bluuebunny/crossref_metadata_2025 huggingface dataset:
Linear shear and nonlinear extensional rheology of unentangled supramolecular side-chain polymers
Authors: Cui Guanghui , Boudara Victor A. H. , Huang Qian , Baeza Guilhem P. , Wilson Andrew J. , Hassager Ole , Read Daniel J. , Mattsson Johan
Published: August 2018

Supramolecular polymers are important within a wide range of applications including printing, adhesives, coatings, cosmetics, surgery, and nano-fabrication. The possibility to tune polymer properties through the control of supramolecular associations makes these materials both versatile and powerful. Here, we present a systematic investigation of the linear shear rheology for a series of unentangled ethylhexyl acrylate-based polymers for which the concentration of randomly distributed supramolecular side groups is systematically varied. We perform a detailed investigation of the applicability of time temperature superposition (TTS) for our polymers; small amplitude oscillatory shear rheology is combined with stress relaxation experiments to identify the dynamic range over which TTS is a reasonable approximation. Moreover, we find that the “sticky-Rouse” model normally used to interpret the rheological response of supramolecular polymers fits our experimental data well in the terminal regime, but is less successful in the rubbery plateau regime. We propose some modifications to the “sticky-Rouse” model, which includes more realistic assumptions with regard to (i) the random placement of the stickers along the backbone, (ii) the contributions from dangling chain ends, and (iii) the chain motion upon dissociation of a sticker and reassociation with a new co-ordination which involves a finite sized “hop” of the chain. Our model provides an improved description of the plateau region. Finally, we measure the extensional rheological response of one of our supramolecular polymers. For the probed extensional flow rates, which are small compared to the characteristic rates of sticker dynamics, we expect a Rouse-type description to work well. We test this by modeling the observed strain hardening using the upper convected Maxwell model and demonstrate that this simple model can describe the data well, confirming the prediction and supporting our determination of sticker dynamics based on linear shear rheology.
Current-induced dynamics of skyrmion strings
Authors: Yokouchi Tomoyuki , Hoshino Shintaro , Kanazawa Naoya , Kikkawa Akiko , Morikawa Daisuke , Shibata Kiyou , Arima Taka-hisa , Taguchi Yasujiro , Kagawa Fumitaka , Nagaosa Naoto , Tokura Yoshinori
Published: August 2018

Nonlinear Hall effect related to current-driven skyrmion string motion is observed experimentally and analyzed theoretically.
Developmental barcoding of whole mouse via homing CRISPR
Authors: Kalhor Reza , Kalhor Kian , Mejia Leo , Leeper Kathleen , Graveline Amanda , Mali Prashant , Church George M.
Published: August 2018

Lineage tracing in mouse using CRISPR

A homing guide RNA (hgRNA) that directs CRISPR-Cas9 to its own DNA locus can diversify its sequence and act as an expressed genetic barcode. Kalhor
et al.
engineered a mouse line carrying 60 independent loci of hgRNAs, thus generating a large number of unique barcodes in various embryonic and extraembryonic tissues in fully developed mice. This method demonstrates lineage tracing from the very first branches of the development tree up to organogenesis events and was used to elucidate embryonic brain patterning.

Science
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eaat9804
The 5′ Untranslated Region of Human Bocavirus Capsid Transcripts Regulates Viral mRNA Biogenesis and Alternative Translation
Authors: Liu Xiaoqian , Hao Sujuan , Chen Zhen , Xu Huanzhou , Wang Hanzhong , Huang Min , Guan Wuxiang
Published: August 2018

Alternative translation of HBoV1 capsid mRNAs is vital for the viral life cycle, as capsid proteins perform essential functions in genome packaging, assembly, and antigenicity. The 5′ untranslated regions (UTRs) of capsid mRNAs are generated by alternative splicing, and they contain different exons. Our study shows that the 5′ UTR not only modulates mRNA abundance but also regulates capsid expression. Two upstream ATGs (uATGs) that were upstream of the capsid translation initiation site in the 5′ UTR were found to affect viral capsid mRNA polyadenylation, alternative translation, and progeny virus production. The results reveal that uATGs play an important role in the viral life cycle and represent a new layer to regulate HBoV1 RNA processing, which could be a target for gene therapy.
Evaluation of ADA HbA1c criteria in the diagnosis of pre-diabetes and diabetes in a population of Chinese adolescents and young adults at high risk for diabetes: a cross-sectional study
Authors: Li Ge , Han Lanwen , Wang Yonghui , Zhao Yanglu , Li Yu , Fu Junling , Li Ming , Gao Shan , Willi Steven M
Published: August 2018

Objective

We aimed to assess haemoglobin A1c (HbA1c) for the diagnosis of pre-diabetes and diabetes in a population of Chinese youths at risk of metabolic syndrome.

Setting

Beijing, China.

Participants

A total of 581 subjects aged 14–28 years underwent evaluation including an oral glucose tolerance test (OGTT). Insulin sensitivity, β-cell function and a number of cardiovascular disease risk factors were evaluated. Receiver operating characteristic (ROC) curves were used to assess the screening efficacy of HbA1c.

