bluuebunny/crossref_metadata_2025 huggingface dataset:
Occurrence of Pesticides Associated with an Agricultural Drainage System in a Mediterranean Environment
Authors: Melendez-Pastor Ignacio , Hernández Encarni I. , Navarro-Pedreño Jose , Almendro-Candel María Belén , Gómez Lucas Ignacio , Jordán Vidal Manuel Miguel
Published: November 2021

Surface water pollution (as a result of pesticides) is a major problem, due to the negative impact on human health and ecosystems. The excessive use and persistence of surface water pollution in the environment may present a notable risk. In this article, DDT and its metabolite DDE hereafter, DDT–DDE), and a commonly used pesticide (herbicide) glyphosate, were analyzed in agricultural drainage waters; afterward, a spatial analysis was applied to identify potential areas of high pesticide occurrence in an agricultural Mediterranean coastal floodplain. The spatial distribution of banned (Directive 79/117/EEC), yet highly persistent pesticides in the environment, such as DDT (and metabolites), was compared with the (currently and mostly used) glyphosate. A sequence of various point patterns, spatial analysis methods, and non-parametric statistics, were computed to elucidate the pesticide pollution hotspots. As a reference value, almost 70% of the water samples were above the World Health Organization (WHO) guideline for DDT (and metabolites) for drinking water (1 µg/L), with a maximum of 6.53 µg/L. Our spatial analysis approach revealed a significantly high concentration of DDT–DDE clusters close to wetlands in natural parks, where mosquitos are abundant, and pesticides persist and flow to the surface waters from soil and groundwater pools. Conversely, glyphosate concentrations were below WHO guidelines; their spatial patterns were related more toward current agricultural uses in the southern sector of the study area.
Evaluation of Investments in Wind Energy Projects, under Uncertainty. State of the Art Review
Authors: Murgas Benjamin , Henao Alvin , Guzman Luceny
Published: November 2021

The use of renewable energy sources, especially wind energy, has been widely developed, mostly during the last decade. The main objective of the present study is to conduct a literature review focused on the evaluation under uncertainty of wind energy investment using the real options approach to find out whether public opposition (NIMBY projects) has been contemplated, and if so, what have been the flexible strategies applied for its intervention. Overall, 97 publications were analyzed, identifying 20 different models or approaches, which were grouped into eight categories: 1. Real options, 2. Optimization, 3. Stochastics, 4. Financial evaluation, 5. Probabilistic, 6. Estimation, 7. Numerical prediction, and 8. Others. The real options approach, present in 32% of the studies, was the most popular. Twenty-eight types of uncertainties were identified, which were grouped, for better analysis, into nine categories. In total, 62.5% of the studies included the price of electricity as a source of uncertainty; 18.8%, the velocity of wind; and 15.6%, the feed-in rates-subsidy. Both random and non-random techniques were applied to assess the real options and to model the uncertainties. When evaluating real options, the Monte Carlo simulation technique was the most preferred, with 16 (51.6%) applications, followed by non-randomized techniques, decision tree, and dynamic programming, with eight (25.8%) applications each. There is a marked tendency to use stochastic processes to model uncertainty, particularly geometric Brownian motion, which was used in 61.3% (19) of the studies in the sample. When searching for “real options AND (nimby OR public opposition)”, no study was found, which shows the possibility of developing research on this aspect to determine its impact on investments in wind energy projects.
Testing a Single-Case Experimental Design to Study Dynamic Light Exposure in People with Dementia Living at Home
Authors: van Lieshout-van Dal Ellen , Snaphaan Liselore , Bouwmeester Samantha , de Kort Yvonne , Bongers Inge
Published: November 2021

Most people with dementia live at home supported by informal caregivers, but disturbed sleep patterns may induce a heavy burden of care. The beneficial effects of bright light on their sleep, health, and well-being have been demonstrated in clinical settings, but not in a home situation. We evaluated a dynamic lighting system in a real-life longitudinal single-case experimental design (SCED) with people with dementia living at home. Eleven people with dementia and their informal caregivers were included in this study with four 4-week periods of alternating exposure and nonexposure in an introduction–withdrawal setup (ABAB). Objective light exposure data were collected and analyzed. The used study design seems applicable for this population and suitable for home use. Participant dropout did occur, but was due to health conditions rather than participant burden. The lighting system led to more light in the homes of the participants, as well as to higher actual individual light exposures, although the latter increased only moderately and not consistently across all participants, seasons, and times of day. The participants appreciated the lighting system even after 6 months. We reflect on individual differences, seasonal and daypart influences, and differential light effects. Recommendations and lessons learned are discussed.
Comparison of the Mechanical Behavior of Concrete Containing Recycled CFRP Fibers and Polypropylene Fibers
Authors: Prieto María Isabel , González María de las Nieves , Cobo Alfonso , Alonso David
Published: November 2021

