bluuebunny/crossref_metadata_2025 huggingface dataset:
Uncertainty of CERES-Maize Calibration under Different Irrigation Strategies Using PEST Optimization Algorithm
Authors: Fang Quanxiao , Ma L. , Harmel R. D. , Yu Q. , Sima M. W. , Bartling P. N. S. , Malone R. W. , Nolan B. T. , Doherty J.
Published: May 2019

An important but rarely studied aspect of crop modeling is the uncertainty associated with model calibration and its effect on model prediction. Biomass and grain yield data from a four-year maize experiment (2008–2011) with six irrigation treatments were divided into subsets by either treatments (Calibration-by-Treatment) or years (Calibration-by-Year). These subsets were then used to calibrate crop cultivar parameters in CERES (Crop Environment Resource Synthesis)-Maize implemented within RZWQM2 (Root Zone Water Quality Model 2) using the automatic Parameter ESTimation (PEST) algorithm to explore model calibration uncertainties. After calibration for each subset, PEST also generated 300 cultivar parameter sets by assuming a normal distribution of each parameter within their reported values in the literature, using the Latin hypercube sampling (LHS) method. The parameter sets that produced similar goodness of fit (11–164 depending on subset used for calibration) were then used to predict all the treatments and years of the entire dataset. Our results showed that the selection of calibration datasets greatly affected the calibrated crop parameters and their uncertainty, as well as prediction uncertainty of grain yield and biomass. The high variability in model prediction of grain yield and biomass among the six (Calibration-by-Treatment) or the four (Calibration-by-Year) scenarios indicated that parameter uncertainty should be considered in calibrating CERES-Maize with grain yield and biomass data from different irrigation treatments, and model predictions should be provided with confidence intervals.
Hybrid Grating in Reduced-Diameter Fiber for Temperature-Calibrated High-Sensitivity Refractive Index Sensing
Authors: Jiang Biqiang , Hao Zhen , Feng Dingyi , Zhou Kaiming , Zhang Lin , Zhao Jianlin
Published: May 2019

We propose and experimentally demonstrate a hybrid grating, in which an excessively tilted fiber grating (Ex-TFG) and a fiber Bragg grating (FBG) were co-inscribed in a reduced-diameter fiber (RDF). The hybrid grating showed strong resonances due to coupling among core mode and a set of polarization-dependent cladding modes. This coupling showed enhanced evanescent fields by the reduced cladding size, thus allowing stronger interaction with the surrounding medium. Moreover, the FBG’s Bragg resonance confined by the thick cladding was exempt from the change of the surrounding medium’s refractive index (RI), and then the FBG can work as a temperature compensator. As a result, the Ex-TFG in RDF promised a highly sensitive RI measurement, with a sensitivity up to ~1224 nm/RIU near the RI of 1.38. Through simultaneous measurement of temperature and RI, the temperature dependence of water’s RI is then determined. Therefore, the proposed hybrid grating with a spectrum of multi-peaks embedded with a sharp Bragg resonance is a promising alternative for the simultaneous measurement of multi-parameters for many RI-based sensing applications.
Risk-Constrained Optimal Chiller Loading Strategy Using Information Gap Decision Theory
Authors: Shi Er , Jabari Farkhondeh , Anvari-Moghaddam Amjad , Mohammadpourfard Mousa , Mohammadi-ivatloo Behnam
Published: May 2019

This paper presents a novel framework for economic cooling load dispatch in conventional water-cooled chillers. Moreover, information gap decision theory (IGDT) is applied to the optimal chiller loading (OCL) problem to find the optimum operating point of the test system in three decision-making modes: (a) risk-neutral approach, (b) risk-aversion or robustness approach, and (c) risk-taker or opportunistic approach. In the robustness mode of the IGDT-based OCL problem, the system operator enters a desired energy cost value in order to find the most appropriate loading points for the chillers so that the total electricity procurement cost over the study horizon is smaller than or equal to this critical value. Meanwhile, the cooling load increase is maximized to the highest possible level to find the most robust performance of the benchmark grid with respect to the overestimated load. Similarly, the risk-taker optimization method finds the on/off status and the partial load ratio (PLR) of the chillers in order to keep the total energy cost as low as the given cost function. In addition, the minimum value of cooling load decrease can be found while satisfying the refrigeration capacity of the chiller and the load-generation balance constraint. Thus, a mixed-integer non-linear programming problem is solved using the branch and reduce optimization (BARON) tool of the generalized algebraic mathematical modeling system (GAMS) for a five-chiller plant, to demonstrate that IGDT is able to find a good solution in robustness/risk-taker OCL problem.
From Nanostructural Characterization of Nanoparticles to Performance Assessment of Low Clinker Fiber–Cement Nanohybrids
Authors: Papatzani Styliani , Paine Kevin
Published: May 2019

With the current paper three nano-Montmorillonites (nMt) are applied in cement nanohybrids: an organomodified nMt dispersion, nC2; an inorganic nMt dispersion, nC3; and an organomodified powder, nC4. nC4 is fully characterized in this paper (X-ray diffraction, scanning electron microscopy/X-ray energy dispersive spectroscopy and thermal gravimetric analysis/differential thermogravimetry. Consecutively a ternary non pozzolanic combination of fiber–cement nanohybrids (60% Portland cement (PC) and 40% limestone (LS)) was investigated in terms of flexural strength, thermal properties, density, porosity, and water impermeability. Flexural strength was improved after day 28, particularly with the addition of the inorganic nMt dispersion. There was no change in density or enhancement in pozzolanic reactions for the powder nMt. Mercury intrusion porosimetry showed that the pore related parameters were increased. This can be attributed to mixing effects and the presence of fibers. Water impermeability tests yielded ambiguous results. Clearly, novel manufacturing processes of cement nanohybrids must be developed to eliminate mixing issues recorded in this research.
Lateral Torsional Buckling of Steel Beams Elastically Restrained at the Support Nodes
Authors: Piotrowski Rafał , Szychowski Andrzej
Published: May 2019

