bluuebunny/crossref_metadata_2025 huggingface dataset:
Deep Learning-Based Segmentation to Establish East Asian Normative Volumes Using Multisite Structural MRI
Authors: Kim Regina E. Y. , Lee Minho , Kang Dong Woo , Wang Sheng-Min , Kim Nak-Young , Lee Min Kyoung , Lim Hyun Kook , Kim Donghyeon
Published: December 2020

Normative brain magnetic resonance imaging (MRI) is essential to interpret the state of an individual’s brain health. However, a normative study is often expensive for small research groups. Although several attempts have been made to establish brain MRI norms, the focus has been limited to certain age ranges. This study aimed to establish East Asian normative brain data using multi-site MRI and determine the robustness of these data for clinical research. Normative MRI was gathered covering a wide range of cognitively normal East Asian populations (age: 18–96 years) from two open sources and three research sites. Eight sub-regional volumes were extracted in the left and right hemispheres using an in-house deep learning-based tool. Repeated measure consistency and multicenter reliability were determined using intraclass correlation coefficients and compared to a widely used tool, FreeSurfer. Our results showed highly consistent outcomes with high reliability across sites. Our method outperformed FreeSurfer in repeated measure consistency for most structures and multicenter reliability for all structures. The normative MRI we constructed was able to identify sub-regional differences in mild cognitive impairments and dementia after covariate adjustments. Our investigation suggests it is possible to provide a sound normative reference for neurodegenerative or aging research.
Dipylidium caninum Infection in Dogs and Humans in Bishoftu Town, Ethiopia
Authors: Gutema Fanta D. , Yohannes Goitom W. , Abdi Reta D. , Abuna Fufa , Ayana Dinka , Waktole Hika , Amenu Kebede , Hiko Adem , Agga Getahun E.
Published: December 2020

Dogs are reservoirs of many zoonotic diseases. In Ethiopia, the majority of owned dogs are semi-stray, freely roaming in the community. Studies reporting dog borne zoonotic diseases are scarce in Ethiopia. This study was conducted to assess Dipylidium caninum infection in dogs and in children with gastrointestinal complaints in Bishoftu Town, Oromia. We collected 384 fecal samples from dogs presented to veterinary teaching hospital and 259 stool samples from children presented to Bishoftu Hospital for clinical examination. Samples were first macroscopically examined for the presence of proglotids, followed by microscopic examination for the presence of eggs with the direct smear following flotation technique. The prevalence of D. caninum was 21% (95% CI: 16.6–24.9) in dogs. Although not statistically significant (p > 0.05), higher prevalence was detected in adult (11.9%), local breed (17.7%), and male (12.6%) dogs compared to young (8.59%), exotic breed (2.86%), and females (7.81%), respectively. Dipylidium caninum was detected in a stool sample obtained from a three year-old child (0.4%, 1/259). This study showed that the prevalence of D. caninum in the dogs is high while it is rare in children. Although the prevalence in children is negligible in this study, the high proportion of infected dogs can pose a significant risk of infection in the general human population. Public health risk can be reduced by eliminating the semi-roaming of owned dogs and proper management of dogs with regular deworming and prevention of environmental contamination with dog feces. Similarly, raising public awareness about dog borne zoonoses and avoiding contact with dog feces are important.
Outcomes of Kidney Transplantation in Fabry Disease: A Meta-Analysis
Authors: Suarez Maria L. Gonzalez , Thongprayoon Charat , Hansrivijit Panupong , Medaura Juan , Vaitla Pradeep , Mao Michael A. , Bathini Tarun , Boonpheng Boonphiphop , Kanduri Swetha R. , Kovvuru Karthik , Basu Arpita , Cheungpasitporn Wisit
Published: December 2020

Background: Fabry disease (FD) is a rare X-linked lysosomal storage disorder with progressive systemic deposition of globotriaosylceramide, leading to life-threatening cardiac, central nervous system, and kidney disease. Current therapy involves symptomatic medical management, enzyme replacement therapy (ERT), dialysis, kidney transplantation, and, more recently, gene therapy. The aim of this systematic review was to assess outcomes of kidney transplantation among patients with FD. Methods: A comprehensive literature review was conducted utilizing MEDLINE, EMBASE, and Cochrane Database, from inception through to 28 February 2020, to identify studies that evaluate outcomes of kidney transplantation including patient and allograft survival among kidney transplant patients with FD. Effect estimates from each study were extracted and combined using the random-effects generic inverse variance method of DerSimonian and Laird. Results: In total, 11 studies, including 424 kidney transplant recipients with FD, were enrolled. The post-transplant median follow-up time ranged from 3 to 11.5 years. Overall, the pooled estimated rates of all-cause graft failure, graft failure before death, and allograft rejection were 32.5% (95%CI: 23.9%–42.5%), 14.5% (95%CI: 8.4%–23.7%), and 20.2% (95%CI: 15.4%–25.9%), respectively. In the sensitivity analysis, limited only to the recent studies (year 2001 or newer when ERT became available), the pooled estimated rates of all-cause graft failure, graft failure before death, and allograft rejection were 28.1% (95%CI: 20.5%–37.3%), 11.7% (95%CI: 8.4%–16.0%), and 20.2% (95%CI: 15.5%–26.0%), respectively. The pooled estimated rate of biopsy proven FD recurrence was 11.1% (95%CI: 3.6%–29.4%), respectively. There are no significant differences in the risks of all-cause graft failure (p = 0.10) or mortality (0.48) among recipients with vs. without FD. Conclusions: Despite possible FD recurrence after transplantation of 11.1%, allograft and patient survival are comparable among kidney transplant recipients with vs. without FD.
NOx Reduction in Ag/Al2O3-SiO2 Converters in the Exhaust of a Compression-Ignition Engine
Authors: Kruczyński Stanisław W. , Orliński Piotr , Ślęzak Marcin
Published: December 2020