The incorporation of natural or recycled fibers in concrete represents a field for improvement in this structural material and a step towards sustainability. The objective of this research is to determine whether the addition of recycled carbon fibers (CFRP), which have been hardened using epoxy resin, improves the behavior of concrete and whether its performance is comparable to that achieved by adding polypropylene fibers, which would result in a viable recycling alternative for this type of fiber. In order to explore this objective, 120 specimens were produced, on which compression, flexural, and impact tests were performed, and into which recycled CFRP fibers or polypropylene fibers were incorporated. By comparing the results obtained, it may be concluded that the addition of fibers substantially improves the ductility of the concrete and reduces the spalling effect when compared to concretes without added fibers. The concretes containing recycled CFRP fibers in quantities of 3 kg/m3 and 6 kg/m3 obtain better flexural and impact behaviors than concretes featuring the same amounts of polypropylene fibers, making this recycling alternative viable for CFRP fibers as well as reducing the amount of energy and raw materials that would be used to manufacture the fibers.
Experimental Comparison of Three Characterization Methods for Two Phase Change Materials Suitable for Domestic Hot Water Storage
Authors: Thonon Maxime , Zalewski Laurent , Gibout Stéphane , Franquet Erwin , Fraisse Gilles , Pailha Mickael
Published: November 2021

This study presents an experimental comparison of three characterization methods for phase change materials (PCM). Two methods were carried out with a calorimeter, the first with direct scanning (DSC) and the second with step scanning (STEP). The third method is a fluxmetric (FM) characterization performed using a fluxmeter bench. For the three methods, paraffin RT58 and polymer PEG6000, two PCM suitable for domestic hot water (DHW) storage, were characterized. For each PCM, no significant difference was observed on the latent heat and the total energy exchanged between the three characterization methods. However, DSC and STEP methods did not enable the accurate characterization of the supercooling process observed with the FM method for polymer PEG6000. For PEG6000, the shape of the enthalpy curve of melting also differed between the experiments on the calorimeter—DSC and STEP—methods, and the FM method. Concerning the PCM comparison, RT58 and PEG6000 appeared to have an equivalent energy density but, as the mass density of PEG6000 is greater, more energy is stored inside the same volume for PEG6000. However, as PEG6000 experienced supercooling, the discharging temperature was lower than for RT58 and the material is therefore less adapted to DHW storage operating with partial phase change cycles where the PCM temperature does not decrease below 52 °C.
The Impact of Stimulation Intensity on Spatial Discrimination with Multi-Pad Finger Electrode
Authors: Malešević Jovana , Isaković Milica , Garenfeld Martin A. , Došen Strahinja , Štrbac Matija
Published: November 2021

Multi-pad electrotactile stimulation can be used to provide tactile feedback in different applications. The electrotactile interface needs to be calibrated before each use, which entails adjusting the intensity to obtain clear sensations while allowing the subjects to differentiate between active pads. The present study investigated how the stimulation intensity affects the localization of sensations using a multi-pad electrode placed on a fingertip and proximal phalange. First, the sensation, localization, smearing and discomfort thresholds were determined in 11 subjects. Then, the same subjects performed a spatial discrimination test across a range of stimulation intensities. The results have shown that all thresholds were significantly different, while there was no difference in the threshold values between the pads and phalanges. Despite the subjective feeling of spreading of sensations, the success rates in spatial discrimination were not significantly different across the tested stimulation intensities. However, the performance was better for distal compared to proximal phalange. Presented results indicate that spatial discrimination is robust to changes in the stimulation intensity. Considering the lack of significant difference in the thresholds between the pads, these results imply that more coarse adjustment of stimulation amplitude (faster calibration) might be enough for practical applications of a multi-pad electrotactile interface.
Matheuristics for the Design of a Multi-Step, Multi-Product Supply Chain with Multimodal Transport
Authors: Ruvalcaba-Sandoval David A. , Olivares-Benitez Elias , Rojas Omar , Sosa-Gómez Guillermo
Published: November 2021

Supply-chain network design is a complex task because there are many decisions involved, and presently, global networks involve many actors and variables, for example, in the automotive, pharmaceutical, and electronics industries. This research addresses a supply-chain network design problem with four levels: suppliers, factories, warehouses, and customers. The problem considered decides on the number, locations, and capacities of factories and warehouses and the transportation between levels in the supply chain. The problem is modeled as a mixed-integer linear program. The main contribution of this work is the proposal of two matheuristic algorithms to solve the problem. Matheuristics are algorithms that combine exact methods and heuristics, attracting interest in the literature because of their fast execution and high-quality solutions. The matheuristics proposed to select the warehouses and their capacities following heuristic rules. Once the warehouses and their capacities are fixed, the algorithms solve reduced models using commercial optimization software. Medium and large instances were generated based on a procedure described in the literature. A comparison is made between the algorithms and the results obtained, solving the model with a time limit. The algorithms proposed are successful in obtaining better results for the largest instances in shorter execution times.
From Social Gaze to Indirect Speech Constructions: How to Induce the Impression That Your Companion Robot Is a Conscious Creature
Authors: Velichkovsky Boris M. , Kotov Artemiy , Arinkin Nikita , Zaidelman Liudmila , Zinina Anna , Kivva Kirill
Published: November 2021