The study shows the results of theoretical investigations into lateral torsional buckling of bisymmetric I-beams elastically restrained against warping and against rotation in the plane of lateral torsional buckling (i.e., against lateral rotation) at the support nodes. The analysis accounted for the whole variation range of node stiffnesses, from complete warping freedom to full restraint, and from complete lateral rotation freedom to full restraint. It was assumed the beams are simply supported against bending about the major axis of the section. To determine the critical moment, the energy method was used. Both the twist angle function and the lateral deflection function of the beam were described using power polynomials with simple physical interpretation. Computer programmes were developed to make numerical and symbolic “computations”. General approximation formulas for the critical moment for lateral torsional buckling were derived. The formulas covered the basic and most frequently found loading diagrams. Detailed computations were performed for different values of the index of fixity against warping and against rotation in the plane of lateral torsional buckling. The critical moments determined using the programmes devised and approximation formulas were compared with the values obtained with LTBeam software (FEM). A very good congruence of results was found.
Deep Forest-Based Monocular Visual Sign Language Recognition
Authors: Xue Qifan , Li Xuanpeng , Wang Dong , Zhang Weigong
Published: May 2019

Sign language recognition (SLR) is a bridge linking the hearing impaired and the general public. Some SLR methods using wearable data gloves are not portable enough to provide daily sign language translation service, while visual SLR is more flexible to work with in most scenes. This paper introduces a monocular vision-based approach to SLR. Human skeleton action recognition is proposed to express semantic information, including the representation of signs’ gestures, using the regularization of body joint features and a deep-forest-based semantic classifier with a voting strategy. We test our approach on the public American Sign Language Lexicon Video Dataset (ASLLVD) and a private testing set. It proves to achieve a promising performance and shows a high generalization capability on the testing set.
Evaluation of Performance of Inexpensive Laser Based PM2.5 Sensor Monitors for Typical Indoor and Outdoor Hotspots of South Korea
Authors: Kim Sungroul , Park Sujung , Lee Jeongeun
Published: May 2019

Inexpensive (<$300) real-time particulate matter monitors (IRMs), using laser as a light source, have been introduced for use with a Wi-Fi function enabling networking with a smartphone. However, the information of measurement error of these inexpensive but convenient IRMs are still limited. Using ESCORTAIR (ESCORT, Seoul, Korea) and PurpleAir (PA) (PurpleAir U.S.A.), we evaluated the performance of these two devices compared with the U.S. Environmental Protection Agency (EPA) Federal Equivalent Monitoring (FEM) devices, that is, GRIMM180 (GRIMM Aerosol, Germany) for the indoor measurement of pork panfrying or secondhand tobacco smoking (SHS) and Beta-ray attenuation monitor (BAM) (MetOne, Grants Pass, OR) for outdoor measurement at the national particulate matter (PM2.5) monitoring site near an urban traffic hotspot in Daejeon, South Korea, respectively. The PM2.5 concentrations measured by ESCORTAIR and PA were strongly correlated to FEM (r = 0.97 and 0.97 from indoor pan frying; 0.92 and 0.86 from indoor SHS; 0.85 and 0.88 from outdoor urban traffic hotspot). The two IRMs showed that PM2.5 mass concentrations were increased with increased outdoor relative humidity (RH) levels. However, after applying correction factors for RH, the Median (Interquartile range) of difference compared to FEM was (14.5 (6.1~23.5) %) for PA and 16.3 (8.5–28.0) % for ESCORTAIR, supporting their usage in the home or near urban hotspots.
Application of Integrated Optical Electric-Field Sensor on the Measurements of Transient Voltages in AC High-Voltage Power Grids
Authors: Xie Shijun , Zhang Yu , Yang Huaiyuan , Yu Hao , Mu Zhou , Zhang Chenmeng , Cao Shupin , Chang Xiaoqing , Hua Ruorong
Published: May 2019

Transient voltages in the power grid are the key for the fault analysis of a power grid, optimized insulation design, and the standardization of the high-voltage testing method. The traditional measuring equipment, based on electrical engineering, normally has a limited bandwidth and response speed, which are also featured by a huge size and heavy weight. In this paper, an integrated optical electric-field sensor based on the Pockels effect was developed and applied to measure the transient voltages on the high-voltage conductors in a non-contact measuring mode. The measuring system has a response speed faster than 6 ns and a wide bandwidth ranging from 5 Hz to 100 MHz. Moreover, the sensors have the dimensions of 18 mm by 18 mm by 48 mm and a light weight of dozens of grams. The measuring systems were employed to monitor the lightning transient voltages on a 220 kV overhead transmission line. The switching transient voltages were also measured by the measuring system during the commissioning of the 500 kV middle Tibet power grid. In 2017, 307 lightning transient voltages caused by induction stroke were recorded. The characteristics of these voltage waveforms are different from the standard lightning impulse voltage proposed by IEC standards. Three types of typical switching transient voltage in 500 kV AC power grid were measured, and the peak values of these overvoltages can reach 1.73 times rated voltage.
Regularized Urdu Speech Recognition with Semi-Supervised Deep Learning
Authors: Ali Humayun Mohammad , Hameed Ibrahim , Muslim Shah Syed , Hassan Khan Sohaib , Zafar Irfan , Bin Ahmed Saad , Shuja Junaid
Published: May 2019

