bluuebunny/crossref_metadata_2025 huggingface dataset:
Transport of Late Pleistocene loess particles by katabatic winds during the lowstands of the English Channel
Authors: Lefort Jean-Pierre , Monnier Jean-Laurent , Danukalova Guzel
Published: July 2019

Studies of the submerged Pleistocene conglomerate cored and dredged in the English Channel show that it resulted from the cementation of stony beaches under a loess blanket. Although the loess cover was later washed out by younger transgressions, the northern limit of the conglomerate corresponds to the original offshore extension of the loess deposits. Compilation of offshore and onshore altitudes of the limits of these deposits shows that loess was deposited by low-level wind fields never thicker than 200 m. Mapping surveys show that the present limits of loess are probably close to their original boundaries. The past proximity of the British Ice Sheet, the accumulation of dusty sediments coating north-facing cliffs of Brittany originating in the outwash of the British–Irish Ice Sheet and in the palaeo-rivers of the English Channel, as well as the southeastward orientation of the palaeo-winds deduced from particle size analysis and heavy minerals distribution, suggest that large volumes of loess were transported by strong katabatic winds blowing from the northern ice-covered regions towards Brittany and Normandy. The existence of katabatic winds is also consistent with the drift of ice rafts that transported Icelandic basalts now grounded in Brittany and possibly with the orientation of
Homo neandertalensis
shelters.
Triassic sand supply to the Slyne Basin, offshore western Ireland – new insights from a multi-proxy provenance approach
Authors: Franklin Jess , Tyrrell Shane , Morton Andrew , Frei Dirk , Mark Chris
Published: July 2019

To assess provenance data and derive basin infill models with a higher level of certainty it is vital to understand how minerals used in sedimentary provenance behave in the sedimentary system. A multi-proxy approach helps ensure rigour in how provenance data are interpreted. U–Pb geochronology of refractory zircon and relatively less stable apatite, and Pb isotopic analysis of labile K-feldspar are employed in this study to reassess the provenance of Triassic sandstones in the Slyne Basin, offshore western Ireland. This approach aims at reducing the potential bias in each method, producing a complementary dataset. U–Pb zircon and apatite geochronology yields Archean–Paleoproterozoic ages, Caledonian ages and previously unrecognized Permo-Triassic ages. Pb isotopic analysis of K-feldspar does not identify the Permo-Triassic as a source. The detection of Permo-Triassic-aged detritus may suggest that volcanism was more widespread than previously recognized. These results support the hypothesis of a Triassic drainage divide between the basins offshore western Ireland and those onshore Britain and in the Irish Sea. Sand supply was dominantly from the north, with significant input from the flanks of the basin, and previously unrecorded sources, such as Permian-aged rocks, playing an important role. The provenance signal is consistent and homogenized throughout the sampled sequence indicating that the drainage system was long-lived.

Supplementary material:
Details of laboratory and sample preparation, data tables and summary pie charts for each sample are available at
https://doi.org/10.6084/m9.figshare.c.4571096
μ-Forcing
Authors: Liu Dayiheng , Xue Yang , He Feng , Chen Yuanyuan , Lv Jiancheng
Published: July 2019

It has been previously observed that training Variational Recurrent Autoencoders (VRAE) for text generation suffers from serious uninformative latent variables problems. The model would collapse into a plain language model that totally ignores the latent variables and can only generate repeating and dull samples. In this article, we explore the reason behind this issue and propose an effective regularizer-based approach to address it. The proposed method directly injects extra constraints on the posteriors of latent variables into the learning process of VRAE, which can flexibly and stably control the tradeoff between the Kullback-Leibler (KL) term and the reconstruction term, making the model learn dense and meaningful latent representations. The experimental results show that the proposed method outperforms several strong baselines and can make the model learn interpretable latent variables and generate diverse meaningful sentences. Furthermore, the proposed method can perform well without using other strategies, such as KL annealing.
Effect of a small-group, active learning, tutorial-based, in-course enrichment program on student performance in medical physiology
Authors: Powell Jacqueline M. , Murray Ian V. J. , Johal Jaspreet , Elks Martha L.
Published: July 2019

Physiology is one of the major foundational sciences for the medical curriculum. This discipline has proven challenging for students to master due to ineffective content acquisition and retention. Preliminary data obtained from a survey completed by “low-performance” students (those maintaining a grade average below the passing mark of 70%) at Morehouse School of Medicine reported that students lacked the ability to adequately recognize and extract important physiological concepts to successfully navigate multiple-choice assessments. It was hypothesized that a specially designed, small-group, active learning, physiology in-course enrichment program would minimize course assessment failure rates by enhancing the ability of low-performance students to effectively identify important course content, successfully perform on multiple-choice assessments, and, thereby, improve overall course performance. Using self-report surveys, study skills and test-taking deficiencies limiting successful comprehension of course material and examination performance were identified. Mini-quiz assessments and assignments in formulating multiple-choice examination questions were given to help students recognize and solidify core concepts and improve test-taking ability. Lastly, self-report surveys evaluated the effectiveness of the enrichment program on overall course performance. Results showed a marked improvement in student confidence levels with regards to approaching multiple-choice assessments, and a significant improvement in grades achieved in the physiology component of the first-year curriculum, as 100% of participants achieved a final passing grade average of ≥70%. It was concluded that students became more proficient in identifying, understanding, and applying core physiological concepts and more successful in mastering multiple-choice questions.
An explorative vs. traditional practical course: how to inspire scientific thinking in medical students
Authors: Eckel Julia , Zavaritskaya Olga , Schüttpelz-Brauns Katrin , Schubert Rudolf
Published: July 2019