NOx emissions in compression-ignition engines can be reduced, either through the application of engine-internal methods, i.e., making sure that as little NOx as possible is produced as a result of the mixture combustion processes, or through the use of catalytic converters designed to reduce nitrogen oxides, including NH3-SCR or HC-SCR converters. Converters using ammonia offer high conversion rates, but they tend to be problematic in terms of their operation. For this reason, converters using hydrocarbons for the purpose of NOx reduction have been gaining in popularity. An Ag/Al2O3-SiO2 converter is an example of such a catalytic converter. This paper describes the process of preparing such a converter and characterises the porosity and acidity of its surface. The dispersion of silver was assessed based on oxygen absorption tests on crystallites of sliver and based on TEM images of crystallites of silver. The conversion of NO2, NO and propane was assessed depending on the temperature. Additionally, NO2, NO and propane conversion was assessed at 500 °C, depending on the admixture of a reducer, and propane selectivity in the process of reduction of NO to N2 was calculated. The test results indicate that the developed converter can be considered the basis for further research into the development of this compression-ignition engine exhaust after-treatment technology.
Investigation of Turbulence Modeling for Point-Absorber-Type Wave Energy Converters
Authors: Windt Christian , Davidson Josh , Ringwood John
Published: December 2020

Reviewing the literature of CFD-based numerical wave tanks for wave energy applications, it can be observed that different flow conditions and different turbulence models are applied during numerical wave energy converter (WEC) experiments. No single turbulence model can be identified as an `industry standard’ for WEC modeling. The complexity of the flow field around a WEC, together with the strong dependency of turbulence effects on the shape, operational conditions, and external forces, hampers the formulation of such an `industry standard’. Furthermore, the conceptually different flow characteristics (i.e., oscillating, free surface flows), compared to the design cases of most turbulence models (i.e., continuous single-phase flow), can be identified as a source for the potential lack of accuracy of turbulence models for WEC applications. This communication performs a first step towards analyzing the accuracy and necessity of modeling turbulence effects, by means of turbulence models, within CFD-based NWTs for WEC applications. To that end, the influence of turbulence models and, in addition, the influence of the initial turbulence intensity is investigated based on different wave–structure interaction cases considering two separately validated WEC models. The results highlight the complexity of such a `turbulence analysis’ and the study suggests specific future work to get a better understanding of the model requirements for the flow field around WECs.
Estimation of Damage Induced by Single-Hole Rock Blasting: A Review on Analytical, Numerical, and Experimental Solutions
Authors: Shadabfar Mahdi , Gokdemir Cagri , Zhou Mingliang , Kordestani Hadi , Muho Edmond V.
Published: December 2020

This paper presents a review of the existing models for the estimation of explosion-induced crushed and cracked zones. The control of these zones is of utmost importance in the rock explosion design, since it aims at optimizing the fragmentation and, as a result, minimizing the fine grain production and recovery cycle. Moreover, this optimization can reduce the damage beyond the set border and align the excavation plan with the geometric design. The models are categorized into three groups based on the approach, i.e., analytical, numerical, and experimental approaches, and for each group, the relevant studies are classified and presented in a comprehensive manner. More specifically, in the analytical methods, the assumptions and results are described and discussed in order to provide a useful reference to judge the applicability of each model. Considering the numerical models, all commonly-used algorithms along with the simulation details and the influential parameters are reported and discussed. Finally, considering the experimental models, the emphasis is given here on presenting the most practical and widely employed laboratory models. The empirical equations derived from the models and their applications are examined in detail. In the Discussion section, the most common methods are selected and used to estimate the damage size of 13 case study problems. The results are then utilized to compare the accuracy and applicability of each selected method. Furthermore, the probabilistic analysis of the explosion-induced failure is reviewed using several structural reliability models. The selection, classification, and discussion of the models presented in this paper can be used as a reference in real engineering projects.
Characteristics of Plastic Waste Processing in the Modern Recycling Plant Operating in Poland
Authors: Szostak Elżbieta , Duda Piotr , Duda Andrzej , Górska Natalia , Fenicki Arkadiusz , Molski Patryk
Published: December 2020

Although Poland is one of the leading recipients of the waste stream in the European Union (EU), it is at the same time below the average in terms of efficiency of their use/utilization. The adopted technological solutions cause waste processing rates to be relatively low in Poland. As a result, the report of the Early Warning and Response System (EWRS) of the EU indicated Poland as one of the 14 countries of the EU which are at risk in terms of possibility of achieving 50% recycling of waste. This article discusses the implemented technological solutions, and shows the profitability of the investment and the values of the process heat demand both for extractor and reactor. The experimental part analyzed the composition of the input and output of the process and compared it to the required fuel specifications. Attention was drawn to the need to improve the recycling process in order to increase the quality of manufactured fuel components. As potential ways of solving the problem of low fuel quality, cleaning the sorted reaction mass from solid particles and extending the technological line with a distillation column have been proposed. The recommended direction of improvement of the technology is also the optimization of the process of the reactor’s purification and removal of contaminants.
Non-Intrusive Measurements to Incorporate the Air Renovations in Dynamic Models Assessing the In-Situ Thermal Performance of Buildings
Authors: Jiménez María José , Díaz José Alberto , Alonso Antonio Javier , Castaño Sergio , Pérez Manuel
Published: December 2020