We implemented different modes of social gaze behavior in our companion robot, F-2, to evaluate the impression of the gaze behaviors on humans in three symmetric communicative situations: (a) the robot telling a story, (b) the person telling a story to the robot, and (c) both parties communicating about objects in the real world while solving a Tangram puzzle. In all the situations the robot localized the human’s eyes and directed its gaze between the human, the environment, and the object of interest in the problem space (if it existed). We examined the balance between different gaze directions as the novel key element to maintaining a feeling of social connection with the robot in humans. We extended the computer model of the robot in order to simulate realistic gaze behavior in the robot and create the impression of the robot changing its internal cognitive states. Other novel results include the implicit, rather than explicit, character of the robot gaze perception for many of our subjects and the role of individual differences, especially the level of emotional intelligence, in terms of human sensitivity to the robotic gaze. Therefore, in this study, we used an iterative approach, extending the applied cognitive architecture in order to simulate the balance between different behavioral reactions and to test it in the experiments. In such a way, we came to a description of the key behavioral cues that suggest to a person that the particular robot can be perceived as an emotional and even conscious creature.
Meteorological Variables That Affect the Beginning of Flowering of the Winter Oilseed Rape in the Czech Republic
Authors: Hájková Lenka , Možný Martin , Oušková Veronika , Bartošová Lenka , Dížková Petra , Žalud Zdeněk
Published: November 2021

Winter oilseed rape (Brassica napus) is one of the most cultivated oilseeds in the Czech Republic and belongs among major pollen allergens. Pollen allergies have an extensive clinical impact worldwide, and as well as in the Czech Republic. In this paper, meteorological variables such as mean air temperature, maximum and minimum air temperature, precipitation total and number of rainy days in the period 1991–2012 were studied using the PhenoClim phenological model to find the best predictor of the beginning of flowering of the Brassica napus in the Czech Republic. In addition, temporal and spatial evaluations of the beginning of flowering of the Brassica napus were examined at individual stations in different climatic zones within the same period. In total, three phenological stations at altitudes from 270 m asl to 533 m asl located in warm (W2), medium warm (MW7) or cold (C7) climatic zones were used for detailed evaluation. Based on the observation results at selected stations, the beginning of flowering of the Brassica napus advanced progressively in timing (nearly −15 days) in the 1991–2012 period. The base temperature and temperature sums were calculated for the beginning of flowering of the winter oilseed rape using the PhenoClim computer tool. As the most accurate predictor for the beginning of flowering of the Brassica napus, the mean air temperature was determined. The optimal start day for calculation was 30th January, the threshold (base temperature) was 6.0 °C and the temperature sum was 157.0 °C. The RMSE value was 4.77 and the MBE value was −3.00. The simulated data had a good correlation with the real observed data (the correlation coefficients were within the range from 0.56 to 0.76), and the PhenoClim model results indicate using them in the forecast modeling of the beginning of flowering of the Brassica napus in the Czech Republic.
Improvement of Heavy Rainfall Simulated with SST Adjustment Associated with Mesoscale Convective Complexes Related to Severe Flash Flood in Luwu, Sulawesi, Indonesia
Authors: Yulihastin Erma , Nuryanto Danang Eko , Trismidianto  , Muharsyah Robi
Published: November 2021

Flash flooding is an important issue as it has a devastating impact over a short time and in a limited area. However, predicting flash floods is challenging because they are connected to convection systems that rapidly evolve and require a high-resolution forecasting system. In addition, modeling a case study of a mesoscale convective complex (MCC) is the key to improving our understanding of the heavy rainfall systems that trigger flash floods. In this study, we aim at improving modeling skills to simulate a heavy rainfall system related to flash-flood-producing MCCs. We simulated a heavy rainfall event related to a severe flash flood in Luwu, Sulawesi, Indonesia, on 13 July 2020. This flood was preceded by persistent heavy rainfall from 11 to 13 July 2020. In this case, we investigated the role of sea surface temperature (SST) in producing the persistent heavy rainfall over the region. Therefore, we explore the physical and dynamic processes that caused the heavy rainfall using a convection-permitting model with 1 km resolution and an experiment comparing the situation with and without updated SST. The results show that the heavy rainfall was modulated by the development of a pair of MCCs during the night. The pair of MCCs was triggered by a meso-low-pressure system with an anti-cyclonic circulation anomaly over the Makassar Strait and was maintained by the warm front passing between the sea and land over central Sulawesi. This front was characterized by moist–warm and cold–dry low-level air, which may have helped extend the lifetime of the MCCs. The north-westward propagation of the MCCs was due to the interaction between predominantly a south-easterly monsoon and SST anomalies. This study suggested that the long-lived (>10 h) MCCs (>80,000 km2 cloud shield) and persistent precipitation are reproduced well in the updated SST scenario in the WRF model. This relatively simple technique in the running model provides a new strategy for improving flash flood forecasting by better predicting rainfall as an input in the hydrological model. Our findings also indicated a long-lived MCC maintained by back-building mechanisms from night to morning inland as an exceptional MCC, which does not correspond to a previous study.
Design and Implementation of a Robotic Arm Assistant with Voice Interaction Using Machine Vision
Authors: Nantzios George , Baras Nikolaos , Dasygenis Minas
Published: November 2021

