bluuebunny/crossref_metadata_2025 huggingface dataset:
Optimal Placement and Sizing of DGs in Distribution Networks Using MLPSO Algorithm
Authors: Karunarathne Eshan , Pasupuleti Jagadeesh , Ekanayake Janaka , Almeida Dilini
Published: November 2020

In today’s world, distributed generation (DG) is an outstanding solution to tackle the challenges in power grids such as the power loss of the system that is intensified by the exponential increase in demand for electricity. Numerous optimization algorithms have been used by several researchers to establish the optimal placement and sizing of DGs to alleviate this power loss of the system. However, in terms of the reduction of active power loss, the performance of these algorithms is weaker. Furthermore, the premature convergence, the precision of the output, and the complexity are a few major drawbacks of these optimization techniques. Thus, this paper proposes the multileader particle swarm optimization (MLPSO) for the determination of the optimal locations and sizes of DGs with the objective of active power loss minimization while surmounting the drawbacks in previous algorithms. A comprehensive performance analysis is carried out utilizing the suggested approach on the standard IEEE 33 bus system and a real radial bus system in the Malaysian context. The findings reveal a 67.40% and an 80.32% reduction of losses in the two systems by integrating three DGs with a unity power factor, respectively. The comparison of the results with other optimization techniques demonstrated the effectiveness of the proposed MLPSO algorithm in optimal placement and sizing of DGs.
Reliability Evaluation in Distribution Networks with Microgrids: Review and Classification of the Literature
Authors: López-Prado Jose L. , Vélez Jorge I. , Garcia-Llinás Guisselle A.
Published: November 2020

Modern power systems must provide efficient, reliable, and environmentally responsible energy. Recently, the inclusion of Microgrids (MGs) has allowed us to overcome some difficulties and face important challenges in this direction, especially related to the use of alternative energy sources. Increased and probabilistic demand, as well as limited energy supply, pose the need to evaluate the reliability of any distribution system (DS) when MGs are introduced. Here we reviewed and classified the state-of-the-art of reliability assessment (RA) in MGs. Initially, we contextualize RA in distribution systems. Next, each of the MGs subsystems components are introduced and the questions (1) why is it important to evaluate the reliability in Microgrids? (2) how do Microgrids influence the reliability of distribution systems? and (3) how does each of its subsystems influence the reliability of the Microgrids? are addressed. A total of 1395 research studies were published between 2002 and 2020. Using the PRISMA model, 147 met the inclusion criteria (71% correspond to research papers and 29% to reviews; 62% were published in journals, 34% were conference papers and 4% were books). The first study dates from 1971. Despite immense advances in MGs, we identified that (1) real test systems constitute an emerging trend; (2) although new MG configurations sound promising, the development and application of new RA techniques are a necessary step towards the identification of potential pitfalls of such architectures; (3) new RA methods or variations of the existing ones, whether analytical or simulation-based, are constantly being proposed, but their comparison for a particular DS, including MGs, are yet to be performed; and (4) more research studies are needed to assess how new control strategies and information and communications technology impact MGs reliability. Future lines of research could build upon these gaps to enhance reliability, especially when alternative energy resources are available.
Thermal Performance Analysis of the Charging/Discharging Process of a Shell and Horizontally Oriented Multi-Tube Latent Heat Storage System
Authors: Fadl Mohamed , Eames Philip
Published: November 2020

In this study, the thermal performance of latent heat thermal energy storage system (LHTESS) prototype to be used in a range of thermal systems (e.g., solar water heating systems, space heating/domestic hot water applications) is designed, fabricated, and experimentally investigated. The thermal store comprised a novel horizontally oriented multitube heat exchanger in a rectangular tank (forming the shell) filled with 37.8 kg of phase change material (PCM) RT62HC with water as the working fluid. The assessment of thermal performance during charging (melting) and discharging (solidification) was conducted under controlled several operational conditions comprising the heat transfer fluid (HTF) volume flow rates and inlet temperatures. The experimental investigations reported are focused on evaluating the transient PCM average temperature distribution at different heights within the storage unit, charging/discharging time, instantaneous transient charging/discharging power, and the total cumulative thermal energy stored/released. From the experimental results, it is noticed that both melting/solidification time significantly decreased with increase HTF volume flow rate and that changing the HTF inlet temperature shows large impacts on charging time compared to changing the HTF volume flow rate. During the discharging process, the maximum power output was initially 4.48 kW for HTF volume flow rate of 1.7 L/min, decreasing to 1.0 kW after 52.3 min with 2.67 kWh of heat delivered. Based on application heat demand characteristics, required power levels and heat demand can be fulfilled by employing several stores in parallel or series.
Deactivation of V2O5−WO3/TiO2 DeNOx Catalyst under Commercial Conditions in Power Production Plant
Authors: Zyrkowski Maciej , Motak Monika , Samojeden Bogdan , Szczepanek Krzysztof
Published: November 2020