Recently, medical students’ scientific thinking skills have been identified as an important issue in medical education. Scientific thinking cannot be imparted in conventional lectures, but rather requires actively involving students. We modified a practical course in physiology. A study was designed to test whether the new course fosters scientific thinking without impairing the transfer of physiological knowledge. The study group consisted of 226 first-year medical students at the Medical Faculty Mannheim of Heidelberg University. Written consent to participate in the study was obtained from all participants. The group was then randomly divided into two groups (traditional vs. modified course). The subject of both courses was a laboratory experiment in skeletal muscle physiology. In the traditional course, the students addressed topics already presented in lectures. In the modified course, students dealt with the same topics as in the traditional course, but the experiment was expanded to include one issue not taught before. When working on this issue, the students were instructed in scientific thinking. All participants filled out a questionnaire with 15 multiple-choice questions addressing the physiological subject matter and four open-ended questions addressing the criteria of scientific methodology. Physiological knowledge in both groups did not differ [ F(1) = 2.08, P = 0.15]. Scores in scientific thinking in the modified course were higher (mean = 4.20, SD = 1.89) than in the traditional course (mean = 2.04, SD = 1.91) with F(1) = 70.69, P < 0.001, η2 = 0.24 (large effect). Our study demonstrates that small adjustments to courses in medical education can promote scientific thinking without impairing knowledge transfer.
A flipped classroom method based on a small private online course in physiology
Authors: Zhang Xiao-Min , Yu Jian-Yun , Yang Yuan , Feng Cui-Ping , Lyu Jing , Xu Shi-Lian
Published: July 2019

A small private online course (SPOC) supports blended learning on a small scale, enabling students to have a more comprehensive and deeper learning experience. It also provides instructors with a flexible and feasible model to better understand the students’ learning needs and to supervise students’ learning behaviors. In this study, we adopted SPOC flipped classroom blended teaching in the physiology course for clinical undergraduate students of Kunming Medical University. Compared with the control group [lecture-based learning (LBL)], the SPOC flipped classroom method significantly increased the scores of students in the preclass test (65.13 ± 12.45 vs. 53.46 ± 8.09, SPOC vs. LBL) and postclass test (80.43 ± 14.29 vs. 69.01 ± 12.81, SPOC vs. LBL), which is induced by students’ increased interest in self-learning. More importantly, the significant difference between the preclass scores of the two groups suggested that the video lecture-based preview is more effective than the textbook-based preview. The study indicated that the SPOC flipped classroom was effective in enhancing the examination scores of students, reflecting an improved learning efficiency and a deeper understanding of the knowledge. In summary, the flipped classroom based on SPOC improves learning outcomes compared with LBL and has a wide application in the learning of basic medical courses.
A Novel Method for Location Privacy Protection in LBS Applications
Authors: Lu Dan , Han Qilong , Zhang Kejia , Zhang Haitao , Gull Bisma
Published: July 2019

Location-based services have become a mainstream in people’s daily lives due to continuous innovations in the field of mobile networking and GPS technologies. Recently they have advanced into a hot topic to which the majority of researchers pay close attention about how to enjoy them while safeguarding the location privacy of mobile users. Existing works involve the injection of random noise that cannot pledge the quality of service. Herein this manuscript, we propose a novel location privacy protection model based on the loss of service quality. This model allows the user to express his/her requirement of service quality by specifying the maximum service quality loss Lmax, which is the user’s tolerance. Lmax can be set to 0. Our comprehensive experimental evaluation using a real-world dataset demonstrates that our modus outdoes other state-of-the-art approaches.
A Cognitive Relay Network Throughput Optimization Algorithm Based on Deep Reinforcement Learning
Authors: Liu Shaojiang , Hu Kejing , Ni Weichuan , Xu Zhiming , Wang Feng , Wan Zhiping
Published: July 2019

In cognitive relay networks, the cognitive user opportunistically accesses the authorized spectrum segment of the primary user and simultaneously serves as the data relay node of the primary user while sharing the spectrum resource of the primary user. This not only improves the utilization efficiency of the network spectrum resources but also improves the throughput of the primary users. However, if the primary user randomly selects the relay node, there is no guarantee for an optimal throughput. Moreover, the system power consumption may increase. In order to improve the throughput of cognitive relay network and optimize system utility, this paper proposes a cognitive relay network throughput optimization algorithm based on deep reinforcement learning. For the system model of cognitive relay networks, the Markov decision process is used to describe the channel transition probability of the system model in the paper. The algorithm proposes a cooperative wireless network cooperative relay strategy, analyzes the system outage probability under different transmission modes, and optimizes the system throughput by minimizing the outage probability. Then, the maximum utility optimization strategy based on deep reinforcement learning is proposed to maximize the system utility revenue by selecting the optimal behavior. The experimental results show that the proposed algorithm has a good effect in improving system throughput and optimizing system energy efficiency.
Suppression of Alzheimer’s Disease-Like Pathology Progression by Mitochondria-Targeted Antioxidant SkQ1: A Transcriptome Profiling Study
Authors: Stefanova Natalia A. , Ershov Nikita I. , Kolosova Nataliya G.
Published: July 2019