It is evident that the technological growth of the last few decades has signaled the development of several application domains. One application domain that has expanded massively in recent years is robotics. The usage and spread of robotic systems in commercial and non-commercial environments resulted in increased productivity, efficiency, and higher quality of life. Many researchers have developed systems that improve many aspects of people’s lives, based on robotics. Most of the engineers use high-cost robotic arms, which are usually out of the reach of typical consumers. We fill this gap by presenting a low-cost and high-accuracy project to be used as a robotic assistant for every consumer. Our project aims to further improve people’s quality of life, and more specifically people with physical and mobility impairments. The robotic system is based on the Niryo-One robotic arm, equipped with a USB (Universal Serial Bus) HD (High Definition) camera on the end-effector. To achieve high accuracy, we modified the YOLO algorithm by adding novel features and additional computations to be used in the kinematic model. We evaluated the proposed system by conducting experiments using PhD students of our laboratory and demonstrated its effectiveness. The experimental results indicate that the robotic arm can detect and deliver the requested object in a timely manner with a 96.66% accuracy.
Isopanduratin A Inhibits Tumor Necrosis Factor (TNF)-α-Induced Nuclear Factor κB Signaling Pathway by Promoting Extracellular Signal-Regulated Kinase-Dependent Ectodomain Shedding of TNF Receptor 1 in Human Lung Adenocarcinoma A549 Cells
Authors: Moriwaki Chihiro , Tanigaki Riho , Miyake Yasunobu , Vo Nghia Trong , Nguyen Mai Thanh Thi , Nguyen Nhan Trung , Do Truong Nhat Van , Nguyen Hai Xuan , Kataoka Takao
Published: November 2021

Tumor necrosis factor α (TNF-α) induces the nuclear factor κB (NF-κB) signaling pathway via TNF receptor 1 (TNF-R1). We recently reported that isopanduratin A inhibited the TNF-α-induced NF-κB signaling pathway in human lung adenocarcinoma A549 cells. In the present study, we found that isopanduratin A did not inhibit the interleukin-1α-induced NF-κB signaling pathway in A549 cells. Isopanduratin A down-regulated the expression of TNF-R1 in these cells. We also revealed that isopanduratin A down-regulated the cell surface expression of TNF-R1 by promoting the cleavage of TNF-R1 into its soluble forms. TAPI-2, an inhibitor of TNF-α-converting enzyme, suppressed the inhibitory activity of isopanduratin A against the TNF-α-induced activation of NF-κB. The mitogen-activated protein (MAP) kinase/extracellular signal-regulated kinase (ERK) kinase inhibitor U0126, but not the p38 MAP kinase inhibitor SB203580, blocked the ectodomain shedding of TNF-R1 induced by isopanduratin A. Consistent with this result, isopanduratin A induced the rapid phosphorylation of ERK, but not p38 MAP kinase. Isopanduratin A also promoted the phosphorylation of eukaryotic initiation factor 2α (eIF2α). The present results indicate that isopanduratin A inhibits TNF-α-induced NF-κB signaling pathway by promoting ERK-dependent ectodomain shedding of cell surface TNF-R1, and also decreases cellular TNF-R1 levels through the phosphorylation of eIF2α in A549 cells.
Advanced Glycation End-Products in Skeletal Muscle Aging
Authors: Olson Lucas C. , Redden James T. , Schwartz Zvi , Cohen David J. , McClure Michael J.
Published: November 2021

Advanced age causes skeletal muscle to undergo deleterious changes including muscle atrophy, fast-to-slow muscle fiber transition, and an increase in collagenous material that culminates in the age-dependent muscle wasting disease known as sarcopenia. Advanced glycation end-products (AGEs) non-enzymatically accumulate on the muscular collagens in old age via the Maillard reaction, potentiating the accumulation of intramuscular collagen and stiffening the microenvironment through collagen cross-linking. This review contextualizes known aspects of skeletal muscle extracellular matrix (ECM) aging, especially the role of collagens and AGE cross-linking, and underpins the motor nerve’s role in this aging process. Specific directions for future research are also discussed, with the understudied role of AGEs in skeletal muscle aging highlighted. Despite more than a half century of research, the role that intramuscular collagen aggregation and cross-linking plays in sarcopenia is well accepted yet not well integrated with current knowledge of AGE’s effects on muscle physiology. Furthermore, the possible impact that motor nerve aging has on intramuscular cross-linking and muscular AGE levels is posited.
Demonstrative Experiment on the Favorable Effects of Static Electric Field Treatment on Vitamin D3-Induced Hypercalcemia
Authors: Kimura Tohru , Inaka Kengo , Ogiso Noboru
Published: November 2021

The purpose of this study was to elucidate the effects of static electric field (SEF) treatment on vitamin D3 (Vit D3)-induced hypercalcemia and renal calcification in mice. The mice were assigned to three groups: Vit D3-treated mice, mice treated with Vit D3 and SEF (Vit D3 + SEF), and untreated mice. After the administration of Vit D3, the Vit D3 + SEF-treated mice were exposed to SEF treatment by a high-voltage alternating current over five days. Serum biochemical examinations revealed that both the creatinine and blood urea nitrogen concentrations were significantly higher in the Vit D3-treated group. Significantly, decreased Cl concentrations, and increased Ca and inorganic phosphorus concentrations, were found in the Vit D3-treated group. In the Vit D3 + SEF-treated group, these parameters returned to the levels of the untreated group. In the Vit D3-treated group, histopathological examinations showed marked multifocal calcification in the lumens of the renal tubules and the renal parenchyma. The myocardium was replaced by abundant granular mineralization (calcification), with degeneration and necrosis of the calcified fibers. The stomach showed calcification of the cardiac mucosa. SEF treatment remarkably attenuated the Vit D3-induced hypervitaminotic injuries. In conclusion, this study provides important evidence that SEF treatment can reduce hypercalcemia and remove calcium deposits from the renal, cardiac, and gastric tissues. SEF treatment is useful in the regulation of disorders caused by an imbalance of serum electrolytes.
Olive Oil Based Methotrexate Loaded Topical Nanoemulsion Gel for the Treatment of Imiquimod Induced Psoriasis-like Skin Inflammation in an Animal Model
Authors: Rashid Sheikh Abdur , Bashir Sajid , Naseem Faiza , Farid Arshad , Rather Irfan A. , Hakeem Khalid Rehman
Published: November 2021