Results

Using OGTT data as a standard, the majority (70.0%, 7/10) of subjects with diabetes would have been diagnosed with HbA1c ≥6.5%. In contrast, only 28.1% (16/57) of subjects with pre-diabetes possessed elevated HbA1cs, while the majority (68.4%) had normal HbA1cs. On the contrary, a total of 8.1% (39/479) of youths in the normal HbA1c category (<5.7%) and 21.3% in the pre-diabetes category had pre-diabetes. In the ROC analysis, the area under the curve (AUC) for HbA1c identifying pre-diabetes was 0.680(95% CI 0.640 to 0.719); the optimal threshold was 5.5%, with a sensitivity of 61.4% and specificity of 68.5%. For type 2 diabetes mellitus, the AUC for HbA1c was 0.970 (0.952 to 0.982), and the optimal threshold was 6.1%, with a sensitivity of 90.0% and a specificity of 98.7%. Applying these new cut-offs, pre-diabetic participants (HbA1c 5.5%–6.1%) had lower disposition index and higher risk of dyslipidaemia (OR=1.61,95% CI 1.10 to 2.37) and metabolic syndrome (OR=2.09, 1.27 to 3.45) than those with normal HbA1c (<5.5%).

Conclusion

The American Diabetes Association’s established HbA1c criteria for pre-diabetes and diabetes (5.7% and 6.5%) may not be appropriately applied to adolescents and young adults in China. Our findings suggest that those with HbA1c of 5.5%–6.1% already exhibit impaired β-cell function and increased cardiometabolic risk factors which may warrant intervention.

Trial registration number

NCT03421444.
Could this be whooping cough?
Authors: Nee Patrick , Weir Elaine , Vardhan Madhur , Vaidya Ankita
Published: August 2018

Whooping cough is a notifiable bacterial respiratory infection caused byBordetella pertussis. It may produce serious disease, especially in immunocompromised individuals and very young children. The number of reported cases increases in the winter months and the incidence peaks every 4–5 years. However, this periodicity is variable and is inconsistent between different geographical regions. Bordetella pertussis infection (BPI) may be underdiagnosed because of its seasonality and the fact that clinical features may be indistinguishable from other respiratory disorders in the paediatric ED setting. Treatment with antibiotics reduces the period of infectivity but may not shorten the illness. This review discusses the epidemiology of the disease, its clinical features, diagnosis, treatment and the disposition of patients with BPI.
Sex differences in 90-day outcomes after mechanical thrombectomy for acute ischemic stroke
Authors: Madsen Tracy E , DeCroce-Movson Eliza , Hemendinger Morgan , McTaggart Ryan A , Yaghi Shadi , Cutting Shawna , Furie Karen L , Saad Ali , Siket Matthew S , Jayaraman Mahesh V
Published: August 2018

Background

It is largely unknown whether functional outcomes after mechanical thrombectomy for large vessel occlusion (LVO) ischemic strokes differ by sex in non-clinical trial populations. We investigated sex differences in 90-day outcomes among ischemic stroke patients receiving mechanical thrombectomy.

Methods

This was a prospective cohort of adults treated with mechanical thrombectomy for LVO at a single academic comprehensive stroke center from July 2015 to April 2017. Data on independence (mRS ≤2) at hospital discharge and 90 days were collected prospectively. Multiple logistic regression was used to determine the association between sex and 90-day independence, first adjusting for demographics, pre-stroke mRS, and NIHSS, then by co-morbidities and time to thrombectomy, and finally by vessel recanalization and use of intravenous thrombolysis.

Results

We included 279 patients, 52% of whom were female. Compared with males, females were older (median years (IQR) 81 (75–88) vs. 71.5 (60–81), P<0.001) and had higher baseline NIHSS (mean SD 18.2±7.5 vs . 16.0±7.1, P=0.02). Similar proportions of males and females had pre-stroke mRS ≤2 (73.3% vs.67.1%, P=0.27). In multivariate analyses, males and females had a similar likelihood of being independent at discharge (aOR 0.71 (95%CI 0.32 to 1.58)), but females were less likely to be independent at 90 days (aOR 0.37 95% CI 0.16 to 0.87).

Conclusions

In patients treated with mechanical thrombectomy for LVOs at a large comprehensive stroke center, females were less likely to be independent at 90 days. Future research should investigate contributors to poor outcomes post-discharge in females with LVOs, along with potential interventions to improve outcomes.
Closed-Loop Quantitative Verification of Rate-Adaptive Pacemakers
Authors: Paoletti Nicola , Patanè Andrea , Kwiatkowska Marta
Published: August 2018

Rate-adaptive pacemakers are cardiac devices able to automatically adjust the pacing rate in patients with chronotropic incompetence, i.e., whose heart is unable to provide an adequate rate at increasing levels of physical, mental, or emotional activity. These devices work by processing data from physiological sensors in order to detect the patient’s activity and update the pacing rate accordingly. Rate adaptation parameters depend on many patient-specific factors, and effective personalization of such treatments can only be achieved through extensive exercise testing, which is normally intolerable for a cardiac patient. In this work, we introduce a data-driven and model-based approach for the automated verification of rate-adaptive pacemakers and formal analysis of personalized treatments. To this purpose, we develop a novel dual-sensor pacemaker model where the adaptive rate is computed by blending information from an accelerometer, and a metabolic sensor based on the QT interval. Our approach enables personalization through the estimation of heart model parameters from patient data (electrocardiogram), and closed-loop analysis through the online generation of synthetic, model-based QT intervals and acceleration signals. In addition to personalization, we also support the derivation of models able to account for the varied characteristics of a virtual patient population, thus enabling safety verification of the device. To capture the probabilistic and nonlinear dynamics of the heart, we define a probabilistic extension of timed I/O automata with data and employ statistical model checking for quantitative verification of rate modulation. We evaluate our rate-adaptive pacemaker design on three subjects and a pool of virtual patients, demonstrating the potential of our approach to provide rigorous, quantitative insights into the closed-loop behavior of the device under different exercise levels and heart conditions.
Child-adult differences in neuromuscular fatigue are muscle dependent
Authors: Piponnier Enzo , Martin Vincent , Bontemps Bastien , Chalchat Emeric , Julian Valérie , Bocock Olivia , Duclos Martine , Ratel Sébastien
Published: August 2018