Automatic Speech Recognition, (ASR) has achieved the best results for English, with end-to-end neural network based supervised models. These supervised models need huge amounts of labeled speech data for good generalization, which can be quite a challenge to obtain for low-resource languages like Urdu. Most models proposed for Urdu ASR are based on Hidden Markov Models (HMMs). This paper proposes an end-to-end neural network model, for Urdu ASR, regularized with dropout, ensemble averaging and Maxout units. Dropout and ensembles are averaging techniques over multiple neural network models while Maxout are units in a neural network which adapt their activation functions. Due to limited labeled data, Semi Supervised Learning (SSL) techniques are also incorporated to improve model generalization. Speech features are transformed into a lower dimensional manifold using an unsupervised dimensionality-reduction technique called Locally Linear Embedding (LLE). Transformed data along with higher dimensional features is used to train neural networks. The proposed model also utilizes label propagation-based self-training of initially trained models and achieves a Word Error Rate (WER) of 4% less than that reported as the benchmark on the same Urdu corpus using HMM. The decrease in WER after incorporating SSL is more significant with an increased validation data size.
Long-Term Effects of a Soft Robotic Suit on Gait Characteristics in Healthy Elderly Persons
Authors: Jin Shanhai , Xiong Xiaogang , Zhao Dejin , Jin Changfu , Yamamoto Motoji
Published: May 2019

As a walking assistive device for elderly persons, one of the major aims should be to improve and rehabilitate gait characteristics after long-term repeated use of the device. However, most of the existing research on walking assistive devices only emphasize their immediate effects, and there is limited research indicating the long-term effects. To address this gap, this paper experimentally validates the effects of our soft wearable robotic suit on gait characteristics of elderly persons after repeated use of the device for six weeks. Experimental results on four elderly subjects (age = 74.8 ± 5.0 year) show that, after six weeks of gait rehabilitation training by the robotic suit, the gait characteristics of the subjects were improved, leading to an increased walk ratio with an average of 9.8% compared with the initial state. The results of this research will benefit the potential use of the robotic suit in gait training and rehabilitation for elderly persons and also will be useful to the establishment of practical guidelines that maximize the training and rehabilitation effectiveness of the robotic suit.
Effects of Hepatic Steatosis on Non-Invasive Liver Fibrosis Measurements Between Hepatitis B and Other Etiologies
Authors: Chen Cheng-Jen , Tsay Pei-Kwei , Huang Shiu-Feng , Tsui Po-Hsiang , Yu Wan-Ting , Hsu Tse-Hwa , Tai Jennifer , Tai Dar-In
Published: May 2019

Fibrosis-4 (FIB4), transient elastography (TE), and acoustic radiation force impulse (ARFI) are popular modalities to assess liver fibrosis. Their cutoff values for degrees of fibrosis vary between studies. The influence of hepatic steatosis on fibrosis measurements for different etiologies was evaluated. Data from a consecutive series of patients who received fibrosis measurement were included for the training group. An additional series with histology served as the validation group. A standardized protocol was performed for both TE and ARFI, mostly by a single technician. Patients with alcoholism, autoimmune disease, active inflammation, or who were receiving therapy were excluded. The training group included 215 patients and the validation group included 221. The correlation of liver stiffness between TE and ARFI was good (R2 linear = 0.798; p < 0.001). Different correlations between ARFI and TE were noted between high and low control attenuation parameter (CAP) values (cutoff: 290 dB/m), especially in the non-hepatitis B subgroups. Relatively lower FIB4 and TE values were seen in the high CAP versus low CAP in patients with histology-proven non-alcoholic fatty liver disease and chronic hepatitis C. FIB4 cutoff values were >25% lower among F2-F4 stages and the TE cutoff value for F4 was 8.5% lower in the high versus low CAP group. Such findings were not observed in chronic hepatitis B. Different fibrogenesis mechanisms between hepatitis B and non-B are discussed. We conclude that hepatic steatosis significantly impacts FIB4 and TE fibrosis measurements in non-hepatitis B-related liver diseases. Fibrosis grade should be interpreted with caution in severe steatosis.
Preparation and Characterization of High Thermal Conductivity and Low CTE Polyimide Composite Reinforced with Diamond Nanoparticles/SiC Whiskers for 3D IC Interposer RDL Dielectric
Authors: Luo Jiangbo , Wu Yongpeng , Sun Yunna , Wang Guilian , Liu Yanmei , Zhao Xiaolin , Ding Guifu
Published: May 2019