This paper reports the analysis of the feasibility to characterise the air leakage and the mechanical ventilation avoiding the intrusiveness of the traditional measurement techniques of the corresponding indicators in buildings. The viability of obtaining the air renovation rate itself from measurements of the concentration of the metabolic CO2, and the possibilities to express this rate as function of other climatic variables, are studied. N2O tracer gas measurements have been taken as reference. A Test Cell and two full size buildings, with and without mechanical ventilation and with different levels of air leakage, are considered as case studies. One-month test campaigns have been used for the reference N2O tracer gas experiments. Longer periods are available for the analysis based on CO2 concentration. When the mechanical ventilation is not active, the results indicate significant correlation between the air renovation rate and the wind speed. The agreement between the N2O reference values and the evolution of the metabolic CO2 is larger for larger initial values of the CO2 concentration. When the mechanical ventilation is active, relevant variations have been observed among the N2O reference values along the test campaigns, without evidencing any correlation with the considered boundary variables.
Construction and Empirical Verification of the Agri-Environmental Index (AEI) as a Tool for Assessing the Green Performance of Agriculture
Authors: Kasztelan Armand , Nowak Anna
Published: December 2020

In this paper, the aggregate index of green performance of agriculture (Agri-Environmental Index (AEI)) was proposed and empirically verified. For this purpose, a taxonomic method was used, i.e., the linear ordering method, which allows for the construction of a synthetic metric for the assessment of performance. Based on 16 agri-environmental indicators from the Organization for Economic Cooperation and Development (OECD) and Eurostat database, green performance indexes were constructed for 20 European countries. The constructed indexes are based on the multi-line impact of agriculture on the environment, with a particular focus on energy issues. During the analyses, answers to the following research questions were sought: Is the AEI an appropriate tool for evaluating the green performance of agriculture? What is the overall situation in this matter in EU countries? Which areas in terms of the impact of agriculture on the environment require remedial actions? The results of surveys show that the level of green performance in countries is still low (an average of 0.3069). The article indicates the areas that require special attention in the context of continuation of greening processes in the agricultural sector.
Application of Ultraviolet-Visible Absorption Spectroscopy with Machine Learning Techniques for the Classification of Cretan Wines
Authors: Philippidis Aggelos , Poulakis Emmanouil , Kontzedaki Renate , Orfanakis Emmanouil , Symianaki Aikaterini , Zoumi Aikaterini , Velegrakis Michalis
Published: December 2020

The present study was aimed at the identification, differentiation and characterization of red and white Cretan wines, which are described with Protected Geographical Indication (PGI), using ultraviolet–visible absorption spectroscopy. Specifically, the grape variety, the wine aging process and the role of barrel/container type were investigated. The combination of spectroscopic results with machine learning-based modelling demonstrated the use of absorption spectroscopy as a facile and low-cost technique in wine analysis. In this study, a clear discrimination among grape varieties was revealed. Moreover, a grouping of samples according to aging period and container type of maturation was accomplished, for the first time.
Antioxidant Efficacy of Olive By-Product Extracts in Human Colon HCT8 Cells
Authors: Centrone Mariangela , D’Agostino Mariagrazia , Difonzo Graziana , De Bruno Alessandra , Di Mise Annarita , Ranieri Marianna , Montemurro Cinzia , Valenti Giovanna , Poiana Marco , Caponio Francesco , Tamma Grazia
Published: December 2020

The production of olive oil is accompanied by the generation of a huge amount of waste and by-products including olive leaves, pomace, and wastewater. The latter represents a relevant environmental issue because they contain certain phytotoxic compounds that may need specific treatments before the expensive disposal. Therefore, reducing waste biomass and valorizing by-products would make olive oil production more sustainable. Here, we explore the biological actions of extracts deriving from olive by-products including olive pomace (OP), olive wastewater (OWW), and olive leaf (OLs) in human colorectal carcinoma HCT8 cells. Interestingly, with the same phenolic concentration, the extract obtained from the OWW showed higher antioxidant ability compared with the extracts derived from OP and OLs. These biological effects may be related to the differential phenolic composition of the extracts, as OWW extract contains the highest amount of hydroxytyrosol and tyrosol that are potent antioxidant compounds. Furthermore, OP extract that contains a higher level of vanillic acid than the other extracts displayed a cytotoxic action at the highest concentration. Together these findings revealed that phenols in the by-product extracts may interfere with signaling molecules that cross-link several intracellular pathways, raising the possibility to use them for beneficial health effects.
Investigation of Phenolic Composition and Anticancer Properties of Ethanolic Extracts of Japanese Quince Leaves
Authors: Zvikas Vaidotas , Urbanaviciute Ieva , Bernotiene Rasa , Kulakauskiene Deimante , Morkunaite Urte , Balion Zbigniev , Majiene Daiva , Liaudanskas Mindaugas , Viskelis Pranas , Jekabsone Aiste , Jakstas Valdas
Published: December 2020