The aim of the present study was to compare the development and etiology of neuromuscular fatigue of the knee extensor (KE) and plantar flexor (PF) muscles during repeated maximal voluntary isometric contractions (MVICs) between children and adults. Prepubertal boys ( n = 21; 9–11 yr) and men ( n = 24; 18–30 yr) performed two fatigue protocols consisting of a repetition of 5-s isometric MVIC of the KE or PF muscles interspersed with 5-s passive recovery periods until MVIC reached 60% of its initial value. The etiology of neuromuscular fatigue of the KE and PF muscles was investigated by means of noninvasive methods, such as the surface electromyography, single and doublet magnetic stimulation, twitch interpolation technique, and near-infrared spectroscopy. The number of repetitions performed was significantly lower in men (15.4 ± 3.8) than boys (38.7 ± 18.8) for the KE fatigue test. In contrast, no significant difference was found for the PF muscles between boys and men (12.1 ± 4.9 and 13.8 ± 4.9 repetitions, respectively). Boys displayed a lower reduction in potentiated twitch torque, low-frequency fatigue, and muscle oxygenation than men whatever the muscle group considered. In contrast, voluntary activation level and normalized electromyography data decreased to a greater extent in boys than men for both muscle groups. To conclude, boys experienced less peripheral and more central fatigue during repeated MVICs than men whatever the muscle group considered. However, child-adult differences in neuromuscular fatigue were muscle-dependent since boys fatigued similarly to men with the PF muscles and to a lower extent with the KE muscles.

NEW & NOTEWORTHY Child-adult differences in neuromuscular fatigue during repeated maximal voluntary contractions are specific to the muscle group since children fatigue similarly to adults with the plantar flexor muscles and to a lower extent with the knee extensor muscles. Children experience less peripheral fatigue and more central fatigue than adults, regardless of the muscle group considered.
Cognitive Function Is Impaired in Patients with Recently Diagnosed Type 2 Diabetes, but Not Type 1 Diabetes
Authors: van Gemert Theresa , Wölwer Wolfgang , Weber Katharina S. , Hoyer Annika , Strassburger Klaus , Bohnau Nora T. , Brüggen Marie A. , Ovelgönne Katharina , Gössmann Eva-Maria , Burkart Volker , Szendroedi Julia , Roden Michael , Müssig Karsten , GDS Group
Published: August 2018

Objective. To test whether cognitive function is impaired in early states of diabetes and to identify possible risk factors for cognitive impairment. Methods. A cross-sectional analysis within the German Diabetes Study included patients with type 1 or type 2 diabetes within the first year after diagnosis or five years after study inclusion and metabolically healthy individuals. Participants underwent comprehensive metabolic phenotyping and testing of different domains of cognitive function. Linear regression models were used to compare cognition test outcomes and to test associations between cognitive function and possible influencing factors within the groups. Results. In participants with recently diagnosed diabetes, verbal memory was poorer in patients with type 2 diabetes (P=0.029), but not in type 1 diabetes (P=0.156), when compared to healthy individuals. Five years after diagnosis, type 2 diabetes patients also showed lower verbal memory than those with type 1 diabetes (P=0.012). In addition to crystallized intelligence, a higher body mass index among individuals with recently diagnosed type 2 diabetes and male sex among individuals with recently diagnosed type 1 diabetes were associated with impaired verbal memory (all P<0.05). Conclusion. Verbal memory is impaired in individuals with recently diagnosed type 2 diabetes and likely associated with higher body mass. This trial is registered with the trial registration number NCT01055093.
Effects of the Attention Training Technique on Auditory Hallucinations in Schizo-Affective Disorder: A Single Case Study
Authors: Carter Karin E. P. , Wells Adrian
Published: August 2018

A 41-year-old female with schizo-affective disorder presenting with an eight-year history of auditory hallucinations participated in a single case treatment study (A-B-A-B-A-C-B) of the effects of the Attention Training Technique (ATT). No antipsychotic medication was prescribed in this case following a serious adverse reaction in the past. The aim of the study was to test the impact of ATT on the frequency and duration of hallucinations using a repeated return to baseline followed by an alternating treatment design. The alternative intervention consisted of autogenic relaxation instructions. The patient monitored the frequency, duration, and her distress over the voices on a daily basis during baseline and intervention phases across a study period of 80 weeks. Visual analysis of the data showed that ATT when introduced at three phases following baselines or control conditions was associated with a reduction in auditory hallucination frequency and duration compared to the other phases. This contrasted with the autogenic relaxation intervention that was associated with an increase in duration and frequency of voices. The perceived benefits of ATT were maintained for varying periods of time.
A Comparative Study on Discrete Shmaliy Moments and Their Texture-Based Applications
Authors: González Germán , Nava Rodrigo , Escalante-Ramírez Boris
Published: August 2018

In recent years, discrete orthogonal moments have attracted the attention of the scientific community because they are a suitable tool for feature extraction. However, the numerical instability that arises because of the computation of high-order moments is the main drawback that limits their wider application. In this article, we propose an image classification method that avoids numerical errors based on discrete Shmaliy moments, which are a new family of moments derived from Shmaliy polynomials. Shmaliy polynomials have two important characteristics: one-parameter definition that implies a simpler definition than popular polynomial bases such as Krawtchouk, Hahn, and Racah; a linear weight function that eases the computation of the polynomial coefficients. We use IICBU-2008 database to validate our proposal and include Tchebichef and Krawtchouk moments for comparison purposes. The experiments are carried out through 5-fold cross-validation, and the results are computed using random forest, support vector machines, naïve Bayes, and k-nearest neighbors classifiers.
Optimal Path-Following Guidance with Generalized Weighting Functions Based on Indirect Gauss Pseudospectral Method
Authors: Chen Qi , Wang Xugang , Yang Jing
Published: August 2018

