bluuebunny/crossref_metadata_2025 huggingface dataset:
Sustainability Performance through Technology Adoption: A Case Study of Land Leveling in a Paddy Field
Authors: Quirós-Vargas Juan , Romanelli Thiago Libório , Rascher Uwe , Agüero José
Published: October 2020

Energy is required in all agricultural activities. Diagramming material flows needed by crop production systems supports the proper analysis of energy flows interactions within a system’s boundaries. The latter complemented with an economic analysis gives a clear view of how beneficial a new practice within a crop cycle is—in this case, the variable slope (VS) land leveling (LL) operation. VS is a global navigation satellite system (GNSS, with real time kinematics—RTK—accuracy) LL technique used to create a smooth continuous surface with a constant slope, by cutting and filling topsoil layers only in those points presenting “anomalies” of micro-relief which make the movement of water difficult. This operation is important for paddy production since: (i) it enables to crop during dry seasons by harnessing the water of rivers and wells, and (ii) improves the production during rainy seasons, by allowing the farmer to manage the drainage timely and homogeneously. The present study aims to analyze, from the energy perspective, the effects of the VS leveling implementation in a paddy field (located in the Costa Rican Pacific), throughout input (labor, gas oil, etc.) and output (yield and price) data of five consecutive years (2011–2015). A material flow diagram was created representing two scenarios: before and after leveling the land. The materials were converted into energy (MJ ha−1) data, used for the estimation of EROI (energy return on investment), EP (energy productivity) and EB (energy balance) indices, while looking for a clearer understanding of the LL impact on the use of energy within the agroecosystem. Moreover, in order to complement the energy perspective, an economic point of view was considered as well through a profitability analysis where the total gain obtained over the years with LL was compared with that obtained without LL. Results showed that the increase in energy consumed by incorporating VS leveling is compensated by the gradual increase of energy embodied in yield, increasing energy balance (EB) from 26,192 MJ ha−1 up to 91,166 MJ ha−1. Similarly, EROI and EP were duplicated with LL. Economic total gain after incorporating the VS increased from less than 500 USD ha−1 up to 1800 USD ha−1 in the third year after leveling. Yield is more affected under adverse weather conditions with irregular water supply, either limited or excessive; and effects are less pronounced when the yield limiting factor is associated with biotic stress unrelated to irrigation and drainage facts. An environmental positive impact should also be noted, since VS allowed the production benefits of having highly-efficient irrigation and drainage systems, while avoiding major damage to topsoil layers.
Phenotypic Divergence Analysis in Pigeonpea [Cajanus cajan (L.) Millspaugh] Germplasm Accessions
Authors: Nyirenda Yohane Esnart , Shimelis Hussein , Laing Mark , Mathew Isack , Shayanowako Admire
Published: October 2020

Pigeonpea (Cajanus cajan (L.) Millspaugh) is an important source of grain protein for low-income countries such as Malawi. Knowledge of the genetic diversity in pigeonpea is essential for an effective breeding program. The study objective was to assess the genetic diversity among diverse pigeonpea accessions to select complementary and unique genotypes for breeding. Eighty-one pigeonpea accessions were evaluated in six environments in Malawi using a 9 × 9 alpha-lattice design with two replications. The cross-tabulation analysis revealed a significant genotype variation on plant growth, flower, and seed traits. The combined analysis of variance identified genotypes MWPLR 14, ICEAP 01170, ICEAP 871091, and ICEAP 01285 as early maturing varieties, while Kachangu, MWPLR 16, TZA 5582, No. 40, and MWPLR 14 were identified as high-yielding genotypes. The correlation analysis revealed a significant positive correlation between grain yield and a hundred seed weight (HSWT) (r = 0.50, p < 0.01), suggesting the usefulness of this trait for selection. The nonlinear principal component analysis identified grain yield (GDY), days to 50% flowering (DTF), days to 75% maturity (DTM), number of pods per plant (NPP), number of racemes per plant (NRP), 100 seed weight (HSWT), leaf hairiness (LH), and number of seeds per pod (NSP) as the most discriminated traits among the test genotypes. The cluster analysis using morphological traits delineated the accessions into three clusters. The selected high-yielding and early-maturing genotypes may be recommended as parental lines for breeding and grain yield improvement in Malawi or similar agro-ecologies.
Effects of Drip Irrigation Emitter Density with Various Irrigation Levels on Physiological Parameters, Root, Yield, and Quality of Cherry Tomato
Authors: Shabbir Abdul , Mao Hanping , Ullah Ikram , Buttar Noman Ali , Ajmal Muhammad , Lakhiar Imran Ali
Published: October 2020