Glioblastoma multiforme is an aggressive and invasive disease with no efficient therapy available, and there is a great need for finding alternative treatment strategies. This study aimed to investigate anticancer activity of the extracts of the Japanese quince (JQ) cultivars ‘Darius’, ‘Rondo’, and ‘Rasa’ leaf extracts on glioblastoma C6 and HROG36 cells. As identified by ultra high performance liquid chromatography electrospray ionization tandem mass spectrometry, the extracts contained three prevailing groups of phenols: hydroxycinnamic acid derivatives; flavan-3-ols; and flavonols. Sixteen phenols were detected; the predominant compound was chlorogenic acid. The sum of detected phenols varied significantly between the cultivars ranging from 9322 µg/g (‘Rondo’) to 17,048 µg/g DW (‘Darius’). Incubation with the extracts decreased the viability of glioblastoma HROG36 cells with an efficiency similar to temozolomide, a drug used for glioblastoma treatment. In the case of C6 glioblastoma cells, the extracts were even more efficient than temozolomide. Interestingly, primary cerebellar neuronal-glial cells were significantly less sensitive to the extracts compared to the cancer cell lines. The results showed that JQ leaf ethanol extracts are rich in phenolic compounds, can efficiently reduce glioblastoma cell viability while preserving non-cancerous cells, and are worth further investigations as potential anticancer drugs.
Yuck, This Biscuit Looks Lumpy! Neophobic Levels and Cultural Differences Drive Children’s Check-All-That-Apply (CATA) Descriptions and Preferences for High-Fibre Biscuits
Authors: Sandvik Pernilla , Laureati Monica , Jilani Hannah , Methven Lisa , Sandell Mari , Hörmann-Wallner Marlies , da Quinta Noelia , Zeinstra Gertrude G. , Almli Valérie L.
Published: December 2020

Food neophobia influences food choice in school-aged children. However, little is known about how children with different degrees of food neophobia perceive food and to what extent different sensory attributes drive their liking. This paper explores liking and sensory perception of fibre-rich biscuits in school-aged children (n = 509, age 9–12 years) with different degrees of food neophobia and from five different European countries (Finland, Italy, Spain, Sweden and United Kingdom). Children tasted and rated their liking of eight commercial biscuits and performed a Check-All-That-Apply task to describe the samples and further completed a Food Neophobia Scale. Children with a higher degree of neophobia displayed a lower liking for all tasted biscuits (p < 0.001). Cross-cultural differences in liking also appeared (p < 0.001). A negative correlation was found between degree of neophobia and the number of CATA-terms used to describe the samples (r = −0.116, p = 0.009). Penalty analysis showed that degree of food neophobia also affected drivers of biscuit liking, where particularly appearance terms were drivers of disliking for neophobic children. Cross-cultural differences in drivers of liking and disliking were particularly salient for texture attributes. Further research should explore if optimizing appearance attributes could be a way to increase liking of fibre-rich foods in neophobic children.
Optimization of the Effects of Different Temperatures and Compositions of Filmogenic Solution on Lactobacillus salivarius Using Predictive Mathematical Models
Authors: Monteiro Shênia Santos , da Silva Wilton Pereira , Monteiro Shirley Santos , Gomes Josivanda Palmeira , Pereira Emmanuel Moreira , de Melo Queiroz Alexandre José , de Figueirêdo Rossana Maria Feitosa , Rocha Ana Paula Trindade , Silva Hanndson Araujo , de Almeida Leyllanne Renalle Batista , de Sena Mábia Ruana Silva , de Lima Antônio Gilson Barbosa
Published: December 2020

It is well known that intake of probiotic brings health benefits. Lactic bacteria with probiotic potential have aroused the interest of the industry in developing food products that incorporate such benefits. However, incorporating probiotic bacteria into food is a challenge for the industry, given the sensitivity of probiotic cultures to process conditions. Therefore, the objective of this study is to evaluate gelatin- and inulin-based filmogenic solutions as a potential vehicle for incorporating probiotics into food products and to model the fermentation kinetics. L. salivarius (Lactobacillus salivarius) growth in filmogenic solutions was analyzed under the influence of a variety gelatin concentrations (1.0–3.0%) and inulin concentrations (4.0–6.0%) and fermented under the effect of different temperatures (25–45 °C). A full 23 factorial plan with three replicates at the central point was used to optimize the process. The impacts of process conditions on cell development are fundamental to optimize the process and make it applicable by the industry. The present study showed that the optimal conditions for the development of probiotic cells in filmogenic solutions are a combination of 1.0% gelatin with 4.0% inulin and fermentation temperature of 45 °C. It was observed that the maximum cell growth occurred in an estimated time of about 4 h of fermentation. L. salivarius cell production and substrate consumption during the fermentation of the filmogenic solution were well simulated by a model proposed in this article, with coefficients of determination of 0.981 (cell growth) and 0.991 (substrate consumption).
5G Poor and Rich Novel Control Scheme Based Load Frequency Regulation of a Two-Area System with 100% Renewables in Africa
Authors: Fayek Hady H.
Published: December 2020