Nitrogen dioxide is one of the most dangerous air pollutants, because its high concentration in air can be directly harmful to human health. It is also responsible for photochemical smog and acid rains. One of the most commonly used techniques to tackle this problem in large combustion plants is selective catalytic reduction (SCR). Commercial SCR installations are often equipped with a V2O5−WO3/TiO2 catalyst. In power plants which utilize a solid fuel boiler, catalysts are exposed to unfavorable conditions. In the paper, factors responsible for deactivation of such a catalyst are comprehensively reviewed where different types of deactivation mechanism, like mechanical, chemical or thermal mechanisms, are separately described. The paper presents the impact of sulfur trioxide and ammonia slip on the catalyst deactivation as well as the problem of ammonium bisulfate formation. The latter is one of the crucial factors influencing the loss of catalytic activity. The majority of issues with fast catalyst deactivation occur when the catalyst work in off-design conditions, in particular in too high or too low temperatures.
Innovative Turbine Intake Air Cooling Systems and Their Rational Designing
Authors: Radchenko Andrii , Trushliakov Eugeniy , Kosowski Krzysztof , Mikielewicz Dariusz , Radchenko Mykola
Published: November 2020

The efficiency of cooling ambient air at the inlet of gas turbines in temperate climatic conditions was analyzed and reserves for its enhancing through deep cooling were revealed. A method of logical analysis of the actual operation efficiency of turbine intake air cooling systems in real varying environment, supplemented by the simplest numerical simulation was used to synthesize new solutions. As a result, a novel trend in engine intake air cooling to 7 or 10 °C in temperate climatic conditions by two-stage cooling in chillers of combined type, providing an annual fuel saving of practically 50%, surpasses its value gained due to traditional air cooling to about 15 °C in absorption lithium-bromide chiller of a simple cycle, and is proposed. On analyzing the actual efficiency of turbine intake air cooling system, the current changes in thermal loads on the system in response to varying ambient air parameters were taken into account and annual fuel reduction was considered to be a primary criterion, as an example. The improved methodology of the engine intake air cooling system designing based on the annual effect due to cooling was developed. It involves determining the optimal value of cooling capacity, providing the minimum system sizes at maximum rate of annual effect increment, and its rational value, providing a close to maximum annual effect without system oversizing at the second maximum rate of annual effect increment within the range beyond the first maximum rate. The rational value of design cooling capacity provides practically the maximum annual fuel saving but with the sizes of cooling systems reduced by 15 to 20% due to the correspondingly reduced design cooling capacity of the systems as compared with their values defined by traditional designing focused to cover current peaked short-term thermal loads. The optimal value of cooling capacity providing the minimum sizes of cooling system is very reasonable for applying the energy saving technologies, for instance, based on the thermal storage with accumulating excessive (not consumed) cooling capacities at lowered current thermal loads to cover the peak loads. The application of developed methodology enables revealing the thermal potential for enhancing the efficiency of any combustion engine (gas turbines and engines, internal combustion engines, etc.).
European Consumers’ Perceptions and Attitudes towards Non-Thermally Processed Fruit and Vegetable Products
Authors: Song Xiao , Pendenza Paola , Díaz Navarro María , Valderrama García Elisa , Di Monaco Rossella , Giacalone Davide
Published: November 2020

In order to meet the demand for high-quality fruit and vegetable (F&V) products, a wide variety of novel non-thermal processing (NTP) technologies are under development. This study used a qualitative focus group approach to investigate consumers’ perception and attitudes towards non-thermally processed F&V products among young (18–30 years old) and middle-aged (45–60 y.o.) consumers across six European countries: Denmark, Germany, Italy, Serbia, Spain, and the Netherlands. Findings show that the expected benefits and social concerns are important factors which affect consumers’ attitudes toward non-thermally processed F&V. Extending shelf-life, being healthier and more nutritious, and better hygiene and safety were important benefits, whilst impacts on product quality, safety risks, higher price and environmental costs were the concerns most often mentioned by participants. However, due to a lack of knowledge and trustworthy information sources, consumers have difficulties in assessing relevant benefits and risks. Targeted communication that could explicitly and efficiently reveal benefits and risks is highly recommended to enhance consumer awareness and trust. This may especially be needed to reach middle-aged consumers who showed less confidence in NTP, compared to young consumers. Consumers from Spain, Denmark, and the Netherlands appeared more interested in consuming NTP F&V, compared to Italy, Serbia, and Germany. These findings are expected to provide recommendations to better communicate non-thermally processed F&V with consumers in the EU.
Analytical Strategies for Fingerprinting of Antioxidants, Nutritional Substances, and Bioactive Compounds in Foodstuffs Based on High Performance Liquid Chromatography–Mass Spectrometry: An Overview
Authors: Donno Dario , Mellano Maria Gabriella , Gamba Giovanni , Riondato Isidoro , Beccaro Gabriele Loris
Published: November 2020

New technology development and globalisation have led to extreme changes in the agri-food sector in recent years that need an important food supply chain characterisation from plant materials to commercial productions. Many analytical strategies are commonly utilised in the agri-food industry, often using complementary technologies with different purposes. Chromatography on-line coupled to mass spectrometry (MS) is one of the most selective and sensitive analytical methodologies. The purpose of this overview is to present the most recent MS-based techniques applied to food analysis. An entire section is dedicated to the recent applications of high-resolution MS. Covered topics include liquid (LC)– and gas chromatography (GC)–MS analysis of natural bioactive substances, including carbohydrates, flavonoids and related compounds, lipids, phenolic compounds, vitamins, and other different molecules in foodstuffs from the perspectives of food composition, food authenticity and food adulteration. The results represent an important contribution to the utilisation of GC–MS and LC–MS in the field of natural bioactive compound identification and quantification.
A Novel Autologous Micrografts Technology in Combination with Negative Pressure Wound Therapy (NPWT) for Quick Granulation Tissue Formation in Chronic/Refractory Ulcer
Authors: Takagi Satoshi , Oyama Takuto , Jimi Shiro , Saparov Arman , Ohjimi Hiroyuki
Published: November 2020