Root morphology and its components’ behavior could show a considerable response under multiple water application points per plant to help the ultimate effect of fruit yield and fruit quality. In this study, a comparison of a single emitter per plant was made with two, three, and four emitters per plant under drip irrigation and two irrigation levels (full irrigation 100% and deficit irrigation 75% of crop evapotranspiration) to investigate their effects on physiological parameters, root, yield, and their associated components for potted cherry tomato under greenhouse conditions in Jiangsu-China. The experimental results showed that the plants cultivated in the spring-summer planting season showed significantly higher results than the fall-winter planting season due to low temperatures in the fall-winter planting season. However, the response root length, root average diameter, root dry mass, leaf area index, photosynthetic rate, transpiration rate, fruit unit fresh weight, the number of fruits, and pH were increased by multiple emitters per plant over a single emitter per plant, but total soluble solids decreased. Besides, a decreasing trend was observed by deficit irrigation for both planting seasons, and vice versa for the case for tomato total soluble solids. Due to an increase in measured parameters for multiple emitters per plant over a single emitter per plant, the yield, water use efficiency, and water use efficiency biomass significantly increased by 18.1%, 17.6%, and 15.1%, respectively. The deficit irrigation caused a decrease in the yield of 5% and an increase in water use efficiency and water use efficiency biomass of 21.4% and 22.9%, respectively. Two, three, and four emitters per plant had no significant effects, and the obtained results were similar. Considering the root morphology, yield, water use efficiency, water use efficiency biomass, and fruit geometry and quality, two emitters per plant with deficit irrigation are recommended for potted cherry tomato under greenhouse conditions. The explanation for the increased biomass production of the plant, yield, and water use efficiency is that two emitters per plant (increased emitter density) reduced drought stress to the roots, causing increased root morphology and leaf area index and finally promoting the plant’s photosynthetic activity.
The Herbicidal Potential of Different Pelargonic Acid Products and Essential Oils against Several Important Weed Species
Authors: Travlos Ilias , Rapti Eleni , Gazoulis Ioannis , Kanatas Panagiotis , Tataridas Alexandros , Kakabouki Ioanna , Papastylianou Panayiota
Published: October 2020

There is growing consideration among farmers and researchers regarding the development of natural herbicides providing sufficient levels of weed control. The aim of the present study was to compare the efficacy of four different pelargonic acid products, three essential oils and two natural products’ mixtures against L. rigidum Gaud., A. sterilis L. and G. aparine L. Regarding grass weeds, it was noticed at 7 days after treatment that PA3 treatment (pelargonic acid 3.102% w/v + maleic hydrazide 0.459% w/v) was the least efficient treatment against L. rigidum and A. sterilis. The mixture of lemongrass oil and pelargonic acid resulted in 77% lower dry weight for L. rigidum in comparison to the control. Biomass reduction reached the level of 90% as compared to the control in the case of manuka oil and the efficacy of manuka oil and pelargonic acid mixture was similar. For sterile oat, weed biomass was recorded between 31% and 33% of the control for lemongrass oil, pine oil, PA1 (pelargonic acid 18.67% + maleic hydrazide 3%) and PA4 (pelargonic acid 18.67%) treatments. In addition, the mixture of manuka oil and pelargonic acid reduced weed biomass by 96% as compared to the control. Regarding the broadleaf species G. aparine, PA4 and PA1 treatments provided a 96–97% dry weight reduction compared to the corresponding value recorded for the untreated plants. PA2 (pelargonic acid 50% w/v) treatment and the mixture of manuka oil and pelargonic acid completely eliminated cleaver plants. The observations made for weed dry weight on the species level were similar to those made regarding plant height values recorded for each species. Further research is needed to study more natural substances and optimize the use of natural herbicides as well as natural herbicides’ mixtures in weed management strategies under different soil and climatic conditions.
The Effect of a Physiotherapy Intervention on Thoracolumbar Posture in Horses
Authors: Shakeshaft Amy , Tabor Gillian
Published: October 2020

Dynamic mobilisation exercises (DME) are often used as part of a physiotherapy rehabilitation programme. Whilst immediate kinematic effects have been measured, the change in posture is anecdotally reported to have a longer duration. This study aimed to test the reliability of a simple objective measurement method, suitable for use in clinical practice, and to objectively measure equine thoracolumbar posture, before and after DME. A single investigator took triplicate measurements of the sagittal thoracolumbar shape using a flexicurve ruler (FCR) then triplicate measurements of the thoracolumbar shape using an adapted FCR (aFCR) in 37 horses. Subsequently, the thoracolumbar shape of 12 horses was measured using the aFCR before random allocation into two groups. Six horses acted as a control group and six horses underwent a series of DME, which included cervical flexion and lateral flexion baited stretches. Measurements were repeated prior to DME, at thirty minutes, one hour and at twenty-four hours after DME to assess thoracolumbar posture. The aFCR ruler had excellent intra-rater reliability compared to a standard FCR (aFCR: p = 0.146; intraclass correlation coefficient (ICC) 0.971; FCR: p = 0.0001; ICC 0.979). Significant increases in flexion occurred in the thoracolumbar region at 30 min (p = 0.027) and one hour (p = 0.046) after DME, but not at 24 h (p > 0.05) with no significant differences in the control group (p > 0.05) between baseline and subsequent times. The results suggest DME create a short-term postural change, determined by using an aFCR, which supports their use as part of a veterinary physiotherapy rehabilitation programme.
Effect of Different Amounts of Hybrid Barley in Diets on the Growth Performance and Selected Biochemical Parameters of Blood Serum Characterizing Health Status in Fattening Pigs
Authors: Szuba-Trznadel Anna , Hikawczuk Tomasz , Korzeniowska Małgorzata , Fuchs Bogusław
Published: October 2020

The aim of the study was to determine the effect of dietary hybrid barley and/or wheat on production parameters, selected biochemical parameters of blood serum characterizing health status in fattening pigs. In group I, hybrid barley constituted 80% of feed; in II—wheat and hybrid barley were used, each in amount of 40% feed; in III—contained 80% of wheat. No significant differences were noted in case of performance results (body weight gains, feed intake, and feed conversion ratio) and meatiness of fatteners. All estimated biochemical indices determined in serum were within normal range. Usage of 80% hybrid barley decreased concentration of total cholesterol, low-density lipoprotein fraction (LDL), and triglycerides in blood (p < 0.05). However, high-density lipoprotein fraction (HDL) content increased (p < 0.01) up to 1.04 mmol·dm−3, comparing to the group with 80% of wheat (0.84 mmol·dm−3). Summarized, the diet with high level of barley had a beneficial effect on blood lipid indices, what indicate a good health status of all animals.
Microbial Profile Antibacterial Properties and Chemical Composition of Raw Donkey Milk
Authors: Massouras Theofilos , Bitsi Nefeli , Paramithiotis Spiros , Manolopoulou Eugenia , Drosinos Eleftherios H. , Triantaphyllopoulos Kostas A.
Published: October 2020

