrada, exulcerada, pouco dolorosa e sangrante, com 1 cm de diâmetro, na asa direita nasal, além de telangiectasias ao redor. A impressão diagnóstica foi carcinoma basocelular. A histopatologia identificou hidradenoma nodular maligno, confirmada pela imuno-histoquímica. A relevância deste relato é devida a raridade da doença e a falta de protocolo para tratamento específico da mesma.