Psoriasis, a chronic inflammatory illness, is on the rise and is linked to several other life-threatening diseases. The primary goal of this study was to create a nanoemulsion gel loaded with methotrexate and olive oil (MTX NEG). The formulation was evaluated for physicochemical characterization, entrapment efficiency, drug release kinetics, skin permeation studies and stability tests. In addition, the efficacy of MTX NEG against psoriasis was tested using imiquimod-induced psoriasis in a rat model. The final optimized MTX NEG was developed with a particle size of 202.6 ± 11.59 nm and a PDI of 0.233 ± 0.01, with a 76.57 ± 2.48% average entrapment efficiency. After 20 h, the release kinetics predicted a 72.47% drug release at pH 5.5. FTIR findings demonstrated that the optimized MTX NEG formulation effectively fluidized both the epidermis and dermis of the skin, potentially increasing drug permeability and retention. The application of Tween 80 and PEG 400, on the other hand, significantly enhanced these effects, as these are well known penetration enhancers. After 24 h, an average of 70.78 ± 5.8 μg/cm2 of methotrexate was permeated from the nanoemulsion gel with a flux value of 2.078 ± 0.42 μg/cm2/h, according to permeation measurements. Finally, in vivo experiments on rabbit skin revealed that the increased skin penetration of methotrexate-loaded nanoemulsion gel was not due to structural alterations in intercellular lipid layers in the stratum corneum. In vivo antipsoriatic studies on rats revealed that MTX NEG produced a PASI decrease that was extremely similar and even better than the 91% reduction seen in the MTX tablet group. According to the pharmacokinetic profile, Cmax was 8.5 μg/mL, Tmax was 12 h, and t1/2 was 15.5 ± 2.37 h. These findings reinforce that MTX-NEG based on olive oil could be a possible treatment for psoriasis and could decrease the remission of psoriasis-like symptoms.
The Contribution of the Hunger Hormone Leptin in the Aetiology of Postoperative Anorexia after Laparoscopic and Open Gastrectomy in Gastric Cancer Patients
Authors: Jagric Tomaz
Published: November 2021

Background: Laparoscopic surgery produces lesser postoperative inflammation with a smaller cytokine and leptin response, and might thus reduce postoperative anorexia compared with open surgery. The aim of the present study was to determine the role of serum leptin in postoperative anorexia after laparoscopic gastric cancer surgery. Methods: Fifty-four consecutive patients with adenocarcinoma of the stomach were operated on either with open or laparoscopic surgery. Correlations were determined between the serum levels of leptin, clinico-pathological characteristics, serum haemoglobin, and albumin. Results: Serum leptin levels on day seven were correlated significantly to gender (p = 0.004), body mass index (BMI) (p = 0.002), and tumour grade (p = 0.033). In the patients with C-reactive protein (CRP) < 100 mg/L (n = 46) the leptin levels on day seven were significantly lower after the laparoscopic operation (p = 0.042) and in patients with lower BMI (p = 0.001). The linear regression model determined a significant correlation between the relative concentration of leptin on day seven and laparoscopic surgery (Beta−0.688; p < 0.0001), gender, BMI, location of the tumour, T stage, N stage, perioperative therapy, tumour grade, perineural invasion, Lauren histological type, and ulceration. In patients with CRP levels below 100 mg/mL, the serum level of albumin on day seven after surgery was significantly higher in patients after laparoscopic surgery. Conclusion: Laparoscopic surgery produced significantly lower relative leptin concentrations on day seven, and higher serum albumin levels in the subgroup with CRP levels below 100 mg/L at discharge. These results suggested that laparoscopic gastric cancer surgery might reduce postoperative leptin response, leading to a better nutritional status at discharge compared with open surgery.
Human Parainfluenza Virus 3 Phosphoprotein Is a Tetramer and Shares Structural and Interaction Features with Ebola Phosphoprotein VP35
Authors: Rodriguez Galvan Joaquin , Donner Brianna , Veseley Cat Hoang , Reardon Patrick , Forsythe Heather M. , Howe Jesse , Fujimura Gretchen , Barbar Elisar
Published: November 2021