The human interest in donkey milk is growing due to its nutritional, functional properties and excellent microbiological quality according to published reports. However, more research needs to be conducted to assess the above variables from various breeds. In the present study, milk samples were collected from 17 Cypriot and six Arcadian healthy Greek donkeys. The microbiological quality, somatic cell counts (SCC), chemical composition analysis, and antimicrobial activity of the samples was assessed. In addition, clustering and identification of the bacterial composition was performed by RAPD-PCR and 16S rDNA sequencing, respectively. The good microbiological quality of the samples as estimated by the total aerobic mesophilic and psychrotrophic counts, which ranged from 2.18 to 2.71 log CFU/mL and from 1.48 to 2.37 log CFU/mL, respectively, was also verified. SCC were below 4.4 log CFU/mL. However, potential pathogenic species of Staphylococcus aureus, Bacillus cereus, and Clostridium spp. were enumerated in the milk of both breeds. The gross chemical composition showed mean values for fat, protein, and lactose from 0.82% to 1.24%, 1.22% to 1.87%, and 6.01% to 6.78%, respectively. All milk samples exhibited an antimicrobial activity against St. haemolyticus and Listeria monocytogenes, although quality control measures should be taken for health and safety prior to human consumption.
Effects of Pirfenidone and Nintedanib on Markers of Systemic Oxidative Stress and Inflammation in Patients with Idiopathic Pulmonary Fibrosis: A Preliminary Report
Authors: Fois Alessandro G. , Sotgiu Elisabetta , Scano Valentina , Negri Silvia , Mellino Sabrina , Zinellu Elisabetta , Pirina Pietro , Pintus Gianfranco , Carru Ciriaco , Mangoni Arduino A. , Zinellu Angelo
Published: October 2020

Introduction: In vitro evidence suggests that pirfenidone and nintedanib, approved agents for the treatment of idiopathic pulmonary fibrosis (IPF), exert anti-inflammatory and anti-oxidant effects. We aimed to investigate such effects in vivo in IPF patients. Methods: Systemic circulating markers of oxidative stress [nuclear factor erythroid 2–related factor 2 (Nrf2), thiobarbituric acid- reactive substances (TBARS), homocysteine (Hcy), cysteine (Cys), asymmetric dimethylarginine (ADMA) and ADMA/Arginine ratio, glutathione (GSH), plasma protein –SH (PSH), and taurine (Tau)] and inflammation [Kynurenine (Kyn), Tryptophan (Trp) and Kyn/Trp ratio] were measured at baseline and after 24-week treatment in 18 IPF patients (10 treated with pirfenidone and 8 with nintedanib) and in 18 age- and sex-matched healthy controls. Results: Compared to controls, IPF patients had significantly lower concentrations of reduced blood GSH (457 ± 73 µmol/L vs 880 ± 212 µmol/L, p < 0.001) and plasma PSH (4.24 ± 0.95 µmol/g prot vs 5.28 ± 1.35 µmol/g prot, p = 0.012). Pirfenidone treatment significantly decreased the Kyn/Trp ratio (0.030 ± 0.011 baseline vs 0.025 ± 0.010 post-treatment, p = 0.048) whilst nintedanib treatment significantly increased blood GSH (486 ± 70 μmol/L vs 723 ± 194 μmol/L, p = 0.006) and reduced ADMA concentrations (0.501 ± 0.094 vs. 0.468 ± 0.071 μmol/L, p = 0.024). Conclusion: pirfenidone and nintedanib exert beneficial effects on specific markers of oxidative stress and inflammation in IPF patients.
Experimental Investigation of Deposition Pattern on the Temperature and Distortion of Direct Energy Deposition-Based Additive Manufactured Part
Authors: Lee Jaemin , Chung Hyun
Published: October 2020

The effect of deposition pattern on the temperature and global distortion of Direct Metal Tooling (DMT) based Additive Manufactured (AM) is investigated through the experimental results of laser deposited SUS316. DMT is one of the Directed Energy Deposition (DED) processes. In situ temperature measurements were used to monitor the temperature of the substrates and global distortion patterns were analyzed using CMM (coordinate Measuring Machine) after the deposition. Six different patterns combining long raster and short raster patterns were considered for the case studies. The results showed that the deposition pattern affects the temperature gradient and that the peak temperature of each layer can increase or decrease according to the sequence of the deposition pattern. Also, the pattern of the first layer had a dominant influence on the longitudinal bending deflection that occurs. Based on these results, appropriate tool path schedule can be utilized to control not only the distortion but also the peak temperature of the DMT-based AM parts.
PetriNet Editor + PetriNet Engine: New Software Tool For Modelling and Control of Discrete Event Systems Using Petri Nets and Code Generation
Authors: Kučera Erik , Haffner Oto , Drahoš Peter , Leskovský Roman , Cigánek Ján
Published: October 2020