Alzheimer’s disease (AD) is the most common type of dementia, with increasing prevalence and no disease-modifying treatment available yet. There is increasing evidence—from interventions targeting mitochondria—that may shed some light on new strategies for the treatment of AD. Previously, using senescence-accelerated OXYS rats that simulate key characteristics of sporadic AD, we have shown that treatment with mitochondria-targeted antioxidant SkQ1 (plastoquinonyl-decyltriphenylphosphonium) from age 12 to 18 months (that is, during active progression of AD-like pathology)—via improvement of mitochondrial function—prevented the neuronal loss and synaptic damage, enhanced neurotrophic supply, and decreased amyloid-β1–42 protein levels and tau hyperphosphorylation in the hippocampus. In the present study, we continued to explore the mechanisms of the anti-AD effects of SkQ1 in an OXYS rat model through deep RNA sequencing (RNA-seq) and focused upon the cell-specific gene expression alterations in the hippocampus. According to RNA-seq results, OXYS rats had 1,159 differentially expressed genes (DEGs) relative to Wistar rats (control), and 6-month treatment with SkQ1 decreased their number twofold. We found that 10.5% of all DEGs in untreated (control) OXYS rats were associated with mitochondrial function, whereas SkQ1 eliminated differences in the expression of 76% of DEGs (93 from 122 genes). Using transcriptome approaches, we found that the anti-AD effects of SkQ1 are associated with an improvement of the activity of many signaling pathways and intracellular processes. SkQ1 changed the expression of genes in neuronal, glial, and endothelial cells, and these genes are related to mitochondrial function, neurotrophic and synaptic activity, calcium processes, immune and cerebrovascular systems, catabolism, degradation, and apoptosis. Thus, RNA-seq analysis yields a detailed picture of transcriptional changes during the development of AD-like pathology and can point to the molecular and genetic mechanisms of action of the agents (including SkQ1) holding promise for the prevention and treatment of AD.
Upper Gastrointestinal Manifestation of Bezoars and the Etiological Factors: A Literature Review
Authors: Khan Samiullah , Jiang Kui , Zhu Lan-ping , Khan Iftikhar-ahmad , Ullah Kifayat , Khan Saima , Chen Xin , Wang Bang-mao
Published: July 2019

A gastric bezoar is a compact mass of indigestible foreign materials that accumulate and consolidate in the stomach; however, it can be found in other sites of the gastrointestinal tract. The causative manner of this condition is complex and multifactorial. The main purpose of the review was to raise awareness among clinicians, particularly gastroenterologists, that patients with certain risk factors or comorbid conditions are predisposed to gastric bezoar formation. Early diagnosis and prompt intervention are crucial to avoid bezoar-induced complications. Upper gastrointestinal endoscopy is the standard diagnostic and therapeutic method for gastric bezoars. However, for large size bezoars, surgical intervention is needed.
Monocytes as an Early Predictor for Patients with Acute Paraquat Poisoning: A Retrospective Analysis
Authors: Zhao Yong , Song Ya Qi , Gao Jie , Feng Shun Yi , Li Yong
Published: July 2019

Background. The predictive values of monocytes in the prognosis of patients with acute paraquat (PQ) poisoning are unclear. This retrospective study investigated the predictive values of monocytes in the prognosis of patients with acute PQ poisoning. Methods. Adult patients who suffered from acute PQ poisoning in the emergency care unit of Cangzhou Central Hospital from May 2012 to December 2018 were enrolled. The patients were divided into groups, namely, survival and nonsurvival, according to a 90-day prognosis. Moreover, correlation, logistic regression, receiver-operator characteristic (ROC), and Kaplan–Meier curve analyses were applied to evaluate the monocyte values used to predict the prognosis of patients with acute PQ poisoning. Result. Among the 109 patients, 45 survived within 90 days after the poisoning, resulting in a 41.28% survival rate. The monocyte count of the nonsurvivors was significantly higher than that of the survivors (P< 0.001). Correlation analysis showed that monocyte count positively correlated with plasma PQ concentration (r= 0.413; P< 0.001) and negatively correlated with survival time (r= 0.512; P< 0.001) and 90-day survival (r= 0.503; P< 0.001). Logistic regression analysis showed that elevated monocytes were the independent risk factors for the 90-day survival. The area under the ROC curve of the monocyte count used to predict the 90-day survival was 0.826 (95% CI: 0.751–0.904), the optimal cut-off was 0.51×109/L, sensitivity was 73.4%, and specificity was 86.7%. Conclusion. This study demonstrated that elevated monocyte count is a useful early predictor of 90-day survival in patients with acute PQ poisoning. However, further studies are warranted to draw firm conclusions.
Hydrogeochemistry, Geothermometry, and Genesis of the Hot Springs in the Simao Basin in Southwestern China
Authors: Zhang Yuqi , Zhou Xun , Liu Haisheng , Yu Mingxiao , Hai Kuo , Tan Mengru , Huo Dongxue
Published: July 2019