An indirect Gauss pseudospectral method based path-following guidance law is presented in this paper. A virtual target moving along the desired path with explicitly specified speed is introduced to formulate the guidance problem. By establishing a virtual target-fixed coordinate system, the path-following guidance is transformed into a terminal guidance with impact angle constraints, which is then solved by using indirect Gauss pseudospectral method. Meanwhile, the acceleration dynamics are modeled as the first-order lag to the command. Using the receding horizon technique a closed-loop guidance law, which considers generalized weighting functions (even discontinuous) of both the states and the control cost, is derived. The accuracy and effectiveness of the proposed guidance law are validated by numerical comparisons. A STM32 Nucleo board based on the ARM Cortex-M7 processor is used to evaluate the real-time computational performance of the proposed indirect Gauss pseudospectral method. Simulations for various types of desired paths are presented to show that the proposed guidance law has better performance when compared with the existing results for pure pursuit, a nonlinear guidance law, and trajectory shaping path-following guidance and provides more degrees of freedom in path-following guidance design applications.
Flavoprotein Fluorescence Correlation with Visual Acuity Response in Patients Receiving Anti‐VEGF Injection for Diabetic Macular Edema
Authors: Andrade Romo Jorge S. , Lynch Giselle , Liu Kevin , Kim Daniel , Jansen Michael , Field Matthew G. , Elner Victor M. , Rosen Richard B.
Published: August 2018

Anti‐VEGF treatment of diabetic macular edema (DME) complicating diabetic retinopathy (DR) has greatly improved structural and visual outcomes for patients with diabetes mellitus. However, up to 50% of patients are either nonresponsive or refractory to anti‐VEGF treatment (no improvement in BCVA or central macular thickness (CMT)). It is believed that factors such as mitochondrial structural and functional damage, due to oxidative stress, are partially responsible for this lack of improvement. Flavoprotein fluorescence (FPF) has been shown to be a sensitive marker of mitochondrial function and has been found to correlate with the degree of diabetic retinopathy. FPF may also provide additional information regarding therapeutic response of patients receiving anti‐VEGF treatment for DME. Eight patients with DR and DME with clinically significant DME (CSDME) who underwent anti‐VEGF (bevacizumab) treatment were imaged before injection and at follow‐up visit using FPF in addition to standard color fundus photography and OCT CMT. A strong correlation r = 0.98 (p = 0.000015) between the FPF decrease and the BCVA improvement was observed; BCVA improved as FPF values decreased. Notably, in the same patients, the correlation between OCT CMT decrease and BCVA improvement (r = 0.688) was not found to be significant (p = 0.13). These findings suggest that FPF can detect improvement in metabolic function preceding structural improvement and even with small changes in edema. Additionally, FPF may be supplementary to current diagnostic methods for earlier detection of therapeutic response to anti‐VEGF treatment in patients with DME.
Production and Modification of Cellulose Nanocrystals fromAgave tequilanaWeber Waste and Its Effect on the Melt Rheology of PLA
Authors: Pech-Cohuo Soledad-Cecilia , Canche-Escamilla Gonzalo , Valadez-González Alex , Fernández-Escamilla Victor Vladimir Amilcar , Uribe-Calderon Jorge
Published: August 2018

The production and surface modification of cellulose nanocrystals (CNC) fromAgave tequilanaWeber waste (ATW) and their effect on the melt rheology of PLA were investigated. For that, CNC were obtained from ATW residues by acid hydrolysis and grafted with 2-ethyl hexyl acrylate (2-EHA) to promote compatibility with nonpolar polymers, such as PLA. The morphology of CNC occurred as rods, spheres, and the so-called porous network observed by scanning electron microscopy (SEM) and electron transmission microscopy (TEM), and the crystallinity of the cellulose fibers was ~73% and increased up to ~94% for CNC followed by X-ray diffraction (XRD). The acid hydrolysis and alkali extraction process produce changes on the native cellulose type I from ATW bagasse resulting in a mixture of cellulose type I and II and was preserved after CNC isolation and surface grafting. Polymer grafting was assessed using Fourier-transform infrared spectroscopy (FTIR) and X-ray electron spectroscopy (XPS). Upon surface modification, the grafted CNC presented better thermal stability than CNC pristine evaluated by thermogravimetric analysis (TGA), and the surface energy of the CNC was decreased which could promote CNC dispersion within polymers. Both pristine and surface modified CNC were melt mixed with PLA to produce nanocomposites at different concentrations of CNC. Dynamic time sweep tests showed that the introduction of CNC and CNC/2-EHA decreased the complex viscosity of PLA due to polymer degradation during compounding.
Orthogonal Experimental Studies on Preparation of Mine‐Filling Materials from Carbide Slag, Granulated Blast‐Furnace Slag, Fly Ash, and Flue‐Gas Desulphurisation Gypsum
Authors: Wu Mingyue , Hu Xiangming , Zhang Qian , Cheng Weimin , Hu Zunxiang
Published: August 2018