Petri nets are an important tool for creation of new platforms for digitised production systems due to their versatility in modelling discrete event systems. For the development of modern complex production processes for Industry 4.0, using advanced mathematical models based on Petri nets is an appropriate and effective option. The main aim of the proposed article is to design a new software tool for modelling and control of discrete event systems using Arduino-type microcontrollers and code generation techniques. To accomplish this task, a new tool called “PetriNet editor + PetriNet engine” based on Petri nets is proposed able to generate the code for the microcontroller according to the modelled Petri net. The developed software tool was successfully verified in control of a laboratory plant. Offering a graphical environment for the design of discrete event system control algorithms, it can be used for education, research and practice in cyber-physical systems (Industry 4.0).
Moisture Buffering in Surface Materials Due to Simultaneous Varying Relative Humidity and Temperatures: Experimental Validation of New Analytical Formulas
Authors: Cascione Valeria , Hagentoft Carl-Eric , Maskell Daniel , Shea Andy , Walker Pete
Published: October 2020

Buildings are subjected to the indoor environment, especially in non-controlled climates. Temperature and humidity variations might effect or even damage materials sensitive to moisture. For this reason, it is important to understand the response of hygroscopic materials to variable indoor environmental conditions. Existing methods looked into the dynamic sorption capacity of materials, by analysing the impact of only humidity fluctuations, with temperature usually considered non-influential or non variable. However, temperature fluctuations may impact the moisture capacity of the materials, as materials properties might substantially vary with temperature. Moreover, in existing protocols, the humidity variations are considered to be varying under square wave fluctuations, which may not be applicable in environments, where the indoor is influenced by daily and seasonal climate variations, which presents more complex fluctuation. In this study, a simulation method that can predict the impact of environmental condition on materials under simultaneous temperature and humidity fluctuations was developed. Clay and gypsum plaster were analysed in the numerical model and results were then validated with experimental data. Materials were subjected to either sinusoidal and triangular temperature and RH variations and different cycle time intervals. The investigation of sinusoidal and triangular environmental variations pushed to a better understanding of materials response to different environments and to the improvement of the simplified model. The development of a simplified model can realistically predict the potential future impact of climate changes on buildings without the use of complex and memory demanding computational methods.
Editorial “High-Performance Green Extraction of Natural Products”
Authors: Makris Dimitris P.
Published: October 2020

There has been, to-date, a large number of studies pertaining to the exploitation of plant resources (herbs, botanicals, processing by-products) for the production of extracts enriched with bioactive substances [...]
Camera-Based Method for Identification of the Layout of a Robotic Workcell
Authors: Huczala Daniel , Oščádal Petr , Spurný Tomáš , Vysocký Aleš , Vocetka Michal , Bobovský Zdenko
Published: October 2020

In this paper, a new method for the calibration of robotic cell components is presented and demonstrated by identification of an industrial robotic manipulator’s base and end-effector frames in a workplace. It is based on a mathematical approach using a Jacobian matrix. In addition, using the presented method, identification of other kinematic parameters of a robot is possible. The Universal Robot UR3 was later chosen to prove the working principle in both simulations and experiment, with a simple repeatable low-cost solution for such a task—image analysis to detect tag markers. The results showing the accuracy of the system are included and discussed.
An MI-SDP Model for Optimal Location and Sizing of Distributed Generators in DC Grids That Guarantees the Global Optimum
Authors: Gil-González Walter , Molina-Cabrera Alexander , Montoya Oscar Danilo , Grisales-Noreña Luis Fernando
Published: October 2020

This paper deals with a classical problem in power system analysis regarding the optimal location and sizing of distributed generators (DGs) in direct current (DC) distribution networks using the mathematical optimization. This optimization problem is divided into two sub-problems as follows: the optimal location of DGs is a problem, with those with a binary structure being the first sub-problem; and the optimal sizing of DGs with a nonlinear programming (NLP) structure is the second sub-problem. These problems originate from a general mixed-integer nonlinear programming model (MINLP), which corresponds to an NP-hard optimization problem. It is not possible to provide the global optimum with conventional programming methods. A mixed-integer semidefinite programming (MI-SDP) model is proposed to address this problem, where the binary part is solved via the branch and bound (B&B) methods and the NLP part is solved via convex optimization (i.e., SDP). The main advantage of the proposed MI-SDP model is the possibility of guaranteeing a global optimum solution if each of the nodes in the B&B search is convex, as is ensured by the SDP method. Numerical validations in two test feeders composed of 21 and 69 nodes demonstrate that in all of these problems, the optimal global solution is reached by the MI-SDP approach, compared to the classical metaheuristic and hybrid programming models reported in the literature. All the simulations have been carried out using the MATLAB software with the CVX tool and the Mosek solver.
Autonomous Underwater Vehicle Powered by Direct Methanol Fuel Cell-Based Power Plants: A Quick Preliminary Design Model
Authors: Villalba-Herreros Antonio , Santiago Ó. , Magistri Loredana , J. Leo Teresa
Published: October 2020