The human parainfluenza virus 3 (HPIV3) poses a risk for pneumonia development in young children and immunocompromised patients. To investigate mechanisms of HPIV3 pathogenesis, we characterized the association state and host protein interactions of HPIV3 phosphoprotein (HPIV3 P), an indispensable viral polymerase cofactor. Sequence analysis and homology modeling predict that HPIV3 P possesses a long, disordered N-terminal tail (PTAIL) a coiled-coil multimerization domain (PMD), similar to the well-characterized paramyxovirus phosphoproteins from measles and Sendai viruses. Using a recombinantly expressed and purified construct of PMD and PTAIL, we show that HPIV3 P in solution is primarily an alpha-helical tetramer that is stable up to 60 °C. Pulldown and isothermal titration calorimetry experiments revealed that HPIV3 P binds the host hub protein LC8, and turbidity experiments demonstrated a new role for LC8 in increasing the solubility of HPIV3 P in the presence of crowding agents such as RNA. For comparison, we show that the multimerization domain of the Zaire Ebola virus phosphoprotein VP35 is also a tetramer and binds LC8 but with significantly higher affinity. Comparative analysis of the domain architecture of various virus phosphoproteins in the order Mononegavirales show multiple predicted and verified LC8 binding motifs, suggesting its prevalence and importance in regulating viral phosphoprotein structures. Our work provides evidence for LC8 binding to phosphoproteins with multiple association states, either tetrameric, as in the HPIV3 and Ebola phosphoproteins shown here, or dimeric as in rabies virus phosphoprotein. Taken together the data suggest that the association states of a virus-specific phosphoprotein and the complex formed by binding of the phosphoprotein to host LC8 are important regulators of viral function.
Targeting Hypoxia: Revival of Old Remedies
Authors: Vilaplana-Lopera Nuria , Besh Maxym , Moon Eui Jung
Published: November 2021

Tumour hypoxia is significantly correlated with patient survival and treatment outcomes. At the molecular level, hypoxia is a major driving factor for tumour progression and aggressiveness. Despite the accumulative scientific and clinical efforts to target hypoxia, there is still a need to find specific treatments for tumour hypoxia. In this review, we discuss a variety of approaches to alter the low oxygen tumour microenvironment or hypoxia pathways including carbogen breathing, hyperthermia, hypoxia-activated prodrugs, tumour metabolism and hypoxia-inducible factor (HIF) inhibitors. The recent advances in technology and biological understanding reveal the importance of revisiting old therapeutic regimens and repurposing their uses clinically.
Diagnostic and Prognostic Utility of the Extracellular Vesicles Subpopulations Present in Pleural Effusion
Authors: Javadi Joman , Görgens André , Vanky Hanna , Gupta Dhanu , Hjerpe Anders , EL-Andaloussi Samir , Hagey Daniel , Dobra Katalin
Published: November 2021

Extracellular vesicles (EVs), comprising exosomes, microvesicles, and apoptotic bodies, are released by all cells into the extracellular matrix and body fluids, where they play important roles in intercellular communication and matrix remodeling in various pathological conditions. Malignant pleural mesothelioma (MPM) is a primary tumor of mesothelial origin, predominantly related to asbestos exposure. The detection of MPM at an early stage and distinguishing it from benign conditions and metastatic adenocarcinomas (AD) is sometimes challenging. Pleural effusion is often the first available biological material and an ideal source for characterizing diagnostic and prognostic factors. Specific proteins have previously been identified as diagnostic markers in effusion, but it is not currently known whether these are associated with vesicles or released in soluble form. Here, we study and characterize tumor heterogeneity and extracellular vesicle diversity in pleural effusion as diagnostic or prognostic markers for MPM. We analyzed extracellular vesicles and soluble proteins from 27 pleural effusions, which were collected and processed at the department of pathology and cytology at Karolinska University Hospital, representing three different patient groups, MPM (n = 9), benign (n = 6), and AD (n = 12). The vesicles were fractionated into apoptotic bodies, microvesicles, and exosomes by differential centrifugation and characterized by nanoparticle tracking analysis and Western blotting. Multiplex bead-based flow cytometry analysis showed that exosomal markers were expressed differently on EVs present in different fractions. Further characterization of exosomes by a multiplex immunoassay (Luminex) showed that all soluble proteins studied were also present in exosomes, though the ratio of protein concentration present in supernatant versus exosomes varied. The proportion of Angiopoietin-1 present in exosomes was generally higher in benign compared to malignant samples. The corresponding ratios of Mesothelin, Galectin-1, Osteopontin, and VEGF were higher in MPM effusions compared to those in the benign group. These findings demonstrate that relevant diagnostic markers can be recovered from exosomes.
MiR-191 as a Key Molecule in Aneurysmal Aortic Remodeling
Authors: Lichołai Sabina , Studzińska Dorota , Plutecka Hanna , Gubała Tomasz , Szczeklik Wojciech , Sanak Marek
Published: November 2021

Abdominal aortic aneurysms (AAA) are a complex disease with an unclear pathomechanism. A positive family history is emphasized as a significant risk factor, and a nonspecific model of inheritance suggests participation of epigenetic regulation in the pathogenesis of this disease. Past studies have implicated microRNAs in the development of AAA; therefore in this project, we measured miR-191 levels in AAA patients and compared them with a control group. We found that miR-191 levels were significantly elevated in aneurysmal patients, although this did not correlate with the available clinical data. We then developed an in vitro model where, using cells with an endothelial phenotype, we determined the effect of miR-191 on the transcriptome using RNA sequencing. Subsequent pathway analysis established that some of the perturbations mediated by miR-191 can be explained by several processes which have long been observed and described in literature as accompanying the development of abdominal aortic aneurysms.
Generation of Functional Cardiomyocytes from Human Gastric Fibroblast-Derived Induced Pluripotent Stem Cells
Authors: Wu Chih-Hsien , Lin Hsuan-Hwai , Wu Yi-Ying , Chiu Yi-Lin , Huang Li-Yen , Cheng Cheng-Chung , Yang Chung-Chi , Tsai Tsung-Neng
Published: November 2021