In the Simao Basin in southwest China widely occur red beds of poor permeability. Nevertheless, more than 100 springs exist in the basin, some of which are hot springs with varying temperature. Hot springs contain abundant information on hydrogeochemical processes and groundwater circulation. In this study, hydrochemical and isotopic analyses and mixed models are used to examine the sources of recharge, heat, and solutes of the hot springs to better understand the subsurface processes and formation mechanisms of different hot springs in the basin. Three types of springs are found in the Simao Basin: springs of HCO3-Na type occur in the metamorphic rocks, springs of HCO3-Ca(Mg) and Cl-HCO3-Na-Ca types in the carbonate rocks, and springs of Cl(SO4)-SO4(Cl)-HCO3-Na(Ca) type in the red beds. Data of δ2H and δ18O indicate that the hot springs in the Simao Basin are meteoric in origin. Incongruent dissolution is the dominant process affecting the chemical compositions of the spring waters. The hydrochemical constituents of the hot springs in the metamorphic rocks, carbonate rocks, and red beds are influenced by the weathering of albite and the dissolution of carbonate, gypsum, anhydrite, and halite. The geothermal waters are mixed with shallow cold waters in their ascending processes, and the mixing ratios of cold water range from 58% to 94%. Due to the effect of mixing, the reservoir temperatures (51°C-127°C) calculated with the quartz geothermometer are regarded as the minimum reservoir temperatures. More reliable reservoir temperatures (91°C-132°C) are estimated with the fixed-Al method. The following mechanisms contribute to the formation of hot springs in the Simao Basin: the groundwater receives recharge from infiltration of precipitation and undergoes deep circulation, during which groundwater is heated by heat flow and incongruently dissolves the subsurface minerals and emerges in the form of hot springs along the permeable fracture or fault zones.
EA at PC6 Promotes Gastric Motility: Role of Brainstem Vagovagal Neurocircuits
Authors: Lu Mengjiang , Chen Chienchih , Li Wen , Yu Zhi , Xu Bin
Published: July 2019

Background. We aimed to assess whether electroacupuncture (EA) at PC6 affects gastric motility via the vagovagal reflex and if so whether brainstem vagovagal neurocircuits and related transmitters are involved. Methods. Gastric motility was measured in male Sprague-Dawley (SD) rats by placing a small manometric balloon in the gastric antrum. The rats were subjected to control, sham surgery, vagotomy, sympathectomy, and microinjection group, including artificial cerebrospinal fluid, gamma-aminobutyric acid (GABA), and glutamic acid (L-Glu). The effect of EA at PC6 on gastric motility was measured. Moreover, electrophysiological testing was used to measure the effect of EA at PC6 on the parasympathetic and sympathetic nerves. In addition, artificial cerebrospinal fluid, L-Glu, and GABA have been microinjected into the dorsal motor nucleus of the vagus (DMV) to measure the changes in gastric motility and parasympathetic nerve discharge induced by EA at PC6. Key Results. EA facilitated the gastric motility in control group. In the vagotomy group, gastric motility was not affected by EA at PC6. However, in the sympathectomy group, gastric motility was similar to control group. Acupuncture at PC6 increased parasympathetic nerve discharge but not sympathetic nerve discharge. Furthermore, the microinjection of L-Glu into the DMV increased gastric motility, although EA at PC6 showed no remarkable change in this group. The injection of GABA reduced gastric motility and parasympathetic nerve discharge, but EA at PC6 significantly increased gastric motility and the parasympathetic nerve discharge in this group. Conclusions and Inferences. EA at PC6—primarily by inhibiting GABA transmission to DMV—reduced the inhibition of efferent vagal motor fibers and thus promoted efferent vagus nerve activity and increased gastric motility.
Method to Calculate Working Surface Abutment Pressure Based on Key Strata Theory
Authors: Han Hongkai , Xu Jialin , Wang Xiaozhen , Xie Jianlin , Xing Yantuan
Published: July 2019

Overburden key strata (KS) have a significant influence on abutment pressure distribution. However, current calculation methods for working surface abutment pressure do not consider the influence of the overburden KS. This study uses KS theory to analyze the overburden load transferred to coal‐rock masses on both sides of the stope through fractured blocks in different layers of the KS in the fissure zone and KS in different layers of the curve subsidence zone. Using Winkler’s elastic foundation beam theory, we consider the fissure zone KS on the coal mass side and the curve subsidence zone KS as many elastic foundation beams interact with each other. A method to calculate the abutment pressure of the coal mass and the goaf was then established, considering the influence of the overburden KS. The abutment pressure distribution of working surface 207 after mining was then calculated using our method, based on mining conditions present in the Tingnan coal mine. The calculated results were verified using measurements from borehole stress meters and microseismic monitoring systems, as well as numerical simulations. In addition, the calculation results were used to determine a reasonable position for the stopping line and remaining width of the roadway’s protection coal pillar in working surface 207. The results of this study can be used to calculate the abutment pressure distribution of the working surface under a variety of overburden KS conditions. The results can also provide guidance for forecasting and preventing mine dynamic hazards, controlling the surrounding rock in mining roadways, determining reasonable widths for protection coal pillars, and designing the layout of mining roadways.
Accuracy of Curable Sexually Transmitted Infections and Genital Mycoplasmas Screening by Multiplex Real-Time PCR Using a Self-Collected Veil among Adult Women in Sub-Saharan Africa
Authors: Nodjikouambaye Zita Aleyo , Compain Fabrice , Sadjoli Damtheou , Mboumba Bouassa Ralph-Sydney , Péré Hélène , Veyer David , Robin Leman , Adawaye Chatté , Tonen-Wolyec Serge , Moussa Ali Mahamat , Koyalta Donato , Belec Laurent
Published: July 2019