Negative pressure wound therapy (NPWT) has been commonly used over the years for a wide range of chronic/refractory lesions. Alternatively, autologous micrografting technology is recently becoming a powerful modality for initiating wound healing. The case presented is of a patient with a lower leg ulcer that had responded poorly to NPWT alone for three weeks. Consequently, the patient was put on a combination therapy of NPWT and micrografting. After injection of a dermal tissue micrografts suspension into the entire wound bed, NPWT was performed successively for two weeks, resulting in fresh granulation tissue formation. Thereafter, the autologous skin graft was taken well. This case study indicates that for a chronic/refractory ulcer patient with poor NPWT outcome, combination therapy using micrografting treatment and NPWT could rapidly initiate and enhance granulation tissue formation, creating a favorable bedding for subsequent skin grafting.
Measuring Temporal Differences in Rural Canadian Children’s Moderate-to-Vigorous Physical Activity
Authors: Button Brenton L. G. , Clark Andrew F. , Martin Gina , Graat Megan , Gilliland Jason A.
Published: November 2020

The purpose of this study was to measure the factors that influence children’s moderate-to-vigorous physical activity (MVPA) during school curriculum time, recess time, and outside school time in a rural area. During the Fall and Winter of 2016, 34 boys and 55 girls aged 8–14 years from rural communities in rural Northwestern Ontario participated in the Spatial Temporal Environment and Activity Monitoring project. The children’s MVPA was measured using an accelerometer, and child-level demographic, behavioral, and environmental data were gathered from surveys, passively logging global positioning units, and municipal datasets. Data on daily temperature and precipitation were gathered from the closest Environment Canada weather station. A mixed model was used to assess the relationship between child- and day-level factors and children’s MVPA. On average, children were getting 12.9 min of MVPA during recess, 17.7 min during curriculum time, and 29.0 min of MVPA outside school time. During all three time points, boys were more active than girls. During curriculum time, children in lower grades were more active, and the weather had differing impacts depending on the time of day. The findings of this study illustrate the differences in MVPA and the factors that influence MVPA by time of day. Examining different time segments provides valuable information for understanding children’s MVPA patterns.
The Development of a Sleep Intervention for Firefighters: The FIT-IN (Firefighter’s Therapy for Insomnia and Nightmares) Study
Authors: Jang Eun Hee , Hong Yujin , Kim Yeji , Lee Sangha , Ahn Yeonsoon , Jeong Kyoung Sook , Jang Tae-Won , Lim Hyejin , Jung Eunha ,   Shift Work Disorder Study Group, Chung Seockhoon , Suh Sooyeon
Published: November 2020

Background: Firefighters are vulnerable to irregular sleep patterns and sleep disturbance due to work characteristics such as shift work and frequent dispatch. However, there are few studies investigating intervention targeting sleep for firefighters. This preliminary study aimed to develop and test a sleep intervention, namely FIT-IN (Firefighter’s Therapy for Insomnia and Nightmares), which was based on existing evidence-based treatment tailored to firefighters in consideration of their occupational characteristics. Methods: This study implemented a single-group pre-post study design, utilizing an intervention developed based on brief behavior therapy for insomnia with imagery rehearsal therapy components. FIT-IN consisted of a total of three sessions (two face-to-face group sessions and one telephone session). Participants were recruited from Korean fire stations, and a total of 39 firefighters participated. Participants completed a sleep diary for two weeks, as well as the following questionnaires to assess their sleep and psychological factors: insomnia severity index (ISI), disturbing dream and nightmare severity index (DDNSI), Epworth sleepiness scale (ESS), depressive symptom inventory-suicidality subscale (DSI), and Patient Health Questionnaire-9 (PHQ-9). These questionnaires were administered before the first session and at the end of the second session. Results: The FIT-IN program produced improvements in sleep indices. There was a significant increase in sleep efficiency (p < 0.01), and a decrease in sleep onset latency, number of awakenings, and time in bed (p < 0.05), as derived from weekly sleep diaries. In addition, significant decreases were shown for insomnia (p < 0.001) and nightmare severity (p < 0.01). Conclusion: There were significant improvements in sleep and other clinical indices (depression, PTSD scores) when comparing pre-and post-intervention scores. FIT-IN may be a feasible and practical option in alleviating sleep disturbance in this population. Further studies will be needed to ascertain FIT-IN’s effectiveness.
Isolation and Identification of Streptomyces spp. from Desert and Savanna Soils in Sudan
Authors: Hamid Mohamed E. , Mahgoub Adil , Babiker Abdulrhman J. O. , Babiker Hussein A. E. , Holie Mohammed A. I. , Elhassan Mogahid M. , Joseph Martin R. P.
Published: November 2020