Low thermal conductivity and large coefficient of thermal expansion (CTE) are the most serious disadvantages of the polymer dielectric for the interposer redistribution layer (RDL). In this paper, a high thermal conductivity and low CTE composite with polyimide (PI) matrix and diamond nanoparticles/SiC whiskers reinforcement is proposed. The preparation and characterization of the composite film are presented and the effects of the composite on the improvement of the interposer properties are investigated. With 10 wt% diamond-nanoparticles and 7 wt% SiC-whiskers, the composite film has a thermal conductivity of 1.63 W/m·K and a CTE of 16.7 ppm/°C (compared with 0.19 W/m·K and 55.6 ppm/°C of the PI). Interposers with PI RDL dielectric and the composite RDL dielectric are fabricated, respectively. The simulation result shows that the composite dielectric can significantly enhance the properties of the interposer compared with the PI dielectric. The thermal resistance of the interposer decreases from 8.04 °C/W to 1.15 °C/W. The maximum von Mises stress decreases from 72.8 MPa to 16.9 MPa and the warpage decreases from 1.13 μm to 0.15 μm. Thermal distribution tests are performed as well. The results show that the maximum temperature of the interposer decreases from 64 °C to 45.1 °C. The composite developed in this study can reduce the temperature and enhance the reliability of the chips with interposers. It has the potential to expand the application of the interposers in high thermal density integration and high reliability devices.
Compressive Mechanical Properties of Porcine Brain: Experimentation and Modeling of the Tissue Hydration Effects
Authors: Prabhu Raj K. , Begonia Mark T. , Whittington Wilburn R. , Murphy Michael A. , Mao Yuxiong , Liao Jun , Williams Lakiesha N. , Horstemeyer Mark F. , Sheng Jianping
Published: May 2019

Designing protective systems for the human head—and, hence, the brain—requires understanding the brain’s microstructural response to mechanical insults. We present the behavior of wet and dry porcine brain undergoing quasi-static and high strain rate mechanical deformations to unravel the effect of hydration on the brain’s biomechanics. Here, native ‘wet’ brain samples contained ~80% (mass/mass) water content and ‘dry’ brain samples contained ~0% (mass/mass) water content. First, the wet brain incurred a large initial peak stress that was not exhibited by the dry brain. Second, stress levels for the dry brain were greater than the wet brain. Third, the dry brain stress–strain behavior was characteristic of ductile materials with a yield point and work hardening; however, the wet brain showed a typical concave inflection that is often manifested by polymers. Finally, finite element analysis (FEA) of the brain’s high strain rate response for samples with various proportions of water and dry brain showed that water played a major role in the initial hardening trend. Therefore, hydration level plays a key role in brain tissue micromechanics, and the incorporation of this hydration effect on the brain’s mechanical response in simulated injury scenarios or virtual human-centric protective headgear design is essential.
Antimicrobial Photodynamic Therapy Protocols on Streptococcus mutans with Different Combinations of Wavelengths and Photosensitizing Dyes
Authors: Merigo Elisabetta , Conti Stefania , Ciociola Tecla , Manfredi Maddalena , Vescovi Paolo , Fornaini Carlo
Published: May 2019

The aim of the study is to test the application of different laser wavelengths, with and without different photosensitizing dyes on different types of cultures. Laser irradiation was realized on Streptococcus mutans in both solid and liquid culture media in continuous mode at three different fluences (10, 20, and 30 J/cm2) with a red diode (650 nm) with toluidine blue dye, a blue-violet diode (405 nm) with curcumin dye, and a green diode (532 nm) with erythrosine dye. Without a photosensitizer, no growth inhibition was obtained with the red diode at any fluence value. Inhibition rates of 40.7% and 40.2% were obtained with the blue diode and green diode. The blue diode laser used with curcumin obtained results in terms of growth inhibition up to 99.26% at a fluence of 30 J/cm2. The red diode laser used with toluidine blue obtained results in terms of growth inhibition up to 100% at fluences of 20 and 30 J/cm2. The KTP (potassium-titanyl-phosphate) laser used with erythrosine was able to determine a complete growth inhibition (100%) at the different fluence values. The combination of a laser and its proper color may dramatically change the results in terms of bactericidal effect. It will be interesting to confirm these data by further in vivo studies.
Mitochondrial Dysfunction and the Aging Immune System
Authors: McGuire Peter J.
Published: May 2019

Mitochondria are ancient organelles that have co-evolved with their cellular hosts, developing a mutually beneficial arrangement. In addition to making energy, mitochondria are multifaceted, being involved in heat production, calcium storage, apoptosis, cell signaling, biosynthesis, and aging. Many of these mitochondrial functions decline with age, and are the basis for many diseases of aging. Despite the vast amount of research dedicated to this subject, the relationship between aging mitochondria and immune function is largely absent from the literature. In this review, three main issues facing the aging immune system are discussed: (1) inflamm-aging; (2) susceptibility to infection and (3) declining T-cell function. These issues are re-evaluated using the lens of mitochondrial dysfunction with aging. With the recent expansion of numerous profiling technologies, there has been a resurgence of interest in the role of metabolism in immunity, with mitochondria taking center stage. Building upon this recent accumulation of knowledge in immunometabolism, this review will advance the hypothesis that the decline in immunity and associated pathologies are partially related to the natural progression of mitochondrial dysfunction with aging.
Mitochondrial Dysfunction and Diabetes: Is Mitochondrial Transfer a Friend or Foe?
Authors: Montgomery Magdalene K
Published: May 2019