Coronary artery diseases are major problems of the world. Coronary artery disease patients frequently suffer from peptic ulcers when they receive aspirin treatment. For diagnostic and therapeutic purposes, the implementation of panendoscopy (PES) with biopsy is necessary. Some biopsy samples are wasted after the assay is completed. In the present study, we established a protocol for human gastric fibroblast isolation and induced pluripotent stem cell (iPSC) generation from gastric fibroblasts via PES with biopsy. We showed that these iPSCs can be differentiated into functional cardiomyocytes in vitro. To our knowledge, this is the first study to generate iPSCs from gastric fibroblasts in vitro.
Highlights of Immunomodulation in Salmonella-Based Cancer Therapy
Authors: Pangilinan Christian R. , Lee Che-Hsin
Published: November 2021

Bacteria-mediated cancer therapy (BMCT) is an emerging tool that may advance potential approaches in cancer immunotherapy, whereby tumors are eradicated by the hosts’ immune system upon recruitment and activation by bacteria such as Salmonella. This paper provides an emphasis on the immunomodulatory effects that encompasses both the innate and adaptive immune responses inherently triggered by Salmonella. Furthermore, modifications of Salmonella-based treatment in the attempt to improve tumor-specific immune responses including cytokine therapy, gene therapy, and DNA vaccine delivery are likewise discussed. The majority of the findings described herein incorporate cell-based experiments and murine model studies, and only a few accounts describe clinical trials. Salmonella-based cancer therapy is still under development; nonetheless, the pre-clinical research and early-phase clinical trials that have been completed so far have shown promising and convincing results. Certainly, the continuous development of, and innovation on, Salmonella-based therapy could pave the way for its eventual emergence as one of the mainstream therapeutic interventions addressing various types of cancer.
Venous Leg Ulcers: Advanced Therapies and New Technologies
Authors: Aleksandrowicz Hubert , Owczarczyk-Saczonek Agnieszka , Placek Waldemar
Published: November 2021

The prevalence of venous leg ulcers (VLUs) differs between 1.5% and 3% in the general population. The challenge in treating VLUs is common recurrence. Moreover, VLUs can be resistant to healing, despite appropriate treatment. In these cases, advanced wound therapies should be considered. The number of new technologies, applied in VLUs treatment, has increased in the last years. These therapies include biophysical interventions such as ultrasound therapy, electrical stimulations, electromagnetic therapy, or phototherapy. Furthermore, stem cell therapies, biologic skin equivalents, platelet-rich plasma therapy, oxygen therapies, anti-TNF therapy, or negative pressure wound therapy are advanced venous ulcer therapeutic methods that may support the standard of care. Medical devices, such as a muscle pump activator, or intermittent pneumatic compression device, may be especially useful for specific subgroups of patients suffering from VLUs. Some of the above-mentioned technologies require broader evidence of clinical efficacy and are still considered experimental therapies in dermatology.
The Hepatitis B Virus Nucleocapsid—Dynamic Compartment for Infectious Virus Production and New Antiviral Target
Authors: Niklasch Matthias , Zimmermann Peter , Nassal Michael
Published: November 2021

Hepatitis B virus (HBV) is a small enveloped DNA virus which replicates its tiny 3.2 kb genome by reverse transcription inside an icosahedral nucleocapsid, formed by a single ~180 amino acid capsid, or core, protein (Cp). HBV causes chronic hepatitis B (CHB), a severe liver disease responsible for nearly a million deaths each year. Most of HBV’s only seven primary gene products are multifunctional. Though less obvious than for the multi-domain polymerase, P protein, this is equally crucial for Cp with its multiple roles in the viral life-cycle. Cp provides a stable genome container during extracellular phases, allows for directed intracellular genome transport and timely release from the capsid, and subsequent assembly of new nucleocapsids around P protein and the pregenomic (pg) RNA, forming a distinct compartment for reverse transcription. These opposing features are enabled by dynamic post-transcriptional modifications of Cp which result in dynamic structural alterations. Their perturbation by capsid assembly modulators (CAMs) is a promising new antiviral concept. CAMs inappropriately accelerate assembly and/or distort the capsid shell. We summarize the functional, biochemical, and structural dynamics of Cp, and discuss the therapeutic potential of CAMs based on clinical data. Presently, CAMs appear as a valuable addition but not a substitute for existing therapies. However, as part of rational combination therapies CAMs may bring the ambitious goal of a cure for CHB closer to reality.
Microbiome First Approaches to Rescue Public Health and Reduce Human Suffering
Authors: Dietert Rodney R.
Published: November 2021