The purpose of this study was to investigate streptomycete populations in desert and savanna ecozones in Sudan and to identify species based on 16S rRNA gene sequences. A total of 49 different Streptomyces phenotypes (22 from sites representing the desert and semi-desert ecozone; 27 representing the savanna ecozone) have been included in the study. The isolates were characterized phenotypically and confirmed using 16S rRNA gene sequence analysis. The two ecozones showed both similarities and uniqueness in the types of isolates. The shared species were in cluster 1 (Streptomyces (S.) werraensis), cluster 2 (Streptomyces sp.), cluster 3 (S. griseomycini-like), and cluster 7 (S. rochei). The desert ecozone revealed unique species in cluster 9 (Streptomyces sp.) and cluster 10 (S. griseomycini). Whereas, the savanna ecozone revealed unique species in cluster 4 (Streptomyces sp.), cluster 5 (S. albogriseolus/ S. griseoincarnatus), cluster 6 (S. djakartensis), and cluster 8 (Streptomyces sp.). Streptomycetes are widely distributed in both desert and the savanna ecozones and many of these require full descriptions. Extending knowledge on Streptomyces communities and their dynamics in different ecological zones and their potential antibiotic production is needed.
SARS-CoV-2 Pandemic Impact on Pediatric Emergency Rooms: A Multicenter Study
Authors: Matera Luigi , Nenna Raffaella , Rizzo Valentina , Ardenti Morini Francesca , Banderali Giuseppe , Calvani Mauro , Calvi Matteo , Cozzi Giorgio , Fabiani Elisabetta , Falsaperla Raffaele , Kantar Ahmad , Lanari Marcello , Lubrano Riccardo , Messini Beatrice , Niccoli Antonio Augusto , Scoppi Pietro , Tipo Vincenzo , Midulla Fabio
Published: November 2020

From 9 March to 3 May 2020, lockdown was declared in Italy due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Our aim was to evaluate how the SARS-CoV-2 pandemic and related preventive strategies affected pediatric emergency rooms (ERs) during this period. We performed a retrospective cohort multicenter study, comparing the lockdown period to the corresponding period in 2019. We examined 15 Italian pediatric ERs in terms of visit rates, specific diagnoses (grouped as air communicable diseases and non-air communicable diseases), and triage categories. During the lockdown period, ER admissions decreased by 81% compared to 2019 (52,364 vs. 10,112). All ER specific diagnoses decreased in 2020 and this reduction was significantly higher for air communicable diseases (25,462 vs. 2934, p < 0.001). Considering the triage category, red codes remained similar (1% vs. 1%), yellow codes increased (11.2% vs. 22.3%), and green codes decreased (80.3% vs. 69.5%). We can speculate that social distancing and simple hygiene measures drastically reduced the spread of air communicable diseases. The increase in yellow codes may have been related to a delay in primary care and, consequently, in ER admissions.
Gender Patterns in Immigrants’ Health Profiles in France: Tobacco, Alcohol, Obesity and Self-Reported Health
Authors: Khlat Myriam , Legleye Stéphane , Bricard Damien
Published: November 2020

Background: to date, little attention has been given to gender differences in the health of migrants relative to native-born. In this study, we examine the health profile of the largest immigrant groups in metropolitan France, considering several health indicators and with a special interest in the gendered patterns. Methods: The data originate from the 2017 Health Barometer survey representative of metropolitan France. A subsample of 19,857 individuals aged 18–70 years was analysed using modified Poisson regression, and risk ratio estimates (RR) were provided for the different migrant groups regarding alcohol use, current smoking, obesity and less-than-good self-reported health, adjusting for age and educational level. Results: None of the groups of male migrants differs from the native-born in terms of self-reported health, and they have healthier behaviours for alcohol (men from sub-Saharan Africa: 0.42 (0.29–0.61)) and from the Maghreb: 0.30 (0.1–0.54)) and smoking (men from sub-Saharan Africa: 0.64 (0.4–0.84)), with less frequent obesity (men from the Maghreb: 0.61 (0.3–0.95)). The latter, however, more frequently report current smoking (1.21 (1.0–1.46)). For women, less-than-good health is more frequently reported by the groups from sub-Saharan Africa (1.42 (1.1–1.75)) and from the Maghreb (1.55 (1.3–1.84)). Healthier behaviours were found for alcohol (women from overseas départements: 0.38 (0.1–0.85)) and from the Maghreb: (0.18 (0.0–0.57)) and current smoking (women from southern Europe: 0.68 (0.4–0.97), from sub-Saharan Africa: 0.23 (0.1–0.38) and from the Maghreb: 0.42 (0.2–0.61)). Conversely, some were more frequently obese (women from overseas départements: 1.79 (1.2–2.56) and from sub-Saharan Africa: 1.67 (1.2–2.23)). In the latter two groups from Africa, there is a larger relative male excess for tobacco than in the native-born (male-to-female ratios of respectively 2.87 (1.6–5.09) and 3.1 (2.0–4.65) vs 1.13 (1.0–1.20)) and there is a female excess for obesity (0.51 (0.2–0.89) and 0.41 (0.2–0.67)) in contrast with the native-born (1.07 (0.9–1.16)). The female disadvantage in terms of less-than-good self-reported health is more pronounced among migrants from the Maghreb than among the natives (0.56(0.4–0.46) vs. 0.86 (0.8–0.91)). Conclusion: Considering a set of four health indicators, we provide evidence for distinctive gender patterns among immigrants in France. Male immigrants have a healthy behavioural profile in comparison with the natives and no health disadvantage. Female immigrants have a more mixed profile, with a health disadvantage for the non-Western groups from Africa. The contribution to this discordance of socioeconomic factors and gender relations needs to be investigated.
Evaluation of Knowledge among Dentists on Symptoms and Treatments of Temporomandibular Disorders in Italy
Authors: Mozhdeh Meysamian , Caroccia Francesco , Moscagiuri Francesco , Festa Felice , D’Attilio Michele
Published: November 2020