Remote farms in Africa are cultivated lands planned for 100% sustainable energy and organic agriculture in the future. This paper presents the load frequency control of a two-area power system feeding those farms. The power system is supplied by renewable technologies and storage facilities only which are photovoltaics, biogas, biodiesel, solar thermal, battery storage and flywheel storage systems. Each of those facilities has 150-kW capacity. This paper presents a model for each renewable energy technology and energy storage facility. The frequency is controlled by using a novel non-linear fractional order proportional integral derivative control scheme (NFOPID). The novel scheme is compared to a non-linear PID controller (NPID), fractional order PID controller (FOPID), and conventional PID. The effect of the different degradation factors related to the communication infrastructure, such as the time delay and packet loss, are modeled and simulated to assess the controlled system performance. A new cost function is presented in this research. The four controllers are tuned by novel poor and rich optimization (PRO) algorithm at different operating conditions. PRO controller design is compared to other state of the art techniques in this paper. The results show that the PRO design for a novel NFOPID controller has a promising future in load frequency control considering communication delays and packet loss. The simulation and optimization are applied on MATLAB/SIMULINK 2017a environment.
Soil Degradation Processes: It’s Time to Take Our Head Out of the Sand
Authors: Nachshon Uri
Published: December 2020

Soil is one of the most important and essential resources on the globe; however, its importance is somewhat underestimated, especially in political and decision-making circles [...]
Virtual Reality Gait Training to Promote Balance and Gait Among Older People: A Randomized Clinical Trial
Authors: Lee Kyeongjin
Published: December 2020

Falls are the leading cause of injury and injury-related death in the elderly. This study evaluated the effect of virtual reality gait training (VRGT) with non-motorized treadmill on balance and gait ability of elderly individuals who had experienced a fall. Fifty-six elderly individuals living in local communities participated in this study. Subjects who met the selection criteria were randomly divided into a VRGT group (n = 28) and a control group (n = 28). The VRGT group received VRGT with non-motorized treadmill for 50 min a day for 4 weeks and 5 days a week. The control group received non-motorized treadmill gait training without virtual reality for the same amount of time as the VRGT group. Before and after the training, the one-leg-standing test, Berg Balance Scale, Functional Reach test, and Timed Up and Go test were used to assess balance ability, and the gait analyzer system was used to evaluate the improvement in gait spatiotemporal parameters. In the VRGT group, the balance ability variable showed a significant decrease in the one-leg-standing test and a significant improvement in the Timed Up and Go test. With respect to spatiotemporal gait parameters, velocity and step width decreased significantly in the VRGT group (p < 0.05), and stride length and step length were significantly improved in the VRGT group (p < 0.05). VRGT with non-motorized treadmill has been shown to improve balance and gait ability in the elderly. This study is expected to provide basic data on exercise programs for the elderly to prevent falls.
What Is Bahai Orientalism?
Authors: Nash Geoffrey
Published: December 2020

Scrutinizing the literature of a modern religious movement this article argues that postcolonial theory can effectively be brought to the analysis of religions and religious writing. The case study focuses on the way in which colonialism impacted the Bahai faith in a specific and formative way, causing its leadership to present aspects of the faith’s development by employing the codes of Western Orientalism. Drawing on nineteenth and early twentieth-century European orientalist texts composed either about their own faith, or the Islamic society out of which it grew, the article demonstrates how these led Bahais “themselves [to]… adopt [..] an essentially Orientalist vision of their own community and of Iranian society”. Edward Said’s Orientalism throws light on an enduring situation in which mutual othering has crossed from culture and religion into politics, however since the late 1990s critics have demonstrated that Orientalism can function in more varied ways than Said allowed. Finally, the possibility is discussed as to whether there can be such a thing as a postcolonial Bahai scholar.
Effect of Treadmill Exercise and Probiotic Ingestion on Motor Coordination and Brain Activity in Adolescent Mice
Authors: Kim Junechul , Yoon Bo-Eun , Jeon Yong Kyun
Published: December 2020

High-intensity exercise can lead to chronic fatigue, which reduces athletic performance. On the contrary, probiotic supplements have many health benefits, including improvement of gastrointestinal health and immunoregulation. However, the effects of probiotics combined with exercise interventions on motor functions and brain activity have not been fully explored. Therefore, this study aimed to identify the effects of probiotic supplements and aerobic exercise on motor function, immune response, and exercise intensity and probiotic ingestion. After four weeks of intervention, the motor functions were assessed by rotarod test, then the levels of cytokines, gamma-aminobutyric acid (GABA), and glutamate were detected. The improvement caused by the intake of probiotics in the moderate-intensity exercise group and the non-exercise group in the accelerating mode rotarod was significant (p = 0.038, p < 0.001, respectively). In constant-speed mode, the moderate-intensity exercise group with probiotic ingestion recorded longer runs than the corresponding non-exercise group (p = 0.023), and the improvement owing to probiotics was significant in all groups—non-exercise, moderate, and high-intensity (p = 0.036, p = 0.036, p = 0.012, respectively). The concentrations of inflammatory cytokines were lower, whereas GABA was higher in the probiotics-ingested group. Taken together, exercise and probiotics in adolescence could positively affect brain and motor function.
The Delta-Specific Opioid Glycopeptide BBI-11008: CNS Penetration and Behavioral Analysis in a Preclinical Model of Levodopa-Induced Dyskinesia
Authors: Bartlett Mitchell J. , Mabrouk Omar S. , Szabò Lajos , Flores Andrew J. , Parent Kate L. , Bidlack Jean M. , Heien Michael L. , Kennedy Robert T. , Polt Robin , Sherman Scott J. , Falk Torsten
Published: December 2020