Background. Sexually transmitted infections (STIs) are highly prevalent in sub-Saharan Africa. Genital self-sampling may facilitate the screening of STIs in hard-to-reach remote populations far from large health care centers and may increase screening rates. The cross-sectionalGYNAUTO-STIstudy was carried out to assess the performance of a novel genital veil (V-Veil-Up Gyn Collection Device, V-Veil-Up Pharma, Ltd., Nicosia, Cyprus) as a genital self-sampling device to collect genital secretions to diagnose STIs by molecular biology as compared to reference clinician-collected genital specimens, in adult African women.Methods. Adult women living in N’Djamena, the capital city of Chad, were recruited from the community and referred to the clinic for women’s sexual health “La Renaissance Plus”. A clinician obtained an endocervical specimen using flocked swab. Genital secretions were also obtained by self-collection using veil. Both clinician- and self-collected specimens were tested for common curable STIs (includingChlamydia trachomatis,Neisseria gonorrhoeae,Mycoplasma genitalium, andTrichomonas vaginalis) and genitalMycoplasmaspp. by multiplex real-time PCR (Allplex™ STI Essential Assay, Seegene, Seoul, South Korea). Test positivities for both collection methods were compared by assessing methods agreement, sensitivity, and specificity.Results. A total of 251 women (mean age, 35.1 years) were prospectively enrolled. Only seven (2.8%) women were found to be infected with at least one common STIs [C. trachomatis: 3 (1.2%),N. gonorrhoeae: 1 (0.4%),M. genitalium: 4 (1.6%) andT. vaginalis: 1 (0.4%)], while the prevalence of genital mycoplasmas was much higher (54.2%) with a predominance ofUreaplasma parvum(42.6%). Self-collection by veil was non-inferior to clinician-based collection for genital microorganisms DNA molecular testing, with “almost perfect” agreement between both methods, high sensitivity (97.0%; 95%CI: 92.5-99.2%), and specificity (88.0%; 95%CI: 80.7-93.3%). Remarkably, the mean total number of genital microorganisms detected per woman was 1.14-fold higher in self-collected specimens compared to that in clinician-collected specimens.Conclusions. Veil-based self-collection of female genital secretions constitutes a convenient tool to collect in gentle way cervicovaginal secretions for accurate molecular detection of genital bacteria. Such sampling procedure could be easily implemented in STIs clinics in sub-Saharan Africa.
The Advanced Algorithmic Method for Navigation System Correction of Spacecraft
Authors: Chen Danhe , Neusypin K. A. , Zhang Xiang , Wang Chuangge
Published: July 2019

In this paper an advanced method for the navigation system correction of a spacecraft using an error prediction model of the system is proposed. Measuring complexes have been applied to determine the parameters of a spacecraft and the processing of signals from multiple measurement systems is carried out. Under the condition of interference in flight, when the signals of external system (such as GPS) disappear, the correction of navigation system in autonomous mode is considered to be performed using an error prediction model. A modified Volterra neural network based on the self‐organization algorithm is proposed in order to build the prediction model, and the modification of algorithm indicates speeding up the neural network. Also, three approaches for accelerating the neural network have been developed; two examples of the sequential and parallel implementation speed of the system are presented by using the improved algorithm. In addition, simulation for a returning spacecraft to atmosphere is performed to verify the effectiveness of the proposed algorithm for correction of navigation system.
Fundamentals, Recent Advances, and Future Challenges in Bioimpedance Devices for Healthcare Applications
Authors: Naranjo-Hernández David , Reina-Tosina Javier , Min Mart
Published: July 2019

This work develops a thorough review of bioimpedance systems for healthcare applications. The basis and fundamentals of bioimpedance measurements are described covering issues ranging from the hardware diagrams to the configurations and designs of the electrodes and from the mathematical models that describe the frequency behavior of the bioimpedance to the sources of noise and artifacts. Bioimpedance applications such as body composition assessment, impedance cardiography (ICG), transthoracic impedance pneumography, electrical impedance tomography (EIT), and skin conductance are described and analyzed. A breakdown of recent advances and future challenges of bioimpedance is also performed, addressing topics such as transducers for biosensors and Lab-on-Chip technology, measurements in implantable systems, characterization of new parameters and substances, and novel bioimpedance applications.
Keratinocyte Growth Factor-2 Is Protective in Oleic Acid-Induced Acute Lung Injury in Rats
Authors: Tenghao S. , Shenmao M. , Zhaojun W. , Jijia B. , Wenjie Z. , Wenyan Z. , Xigang M.
Published: July 2019

Objective. The aim of this study was to examine the role of keratinocyte growth factor-2 (KGF-2) in oleic acid-induced acute lung injury (ALI) in rats. Methods. Forty-five healthy adult male Sprague Dawley rats were divided into 3 groups. Rat ALI model was established by injection of 0.01 mL/kg oleic acid into the tail vein. Rats in the control group were injected with the same amount of normal saline (NS). In the ALI + KGF-2 group, 5 mg/kg of KGF-2 was instilled into the airway of rats 72 hours before the model preparation, and the control group and the ALI model group were instilled with the same amount of NS. The lung permeability index (LPI) and lung wet/dry weight (W / D) ratios were measured 8 hours after the model preparation. The permeability of pulmonary microvascular endothelium was evaluated by Evans blue leakage test. Histopathological changes were observed under light microscope and the ALI pathology score (LIS) was calculated. Ultrastructural changes of lung tissue were observed under electron microscope. The apoptosis was detected by TUNEL assay. The expression of Claudin-5, ZO-1, and VE Cadherin in lung tissue was qualitatively and quantitatively analyzed by immunohistochemistry, Western Blot, and qRT-PCR, respectively. Results. The ALI model group had severe lung injury and obvious pathological changes, including alveolar septal thickening and inflammatory cell infiltration. TUNEL assay showed that the apoptosis of ALI group was significantly increased. The LIS score, lung W/D ratio, LPI, and Evans blue leakage were significantly higher than those in the control group; electron microscopy showed that the alveolar-capillary barrier was severely damaged in the ALI group. Compared with the control group, the expression of Claudin-5, ZO-1, and VE cadherin in the lung tissue of the ALI model group was significantly attenuated. After pretreatment with KGF-2, the degree of lung tissue damage was significantly reduced and the pathological changes were significantly improved. TUNEL assay showed that the apoptosis of ALI group was decreased. Lung W/D ratio, LPI, and Evans blue leakage decreased; electron microscopy showed that the alveolar-capillary barrier of ALI group recovered significantly. Compared with the ALI model group, the expression of Claudin-5, ZO-1, and VE cadherin in the lung tissue of the KGF-2 pretreatment group increased. Conclusion. The results indicate that KGF-2 may attenuate oleic acid-induced ALI in rats by maintaining the pulmonary microvascular endothelial barrier, which is an effective ALI preventive measure.
ID-Based Strong Designated Verifier Signature over R-SIS Assumption
Authors: Cai Jie , Jiang Han , Zhang Pingyuan , Zheng Zhihua , Wang Hao , Lü Guangshi , Xu Qiuliang
Published: July 2019