To determine the knowledge of general dentists and dental specialists on temporomandibular disorders (TMD) in Italy, a web-based questionnaire including 20 multiple- choice questions was sent to all general dental practitioners and specialists in Italy. Mean score of diagnosis and treatment knowledge of all participants was 23.8 ± 7.3 out of 40 achievable scores. There was a significant difference between the knowledge of dentists and the variables of sex, age, and years of experience (p < 0.05). However, overall, it is not possible to state a significant difference between the final score of dentists with different specializations (p = 0.89). The results of this study showed an acceptable knowledge of participants regarding TMD.
A Theoretical Approach for Forecasting Different Types of Drought Simultaneously, Using Entropy Theory and Machine-Learning Methods
Authors: Aghelpour Pouya , Mohammadi Babak , Biazar Seyed Mostafa , Kisi Ozgur , Sourmirinezhad Zohreh
Published: November 2020

Precipitation deficit can affect different natural resources such as water, soil, rivers and plants, and cause meteorological, hydrological and agricultural droughts. Multivariate drought indexes can theoretically show the severity and weakness of various drought types simultaneously. This study introduces an approach for forecasting joint deficit index (JDI) and multivariate standardized precipitation index (MSPI) by using machine–learning methods and entropy theory. JDI and MSPI were calculated for the 1–12 months’ time window (JDI1–12 and MSPI1–12), using monthly precipitation data. The methods implemented for forecasting are group method of data handling (GMDH), generalized regression neural network (GRNN), least squared support vector machine (LSSVM), adaptive neuro-fuzzy inference system (ANFIS) and ANFIS optimized with three heuristic optimization algorithms, differential evolution (DE), genetic algorithm (GA) and particle swarm optimization (PSO) as meta-innovative methods (ANFIS-DE, ANFIS-GA and ANFIS-PSO). Monthly precipitation, monthly temperature and previous amounts of the index’s values were used as inputs to the models. Data from 10 synoptic stations situated in the widest climatic zone of Iran (extra arid-cold climate) were employed. Optimal model inputs were selected by gamma test and entropy theory. The evaluation results, which were given using mean absolute error (MAE), root mean squared error (RMSE) and Willmott index (WI), show that the machine learning and meta-innovative models can present acceptable forecasts of general drought’s conditions. The algorithms DE, GA and PSO, could improve the ANFIS’s performance by 39.4%, 38.7% and 22.6%, respectively. Among all the applied models, the GMDH shows the best forecasting accuracy with MAE = 0.280, RMSE = 0.374 and WI = 0.955. In addition, the models could forecast MSPI better than JDI in the majority of cases (stations). Among the two methods used to select the optimal inputs, it is difficult to select one as a better input selector, but according to the results, more attention can be paid to entropy theory in drought studies.
Novel miRNA Targets and Therapies in the Triple-Negative Breast Cancer Microenvironment: An Emerging Hope for a Challenging Disease
Authors: Qattan Amal
Published: November 2020

Treatment of triple-negative breast cancer (TNBC) remains challenging because of the heterogeneity of the disease and lack of single targetable driving mutations. TNBC does not rely on estrogen, progesterone or epidermal growth factor receptors and is associated with aggressive disease progression and poor prognosis. TNBC is also characterized by resistance to chemotherapeutics, and response to immunotherapies is limited despite promising results in a subset of TNBC patients. MicroRNAs (miRNAs) have emerged as significant drivers of tumorigenesis and tumor progression in triple-negative breast cancer (TNBC) and present unique opportunities to target various components of the TNBC microenvironment for improved efficacy against this difficult to treat cancer. Effects of miRNAs on multiple targets may improve response rates in the context of this genetically and biologically heterogeneous disease. In this review, we offer a comprehensive view of miRNA regulation in TNBC, treatment challenges presented by TNBC in the context of the tumor microenvironment and stem cell subpopulations, and current and emerging miRNA-based therapeutic strategies targeting various components of the TNBC microenvironment. In addition, we offer insight into novel targets that have potential for treating TNBC through multiple mechanisms in the tumor microenvironment simultaneously and those that may be synergistic with standard chemotherapies.
Functional Domain Order of an Anti-EGFR × Anti-CD16 Bispecific Diabody Involving NK Cell Activation
Authors: Kuwahara Atsushi , Nagai Keisuke , Nakanishi Takeshi , Kumagai Izumi , Asano Ryutaro
Published: November 2020