Environmentally friendly and cheap composite green cementitious materials have been prepared from carbide slag, fly ash, flue‐gas desulphurisation (FGD) gypsum, and granulated blast‐furnace slag (GBFS) without using cement clinker. Orthogonal testing was used to investigate the effects of the raw materials on the amount of water required for reaching standard consistency and consistency, setting time, slump value, and strength of the produced materials after curing for 7 d and 28 d. Scanning electron microscopy (SEM) and X‐ray diffraction (XRD) techniques were used for the analysis of the sample microstructure and hydration products as well as for the exploration of possible hydration mechanisms. We found that, among the utilised raw materials, the addition of FGD gypsum had the most significant effect on the setting time and amount of water required for reaching standard consistency and consistency, while the addition of GBFS deeply affected the slump value. The optimal activation results were obtained when the mass ratio of carbide slag : fly ash : GBFS : FGD gypsum was equal to 12.1 : 60.6 : 18.2 : 9.1.
Preliminary Capture Trajectory Design for Europa Tomography Probe
Authors: Federici Lorenzo , Zavoli Alessandro , Colasurdo Guido
Published: August 2018

The objective of this work is the preliminary design of a low-ΔV transfer from an initial elliptical orbit around Jupiter into a final circular orbit around the moon Europa. This type of trajectory represents an excellent opportunity for a low-cost mission to Europa, accomplished through a small orbiter, as in the proposed Europa Tomography Probe mission, a European contribution to NASA’s Europa Multiple-Flyby Mission (or Europa Clipper). The mission strategy is based on the v∞ leveraging concept, and the use of resonant orbits to exploit multiple gravity-assist from the moon. Possible sequences of resonant orbits are selected with the help of the Tisserand graph. Suitable trajectories are provided by an optimization code based on the parallel running of several differential evolution algorithms. Different solutions are finally compared in terms of propellant consumption and flight time.
Protective Role of Coxsackie-Adenovirus Receptor in the Pathogenesis of Inflammatory Bowel Diseases
Authors: Chen Xiong , Liu Rui , Liu Xiaoming , Xu Canxia , Wang Xiaoyan
Published: August 2018

Aim. To investigate the role of Coxsackie-adenovirus receptor (CAR) in inflammatory bowel disease (IBD). Background. CAR, a type I transmembrane protein with functions in virus attachment, has been shown to be associated with epithelial tight junctions (TJs) and mediates cell adhesion, implying its potential roles in the pathogenesis of IBD. Methods and Materials. To determine the effect of CAR in IBD using QPCR and Western blotting to determine the expression of CAD in TNF-α induced NCM460 and SW480 cells and IBD tissues compared to control groups. Furthermore, TJs dysregulation, FITC-Dextran permeability assay, qRT-PCR, Western blot, and IF assessed the permeability in CAR overexpressed cells treated with TNF-α. HE, qRT-PCR, Western blot, and IHC assay were used to assess the CAR overexpressed cells whether they have the effect to cure DSS induced ulcerative colitis rat model in vivo. Result. We found CAR levels in human colon cell lines are significantly downregulated under the treatment of tumor necrosis factor-alpha (TNF-α). Furthermore, overexpression of CAR markedly prevented TNF-α induced inflammatory response, TJs dysregulation, and permeability disruption (FITC-Dextran permeability assay) in cells. Consistent with these findings in vitro, we found that CAR overexpression could suppress gut inflammation, attenuate the downregulation of TJ protein ZO-1 and Occludin, and limit the induction of barrier permeability in a DSS induced ulcerative colitis rat model in vivo. Together, our findings strongly suggest that CAR could protect tight junctions and has an anti-inflammatory effect during the pathogenesis of IBD. Thus CAR may serve as a therapeutic target for the diagnosis and treatment of IBD.
Endoscopic Mucosal Resection Performed Underwater for Nonampullary Duodenal Epithelial Tumor: Evaluation of Feasibility and Safety
Authors: Shibukawa Goro , Irisawa Atsushi , Sato Ai , Abe Yoko , Yamabe Akane , Arakawa Noriyuki , Takasaki Yusuke , Maki Takumi , Yoshida Yoshitsugu , Igarashi Ryo , Yamamoto Shogo , Ikeda Tsunehiko , Hojo Hiroshi
Published: August 2018

Objectives. Recently, opportunities to encounter superficial nonampullary duodenal epithelial tumor (SNADET) have increased. EMR and ESD are performed to treat SNADET. However, the rate of perforation is higher than that of other gastrointestinal lesions, regardless of which method is used. Underwater EMR (UW-EMR) is immersion treatment of SNADET, which has low risk of perforation and can remove lesions safely and completely. In the present study, we retrospectively investigated patients in whom UW-EMR was performed to evaluate the feasibility and safety of UW-EMR for the treatment of SNADET. Methods. The primary endpoint was to evaluate the feasibility of UW-EMR for the treatment of SNADET, and secondary objective was to determine the operation’s safety. Results. There were 14 participants, with a total of 16 lesions, who underwent UW-EMR between August 2015 and December 2017. Histological heteromorphism revealed that seven patients had low-grade adenoma, seven had high-grade adenoma, and two had adenocarcinoma. En bloc resection was performed in 14 lesions. In two patients, nodular lesions were observed in the scar and biopsy confirmed recurrences. There were no serious adverse events including bleeding or perforation. Conclusions. UW-EMR may be a safe and effective treatment method for SNADET, if its therapeutic indication is adequately considered.
Characteristics of Stress Transfer and Progressive Fracture in Overlying Strata due to Mining‐Induced Disturbances
Authors: Lv Xiang-feng , Zhou Hong-yuan , Wang Ai-wen , Feng Chun , Xiao Xiao-chun
Published: August 2018