In this paper, we propose an ID-based strong designated verifier signature (SDVS) over R-SIS assumption in the random model. We remove pre-image sampling function and Bonsai trees such complex structures used in previous lattice-based SDVS schemes. We only utilize simple rejection sampling to protect the security of our scheme. Hence, we will show our design has the shortest signature size comparing with existing lattice-based ID-based SDVS schemes. In addition, our scheme satisfies anonymity (privacy of signer’s identity) proved in existing schemes rarely, and it can resist side-channel attacks with uniform sampling.
SET Domain–Containing Protein 4 Epigenetically Controls Breast Cancer Stem Cell Quiescence
Authors: Ye Sen , Ding Yan-Fu , Jia Wen-Huan , Liu Xiao-Li , Feng Jing-Yi , Zhu Qian , Cai Sun-Li , Yang Yao-Shun , Lu Qian-Yun , Huang Xue-Ting , Yang Jin-Shu , Jia Sheng-Nan , Ding Guo-Ping , Wang Yue-Hong , Zhou Jiao-Jiao , Chen Yi-Ding , Yang Wei-Jun
Published: July 2019

Quiescent cancer stem cells (CSC) play important roles in tumorigenesis, relapse, and resistance to chemoradiotherapy. However, the determinants of CSC quiescence and how they sustain themselves to generate tumors and relapse beyond resistance to chemoradiotherapy remains unclear. Here, we found that SET domain–containing protein 4 (SETD4) epigenetically controls breast CSC (BCSC) quiescence by facilitating heterochromatin formation via H4K20me3 catalysis. H4K20me3 localized to the promoter regions and regulated the expression of a set of genes in quiescent BCSCs (qBCSC). SETD4-defined qBCSCs were resistant to chemoradiotherapy and promoted tumor relapse in a mouse model. Upon activation, a SETD4-defined qBCSC sustained itself in a quiescent state by asymmetric division and concurrently produced an active daughter cell that proliferated to produce a cancer cell population. Single-cell sequence analysis indicated that SETD4+ qBCSCs clustered together as a distinct cell type within the heterogeneous BCSC population. SETD4-defined quiescent CSCs were present in multiple cancer types including gastric, cervical, ovarian, liver, and lung cancers and were resistant to chemotherapy. SETD4-defined qBCSCs had a high tumorigenesis potential and correlated with malignancy and chemotherapy resistance in clinical breast cancer patients. Taken together, the results from our previous study and current study on six cancer types reveal an evolutionarily conserved mechanism of cellular quiescence epigenetically controlled by SETD4. Our findings provide insights into the mechanism of tumorigenesis and relapse promoted by SETD4-defined quiescent CSCs and have broad implications for clinical therapies.

Significance:

These findings advance our knowledge on the epigenetic determinants of quiescence in cancer stem cell populations and pave the way for future pharmacologic developments aimed at targeting drug-resistant quiescent stem cells.
COTI-2, A Novel Thiosemicarbazone Derivative, Exhibits Antitumor Activity in HNSCC through p53-dependent and -independent Mechanisms
Authors: Lindemann Antje , Patel Ameeta A. , Silver Natalie L. , Tang Lin , Liu Zhiyi , Wang Li , Tanaka Noriaki , Rao Xiayu , Takahashi Hideaki , Maduka Nakachi K. , Zhao Mei , Chen Tseng-Cheng , Liu WeiWei , Gao Meng , Wang Jing , Frank Steven J. , Hittelman Walter N. , Mills Gordon B. , Myers Jeffrey N. , Osman Abdullah A.
Published: July 2019

Purpose:

TP53 mutations are highly prevalent in head and neck squamous cell carcinoma (HNSCC) and associated with increased resistance to conventional treatment primarily consisting of chemotherapy and radiation. Restoration of wild-type p53 function in TP53-mutant cancer cells represents an attractive therapeutic approach and has been explored in recent years. In this study, the efficacy of a putative p53 reactivator called COTI-2 was evaluated in HNSCC cell lines with different TP53 status.

Experimental Design: Clonogenic survival assays and an orthotopic mouse model of oral cancer were used to examine in vitro and in vivo sensitivity of HNSCC cell lines with either wild-type, null, or mutant TP53 to COTI-2 alone, and in combination with cisplatin and/or radiation. Western blotting, cell cycle, live-cell imaging, RNA sequencing, reverse-phase protein array, chromatin immunoprecipitation, and apoptosis analyses were performed to dissect molecular mechanisms.