Bispecific antibodies (bsAbs) have emerged as promising therapeutics. A bispecific diabody (bsDb) is a small bsAb consisting of two distinct chimeric single-chain components, with two possible arrangements of the domains. We previously reported the effect of domain order on the function of a humanized bsDb targeting the epidermal growth factor receptor (EGFR) on cancer cells, and CD3 on T cells. Notably, the co-localization of a T-cell receptor (TCR) with CD3 is bulky, potentially affecting the cross-linking ability of bsDbs, due to steric hindrance. Here, we constructed and evaluated humanized bsDbs, with different domain orders, targeting EGFR and CD16 on natural killer (NK) cells (hEx16-Dbs). We predicted minimal effects due to steric hindrance, as CD16 lacks accessory molecules. Interestingly, one domain arrangement displayed superior cytotoxicity in growth inhibition assays, despite similar cross-linking abilities for both domain orders tested. In hEx16-Dbs specifically, domain order might affect the agonistic activity of the anti-CD16 portion, which was supported by a cytokine production test, and likely contributed to the superiority of one of the hEx16-Dbs. Our results indicate that both the target antigen and mode of action of an antibody must be considered in the construction of highly functional bsAbs.
Functional and Structural Variation among Sticholysins, Pore-Forming Proteins from the Sea Anemone Stichodactyla helianthus
Authors: Rivera-de-Torre Esperanza , Palacios-Ortega Juan , Slotte J. Peter , Gavilanes José G. , Martínez-del-Pozo Álvaro , García-Linares Sara
Published: November 2020

Venoms constitute complex mixtures of many different molecules arising from evolution in processes driven by continuous prey–predator interactions. One of the most common compounds in these venomous cocktails are pore-forming proteins, a family of toxins whose activity relies on the disruption of the plasmatic membranes by forming pores. The venom of sea anemones, belonging to the oldest lineage of venomous animals, contains a large amount of a characteristic group of pore-forming proteins known as actinoporins. They bind specifically to sphingomyelin-containing membranes and suffer a conformational metamorphosis that drives them to make pores. This event usually leads cells to death by osmotic shock. Sticholysins are the actinoporins produced by Stichodactyla helianthus. Three different isotoxins are known: Sticholysins I, II, and III. They share very similar amino acid sequence and three-dimensional structure but display different behavior in terms of lytic activity and ability to interact with cholesterol, an important lipid component of vertebrate membranes. In addition, sticholysins can act in synergy when exerting their toxin action. The subtle, but important, molecular nuances that explain their different behavior are described and discussed throughout the text. Improving our knowledge about sticholysins behavior is important for eventually developing them into biotechnological tools.
Effect of Ionic Strength on Thioflavin-T Affinity to Amyloid Fibrils and Its Fluorescence Intensity
Authors: Mikalauskaite Kamile , Ziaunys Mantas , Sneideris Tomas , Smirnovas Vytautas
Published: November 2020

The formation of amyloid fibrils is linked to multiple neurodegenerative disorders, including Alzheimer’s and Parkinson’s disease. Despite years of research and countless studies on the topic of such aggregate formation, as well as their resulting structure, the current knowledge is still fairly limited. One of the main aspects prohibiting effective aggregation tracking is the environment’s effect on amyloid-specific dyes, namely thioflavin-T (ThT). Currently, there are only a few studies hinting at ionic strength being one of the factors that modulate the dye’s binding affinity and fluorescence intensity. In this work we explore this effect under a range of ionic strength conditions, using insulin, lysozyme, mouse prion protein, and α-synuclein fibrils. We show that ionic strength is an extremely important factor affecting both the binding affinity, as well as the fluorescence intensity of ThT.
Antibody Fragments as Tools for Elucidating Structure-Toxicity Relationships and for Diagnostic/Therapeutic Targeting of Neurotoxic Amyloid Oligomers
Authors: Bitencourt André L. B. , Campos Raquel M. , Cline Erika N. , Klein William L. , Sebollela Adriano
Published: November 2020

The accumulation of amyloid protein aggregates in tissues is the basis for the onset of diseases known as amyloidoses. Intriguingly, many amyloidoses impact the central nervous system (CNS) and usually are devastating diseases. It is increasingly apparent that neurotoxic soluble oligomers formed by amyloidogenic proteins are the primary molecular drivers of these diseases, making them lucrative diagnostic and therapeutic targets. One promising diagnostic/therapeutic strategy has been the development of antibody fragments against amyloid oligomers. Antibody fragments, such as fragment antigen-binding (Fab), scFv (single chain variable fragments), and VHH (heavy chain variable domain or single-domain antibodies) are an alternative to full-length IgGs as diagnostics and therapeutics for a variety of diseases, mainly because of their increased tissue penetration (lower MW compared to IgG), decreased inflammatory potential (lack of Fc domain), and facile production (low structural complexity). Furthermore, through the use of in vitro-based ligand selection, it has been possible to identify antibody fragments presenting marked conformational selectivity. In this review, we summarize significant reports on antibody fragments selective for oligomers associated with prevalent CNS amyloidoses. We discuss promising results obtained using antibody fragments as both diagnostic and therapeutic agents against these diseases. In addition, the use of antibody fragments, particularly scFv and VHH, in the isolation of unique oligomeric assemblies is discussed as a strategy to unravel conformational moieties responsible for neurotoxicity. We envision that advances in this field may lead to the development of novel oligomer-selective antibody fragments with superior selectivity and, hopefully, good clinical outcomes.
WWOX Loss of Function in Neurodevelopmental and Neurodegenerative Disorders
Authors: Aldaz C. Marcelo , Hussain Tabish
Published: November 2020