In this study, based on the mining of the 13210 working face in the Yima coal mine of the Gengcun village, China, a simplified mechanical model for the analysis of dynamic destabilization of the overlying strata during underground mining was constructed. The numerical simulation was used to analyze the stress patterns in the advanced abutments of the tunnel face and the characteristics of dynamic failures in the overlying strata. Furthermore, similitude experiments were conducted to study the process of stress release and deformation in the overlying strata, and to analyze the effects of overburden destabilization on the ground surface settlement. The theoretical analysis indicated that if the geometric parameters of a working face are fully determined, a stiffness ratio no greater than 1 is required for dynamic destabilization to occur. The numerical simulation results show that the stress in the overlying strata decreases with a decrease in distance from the tunnel face. The stresses in the advanced abutments initially increase with an increase in distance from the tunnel face, followed by a decrease in stress, and an eventual stabilization of the stress levels; this corresponds to the existence of a “stress build‐up zone,” “stress reduction zone,” and “native rock stress zone.” In similitude experiments, it was observed that a “pseudoplastic beam” state arises after the local stresses of the overlying strata have been completely released, and the “trapezoidal” fractures begin to form at stress concentrations. If the excavation of the working face continues to progress, the area of collapse expands upward, thereby increasing the areas of the fracture and densification zones. Owing to the nonuniform settlement of the overlying strata and the continuous development of bed‐separating cracks, secondary fractures will be generated on both sides of the working face, which increase the severity of the ground surface settlement.
A New Fuzzy Logic-Based Similarity Measure Applied to Large Gap Imputation for Uncorrelated Multivariate Time Series
Authors: Phan Thi-Thu-Hong , Bigand André , Caillault Émilie Poisson
Published: August 2018

The completion of missing values is a prevalent problem in many domains of pattern recognition and signal processing. Analyzing data with incompleteness may lead to a loss of power and unreliable results, especially for large missing subsequence(s). Therefore, this paper aims to introduce a new approach for filling successive missing values in low/uncorrelated multivariate time series which allows managing a high level of uncertainty. In this way, we propose using a novel fuzzy weighting-based similarity measure. The proposed method involves three main steps. Firstly, for each incomplete signal, the data before a gap and the data after this gap are considered as two separated reference time series with their respective query windowsQbandQa. We then find the most similar subsequence (Qbs) to the subsequence before this gapQband the most similar one (Qas) to the subsequence after the gapQa. To find these similar windows, we build a new similarity measure based on fuzzy grades of basic similarity measures and on fuzzy logic rules. Finally, we fill in the gap with average values of the window followingQbsand the one precedingQas. The experimental results have demonstrated that the proposed approach outperforms the state-of-the-art methods in case of multivariate time series having low/noncorrelated data but effective information on each signal.
Loss of MST/Hippo Signaling in a Genetically Engineered Mouse Model of Fusion-Positive Rhabdomyosarcoma Accelerates Tumorigenesis
Authors: Oristian Kristianne M. , Crose Lisa E.S. , Kuprasertkul Nina , Bentley Rex C. , Lin Yi-Tzu , Williams Nerissa , Kirsch David G. , Linardic Corinne M.
Published: August 2018

A hallmark of fusion-positive alveolar rhabdomyosarcoma (aRMS) is the presence of a chromosomal translocation encoding the PAX3–FOXO1 fusion oncogene. Primary cell-based modeling experiments have shown that PAX3–FOXO1 is necessary, but not sufficient for aRMS tumorigenesis, indicating additional molecular alterations are required to initiate and sustain tumor growth. Previously, we showed that PAX3–FOXO1-positive aRMS is promoted by dysregulated Hippo pathway signaling, as demonstrated by increased YAP1 expression and decreased MST activity. We hypothesized that ablating MST/Hippo signaling in a genetically engineered mouse model (GEMM) of aRMS would accelerate tumorigenesis. To this end, MST1/2-floxed (Stk3F/F;Stk4F/F) mice were crossed with a previously established aRMS GEMM driven by conditional expression of Pax3:Foxo1 from the endogenous Pax3 locus and conditional loss of Cdkn2a in Myf6 (myogenic factor 6)-expressing cells. Compared with Pax3PF/PF;Cdkn2aF/F;Myf6ICN/+ controls, Stk3F/F;Stk4F/F;Pax3PF/PF;Cdkn2aF/F;Myf6ICN/+ animals displayed accelerated tumorigenesis (P < 0.0001) and increased tumor penetrance (88% vs. 27%). GEMM tumors were histologically consistent with aRMS. GEMM tumor-derived cell lines showed increased proliferation and invasion and decreased senescence and myogenic differentiation. These data suggest that loss of MST/Hippo signaling acts with Pax3:Foxo1 expression and Cdkn2a loss to promote tumorigenesis. The rapid onset and increased penetrance of tumorigenesis in this model provide a powerful tool for interrogating aRMS biology and screening novel therapeutics.

Significance: A novel mouse model sheds light on the critical role of Hippo/MST downregulation in PAX3-FOXO1–positive rhabdomyosarcoma tumorigenesis. Cancer Res; 78(19); 5513–20. ©2018 AACR.
Inhibition of the Stromal p38MAPK/MK2 Pathway Limits Breast Cancer Metastases and Chemotherapy-Induced Bone Loss
Authors: Murali Bhavna , Ren Qihao , Luo Xianmin , Faget Douglas V. , Wang Chun , Johnson Radia Marie , Gruosso Tina , Flanagan Kevin C. , Fu Yujie , Leahy Kathleen , Alspach Elise , Su Xinming , Ross Michael H. , Burnette Barry , Weilbaecher Katherine N. , Park Morag , Mbalaviele Gabriel , Monahan Joseph B. , Stewart Sheila A.
Published: August 2018