Investigation, conservation, and exploitation of seas require platforms capable of accomplishing a wide variety of missions in harsh environments with restricted human intervention for long periods of time. Autonomous Underwater Vehicles (AUVs) are excellent tools for carrying out these missions due to their versatility and ability to access remote sites. However, despite the improvement of their capabilities, their development is not devoid of challenges. Endurance, among others, such as underwater communications or autonomy, is still a pending subject. Current battery-based solutions do not offer sufficient endurance and innovative power plants with higher energy content are needed. This work studies the advantages, in terms of endurance, of using a power plant based on Direct Methanol Fuel Cells (DMFCs) to power AUVs. In order to accomplish this, a multi-objective optimization tool that makes use of a genetic algorithm was developed. This tool allows quick preliminary design of AUVs with a DMFC-based power plant, complying with a user-defined payload, operation profile, and restrictions. Six designs based on a real AUV model were studied, and endurance values up to 2 times longer than the corresponding reference AUV were obtained. These results support the benefits of using DMFCs to power AUVs to increase their endurance.
Achieve Personalized Exercise Intensity through an Intelligent System and Cycling Equipment: A Machine Learning Approach
Authors: Wu Yichen , Ma Zuchang , Zhao Huanhuan , Li Yibing , Sun Yining
Published: October 2020

Using absolute intensity methods (metabolic equivalent of energy (METs), etc.) to determine exercise intensity in exercise prescriptions is straightforward and convenient. Using relative intensity methods (heart rate reserve (%HRR), maximal heart rate (%HRmax), etc.) is more recommended because it is more personalized. Taking target heart rate (THR) given by the relative method as an example, compared with just presenting the THR value, intuitively providing the setting parameters for achieving the THR with specific sport equipment is more user-friendly. The objective of this study was to find a method which combines the advantages (convenient and personalized) of the absolute and relative methods and relatively avoids their disadvantages, helping individuals to meet the target intensity by simply setting equipment parameters. For this purpose, we recruited 32 males and 29 females to undergo incremental cardiopulmonary exercise testing with cycling equipment. The linear regression model of heart rate and exercise wattage (the setting parameter of the equipment) was constructed for each one (R2 = 0.933, p < 0.001), and the slopes of the graph of these models were obtained. Next, we used an iterative algorithm to obtain a multiple regression model (adjusted R2 = 0.8336, p < 0.001) of selected static body data and the slopes of participants. The regression model can accurately predict the slope of the general population through their static body data. Moreover, other populations can guarantee comparable accuracy by using questionnaire data for calibration. Then, the predicted slope can be utilized to calculate the equipment’s settings for achieving a personalized THR through our equation. All of these steps can be assigned to the intelligent system.
Analysis of the Use of Geomorphic Elements Mapping to Characterize Subaqueous Bedforms Using Multibeam Bathymetric Data in River System
Authors: Yan Ge , Cheng Heqin , Teng Lizhi , Xu Wei , Jiang Yuehua , Yang Guoqiang , Zhou Quanping
Published: October 2020

Riverbed micro-topographical features, such as crest and trough, flat bed, and scour pit, indicate the evolution of fluvial geomorphology, and have an influence on the stability of underwater structures and overall scour pits. Previous studies on bedform feature extraction have focused mainly on the rhythmic bed surface morphology and have extracted crest and trough, while flat bed and scour pit have been ignored. In this study, to extend the feature description of riverbeds, geomorphic elements mapping was used by employing three geomorphic element classification methods: Wood’s criteria, a self-organization map (SOM) technique, and geomorphons. The results showed that geomorphic element mapping can be controlled by adjusting the slope tolerance and curvature tolerance of Wood’s criteria, using the map unit number and combination of the SOM technique and the flatness of geomorphons. Relatively flat bed can be presented using “plane”, “flat planar”, and “flat” elements, while scour pit can be presented using a “pit” element. A comparison of the difference between parameter settings for landforms and bedforms showed that SOM using 8 or 10 map units is applicable for land and underwater surface and is thus preferentially recommended for use. Furthermore, the use of geomorphons is recommended as the optimal method for characterizing bedform features because it provides a simple element map in the absence of area loss.
VDAC1 at the Intersection of Cell Metabolism, Apoptosis, and Diseases
Authors: Shoshan-Barmatz Varda , Shteinfer-Kuzmine Anna , Verma Ankit
Published: October 2020

The voltage-dependent anion channel 1 (VDAC1) protein, is an important regulator of mitochondrial function, and serves as a mitochondrial gatekeeper, with responsibility for cellular fate. In addition to control over energy sources and metabolism, the protein also regulates epigenomic elements and apoptosis via mediating the release of apoptotic proteins from the mitochondria. Apoptotic and pathological conditions, as well as certain viruses, induce cell death by inducing VDAC1 overexpression leading to oligomerization, and the formation of a large channel within the VDAC1 homo-oligomer. This then permits the release of pro-apoptotic proteins from the mitochondria and subsequent apoptosis. Mitochondrial DNA can also be released through this channel, which triggers type-Ι interferon responses. VDAC1 also participates in endoplasmic reticulum (ER)-mitochondria cross-talk, and in the regulation of autophagy, and inflammation. Its location in the outer mitochondrial membrane, makes VDAC1 ideally placed to interact with over 100 proteins, and to orchestrate the interaction of mitochondrial and cellular activities through a number of signaling pathways. Here, we provide insights into the multiple functions of VDAC1 and describe its involvement in several diseases, which demonstrate the potential of this protein as a druggable target in a wide variety of pathologies, including cancer.
Virtual Screening for Reactive Natural Products and Their Probable Artifacts of Solvolysis and Oxidation
Authors: Xu Tingjun , Chen Weiming , Zhou Junhong , Dai Jingfang , Li Yingyong , Zhao Yingli
Published: October 2020