Obesity, insulin resistance and type 2 diabetes are accompanied by a variety of systemic and tissue-specific metabolic defects, including inflammation, oxidative and endoplasmic reticulum stress, lipotoxicity, and mitochondrial dysfunction. Over the past 30 years, association studies and genetic manipulations, as well as lifestyle and pharmacological invention studies, have reported contrasting findings on the presence or physiological importance of mitochondrial dysfunction in the context of obesity and insulin resistance. It is still unclear if targeting mitochondrial function is a feasible therapeutic approach for the treatment of insulin resistance and glucose homeostasis. Interestingly, recent studies suggest that intact mitochondria, mitochondrial DNA, or other mitochondrial factors (proteins, lipids, miRNA) are found in the circulation, and that metabolic tissues secrete exosomes containing mitochondrial cargo. While this phenomenon has been investigated primarily in the context of cancer and a variety of inflammatory states, little is known about the importance of exosomal mitochondrial transfer in obesity and diabetes. We will discuss recent evidence suggesting that (1) tissues with mitochondrial dysfunction shed their mitochondria within exosomes, and that these exosomes impair the recipient’s cell metabolic status, and that on the other hand, (2) physiologically healthy tissues can shed mitochondria to improve the metabolic status of recipient cells. In this context the determination of whether mitochondrial transfer in obesity and diabetes is a friend or foe requires further studies.
Mitochondrial Dysfunction and Stress Responses in Alzheimer’s Disease
Authors: Weidling Ian , Swerdlow Russell H.
Published: May 2019

Alzheimer’s disease (AD) patients display widespread mitochondrial defects. Brain hypometabolism occurs alongside mitochondrial defects, and correlates well with cognitive decline. Numerous theories attempt to explain AD mitochondrial dysfunction. Groups propose AD mitochondrial defects stem from: (1) mitochondrial-nuclear DNA interactions/variations; (2) amyloid and neurofibrillary tangle interactions with mitochondria, and (3) mitochondrial quality control defects and oxidative damage. Cells respond to mitochondrial dysfunction through numerous retrograde responses including the Integrated Stress Response (ISR) involving eukaryotic initiation factor 2α (eIF2α), activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP). AD brains activate the ISR and we hypothesize mitochondrial defects may contribute to ISR activation. Here we review current recognized contributions of the mitochondria to AD, with an emphasis on their potential contribution to brain stress responses.
Inhibiting Extracellular Cathepsin D Reduces Hepatic Steatosis in Sprague–Dawley Rats
Authors: Khurana Princy , Yadati Tulasi , Goyal Sandeep , Dolas Atul , Houben Tom , Oligschlaeger Yvonne , Agarwal Anil , Kulkarni Aditya , Shiri-Sverdlov Ronit
Published: May 2019

Dietary and lifestyle changes are leading to an increased occurrence of non-alcoholic fatty liver disease (NAFLD). Using a hyperlipidemic murine model for non-alcoholic steatohepatitis (NASH), we have previously demonstrated that the lysosomal protease cathepsin D (CTSD) is involved with lipid dysregulation and inflammation. However, despite identifying CTSD as a major player in NAFLD pathogenesis, the specific role of extracellular CTSD in NAFLD has not yet been investigated. Given that inhibition of intracellular CTSD is highly unfavorable due to its fundamental physiological function, we here investigated the impact of a highly specific and potent small-molecule inhibitor of extracellular CTSD (CTD-002) in the context of NAFLD. Treatment of bone marrow-derived macrophages with CTD-002, and incubation of hepatic HepG2 cells with a conditioned medium derived from CTD-002-treated macrophages, resulted in reduced levels of inflammation and improved cholesterol metabolism. Treatment with CTD-002 improved hepatic steatosis in high fat diet-fed rats. Additionally, plasma levels of insulin and hepatic transaminases were significantly reduced upon CTD-002 administration. Collectively, our findings demonstrate for the first time that modulation of extracellular CTSD can serve as a novel therapeutic modality for NAFLD.
HIV Vaccine Mystery and Viral Shell Disorder
Authors: Goh Gerard , Dunker A. , Foster James , Uversky Vladimir
Published: May 2019

Hundreds of billions of dollars have been spent for over three decades in the search for an effective human immunodeficiency virus (HIV) vaccine with no success. There are also at least two other sexually transmitted viruses, for which no vaccine is available, the herpes simplex virus (HSV) and the hepatitis C virus (HCV). Traditional textbook explanatory paradigm of rapid mutation of retroviruses cannot adequately address the unavailability of vaccine for many sexually transmissible viruses, since HSV and HCV are DNA and non-retroviral RNA viruses, respectively, whereas effective vaccine for the horsefly-transmitted retroviral cousin of HIV, equine infectious anemia virus (EIAV), was found in 1973. We reported earlier the highly disordered nature of proteins in outer shells of the HIV, HCV, and HSV. Such levels of disorder are completely absent among the classical viruses, such as smallpox, rabies, yellow fever, and polio viruses, for which efficient vaccines were discovered. This review analyzes the physiology and shell disorder of the various related and non-related viruses to argue that EIAV and the classical viruses need harder shells to survive during harsher conditions of non-sexual transmissions, thus making them vulnerable to antibody detection and neutralization. In contrast, the outer shell of the HIV-1 (with its preferential sexual transmission) is highly disordered, thereby allowing large scale motions of its surface glycoproteins and making it difficult for antibodies to bind to them. The theoretical underpinning of this concept is retrospectively traced to a classical 1920s experiment by the legendary scientist, Oswald Avery. This concept of viral shapeshifting has implications for improved treatment of cancer and infections via immune evasion.
Membrane Permeabilization by Bordetella Adenylate Cyclase Toxin Involves Pores of Tunable Size
Authors: González-Bullón David , B. Uribe Kepa , Largo Eneko , Guembelzu Garazi , García-Arribas Aritz B. , Martín César , Ostolaza Helena
Published: May 2019