In previous work we evaluated an opioid glycopeptide with mixed μ/δ-opioid receptor agonism that was a congener of leu-enkephalin, MMP-2200. The glycopeptide analogue showed penetration of the blood–brain barrier (BBB) after systemic administration to rats, as well as profound central effects in models of Parkinson’s disease (PD) and levodopa (L-DOPA)-induced dyskinesia (LID). In the present study, we tested the glycopeptide BBI-11008 with selective δ-opioid receptor agonism, an analogue of deltorphin, a peptide secreted from the skin of frogs (genus Phyllomedusa). We tested BBI-11008 for BBB-penetration after intraperitoneal (i.p.) injection and evaluated effects in LID rats. BBI-11008 (10 mg/kg) demonstrated good CNS-penetrance as shown by microdialysis and mass spectrometric analysis, with peak concentration levels of 150 pM in the striatum. While BBI-11008 at both 10 and 20 mg/kg produced no effect on levodopa-induced limb, axial and oral (LAO) abnormal involuntary movements (AIMs), it reduced the levodopa-induced locomotor AIMs by 50% after systemic injection. The N-methyl-D-aspartate receptor antagonist MK-801 reduced levodopa-induced LAO AIMs, but worsened PD symptoms in this model. Co-administration of MMP-2200 had been shown prior to block the MK-801-induced pro-Parkinsonian activity. Interestingly, BBI-11008 was not able to block the pro-Parkinsonian effect of MK-801 in the LID model, further indicating that a balance of mu- and delta-opioid agonism is required for this modulation. In summary, this study illustrates another example of meaningful BBB-penetration of a glycopeptide analogue of a peptide to achieve a central behavioral effect, providing additional evidence for the glycosylation technique as a method to harness therapeutic potential of peptides.
Treatment of Men with Central Hypogonadism: Alternatives for Testosterone Replacement Therapy
Authors: Ide Veerle , Vanderschueren Dirk , Antonio Leen
Published: December 2020

Central hypogonadism is a clinical condition, characterized by sexual symptoms and low serum testosterone levels, due to an impaired function of the hypothalamus or pituitary gland. Testosterone replacement therapy (TRT) is the standard treatment for hypogonadism, but it has some disadvantages. TRT is not a good option in men wishing to preserve fertility, nor in men with (a high risk of) prostate cancer, polycythemia, thrombophilia and severe cardiovascular disease. In this review, we discuss alternative treatments for central hypogonadism. If reversible causes are present, non-pharmacological interventions can be therapeutic. Gonadotropins are a good alternative to TRT when fertility is desired in the near future though they require frequent injections. Clomiphene citrate and tamoxifen seem to be a safe alternative for the treatment of functional central hypogonadism in men, as several studies reported a significant increase in testosterone levels with these drugs. However, their use is off-label and data supporting the efficacy of clomiphene citrate and tamoxifen on hypogonadal symptoms are insufficient. For this reason, clomiphene citrate and tamoxifen should not be used in routine clinical practice to treat sexual symptoms in men with central hypogonadism.
Novel Allergen Discovery through Comprehensive De Novo Transcriptomic Analyses of Five Shrimp Species
Authors: Karnaneedi Shaymaviswanathan , Huerlimann Roger , Johnston Elecia B. , Nugraha Roni , Ruethers Thimo , Taki Aya C. , Kamath Sandip D. , Wade Nicholas M. , Jerry Dean R. , Lopata Andreas L.
Published: December 2020

Shellfish allergy affects 2% of the world’s population and persists for life in most patients. The diagnosis of shellfish allergy, in particular shrimp, is challenging due to the similarity of allergenic proteins from other invertebrates. Despite the clinical importance of immunological cross-reactivity among shellfish species and between allergenic invertebrates such as dust mites, the underlying molecular basis is not well understood. Here we mine the complete transcriptome of five frequently consumed shrimp species to identify and compare allergens with all known allergen sources. The transcriptomes were assembled de novo, using Trinity, from raw RNA-Seq data of the whiteleg shrimp (Litopenaeus vannamei), black tiger shrimp (Penaeus monodon), banana shrimp (Fenneropenaeus merguiensis), king shrimp (Melicertus latisulcatus), and endeavour shrimp (Metapenaeus endeavouri). BLAST searching using the two major allergen databases, WHO/IUIS Allergen Nomenclature and AllergenOnline, successfully identified all seven known crustacean allergens. The analyses revealed up to 39 unreported allergens in the different shrimp species, including heat shock protein (HSP), alpha-tubulin, chymotrypsin, cyclophilin, beta-enolase, aldolase A, and glyceraldehyde-3-phosphate dehydrogenase (G3PD). Multiple sequence alignment (Clustal Omega) demonstrated high homology with allergens from other invertebrates including mites and cockroaches. This first transcriptomic analyses of allergens in a major food source provides a valuable resource for investigating shellfish allergens, comparing invertebrate allergens and future development of improved diagnostics for food allergy.
A Review on the Current Knowledge on ZIKV Infection and the Interest of Organoids and Nanotechnology on Development of Effective Therapies against Zika Infection
Authors: Gasco Samanta , Muñoz-Fernández María Ángeles
Published: December 2020