Chemically unstable natural products are prone to show their reactivity in the procedures of extraction, purification, or identification and turn into contaminants as so-called “artifacts”. However, identification of artifacts requires considerable investments in technical equipment, time, and human resources. For revealing these reactive natural products and their artifacts by computational approaches, we set up a virtual screening system to seek cases in a biochemical database. The screening system is based on deep learning models of predicting the two main classifications of conversion reactions from natural products to artifacts, namely solvolysis and oxidation. A set of result data was reviewed for checking validity of the screening system, and we screened out a batch of reactive natural products and their probable artifacts. This work provides some insights into the formations of natural product artifacts, and the result data may act as warnings regarding the improper handling of biological matrixes in multicomponent extraction.
Extracellular Vesicles in the Development of the Non-Alcoholic Fatty Liver Disease: An Update
Authors: Dorairaj Vicneswarry , Sulaiman Siti Aishah , Abu Nadiah , Abdul Murad Nor Azian
Published: October 2020

Non-alcoholic fatty liver disease (NAFLD) is a broad spectrum of liver damage disease from a simple fatty liver (steatosis) to more severe liver conditions such as non-alcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Extracellular vesicles (EVs) are a heterogeneous group of small membrane vesicles released by various cells in normal or diseased conditions. The EVs carry bioactive components in their cargos and can mediate the metabolic changes in recipient cells. In the context of NAFLD, EVs derived from adipocytes are implicated in the development of whole-body insulin resistance (IR), the hepatic IR, and fatty liver (steatosis). Excessive fatty acid accumulation is toxic to the hepatocytes, and this lipotoxicity can induce the release of EVs (hepatocyte-EVs), which can mediate the progression of fibrosis via the activation of nearby macrophages and hepatic stellate cells (HSCs). In this review, we summarized the recent findings of adipocyte- and hepatocyte-EVs on NAFLD disease development and progression. We also discussed previous studies on mesenchymal stem cell (MSC) EVs that have garnered attention due to their effects on preventing liver fibrosis and increasing liver regeneration and proliferation.
Multimodal Treatment of Advanced Mucosal Melanoma in the Era of Modern Immunotherapy
Authors: Teterycz Pawel , Czarnecka Anna M. , Indini Alice , Spałek Mateusz J. , Labianca Alice , Rogala Pawel , Cybulska-Stopa Bożena , Quaglino Pietro , Ricardi Umberto , Badellino Serena , Szumera-Ciećkiewicz Anna , Falkowski Slawomir , Mandala Mario , Rutkowski Piotr
Published: October 2020

Mucosal melanoma is a rare disease epidemiologically and molecularly distinct from cutaneous melanoma developing from melanocytes located in mucosal membranes. Little is known about its therapy. In this paper, we aimed to evaluate the results of immunotherapy and radiotherapy in a group of patients with advanced mucosal melanoma, based on the experience of five high-volume centers in Poland and Italy. There were 82 patients (53 female, 29 male) included in this retrospective study. The median age in this group was 67.5 (IQR: 57.25–75.75). All patients received anti-PD1 or anti-CTLA4 antibodies in the first or second line of treatment. Twenty-three patients received radiotherapy during anti-PD1 treatment. In the first-line treatment, the median progression-free survival (PFS) reached six months in the anti-PD1 group, which was statistically better than 3.1 months in the other modalities group (p = 0.004). The median overall survival (OS) was 16.3 months (CI: 12.1–22.3) in the whole cohort. Patients who received radiotherapy (RT) during the anti-PD1 treatment had a median PFS of 8.9 months (CI: 7.4–NA), whereas patients treated with single-modality anti-PD1 therapy had a median PFS of 4.2 months (CI: 3.0–7.8); this difference was statistically significant (p = 0.047). Anti-PD1 antibodies are an effective treatment option in advanced mucosal melanoma (MM). The addition of RT may have been beneficial in the selected subgroup of mucosal melanoma patients.
Prognostic Stratification of Bladder Cancer Patients with a MicroRNA-Based Approach
Authors: Cavallari Ilaria , Grassi Angela , Del Bianco Paola , Aceti Alberto , Zaborra Carlotta , Sharova Evgeniya , Bertazzolo Irene , D’Agostino Donna M. , Iafrate Massimo , Ciminale Vincenzo
Published: October 2020

Robust non-invasive tests for prognostic stratification of bladder cancer (BCa) patients are in high demand. Following a comprehensive analysis of studies on BCa, we selected a panel of 29 microRNAs (miRNAs) and analyzed their levels in urine and plasma samples in a prospective cohort of 63 BCa patients (32 at high risk of recurrence and 31 low-risk cases) and 37 healthy controls using RT-qPCR. To design an assay suitable for large-scale testing, we applied a hierarchical pipeline to select the miRNAs that were not affected by confounding factors such as haematuria and urine specific gravity, and exceeded stringent cut-off criteria (fold change > 2.5 and p-value < 0.005). Using a two-step decision tree based on the urine levels of miR-34a-5p, miR-200a-3p and miR-193a-5p, normalized against miR-125b-5p, patients could be classified as high- or low-risk with a sensitivity of 0.844, specificity of 0.806 and accuracy of 0.825. Furthermore, univariate Cox proportional hazards regression analyses indicated that increased urine levels of miR-29a-3p, miR-34a-5p, miR-193a-5p, miR-200c-3p, miR-205-5p and miR-532-5p were associated with a shorter event-free survival (hazard ratios > 3.1, p-value < 0.05). Taken together, our findings suggest that measuring the urine levels of these miRNAs could provide a novel cost-effective, noninvasive test for risk assessment of BCa patients.
Biomimetic Upconversion Nanoparticles and Gold Nanoparticles for Novel Simultaneous Dual-Modal Imaging-Guided Photothermal Therapy of Cancer
Authors: Wang Ruliang , Yang Han , Fu Rongxin , Su Ya , Lin Xue , Jin Xiangyu , Du Wenli , Shan Xiaohui , Huang Guoliang
Published: October 2020