The role of the stromal compartment in tumor progression is best illustrated in breast cancer bone metastases, where the stromal compartment supports tumor growth, albeit through poorly defined mechanisms. p38MAPKα is frequently expressed in tumor cells and surrounding stromal cells, and its expression levels correlate with poor prognosis. This observation led us to investigate whether inhibition of p38MAPKα could reduce breast cancer metastases in a clinically relevant model. Orally administered, small-molecule inhibitors of p38MAPKα or its downstream kinase MK2 each limited outgrowth of metastatic breast cancer cells in the bone and visceral organs. This effect was primarily mediated by inhibition of the p38MAPKα pathway within the stromal compartment. Beyond effectively limiting metastatic tumor growth, these inhibitors reduced tumor-associated and chemotherapy-induced bone loss, which is a devastating comorbidity that drastically affects quality of life for patients with cancer. These data underscore the vital role played by stromal-derived factors in tumor progression and identify the p38MAPK-MK2 pathway as a promising therapeutic target for metastatic disease and prevention of tumor-induced bone loss.

Significance: Pharmacologically targeting the stromal p38MAPK-MK2 pathway limits metastatic breast cancer growth, preserves bone quality, and extends survival. Cancer Res; 78(19); 5618–30. ©2018 AACR.
Early Reduction in ctDNA Predicts Survival in Patients with Lung and Bladder Cancer Treated with Durvalumab
Authors: Raja Rajiv , Kuziora Michael , Brohawn Philip Z. , Higgs Brandon W. , Gupta Ashok , Dennis Phillip A. , Ranade Koustubh
Published: August 2018

Purpose:

Immunotherapy has transformed the treatment of many solid tumors, with some patients deriving long-term benefit, but how to identify such patients remains unclear. Somatic mutations detected in circulating tumor DNA (ctDNA) from plasma can be an indicator of disease progression, response to therapy, and clonality of primary and metastatic lesions. Hence, ctDNA analysis can provide a valuable noninvasive and tumor-specific marker for longitudinal monitoring of tumor burden. We explored the use of ctDNA to predict survival on durvalumab, an anti-PD-L1 therapy.

Experimental Design:

Variant allele frequencies (VAF) of somatic mutations in 73 genes were assessed in ctDNA using targeted sequencing in a discovery cohort consisting of 28 patients with non–small cell lung cancer (NSCLC) and two validation NSCLC and urothelial cancer (UC) cohorts of 72 and 29 patients, respectively, to correlate ctDNA changes with clinical outcomes.

Results:

Somatic variants were detected in 96% of patients. Changes in VAF preceded radiographic responses, and patients with reduction in VAF at 6 weeks had significantly greater reduction in tumor volume, with longer progression-free and overall survival.

Conclusions:

ctDNA VAF changes are strongly correlated with duration of treatment, antitumor activity, and clinical outcomes in NSCLC and UC. Early on-treatment reduction in ctDNA VAF may be a useful predictor of long-term benefit from immunotherapy. Prospective studies should validate these findings and the value of utilizing early changes in ctDNA for therapeutic decision making by identifying nonresponders to checkpoint inhibitor monotherapies and guiding combination therapies.
Augmenting Trait-Dependent Diversification Estimations with Fossil Evidence: A Case Study Using Osmoregulatory Neurovasculature
Authors: O’Brien Haley D.
Published: August 2018

When comparative neuromorphological studies are extended into evolutionary contexts, traits of interest are often linked to diversification patterns. Features demonstrably associated with increases in diversification rates and the infiltration or occupation of novel niche spaces are often termed “key innovations.” Within the past decade, phylogenetically informed methods have been developed to test key innovation hypotheses and evaluate the influence these traits have had in shaping modern faunas. This is primarily accomplished by estimating state-dependent speciation and extinction rates. These methods have important caveats and guidelines related to both calculation and interpretation, which are necessary to understand in cases of discrete (qualitative) character analysis, as can be common when studying the evolution of neuromorphology. In such studies, inclusion of additional characters, acknowledgement of character codistribution, and addition of sister clade comparison should be explored to ensure model accuracy. Even so, phylogenies provide a survivor-only examination of character evolution, and paleontological contexts may be necessary to replicate and confirm results. Here, I review these issues in the context of selective brain cooling – a neurovascular-mediated osmoregulatory physiology that dampens hypothalamic responses to heat stress and reduces evaporative water loss in large-bodied mammals. This binary character provides an example of the interplay between sample size, evenness, and character codistribution. Moreover, it allows for an opportunity to compare phylogenetically constrained results with paleontological data, augmenting survivor-only analyses with observable extinction patterns. This trait- dependent diversification example indicates that selective brain cooling is significantly associated with the generation of modern large-mammal faunas. Importantly, paleontological data validate phylogenetic patterns and demonstrate how suites of characters worked in concert to establish the large-mammal communities of today.
Utility of Horizontal Sections of Scalp Biopsies in Differentiating between Androgenetic Alopecia and Alopecia Areata
Authors: Yadav Deepika , Khandpur Sujay , Ramam M. , Singh Manoj K. , Sharma Vinod K.
Published: August 2018