RTX (Repeats in ToXin) pore-forming toxins constitute an expanding family of exoproteins secreted by many Gram-negative bacteria and involved in infectious diseases caused by said pathogens. Despite the relevance in the host/pathogen interactions, the structure and characteristics of the lesions formed by these toxins remain enigmatic. Here, we capture the first direct nanoscale pictures of lytic pores formed by an RTX toxin, the Adenylate cyclase (ACT), secreted by the whooping cough bacterium Bordetella pertussis. We reveal that ACT associates into growing-size oligomers of variable stoichiometry and heterogeneous architecture (lines, arcs, and rings) that pierce the membrane, and that, depending on the incubation time and the toxin concentration, evolve into large enough “holes” so as to allow the flux of large molecular mass solutes, while vesicle integrity is preserved. We also resolve ACT assemblies of similar variable stoichiometry in the cell membrane of permeabilized target macrophages, proving that our model system recapitulates the process of ACT permeabilization in natural membranes. Based on our data we propose a non-concerted monomer insertion and sequential mechanism of toroidal pore formation by ACT. A size-tunable pore adds a new regulatory element to ACT-mediated cytotoxicity, with different pore sizes being putatively involved in different physiological scenarios or cell types.
Meditation-Induced States, Vagal Tone, and Breathing Activity Are Related to Changes in Auditory Temporal Integration
Authors: Linares Gutierrez Damisela , Kübel Sebastian , Giersch Anne , Schmidt Stefan , Meissner Karin , Wittmann Marc
Published: May 2019

This study is based on the relationship between meditation, the present moment, and psychophysiology. We employed the metronome task to operationalize the extension of the present moment. A pre-post longitudinal study was conducted. The performance in the metronome task was compared before and after the interventions (meditation, story). The aim was to assess whether physiological changes (heart, breathing) during meditation influence the temporal-integration (TI) of metronome beats. Mindfulness meditators either meditated (n = 41) or listened to a story (n = 43). The heart and breathing activity were recorded during the intervention and compared to a resting-state condition. By applying path analyses we found that meditation led to an increase of the duration of integration intervals at the slowest metronome frequency (inter-stimulus interval, ISI = 3 s). After meditation, the higher the heart-rate variability (i.e., the root mean square of successive differences, RMSSD), the longer the duration of integration intervals at the fastest frequency (ISI = 0.33 s). Moreover, the higher the breathing rate during meditation, the greater the integration of intervals at ISI = 1 s. These findings add evidence to meditation-induced changes on the TI of metronome beats and the concept of the embodiment of mental functioning.
Developing a Methodology for Integration of Whole Life Costs into BIM Processes to Assist Design Decision Making
Authors: Zanni Mariangela , Sharpe Tim , Lammers Philipp , Arnold Leo , Pickard James
Published: May 2019

A common barrier to achieving design intent is the absence of comprehensive information about operational performance during design development. This results in uninformed decision-making which impacts on actual building performance, in particular Whole Life Costs (WLC). It is proposed that Building Information Modelling (BIM) has the potential to facilitate a more comprehensive and accurate design approach from the initial stages if the model can utilize reliable and robust cost and performance data from buildings in use. This paper describes the initial findings of a research project that has investigated the integration of WLC estimation into BIM processes. The study focusses specifically on the rapidly emerging Private Rental Sector (PRS) as the build-to-rent market has repeatable tasks and similar workflow patterns, roles and responsibilities, but impacts of WLC can significantly influence the business model. The study adopted a mixed method approach for the development and validation of a structured standardized process for timely WLC estimation through BIM. The research identified a number of barriers. These included varying definitions of WLC calculation methodologies; the availability and standards of data sources, in particular, the misalignment of coding systems for identification and classification of components at various levels of development, proprietary ownership of data, lack of knowledge and skills in team members to produce and/or utilize data sources, and limitations of software. However, the research proposes that these may be addressed by a reverse-engineered systematic process that uses the Integrated DEFinition (IDEF) 3 structured diagramming modelling technique that can be incorporated into a software model and has developed a model for a systematic approach for BIM-enabled WLC assessment based on CE principles which would include access to live data streams from completed buildings. The paper describes this model development which has the potential to enhance BIM lifecycle management through an augmented decision-making approach that is integral to the natural design development process.
Rehabilitation of Corrosion-Defected RC Beam-Column Members Using Patch Repair Technique
Authors: A. Alwash Nameer , M. Kadhum Mohammed , M. Mahdi Ahmed
Published: May 2019

An experimental study was conducted to evaluate the efficiency of patch repair to rehabilitate corrosion-defected reinforced concrete (RC) beam-column members when exposed to bending moments and axial forces. Ten RC beam-column members were tested under combined constant axial force and four-point transverse load up to failure. Two levels of the constant axial force were applied at either 15 kN or 30 kN (i.e., 25% or 50% of the ultimate design load of the control specimen). The accelerated corrosion process was used to get steel reinforcement corrosion inside the concrete of three levels, 0% and approximately 5% and 20%, according to Faraday’s law. The patch repair technique of cleaning or replacing corroded steel bars and replacing the damaged concrete cover with new mortar was used in this study. The experimental results of the corrosion-defected specimens showed a significant deterioration in the structural performance and the integrity by reducing ultimate capacity, stiffness, serviceability, and ductility. Additionally, the effect of increasing axial force was recorded clearly by reducing the adverse effect of corrosion, especially for defected specimens with high corrosion level. The deterioration of corrosion reinforcement could be overcome when using a patch repair technique, which restored the undamaged state and was shown clearly by using a patch repair technique with replacing corroded steel bars.
Oncogenic Signaling in Tumorigenesis and Applications of siRNA Nanotherapeutics in Breast Cancer
Authors: Kamaruzman Nur Izyani , Aziz Noraini Abd , Poh Chit Laa , Chowdhury Ezharul Hoque
Published: May 2019