Multimodal imaging-guided near-infrared (NIR) photothermal therapy (PTT) is an interesting and promising cancer theranostic method. However, most of the multimodal imaging systems provide structural and functional information used for imaging guidance separately by directly combining independent imaging systems with different detectors, and many problems arise when trying to fuse different modal images that are serially taken by inviting extra markers or image fusion algorithms. Further, most imaging and therapeutic agents passively target tumors through the enhanced permeability and retention (EPR) effect, which leads to low utilization efficiency. To address these problems and systematically improve the performance of the imaging-guided PTT methodology, we report a novel simultaneous dual-modal imaging system combined with cancer cell membrane-coated nanoparticles as a platform for PTT-based cancer theranostics. A novel detector with the ability to detect both high-energy X-ray and low-energy visible light at the same time, as well as a dual-modal imaging system based on the detector, was developed for simultaneous dual-modal imaging. Cancer cell membrane-coated upconversion nanoparticles (CC-UCNPs) and gold nanoparticles (CC-AuNPs) with the capacity for immune evasion and active tumor targeting were engineered for highly specific imaging and high-efficiency PTT therapy. In vitro and in vivo evaluation of macrophage escape and active homologous tumor targeting were performed. Cancer cell membrane-coated nanoparticles (CC-NPs) displayed excellent immune evasion ability, longer blood circulation time, and higher tumor targeting specificity compared to normal PEGylated nanoparticles, which led to highly specific upconversion luminescence (UCL) imaging and PTT-based anti-tumor efficacy. The anti-cancer efficacy of the dual-modal imaging-guided PTT was also evaluated both in vitro and in vivo. Dual-modal imaging yielded precise anatomical and functional information for the PTT process, and complete tumor ablation was achieved with CC-AuNPs. Our biomimetic UCNP/AuNP and novel simultaneous dual-modal imaging combination could be a promising platform and methodology for cancer theranostics.
A Molecular Test for Quantifying Functional Notch Signaling Pathway Activity in Human Cancer
Authors: Canté-Barrett Kirsten , Holtzer Laurent , van Ooijen Henk , Hagelaar Rico , Cordo’ Valentina , Verhaegh Wim , van de Stolpe Anja , Meijerink Jules P. P.
Published: October 2020

Background: The Notch signal transduction pathway is pivotal for various physiological processes, including immune responses, and has been implicated in the pathogenesis of many diseases. The effectiveness of various targeted Notch pathway inhibitors may vary due to variabilities in Notch pathway activity among individual patients. The quantitative measurement of Notch pathway activity is therefore essential to identify patients who could benefit from targeted treatment. Methods: We here describe a new assay that infers a quantitative Notch pathway activity score from the mRNA levels of generally conserved direct NOTCH target genes. Following the calibration and biological validation of our Notch pathway activity model over a wide spectrum of human cancer types, we assessed Notch pathway activity in a cohort of T-ALL patient samples and related it to biological and clinical parameters, including outcome. Results: We developed an assay using 18 select direct target genes and high-grade serous ovarian cancer for calibration. For validation, seven independent human datasets (mostly cancer series) were used to quantify Notch activity in agreement with expectations. For T-ALL, the median Notch pathway activity was highest for samples with strong NOTCH1-activating mutations, and T-ALL patients of the TLX subtype generally had the highest levels of Notch pathway activity. We observed a significant relationship between ICN1 levels and the absence/presence of NOTCH1-activating mutations with Notch pathway activity scores. Patients with the lowest Notch activity scores had the shortest event-free survival compared to other patients. Conclusions: High Notch pathway activity was not limited to T-ALL samples harboring strong NOTCH1 mutations, including juxtamembrane domain mutations or hetero-dimerization combined with PEST-domain or FBXW7 mutations, indicating that additional mechanisms may activate Notch signaling. The measured Notch pathway activity was related to intracellular NOTCH levels, indicating that the pathway activity score more accurately reflects Notch pathway activity than when it is predicted on the basis of NOTCH1 mutations. Importantly, patients with low Notch pathway activity had a significantly shorter event-free survival compared to patients showing higher activity.
A Gene Expression High-Throughput Screen (GE-HTS) for Coordinated Detection of Functionally Similar Effectors in Cancer
Authors: Rao Chaitra , Huisman Dianna H. , Vieira Heidi M. , Frodyma Danielle E. , Neilsen Beth K. , Chakraborty Binita , Hight Suzie K. , White Michael A. , Fisher Kurt W. , Lewis Robert E.
Published: October 2020