Zika virus (ZIKV) acquired a special relevance due to the pandemic that occurred in the Americas in 2015, when an important number of fetal microcephaly cases occurred. Since then, numerous studies have tried to elucidate the pathogenic mechanisms and the potential therapeutic approaches to combat the virus. Cellular and animal models have proved to be a basic resource for this research, with the more recent addition of organoids as a more realistic and physiological 3D culture for the study of ZIKV. Nanotechnology can also offer a promising therapeutic tool, as the nanoparticles developed by this field can penetrate cells and deliver a wide array of drugs in a very specific and controlled way inside the cells. These two state-of-the-art scientific tools clearly provide a very relevant resource for the study of ZIKV, and will help researchers find an effective treatment or vaccine against the virus.
Role of NMR in High Ordered Structure Characterization of Monoclonal Antibodies
Authors: Tokunaga Yuji , Takeuchi Koh
Published: December 2020

Obtaining high ordered structure (HOS) information is of importance to guarantee the efficacy and safety of monoclonal antibodies (mAbs) in clinical application. Assessment of HOS should ideally be performed in a non-invasive manner under their formulated storage conditions, as any perturbation can introduce unexpected detritions. However, most of the currently available techniques only indirectly report HOS of mAbs and/or require a certain condition to conduct the analyses. Besides, the flexible multidomain architecture of mAbs has hampered atomic-resolution structural analyses using X-ray crystallography and cryo-electron microscopy. In contrast, the ability of nuclear magnetic resonance (NMR) spectroscopy to structurally analyze biomolecules in various conditions in a non-invasive and quantitative manner is suitable to meet the needs. However, the application of NMR to mAbs is not straightforward due to the high molecular weight of the system. In this review, we will discuss how NMR techniques have been applied to HOS analysis of mAbs, along with the recent advances of the novel 15N direct detection NMR strategy that allows for obtaining the structural fingerprint of mAbs at lower temperatures under multiple formulation conditions. The potential application of these NMR strategies will benefit next-generation mAbs, such as antibody-drug conjugates and bispecific antibodies.
Deficiency in Tissue Non-Specific Alkaline Phosphatase Leads to Steatohepatitis in Mice Fed a High Fat Diet Similar to That Produced by a Methionine and Choline Deficient Diet
Authors: Gámez-Belmonte Reyes , Tena-Garitaonaindia Mireia , Hernández-Chirlaque Cristina , Córdova Samir , Ceacero-Heras Diego , de Medina Fermín Sánchez , Martínez-Augustin Olga
Published: December 2020

The liver expresses tissue-nonspecific alkaline phosphatase (TNAP), which may participate in the defense against bacterial components, in cell regulation as part of the purinome or in bile secretion, among other roles. We aimed to study the role of TNAP in the development of hepatosteatosis. TNAP+/− haplodeficient and wild type (WT) mice were fed a control diet (containing 10% fat w/w) or the same diet deficient in methionine and choline (MCD diet). The MCD diet induced substantial weight loss together with hepatic steatosis and increased alanine aminotransferase (ALT) plasma levels, but no differences in IL-6, TNF, insulin or resistin. There were no substantial differences between TNAP+/− and WT mice fed the MCD diet. In turn, TNAP+/− mice receiving the control diet presented hepatic steatosis with alterations in metabolic parameters very similar to those induced by the MCD diet. Nevertheless, no weight loss, increased ALT plasma levels or hypoglycemia were observed. These mice also presented increased levels of liver TNF and systemic resistin and glucagon compared to WT mice. The phenotype of TNAP+/− mice fed a standard diet was normal. In conclusion, TNAP haplodeficiency induces steatosis comparable to that produced by a MCD diet when fed a control diet.
New Omics—Derived Perspectives on Retinal Dystrophies: Could Ion Channels-Encoding or Related Genes Act as Modifier of Pathological Phenotype?
Authors: Donato Luigi , Scimone Concetta , Alibrandi Simona , Abdalla Ebtesam Mohamed , Nabil Karim Mahmoud , D’Angelo Rosalia , Sidoti Antonina
Published: December 2020

Ion channels are membrane-spanning integral proteins expressed in multiple organs, including the eye. Here, ion channels play a role in several physiological processes, like signal transmission and visual processing. A wide range of mutations have been reported in the corresponding genes and their interacting subunit coding genes, which contribute significantly to a wide spectrum of ocular diseases collectively called channelopathies, a subgroup of inherited retinal dystrophies. Such mutations result in either a loss or gain-of channel functions affecting the structure, assembly, trafficking and localization of channel proteins. We investigated the probands of seven Italian and Egyptian families affected by not completely defined forms of inherited retinal dystrophies, by whole exome sequencing (WES) experiments, and found interesting variants in already known causative genes probably able to impair retinal functionalities. However, because such variants did not completely explain the phenotype manifested by each patient, we proceed to further investigate possible related genes carrying mutations that might complement previously found data, based on the common aspect linked to neurotransmission impairments. We found 10 mutated genes whose variants might alter important ligand binding sites differently distributed through all considered patients. Such genes encode for ion channels, or their regulatory proteins, and strictly interact with known causative genes, also sharing with them synaptic-related pathways. Taking into account several limitations that will be resolved by further experiments, we believe that our exploratory investigation will help scientists to provide a new promising paradigm for precise diagnosis of retinal dystrophies to facilitate the development of rational treatments.
Reduced Gonadotrophin Receptor Expression Is Associated with a More Aggressive Ovarian Cancer Phenotype
Authors: Cheung Janelle , Lokman Noor A. , Abraham Riya D. , Macpherson Anne M. , Lee Eunice , Grutzner Frank , Ghinea Nicolae , Oehler Martin K. , Ricciardelli Carmela
Published: December 2020