Overexpression of oncogenes and cross-talks of the oncoproteins-regulated signaling cascades with other intracellular pathways in breast cancer could lead to massive abnormal signaling with the consequence of tumorigenesis. The ability to identify the genes having vital roles in cancer development would give a promising therapeutics strategy in combating the disease. Genetic manipulations through siRNAs targeting the complementary sequence of the oncogenic mRNA in breast cancer is one of the promising approaches that can be harnessed to develop more efficient treatments for breast cancer. In this review, we highlighted the effects of major signaling pathways stimulated by oncogene products on breast tumorigenesis and discussed the potential therapeutic strategies for targeted delivery of siRNAs with nanoparticles in suppressing the stimulated signaling pathways.
(−)-Oleocanthal Prevents Breast Cancer Locoregional Recurrence After Primary Tumor Surgical Excision and Neoadjuvant Targeted Therapy in Orthotopic Nude Mouse Models
Authors: Siddique Abu Bakar , Ayoub Nehad M. , Tajmim Afsana , Meyer Sharon A. , Hill Ronald A. , El Sayed Khalid A.
Published: May 2019

Breast cancer (BC) recurrence represents a challenge for survivors who have had their primary tumors surgically excised, and/or have completed radiation, neoadjuvant, or adjuvant therapeutic regimens. Current BC treatments mostly lack the ability to reduce the risk of disease recurrence. About 70% of BC patients will subsequently suffer disease relapse, manifesting as local, regional, or distant tumor recurrence, which clearly underscores the urgent need to discover novel recurrence inhibitors. (−)-Oleocanthal (OC) is a natural phenolic, found so far exclusively in extra-virgin olive oil (EVOO). OC exerts documented bioactivities against diverse cancer types, inflammation, and neurodegenerative diseases. Herein we report the novel activity of daily oral treatment with OC (10 mg/kg) in preventing BC locoregional recurrence in a nude mouse xenograft model generated by orthotopic inoculation with BT-474 cells as a luminal type B model. We further report inhibition of tumor recurrence by OC after completion of a lapatinib neoadjuvant regimen. However, in a recurrence model of triple-negative breast cancer (TNBC), OC treatment (10 mg/kg) did not effectively prevent tumor recurrence, but rather, was seen to significantly reduce the growth of recurrent tumors as compared to vehicle control-treated animals. Inhibition of tumor recurrence was associated with significant serum level reductions of the human BC recurrence marker CA 15-3 at the study end in animals treated with OC. OC treatment upregulated the expression of the epithelial marker E-cadherin and downregulated the levels of the mesenchymal marker vimentin in recurrent tumors vs. untreated control animals. OC treatment also reduced the activation of MET and HER2 receptors, as indicated by reduced phosphorylation levels of these proteins in recurrent tumors vs. controls. Collectively, the results of our studies provide the first evidence for suppression of BC tumor recurrence by oral OC treatment in an animal model for such recurrence, and furthermore, highlight favorable prospects for this natural product to emerge as a first-in-class BC recurrence inhibitor.
Cannabidiol Enhances the Therapeutic Effects of TRAIL by Upregulating DR5 in Colorectal Cancer
Authors: Kim Jung Lim , Kim Bo Ram , Kim Dae Yeong , Jeong Yoon A. , Jeong Soyeon , Na Yoo Jin , Park Seong Hye , Yun Hye Kyeong , Jo Min Jee , Kim Bu Gyeom , Kim Han Do , Kim Dae Hyun , Oh Sang Cheul , Lee Sun Il , Lee Dae-Hee
Published: May 2019

Cannabidiol, a major non-psychotomimetic compound derived from Cannabis sativa, is a potential therapeutic agent for a variety of diseases such as inflammatory diseases, chronic neurodegenerative diseases, and cancers. Here, we found that the combination of cannabidiol and TNF-related apoptosis-inducing ligand (TRAIL) produces synergistic antitumor effects in vitro. However, this synergistic effect was not observed in normal colonic cells. The levels of ER stress-related proteins, including C/EBP homologous protein (CHOP) and phosphorylated protein kinase RNA-like ER kinase (PERK) were increased in treatment of cannabidiol. Cannabidiol enhanced significantly DR5 expression by ER stress. Knockdown of DR5 decreased the combined effect of cannabidiol and TRAIL. Additionally, the combination of TRAIL and cannabidiol decreased tumor growth in xenograft models. Our studies demonstrate that cannabidiol enhances TRAIL-induced apoptosis by upregulating DR5 and suggests that cannabidiol is a novel agent for increasing sensitivity to TRAIL.
Targeting ATG4 in Cancer Therapy
Authors: Fu Yuanyuan , Huang Zhiying , Hong Liang , Lu Jia-Hong , Feng Du , Yin Xiao-Ming , Li Min
Published: May 2019