The WWOX gene was initially discovered as a putative tumor suppressor. More recently, its association with multiple central nervous system (CNS) pathologies has been recognized. WWOX biallelic germline pathogenic variants have been implicated in spinocerebellar ataxia type 12 (SCAR12; MIM:614322) and in early infantile epileptic encephalopathy (EIEE28; MIM:616211). WWOX germline copy number variants have also been associated with autism spectrum disorder (ASD). All identified germline genomic variants lead to partial or complete loss of WWOX function. Importantly, large-scale genome-wide association studies have also identified WWOX as a risk gene for common neurodegenerative conditions such as Alzheimer’s disease (AD) and multiple sclerosis (MS). Thus, the spectrum of CNS disorders associated with WWOX is broad and heterogeneous, and there is little understanding of potential mechanisms at play. Exploration of gene expression databases indicates that WWOX expression is comparatively higher in the human cerebellar cortex than in other CNS structures. However, RNA in-situ hybridization data from the Allen Mouse Brain Atlas show that specific regions of the basolateral amygdala (BLA), the medial entorhinal cortex (EC), and deep layers of the isocortex can be singled out as brain regions with specific higher levels of Wwox expression. These observations are in close agreement with single-cell RNA-seq data which indicate that neurons from the medial entorhinal cortex, Layer 5 from the frontal cortex as well as GABAergic basket cells and granule cells from cerebellar cortex are the specific neuronal subtypes that display the highest Wwox expression levels. Importantly, the brain regions and cell types in which WWOX is most abundantly expressed, such as the EC and BLA, are intimately linked to pathologies and syndromic conditions in turn associated with this gene, such as epilepsy, intellectual disability, ASD, and AD. Higher Wwox expression in interneurons and granule cells from cerebellum points to a direct link to the described cerebellar ataxia in cases of WWOX loss of function. We now know that total or partial impairment of WWOX function results in a wide and heterogeneous variety of neurodegenerative conditions for which the specific molecular mechanisms remain to be deciphered. Nevertheless, these observations indicate an important functional role for WWOX in normal development and function of the CNS. Evidence also indicates that disruption of WWOX expression at the gene or protein level in CNS has significant deleterious consequences.
Absence of Mal/TIRAP Results in Abrogated Imidazoquinolinones-Dependent Activation of IRF7 and Suppressed IFNβ and IFN-I Activated Gene Production
Authors: Leszczyńska Ewa , Makuch Edyta , Mitkiewicz Małgorzata , Jasyk Izabella , Narita Miwako , Górska Sabina , Lipiński Tomasz , Siednienko Jakub
Published: November 2020

Activation of TLR7 by small imidazoquinoline molecules such as R848 or R837 initiates signaling cascades leading to the activation of transcription factors, such as AP-1, NF-κB, and interferon regulatory factors (IRFs) and afterward to the induction of cytokines and anti-viral Type I IFNs. In general, TLRs mediate these effects by utilizing different intracellular signaling molecules, one of them is Mal. Mal is a protein closely related to the antibacterial response, and its role in the TLR7 pathways remains poorly understood. In this study, we show that Mal determines the expression and secretion of IFNβ following activation of TLR7, a receptor that recognizes ssRNA and imidazoquinolines. Moreover, we observed that R848 induces Mal-dependent IFNβ production via ERK1/2 activation as well as the transcription factor IRF7 activation. Although activation of TLR7 leads to NF-κB-dependent expression of IRF7, this process is independent of Mal. We also demonstrate that secretion of IFNβ regulated by TLR7 and Mal in macrophages and dendritic cells leads to the IP-10 chemokine expression. In conclusion, our data demonstrate that Mal is a critical regulator of the imidazoquinolinones-dependent IFNβ production via ERK1/2/IRF7 signaling cascade which brings us closer to understanding the molecular mechanism’s regulation of innate immune response.
The Predicted Functional Compartmentation of Rice Terpenoid Metabolism by Trans-Prenyltransferase Structural Analysis, Expression and Localization
Authors: You Min Kyoung , Lee Yeo Jin , Yu Ji Su , Ha Sun-Hwa
Published: November 2020