The is a sequential article to an initial review suggesting that Microbiome First medical approaches to human health and wellness could both aid the fight against noncommunicable diseases and conditions (NCDs) and help to usher in sustainable healthcare. This current review article specifically focuses on public health programs and initiatives and what has been termed by medical journals as a catastrophic record of recent failures. Included in the review is a discussion of the four priority behavioral modifications (food choices, cessation of two drugs of abuse, and exercise) advocated by the World Health Organization as the way to stop the ongoing NCD epidemic. The lack of public health focus on the majority of cells and genes in the human superorganism, the microbiome, is highlighted as is the “regulatory gap” failure to protect humans, particularly the young, from a series of mass population toxic exposures (e.g., asbestos, trichloroethylene, dioxin, polychlorinated biphenyls, triclosan, bisphenol A and other plasticizers, polyfluorinated compounds, herbicides, food emulsifiers, high fructose corn syrup, certain nanoparticles, endocrine disruptors, and obesogens). The combination of early life toxicity for the microbiome and connected human physiological systems (e.g., immune, neurological), plus a lack of attention to the importance of microbial rebiosis has facilitated rather than suppressed, the NCD epidemic. This review article concludes with a call to place the microbiome first and foremost in public health initiatives as a way to both rescue public health effectiveness and reduce the human suffering connected to comorbid NCDs.
Pre-Existing Humoral Immunological Memory Is Retained in Patients with Multiple Sclerosis Receiving Cladribine Therapy
Authors: Moser Tobias , O’Sullivan Ciara , Puttinger Christian , Feige Julia , Pilz Georg , Haschke-Becher Elisabeth , Cadamuro Janne , Oberkofler Hannes , Hitzl Wolfgang , Harrer Andrea , Kraus Jörg , Trinka Eugen , Wipfler Peter
Published: November 2021

Cladribine (CLAD) is a lymphodepleting agent approved for active relapsing multiple sclerosis (MS). The impact of CLAD on the adaptive humoral immune system has not sufficiently been studied. This study aimed to assess the influence of CLAD treatment on specific antibody titers to common pathogens. We included 18 MS patients treated with CLAD. Serum IgG antibody levels to measles, mumps, rubella, hepatitis B and varicella zoster virus (VZV), as well as diphtheria and tetanus toxins, were measured prior to the initiation of treatment and at 12 and 24 months after first CLAD administration. Moreover, specimens were longitudinally analyzed regarding absolute blood concentrations of IgG and main lymphocyte subsets. No reduction in antibody levels against measles, mumps, rubella, VZV, hepatitis B, diphtheria toxin and tetanus toxin associated with CLAD treatment was observed. Loss of seroprotection occurred in <1%. We found no significant impact of CLAD on absolute serum IgG levels. Absolute lymphocyte counts were significantly reduced at the end of each treatment year (p < 0.00001 and p < 0.000001). This study suggests that CLAD does not interfere with the pre-existing humoral immunologic memory in terms of pathogen-specific antibody titers.
Mitochondrial Electron Transport Chain Protein Abnormalities Detected in Plasma Extracellular Vesicles in Alzheimer’s Disease
Authors: Yao Pamela J. , Eren Erden , Goetzl Edward J. , Kapogiannis Dimitrios
Published: November 2021

Mitochondria provide energy to neurons through oxidative phosphorylation and eliminate Reactive Oxygen Species (ROS) through Superoxide Dismutase 1 (SOD1). Dysfunctional mitochondria, manifesting decreased activity of electron transport chain (ETC) complexes and high ROS levels, are involved in Alzheimer’s disease (AD) pathogenesis. We hypothesized that neuronal mitochondrial dysfunction in AD is reflected in ETC and SOD1 levels and activity in plasma neuron-derived extracellular vesicles (NDEVs). We immunoprecipitated NDEVs targeting neuronal marker L1CAM from two cohorts: one including 22 individuals with early AD and 29 control subjects; and another including 14 individuals with early AD and 14 control subjects. In the first cohort, we measured levels of complexes I, III, IV, ATP synthase, and SOD1; in the second cohort, we measured levels and catalytic activity of complexes IV and ATP synthase. AD individuals had lower levels of complexes I (p < 0.0001), III (p < 0.0001), IV (p = 0.0061), and V (p < 0.0001), and SOD1 (p < 0.0001) compared to controls. AD individuals also had lower levels of catalytic activity of complex IV (p = 0.0214) and ATP synthase (p < 0.0001). NDEVs confirm quantitative and functional abnormalities in ECT complexes and SOD1 previously observed in AD models and during autopsy, opening the way for using them as biomarkers for mitochondrial dysfunction in AD.
Neoplastic Implications in Patients Suffering from Hidradenitis Suppurativa under Systemic Treatments
Authors: Li Pomi Federica , Macca Laura , Motolese Alfonso , Ingrasciotta Ylenia , Berretta Massimiliano , Guarneri Claudio
Published: November 2021

Hidradenitis suppurativa (HS) is a chronic, recurrent, inflammatory skin disease of the apocrine glands. It typically involves the axillary, submammary, genital, inguinal, perineal, and perianal regions. The development of abscesses, sinus tracts, and scars can lead to pain, scarring, disfigurement and decreased quality of life. HS is associated with a wide range of comorbidities. Several studies of co-occurrence of HS and nonmelanoma skin cancer suggest a causal relationship. In an attempt to assess the link between HS and cancer, we performed a systematic review of the current scientific knowledge through a PubMed-based literature search. Results show that HS could be associated with an overall risk of cancer and numerous specific cancers such as: nonmelanoma skin cancer (NMSC), hematologic malignancies, and metastatic cancer. Among NMSC, squamous cell carcinoma (SCC) is considered the most common complication arising in long-standing HS. Based on our review, we suggest that cautious surveillance and active intervention may be warranted in patients with HS. Moreover, an age-appropriate cancer screening should be offered to all patients, especially those who developed HS later in their life or in long-standing moderate to severe HS with multiple comorbidities.