Results:

COTI-2 decreased clonogenic survival of HNSCC cells and potentiated response to cisplatin and/or radiation in vitro and in vivo irrespective of TP53 status. Mechanistically, COTI-2 normalized wild-type p53 target gene expression and restored DNA-binding properties to the p53-mutant protein in HNSCC. In addition, COTI-2 induced DNA damage and replication stress responses leading to apoptosis and/or senescence. Furthermore, COTI-2 lead to activation of AMPK and inhibition of the mTOR pathways in vitro in HNSCC cells.

Conclusions:

COTI-2 inhibits tumor growth in vitro and in vivo in HNSCC likely through p53-dependent and p53-independent mechanisms. Combination of COTI-2 with cisplatin or radiation may be highly relevant in treating patients with HNSCC harboring TP53 mutations.
Targeting MUC1-C Inhibits TWIST1 Signaling in Triple-Negative Breast Cancer
Authors: Hata Tsuyoshi , Rajabi Hasan , Yamamoto Masaaki , Jin Caining , Ahmad Rehan , Zhang Yan , Kui Ling , Li Wei , Yasumizu Yota , Hong Deli , Miyo Masaaki , Hiraki Masayuki , Maeda Takahiro , Suzuki Yozo , Takahashi Hidekazu , Samur Mehmet , Kufe Donald
Published: July 2019

The oncogenic MUC1-C protein and the TWIST1 epithelial–mesenchymal transition transcription factor (EMT-TF) are aberrantly expressed in triple-negative breast cancer (TNBC) cells. However, there is no known association between MUC1-C and TWIST1 in TNBC or other cancer cells. Here, we show that MUC1-C activates STAT3, and that MUC1-C and pSTAT3 drive induction of the TWIST1 gene. In turn, MUC1-C binds directly to TWIST1, and MUC1-C/TWIST1 complexes activate MUC1-C expression in an autoinductive circuit. The functional significance of the MUC1-C/TWIST1 circuit is supported by the demonstration that this pathway is sufficient for driving (i) the EMT-TFs, ZEB1 and SNAIL, (ii) multiple genes in the EMT program as determined by RNA-seq, and (iii) the capacity for cell invasion. We also demonstrate that the MUC1-C/TWIST1 circuit drives (i) expression of the stem cell markers SOX2, BMI1, ALDH1, and CD44, (ii) self-renewal capacity, and (iii) tumorigenicity. In concert with these results, we show that MUC1-C and TWIST1 also drive EMT and stemness in association with acquired paclitaxel (PTX) resistance. Of potential therapeutic importance, targeting MUC1-C and thereby TWIST1 reverses the PTX refractory phenotype as evidenced by synergistic activity with PTX against drug-resistant cells. These findings uncover a master role for MUC1-C in driving the induction of TWIST1, EMT, stemness, and drug resistance, and support MUC1-C as a highly attractive target for inhibiting TNBC plasticity and progression.
A Randomized Phase II Trial of Pioglitazone for Lung Cancer Chemoprevention in High-Risk Current and Former Smokers
Authors: Keith Robert L. , Blatchford Patrick J. , Merrick Daniel T. , Bunn Paul A. , Bagwell Brandi , Dwyer-Nield Lori D. , Jackson Mary K. , Geraci Mark W. , Miller York E.
Published: July 2019

Lung cancer chemoprevention, especially in high-risk former smokers, has great potential to reduce lung cancer incidence and mortality. Thiazolidinediones prevent lung cancer in preclinical studies, and diabetics receiving thiazolidinediones have lower lung cancer rates which led to our double-blind, randomized, phase II placebo-controlled trial of oral pioglitazone in high-risk current or former smokers with sputum cytologic atypia or known endobronchial dysplasia. Bronchoscopy was performed at study entry and after completing 6 months of treatment. Biopsies were histologically scored, and primary endpoint analysis tested worst biopsy scores (Max) between groups; Dysplasia index (DI) and average score (Avg) changes were secondary endpoints. Biopsies also received an inflammation score. The trial accrued 92 subjects (47 pioglitazone, 45 placebo), and 76 completed both bronchoscopies (39 pioglitazone, 37 placebo). Baseline dysplasia was significantly worse for current smokers, and 64% of subjects had mild or greater dysplasia at study entry. Subjects receiving pioglitazone did not exhibit improvement in bronchial dysplasia. Former smokers treated with pioglitazone exhibited a slight improvement in Max, while current smokers exhibited slight worsening. While statistically significant changes in Avg and DI were not observed in the treatment group, former smokers exhibited a slight decrease in both Avg and DI. Negligible Avg and DI changes occurred in current smokers. A trend toward decreased Ki-67 labeling index occurred in former smokers with baseline dysplasia receiving pioglitazone. While pioglitazone did not improve endobronchial histology in this high-risk cohort, specific lesions showed histologic improvement, and further study is needed to better characterize responsive dysplasia.
Deep Learning Algorithms for Corneal Amyloid Deposition Quantitation in Familial Amyloidosis
Authors: Kessel Klaus , Mattila Jaakko , Linder Nina , Kivelä Tero , Lundin Johan
Published: July 2019