Most terpenoids are derived from the basic terpene skeletons of geranyl pyrophosphate (GPP, C10), farnesyl-PP (FPP, C15) and geranylgeranyl-PP (GGPP, C20). The trans-prenyltransferases (PTs) mediate the sequential head-to-tail condensation of an isopentenyl-PP (C5) with allylic substrates. The in silico structural comparative analyses of rice trans-PTs with 136 plant trans-PT genes allowed twelve rice PTs to be identified as GGPS_LSU (OsGGPS1), homomeric G(G)PS (OsGPS) and GGPS_SSU-II (OsGRP) in Group I; two solanesyl-PP synthase (OsSPS2 and 3) and two polyprenyl-PP synthases (OsSPS1 and 4) in Group II; and five FPSs (OsFPS1, 2, 3, 4 and 5) in Group III. Additionally, several residues in “three floors” for the chain length and several essential domains for enzymatic activities specifically varied in rice, potentiating evolutionarily rice-specific biochemical functions of twelve trans-PTs. Moreover, expression profiling and localization patterns revealed their functional compartmentation in rice. Taken together, we propose the predicted topology-based working model of rice PTs with corresponding terpene metabolites: GPP/GGPPs mainly in plastoglobuli, SPPs in stroma, PPPs in cytosol, mitochondria and chloroplast and FPPs in cytosol. Our findings could be suitably applied to metabolic engineering for producing functional terpene metabolites in rice systems.
The Immune Endocannabinoid System of the Tumor Microenvironment
Authors: Kienzl Melanie , Kargl Julia , Schicho Rudolf
Published: November 2020

Leukocytes are part of the tumor microenvironment (TME) and are critical determinants of tumor progression. Because of the immunoregulatory properties of cannabinoids, the endocannabinoid system (ECS) may have an important role in shaping the TME. Members of the ECS, an entity that consists of cannabinoid receptors, endocannabinoids and their synthesizing/degrading enzymes, have been associated with both tumor growth and rejection. Immune cells express cannabinoid receptors and produce endocannabinoids, thereby forming an “immune endocannabinoid system”. Although in vitro effects of exogenous cannabinoids on immune cells are well described, the role of the ECS in the TME, and hence in tumor development and immunotherapy, is still elusive. This review/opinion discusses the possibility that the “immune endocannabinoid system” can fundamentally influence tumor progression. The widespread influence of cannabinoids on immune cell functions makes the members of the ECS an interesting target that could support immunotherapy.
The Protective Effects of the Autophagic and Lysosomal Machinery in Vascular and Valvular Calcification: A Systematic Review
Authors: Neutel Cédric H. G. , Hendrickx Jhana O. , Martinet Wim , De Meyer Guido R. Y. , Guns Pieter-Jan
Published: November 2020

Background: Autophagy is a highly conserved catabolic homeostatic process, crucial for cell survival. It has been shown that autophagy can modulate different cardiovascular pathologies, including vascular calcification (VCN). Objective: To assess how modulation of autophagy, either through induction or inhibition, affects vascular and valvular calcification and to determine the therapeutic applicability of inducing autophagy. Data sources: A systematic review of English language articles using MEDLINE/PubMed, Web of Science (WoS) and the Cochrane library. The search terms included autophagy, autolysosome, mitophagy, endoplasmic reticulum (ER)-phagy, lysosomal, calcification and calcinosis. Study characteristics: Thirty-seven articles were selected based on pre-defined eligibility criteria. Thirty-three studies (89%) studied vascular smooth muscle cell (VSMC) calcification of which 27 (82%) studies investigated autophagy and six (18%) studies lysosomal function in VCN. Four studies (11%) studied aortic valve calcification (AVCN). Thirty-four studies were published in the time period 2015–2020 (92%). Conclusion: There is compelling evidence that both autophagy and lysosomal function are critical regulators of VCN, which opens new perspectives for treatment strategies. However, there are still challenges to overcome, such as the development of more selective pharmacological agents and standardization of methods to measure autophagic flux.
From Mice to Humans: An Overview of the Potentials and Limitations of Current Transgenic Mouse Models of Major Muscular Dystrophies and Congenital Myopathies
Authors: Sztretye Mónika , Szabó László , Dobrosi Nóra , Fodor János , Szentesi Péter , Almássy János , Magyar Zsuzsanna É. , Dienes Beatrix , Csernoch László
Published: November 2020

Muscular dystrophies are a group of more than 160 different human neuromuscular disorders characterized by a progressive deterioration of muscle mass and strength. The causes, symptoms, age of onset, severity, and progression vary depending on the exact time point of diagnosis and the entity. Congenital myopathies are rare muscle diseases mostly present at birth that result from genetic defects. There are no known cures for congenital myopathies; however, recent advances in gene therapy are promising tools in providing treatment. This review gives an overview of the mouse models used to investigate the most common muscular dystrophies and congenital myopathies with emphasis on their potentials and limitations in respect to human applications.
The Controversial Role of Fibrosis in Autosomal Dominant Polycystic Kidney Disease
Authors: Fragiadaki Maria , Macleod Fiona M. , Ong Albert C. M.
Published: November 2020

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is characterized by the progressive growth of cysts but it is also accompanied by diffuse tissue scarring or fibrosis. A number of recent studies have been published in this area, yet the role of fibrosis in ADPKD remains controversial. Here, we will discuss the stages of fibrosis progression in ADPKD, and how these compare with other common kidney diseases. We will also provide a detailed overview of some key mechanistic pathways to fibrosis in the polycystic kidney. Specifically, the role of the ‘chronic hypoxia hypothesis’, persistent inflammation, Transforming Growth Factor beta (TGFβ), Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) and microRNAs will be examined. Evidence for and against a pathogenic role of extracellular matrix during ADPKD disease progression will be provided.