Genome-wide, loss-of-function screening can be used to identify novel vulnerabilities upon which specific tumor cells depend for survival. Functional Signature Ontology (FUSION) is a gene expression-based high-throughput screening (GE-HTS) method that allows researchers to identify functionally similar proteins, small molecules, and microRNA mimics, revealing novel therapeutic targets. FUSION uses cell-based high-throughput screening and computational analysis to match gene expression signatures produced by natural products to those produced by small interfering RNA (siRNA) and synthetic microRNA libraries to identify putative protein targets and mechanisms of action (MoA) for several previously undescribed natural products. We have used FUSION to screen for functional analogues to Kinase suppressor of Ras 1 (KSR1), a scaffold protein downstream of Ras in the Raf-MEK-ERK kinase cascade, and biologically validated several proteins with functional similarity to KSR1. FUSION incorporates bioinformatics analysis that may offer higher resolution of the endpoint readout than other screens which utilize Boolean outputs regarding a single pathway activation (i.e., synthetic lethal and cell proliferation). Challenges associated with FUSION and other high-content genome-wide screens include variation, batch effects, and controlling for potential off-target effects. In this review, we discuss the efficacy of FUSION to identify novel inhibitors and oncogene-induced changes that may be cancer cell-specific as well as several potential pitfalls within FUSION and best practices to avoid them.
LDOC1 Suppresses Microbe-Induced Production of IL-1β in Human Normal and Cancerous Oral Cells through the PI3K/Akt/GSK-3β Axis
Authors: Lee Chia-Huei , Hung Pin-Feng , Liu Ko-Jiunn , Chung Hsuan-Lien , Yang Wen-Chan , Hsu Kai-Cheng , Fong Tsorng-Harn , Lo Hsiu-Jung , Chen Ya-Ping , Yang Ji-Rui , Yen Ching-Yu
Published: October 2020

Poor oral hygiene (POH) is associated with oral squamous cell carcinoma (OSCC). Oral microbes often proliferate due to POH. Array data show that LDOC1 plays a role in immunity against pathogens. We investigated whether LDOC1 regulates the production of oral microbe-induced IL-1β, an oncogenic proinflammatory cytokine in OSCC. We demonstrated the presence of Candida albicans (CA) in 11.3% of OSCC tissues (n = 80). CA and the oral bacterium Fusobacterium nucleatum stimulate higher levels of IL-1β secretion by LDOC1-deficient OSCC cells than by LDOC1-expressing oral cells. CA SC5314 increased OSCC incidence in 4-NQO (a synthetic tobacco carcinogen) and arecoline-cotreated mice. Loss and gain of LDOC1 function significantly increased and decreased, respectively, CA SC5314-induced IL-1β production in oral and OSCC cell lines. Mechanistic studies showed that LDOC1 deficiency increased active phosphorylated Akt upon CA SC5314 stimulation and subsequent inhibitory phosphorylation of GSK-3βS9 by activated Akt. PI3K and Akt inhibitors and expression of the constitutively active mutant GSK-3βS9A significantly reduced the CA SC5314-stimulated IL-1β production in LDOC1-deficient cells. These results indicate that the PI3K/Akt/pGSK-3β signaling pathway contributes to LDOC1-mediated inhibition of oral microbe-induced IL-1β production, suggesting that LDOC1 may determine the pathogenic role of oral microbes in POH-associated OSCC.
Efficacy and Safety of CAP7.1 as Second-Line Treatment for Advanced Biliary Tract Cancers: Data from a Randomised Phase II Study
Authors: Pape Ulrich-Frank , Kasper Stefan , Meiler Johannes , Sinn Marianne , Vogel Arndt , Müller Lothar , Burkhard Oswald , Caca Karel , Heeg Steffen , Büchner-Steudel Petra , Rodriguez-Laval Victor , Kühl Anja A , Arsenic Ruza , Jansen Holger , Treasure Peter , Utku Nalân
Published: October 2020

CAP7.1 is a novel topoisomerase II inhibitor, converted to active etoposide via carboxylesterase 2 (CES2), with signals of efficacy in treatment-refractory solid tumours. In a Phase II trial, 27 patients with advanced biliary tract cancers (BTC) were randomised 1:1 to CAP7.1 plus best supportive care (BSC), or BSC alone, with crossover to CAP7.1 upon disease progression. The primary objective was disease control rate (DCR) following 28-day cycles of CAP7.1 (200/150 mg/m2; iv), or BSC until progression. Secondary objectives included progression-free survival (PFS), time-to-treatment failure (TTF), overall survival (OS) and safety. Fourteen patients received CAP7.1 and 13 BSC. DCR favoured CAP7.1 vs. BSC (50% vs. 20%; treatment difference: 30%, 95%CI −18.44, 69.22, full analysis set [FAS]), with disease progression in 40% vs. 70%, respectively. Significantly longer median PFS was achieved for CAP7.1 vs. BSC: 66 vs. 39 days, respectively (hazard ratio [HR] 0.31; 95%CI 0.11, 0.86; p = 0.009; FAS). Similar trends were observed for TTF and OS. CES2-positive patients had longer median PFS (158 vs. 56 days) and OS (228 vs. 82 days) vs. CES2-negative patients. Adverse events were predictable, dose-dependent and consistent with those previously observed with etoposide. These efficacy and safety findings in second-line BTC warrant further clinical investigation of CAP7.1.
Selected Patients with Unresectable Perihilar Cholangiocarcinoma (pCCA) Derive Long-Term Benefit from Liver Transplantation
Authors: Azad Adiba I. , Rosen Charles B. , Taner Timucin , Heimbach Julie K. , Gores Gregory J.
Published: October 2020

Selected patients with unresectable perihilar cholangiocarcinoma (pCCA) derive long-term benefits from liver transplantation. Between 1993–2019, our group at Mayo Clinic performed 237 transplants for pCCA. With this experience, we note that two distinct patient populations comprise this group of pCCA patients: those with underlying primary sclerosing cholangitis (PSC) and those without identifiable risk factors termed sporadic or de novo pCCA. Long-term survival after transplant is better in PSC patients (74% five-year survival) than in those with de novo pCCA (58% five-year survival). Herein, we review the likely clinical factors contributing to the divergence in outcomes for these two patient populations. We also offer our insights on how further advances may improve patient selection and survival, focusing on the de novo pCCA patient population.