Autophagy is a lysosome-mediated degradation pathway that enables the degradation and recycling of cytoplasmic components to sustain metabolic homoeostasis. Recently, autophagy has been reported to have an astonishing number of connections to cancer, as tumor cells require proficient autophagy in response to metabolic and therapeutic stresses to sustain cell proliferation. Autophagy-related gene 4 (ATG4) is essential for autophagy by affecting autophagosome formation through processing full-length microtubule-associated protein 1A/1B-light chain 3 (pro-LC3) and lipidated LC3. An increasing amount of evidence suggests that ATG4B expression is elevated in certain types of cancer, implying that ATG4B is a potential anticancer target. In this review, we address the central roles of ATG4B in the autophagy machinery and in targeted cancer therapy. Specifically, we discuss how pharmacologically inhibiting ATG4B can benefit cancer therapies.
FAM83A and FAM83B as Prognostic Biomarkers and Potential New Therapeutic Targets in NSCLC
Authors: Richtmann Sarah , Wilkens Dennis , Warth Arne , Lasitschka Felix , Winter Hauke , Christopoulos Petros , Herth Felix J. F. , Muley Thomas , Meister Michael , Schneider Marc A.
Published: May 2019

Although targeted therapy has improved the survival rates in the last decade, non-small-cell lung cancer (NSCLC) is still the most common cause of cancer-related death. The challenge of identifying new targets for further effective therapies still remains. The FAMily with sequence similarity 83 (FAM83) members have recently been described as novel oncogenes in numerous human cancer specimens and shown to be involved in epidermal growth factor receptor (EGFR) signaling. Here, gene expression of FAM83A and B was analyzed in a cohort of 362 NSCLC patients using qPCR. We further investigated relations in expression and their prognostic value. Functional assays in NSCLC cell lines were performed to evaluate FAM83A and B involvement in proliferation, anchorage-independent growth, migration, and the EGFR pathway. We observed a highly increased gene expression level of FAM83A (ø = 68-fold) and FAM83B (ø = 20-fold) which resulted in poor survival prognosis (p < 0.0001 and p = 0.002). Their expression was influenced by EGFR levels, pathway signaling, and mutation status. Both genes affected cell proliferation, and FAM83A depletion resulted in reduced migration and anchorage-independent growth. The results support the hypothesis that FAM83A and B have different functions in different histological subtypes of NSCLC and might be new therapeutic targets.
Countering TRAIL Resistance in Melanoma
Authors: Eberle Jürgen
Published: May 2019

Melanoma of the skin has become a prime example for demonstrating the success of targeted cancer therapy. Nevertheless, high mortality has remained, mainly related to tumor heterogeneity and inducible therapy resistance. But the development of new therapeutic strategies and combinations has raised hope of finally defeating this deadly disease. TNF-related apoptosis-inducing ligand (TRAIL) represents a promising antitumor strategy. The principal sensitivity of melanoma cells for TRAIL was demonstrated in previous studies; however, inducible resistance appeared as a major problem. To address this issue, combination strategies were tested, and survival pathway inhibitors were shown to sensitize melanoma cells for TRAIL-induced apoptosis. Finally, cell cycle inhibition was identified as a common principle of TRAIL sensitization in melanoma cells. Mitochondrial apoptosis pathways, pro- and antiapoptotic Bcl-2 proteins as well as the rheostat consisted of Smac (Second mitochondria-derived activator of caspase) and XIAP (X-linked inhibitor of apoptosis protein) appeared to be of particular importance. Furthermore, the role of reactive oxygen species (ROS) was recognized in this setting. Inducible TRAIL resistance in melanoma can be explained by (i) high levels of antiapoptotic Bcl-2 proteins, (ii) high levels of XIAP, and (iii) suppressed Bax activity. These hurdles have to be overcome to enable the use of TRAIL in melanoma therapy. Several strategies appear as particularly promising, including new TRAIL receptor agonists, Smac and BH3 mimetics, as well as selective kinase inhibitors.
Analysis of Short-term Blood Pressure Variability in Pheochromocytoma/Paraganglioma Patients
Authors: Bisogni Valeria , Petramala Luigi , Oliviero Gaia , Bonvicini Maria , Mezzadri Martina , Olmati Federica , Concistrè Antonio , Saracino Vincenza , Celi Monia , Tonnarini Gianfranco , Iannucci Gino , De Toma Giorgio , Ciardi Antonio , La Torre Giuseppe , Letizia Claudio
Published: May 2019

Data on short-term blood pressure variability (BPV), which is a well-established cardiovascular prognostic tool, in pheochromocytoma and paraganglioma (PPGL) patients is still lack and conflicting. We retrospectively evaluated 23 PPGL patients referred to our unit from 2010 to 2019 to analyze 24 h ambulatory blood pressure monitoring (24-h ABPM)-derived markers of short-term BPV, before and after surgical treatment. PPGL diagnosis was assessed according to guidelines and confirmed by histologic examination. The 24-h ABPM-derived markers of short-term BPV included: circadian pressure rhythm; standard deviation (SD) and weighted SD (wSD) of 24-h, daytime, and night-time systolic and diastolic blood pressure (BP); average real variability (ARV) of 24-h, daytime, and night-time systolic and diastolic BP. 7 males and 16 females of 53 ± 18 years old were evaluated. After surgical resection of PPGL we found a significant decrease in 24-h systolic BP ARV (8.8 ± 1.6 vs. 7.6 ± 1.3 mmHg, p < 0.001), in 24-h diastolic BP ARV (7.5 ± 1.6 vs. 6.9 ± 1.4 mmHg, p = 0.031), and in wSD of 24-h diastolic BP (9.7 ± 2.0 vs 8.8 ± 2.1 mmHg, p = 0.050) comparing to baseline measurements. Moreover, baseline 24-h urinary metanephrines significantly correlated with wSD of both 24-h systolic and diastolic BP. Our study highlights as PPGL patients, after proper treatment, show a significant decrease in some short-term BPV markers, which might represent a further cardiovascular risk factor.