Background: Androgenetic alopecia (AGA) and alopecia areata (AA) are common causes of alopecia which can sometimes be difficult to differentiate clinically. Horizontal sections of scalp biopsies are used to study non-cicatricial alopecias due to the ability to perform both quantitative and morphometric analysis of hair follicles on them. Methods: It was a prospective, cross-sectional study conducted to assess the utility of horizontal sections to differentiate between the alopecias. Fifty-two cases were included: 20 cases of male AGA, 11 of female AGA and 21 cases of AA. After clinical examination and dermoscopy, a skin biopsy was taken and subjected to transverse sectioning. Histopathological assessment was done by two dermatopathologists blinded to clinical details. Results: Among the quantitative parameters, terminal:vellus hair ratio (3.08 in AGA and 1.83 in AA, p = 0.0091) and anagen:non-anagen hair ratio (9.25 in AGA and 3.56 in AA, p = 0.0021) were significantly lower in AA. In qualitative parameters, peribulbar inflammation was seen in 63% of AA cases (p = 0.0001). Pigment casts were seen in twice the number of AA (57%) than AGA (26%) cases. Broad avascular stelae and focal trichomalacia were seen in 9.5% of AA cases. Conclusion: Besides peribulbar inflammation, we found a lower anagen:non-anagen hair ratio and presence of pigment casts in transverse sections of scalp biopsies favouring AA over AGA.
γ-Acetylcholine Receptor Mediating Dynamic Changes of Resistance to Rocuronium in the Denervated Skeletal Muscle
Authors: Wang Hong , Fu Wei , Chen Lian-hua , Li Shi-tong
Published: August 2018

Background/Aims: Denervation resulted in resistance to non-depolarizing muscle relaxants (NDMRs), the magnitude of which changed after denervation in the skeletal muscle. The aim of this study was to investigate whether changed potencies of rocuronium were due to altered γ-acetylcholine receptor (γ-AChR) expression after skeletal muscle denervation. Methods: Innervated and denervated muscle cells were used in this study. Patch clamp and Western blotting techniques were separately applied to examine IC50 values of rocuronium and γ-AChR protein expression at different times after denervation. Then, using the linear Pearson correlation analysis, the relationship between IC50 values of rocuronium and γ-AChR expression was tested. Results: Compared with the innervated control, both IC50 values of rocuronium and γ-AChR expression significantly increased at Day 4, 7, and 14 after denervation in the skeletal muscle. Furthermore, γ-AChR protein and IC50 values of rocuronium exibited a significant positive correlation (r = 0.7678, p < 0.0001). Conclusion: These above results indicated that dynamic changes of resistance to NDMRs may be due to altered γ-AChR expression after skeletal muscle denervation.
Serum Vitamin D Concentrations and Cognitive Change Over 20 Years: The Atherosclerosis Risk in Communities Neurocognitive Study
Authors: Schneider Andrea L.C. , Zhao Di , Lutsey Pamela L. , Gottesman Rebecca F. , Sharrett A. Richey , Rawlings Andreea M. , Alonso Alvaro , Knopman David , Mosley Thomas H. , Selvin Elizabeth , Michos Erin D.
Published: August 2018

Background/Aims: 25-hydroxyvitamin D (25[OH]D) concentrations have been associated with cognitive decline and incident dementia in elderly populations; however, these relationships are susceptible to reverse causation. Less is known about the association of midlife 25(OH)D with long-term cognitive decline. Methods: This was a prospective cohort study of 13,044 participants (mean age 57 years at baseline) in the Atherosclerosis Risk in Communities Study. 25(OH)D was measured from serum collected at baseline (1990–1992) using liquid chromatography tandem high-sensitivity mass spectrometry. Cognition was assessed using 3 neuropsychological tests at 3 time points, which were combined into a composite cognitive Z-score. Multivariable-adjusted linear mixed-effects models with random intercepts and slopes were used to estimate associations between 25(OH)D and cognitive change over 20 years. Results: Compared to persons with sufficient 25(OH)D (≥30 ng/mL), those with deficient (< 20 ng/mL) and intermediate (20–< 30 ng/mL) 25(OH)D concentrations had similar cognitive decline in composite cognitive Z-scores (deficient versus sufficient: –0.035 [95% CI –0.104 to 0.033] and intermediate versus sufficient: –0.029 [95% CI –0.080 to 0.023]). Conclusions: Lower concentrations of 25(OH)D measured in midlife were not significantly associated with more rapid cognitive decline over a 20-year follow-up period. The results of this prospective study are less susceptible to reverse causation than prior studies.
A pan-NADPH Oxidase Inhibitor Ameliorates Kidney Injury in Type 1 Diabetic Rats
Authors: Dorotea Debra , Kwon Guideock , Lee Jung Hwa , Saunders Erika , Bae Yun Soo , Moon Sung Hwan , Lee Soo Jin , Cha Dae Ryong , Ha Hunjoo
Published: August 2018

Background: NADPH oxidases (Nox) is a major enzyme system contributing to oxidative stress, which plays an important role in the pathogenesis of diabetic kidney disease (DKD). We have shown an elevation of renal Nox1, Nox2, and Nox4 in diabetic mice. APX-115, a pan-Nox inhibitor, attenuated the progression of DKD in mice. As the standard diabetic mice cannot fully mimic human DKD, the present study was aimed to show the dose-dependent effect and to provide a confirmatory evidence of APX-115 in attenuating DKD in diabetic rats. Method: Type 1 diabetes was induced by a single 60 mg/kg intraperitoneal injection of streptozotocin in Sprague-Dawley rats. 0.5, 5, or 30 mg APX-115/kg/day or losartan 1 mg/kg/day were administered orally to diabetic rats for 8 weeks. Results: APX-115 treatment showed an improvement in kidney function and tubular and podocyte ­injury, as well as attenuation of inflammation, fibrosis, and oxidative stress as much as losartan, a comparative drug and mainstay treatment in DKD. Therapeutic effect of APX-115 was exhibited in a dose-dependent manner; a dose of 30 mg/kg displayed a superior efficacy. Conclusion: This finding verified the pre-clinical data of APX-115 in protecting against DKD, which is important to bring APX-115 toward the next stage of drug development.