Follicle-stimulating hormone (FSH) and luteinising hormone (LH) play important roles in regulating cell growth and proliferation in the ovary. However, few studies have explored the expression of FSH and LH receptors (FSHR and LHCGR) in ovarian cancer, and their functional roles in cancer progression remain inconclusive. This study investigated the potential impact of both mRNA (FSHR, LHCGR) and protein (FSHR, LHCGR) expression on ovarian cancer progression using publicly available online databases, qRT-PCR (high grade serous ovarian cancers, HGSOC, n = 29 and benign ovarian tumors, n = 17) and immunohistochemistry (HGSOC, n = 144). In addition, we investigated the effect of FSHR and LHCGR siRNA knockdown on the pro-metastatic behavior of serous ovarian cancer cells in vitro. High FSHR or high LHCGR expression in patients with all subtypes of high-grade ovarian cancer was significantly associated with longer progression-free survival (PFS) and overall survival (OS). High FSHR protein expression was associated with increased PFS (p = 0.050) and OS (p = 0.025). HGSOC patients with both high FSHR and high LHCGR protein levels had the best survival outcome, whilst both low FSHR and low LHCGR expression was associated with poorest survival (p = 0.019). Knockdown of FSHR significantly increased the invasion of serous ovarian cancer cells (OVCAR3 and COV362) in vitro. LHCGR knockdown also promoted invasion of COV362 cells. This study highlights that lower FSHR and LHCGR expression is associated with a more aggressive epithelial ovarian cancer phenotype and promotes pro-metastatic behaviour.
SATB1-Mediated Upregulation of the Oncogenic Receptor Tyrosine Kinase HER3 Antagonizes MET Inhibition in Gastric Cancer Cells
Authors: Jenke Robert , Holzhäuser-Rein Miriam , Mueller-Wilke Stefanie , Lordick Florian , Aigner Achim , Büch Thomas
Published: December 2020

MET-amplified gastric cancer cells are extremely sensitive to MET inhibition in vitro, whereas clinical efficacy of MET inhibitors is disappointing. The compensatory activation of other oncogenic growth factor receptors may serve as an underlying mechanism of resistance. In this study, we analyzed the role of HER receptors, in particular HER3 and its ligand heregulin, in this respect. This also included the chromatin-organizer protein SATB1, as an established regulator of HER expression in other tumor entities. In a panel of MET-amplified gastric carcinoma cell lines, cell growth under anchorage-dependent and independent conditions was studied upon inhibitor treatment or siRNA-mediated knockdown. Expression analyses were performed using RT-qPCR, FACS, and immunoblots. Signal transduction was monitored via antibody arrays and immunoblots. As expected, MET inhibition led to a growth arrest and inhibition of MAPK signaling. Strikingly, however, this was accompanied by a rapid and profound upregulation of the oncogenic receptor HER3. This finding was determined as functionally relevant, since HER3 activation by HRG led to partial MET inhibitor resistance, and MAPK/Akt signaling was even found enhanced upon HRG+MET inhibitor treatment compared to HRG alone. SATB1 was identified as mediator of HER3 upregulation. Concomitantly, SATB1 knockdown prevented upregulation of HER3, thus abrogating the HRG-promoted rescue from MET inhibition. Taken together, our results introduce the combined HER3/MET inhibition as strategy to overcome resistance towards MET inhibitors.
Transient Receptor Potential Ankyrin 1 (TRPA1) Is Involved in Upregulating Interleukin-6 Expression in Osteoarthritic Chondrocyte Models
Authors: Nummenmaa Elina , Hämäläinen Mari , Pemmari Antti , Moilanen Lauri J. , Tuure Lauri , Nieminen Riina M. , Moilanen Teemu , Vuolteenaho Katriina , Moilanen Eeva
Published: December 2020

Transient receptor potential ankyrin 1 (TRPA1) is a membrane-bound ion channel found in neurons, where it mediates nociception and neurogenic inflammation. Recently, we have discovered that TRPA1 is also expressed in human osteoarthritic (OA) chondrocytes and downregulated by the anti-inflammatory drugs aurothiomalate and dexamethasone. We have also shown TRPA1 to mediate inflammation, pain, and cartilage degeneration in experimental osteoarthritis. In this study, we investigated the role of TRPA1 in joint inflammation, focusing on the pro-inflammatory cytokine interleukin-6 (IL-6). We utilized cartilage/chondrocytes from wild-type (WT) and TRPA1 knockout (KO) mice, along with primary chondrocytes from OA patients. The results show that TRPA1 regulates the synthesis of the OA-driving inflammatory cytokine IL-6 in chondrocytes. IL-6 was highly expressed in WT chondrocytes, and its expression, along with the expression of IL-6 family cytokines leukemia inhibitory factor (LIF) and IL-11, were significantly downregulated by TRPA1 deficiency. Furthermore, treatment with the TRPA1 antagonist significantly downregulated the expression of IL-6 in chondrocytes from WT mice and OA patients. The results suggest that TRPA1 is involved in the upregulation of IL-6 production in chondrocytes. These findings together with previous results on the expression and functions of TRPA1 in cellular and animal models point to the role of TRPA1 as a potential mediator and novel drug target in osteoarthritis.