Objectives: The aim of this study was to train and validate deep learning algorithms to quantitate relative amyloid deposition (RAD; mean amyloid deposited area per stromal area) in corneal sections from patients with familial amyloidosis, Finnish (FAF), and assess its relationship with visual acuity. Methods: Corneal specimens were obtained from 42 patients undergoing penetrating keratoplasty, stained with Congo red, and digitally scanned. Areas of amyloid deposits and areas of stromal tissue were labeled on a pixel level for training and validation. The algorithms were used to quantify RAD in each cornea, and the association of RAD with visual acuity was assessed. Results: In the validation of the amyloid area classification, sensitivity was 86%, specificity 92%, and F-score 81. For corneal stromal area classification, sensitivity was 74%, specificity 82%, and F-score 73. There was insufficient evidence to demonstrate correlation (Spearman’s rank correlation, –0.264, p = 0.091) between RAD and visual acuity (logMAR). Conclusions: Deep learning algorithms can achieve a high sensitivity and specificity in pixel-level classification of amyloid and corneal stromal area. Further modeling and development of algorithms to assess earlier stages of deposition from clinical images is necessary to better assess the correlation between amyloid deposition and visual acuity. The method might be applied to corneal dystrophies as well.
The Cholinergic Anti-Inflammatory Pathway as a Conceptual Framework to Treat Inflammation-Mediated Renal Injury
Authors: Jarczyk Jonas , Yard Benito A. , Hoeger Simone
Published: July 2019

Background: The cholinergic anti-inflammatory pathway, positioned at the interface of the nervous and immune systems, is the efferent limb of the “inflammatory reflex” which mainly signals through the vagus nerve. As such, the brain can modulate peripheral inflammatory responses by the activation of vagal efferent fibers. Importantly, immune cells in the spleen express most cholinergic system components such as acetylcholine (ACh), choline acetyltransferase, acetylcholinesterase, and both muscarinic and nicotinic ACh receptors, making communication between both systems possible. In general, this communication down-regulates the inflammation, achieved through different mechanisms and depending on the cells involved. Summary: With the awareness that the cholinergic anti-inflammatory pathway serves to prevent or limit inflammation in peripheral organs, vagus nerve stimulation has become a promising strategy in the treatment of several inflammatory conditions. Both pharmacological and non-pharmacological methods have been used in many studies to limit organ injury as a consequence of inflammation. Key Messages: In this review, we will highlight our current knowledge of the cholinergic anti-inflammatory pathway, with emphasis on its potential clinical use in the treatment of inflammation-triggered kidney injury.
Validity and Utility of the Center for Epidemiological Studies Depression Scale for Detecting Depression in Family Caregivers of Persons with Dementia
Authors: Ying Jiangbo , Yap Philip , Gandhi Mihir , Liew Tau Ming
Published: July 2019

Background/Aims: The psychometric properties of Center for Epidemiological Studies Depression Scale (CES-D) have never been substantively investigated in caregivers of persons with dementia (PwD). We evaluated the validity and reliability of CES-D for detecting caregiver depression in dementia, and assessed whether CES-D could provide added utility beyond Zarit Burden Interview (ZBI). Method: Family caregivers of community-dwelling PwD (n = 394) completed self-administered questionnaires containing CES-D. Factorial validity was evaluated with confirmatory factor analysis; convergent and discriminant validity with Pearson’s correlation coefficient; known-group validity by comparing across key variables; and internal consistency reliability with Cronbach’s α. Cohen’s κ was used to compare the agreement between those with depression (CES-D ≥16) and those with high caregiver burden (ZBI >60). Results: CES-D demonstrated convergent, discriminant and known-group validity, consistent with a priori hypotheses. The original four-factor model of CES-D produced the best model-fit indices. Internal consistency reliability was good for the CES-D total scale (α = 0.92), but lower for the Positive affect and Interpersonal problems subscales (α = 0.70–0.74). Forty-five percent of the caregivers had depression as identified by CES-D (95% CI 40–50%), but most of them were not identified by high ZBI scores (κ = 0.16). Conclusions: CES-D is a valid and reliable scale for detecting caregiver depression in dementia. It has added utility, beyond that of a caregiver burden scale, in identifying a subgroup of caregivers with depression but not burden. However, two subscales (Positive affect and Interpersonal problems) may require caution in interpretation among non-Caucasian caregivers.
HIV-1 Integrase Resistance among Highly Antiretroviral Experienced Patients from Morocco
Authors: Alaoui Najwa , El Alaoui Moulay Abdelaziz , El Annaz Hicham , Farissi Fatima Zahra , Alaoui Amine Sanaâ , El Fahime Elmostapha , Mrani Saad 
Published: July 2019

Background: We aimed to analyze for the first time in Morocco the integrase (IN) sequence variability among highly experienced HIV-1-infected patients with no prior IN strand transfer inhibitor (INSTI) exposure who failed on reverse transcriptase inhibitors and protease inhibitors. Methods: The HIV-1 IN region was sequenced from plasma samples of all 78 recruited patients. The amino acid IN sequences were HIV-1 subtyped and screened for the presence of polymorphisms against the HxB2 clade B consensus sequence by the geno2pheno subtyping tool and interpreted for drug resistance according to the Stanford algorithm. Results: The viral subtypes were subtype B (88.4%), CRF02_AG (8.9%), CRF01_AE (1.28%), and subtype C (1.28%). The major INSTI resistance mutations at positions 66, 92, 118, 138, 140, 143, 147, 148, 155, and 263 were absent, while two accessory mutations, L74M/I, known to have no clinical impact to INSTIs in the absence of the major resistance mutations, were detected in three samples (3.84%; two CRF02_AG and one CRF01_AE). Others specific substitutions with an uncertain role on the HIV-1 susceptibility to INSTIs at positions 72, 101, 119, 124, 156, 165, 193, 201, 203, 206, 230, 232, and 249 were found to be relatively common. Conclusion: This study demonstrated that INSTIs should be an excellent alternative for salvage therapy in highly experienced patients with multidrug resistant viruses in Morocco.