bluuebunny/crossref_metadata_2025 huggingface dataset:
Epidemiology of Sports-Related Injuries and Associated Risk Factors in Adolescent Athletes: An Injury Surveillance
Authors: Prieto-González Pablo , Martínez-Castillo Jose Luis , Fernández-Galván Luis Miguel , Casado Arturo , Soporki Sergio , Sánchez-Infante Jorge
Published: May 2021

The present study aimed to determine the epidemiology of sport-related injuries in amateur and professional adolescent athletes and the incidence of different risk factors on those injuries. Four hundred ninety-eight athletes aged 14 to 21 voluntarily participated in this prospective injury surveillance, conducted from 1 January 2019 to 31 December 2019. The information collected included: personal data, sports aspects, characteristics of the injuries, and lifestyle. Forty point four percent of the participants suffered an injury in 2019 (39% of them in a previously injured area). The average injury rate was 2.64 per 1000 h. Soccer presented the highest rate (7.21). The most common injuries were: lumbar muscle strains (12.24%), ankle sprains (11.98%), and bone fractures (9.31%). Ankles (36.12%), knees (19.32%), and shoulders (6.47%) concentrated the highest number of injuries. Fifty-nine point twenty-eight percent of the injuries occurred during practices, and 40.72% during competition or peri-competition. Higher injury rates were associated (in this order) with the following factors: (a) Greater number of hours of practice per week. (b) Not performing warm-ups. (c) Using inadequate sports facilities. (d) Being aged 14–17. (e) Not performing physical preparation. (f) Inappropriate training load. (g) Not performing injury-preventive activities. (h) Performing sports technique without the supervision of one sports coach. (i) Inadequate sports equipment. In conclusion, since most injury risk factors are modifiable, it is imperative to implement strategies to reduce amateur and professional adolescent athletes’ injury rates.
The Seasonality Impact of the BTEX Pollution on the Atmosphere of Arad City, Romania
Authors: Popitanu Corina , Cioca Gabriela , Copolovici Lucian , Iosif Dennis , Munteanu Florentina-Daniela , Copolovici Dana
Published: May 2021

Benzene, toluene, and total BTEX (benzene, toluene, ethylbenzene, and xylene) concentrations registered for one year (2016) have been determined every month for one high-density traffic area. The assessment was performed in Arad City, Romania, to evaluate these pollutants and their influence on the inhabitants’ health. The contaminants were sampled using a static sampling method and analyzed by gas chromatography coupled with mass spectrometry. Benzene was the most dominant among the BTEX compounds—the average concentrations ranged from 18.00 ± 1.32 µg m−3 in December to 2.47 ± 0.74 µg m−3 in August. The average toluene concentration over the year was 4.36 ± 2.42 µg m−3 (with a maximum of 9.60 ± 2.39 µg m−3 in November and a minimum of 1.04 ± 0.29 µg m−3 in May). The toluene/benzene ratio (T/B) was around 0.5, indicating substantial contributions from mobile sources (vehicles). The emission and accumulation of different aromatic compounds (especially benzene) could deteriorate the urban air quality. The lifetime cancer risk (LTCR) for benzene was found to be more than 10−5 in winter, including the inhabitants in the “probable cancer risk” category.
A Network Approach for the Study of Drug Prescriptions: Analysis of Administrative Records from a Local Health Unit (ASL TO4, Regione Piemonte, Italy)
Authors: Miglio Gianluca , Basso Lara , Armando Lucrezia G. , Traina Sara , Benetti Elisa , Diarassouba Abdoulaye , Baroetto Parisi Raffaella , Esiliato Mariangela , Rolando Cristina , Remani Elisa , Cena Clara
Published: May 2021

In a Drug Prescription Network (DPN), each drug is represented as a node and two drugs co-prescribed to the same patient are represented as an edge linking the nodes. The use of DPNs is a novel approach that has been proposed as a means to study the complexity of drug prescription. The aim of this study is to demonstrate the analytical power of the DPN-based approach when it is applied to the analysis of administrative data. Drug prescription data that were collected at a local health unit (ASL TO4, Regione Piemonte, Italy), over a 12-month period (July 2018–June 2019), were used to create several DPNs that correspond to the five levels of the Anatomical Therapeutic Chemical classification system. A total of 5,431,335 drugs prescribed to 361,574 patients (age 0–100 years; 54.7% females) were analysed. As indicated by our results, the DPNs were dense networks, with giant components that contain all nodes. The disassortative mixing of node degrees was observed, which implies that non-random connectivity exists in the networks. Network-based methods have proven to be a flexible and efficient approach to the analysis of administrative data on drug prescription.
Associations between Health Literacy and Sociodemographic Factors: A Cross-Sectional Study in Malaysia Utilising the HLS-M-Q18
Authors: Azlan Arina Anis , Hamzah Mohammad Rezal , Tham Jen Sern , Ayub Suffian Hadi , Ahmad Abdul Latiff , Mohamad Emma
Published: May 2021

Health literacy is progressively seen as an indicator to describe a nation’s health status. To improve health literacy, countries need to address health inequalities by examining different social demographic factors across the population. This assessment is crucial to identify and evaluate the strengths and limitations of a country in addressing health issues. By addressing these health inequalities, a country would be better informed to take necessary steps to improve the nation’s health literacy. This study examines health literacy levels in Malaysia and analyses socio-demographic factors that are associated with health literacy. A cross-sectional survey was carried out using the HLS-M-Q18 instrument, which was validated for the Malaysian population. Multi-stage random sampling strategy was used in this study, utilising several sampling techniques including quota sampling, cluster sampling, and simple random sampling to allow random data collection. A total of 855 respondents were sampled. Our results showed that there were significant associations between health literacy and age, health status, and health problems. Our findings also suggest that lower health literacy levels were associated with the younger generation. This study’s findings have provided baseline data on Malaysians’ health literacy and provide evidence showing potential areas of intervention.
The Effects of the Combination of High-Intensity Interval Training with 3D-Multiple Object Tracking Task on Perceptual-Cognitive Performance: A Randomized Controlled Intervention Trial
Authors: Park Soo-Yong , Klotzbier Thomas Jürgen , Schott Nadja
Published: May 2021

The ability to process goal-related visual information while ignoring goal-irrelevant information is essential for the human attention system. The study aimed to investigate how perceptual–cognitive performance was affected during high-intensity interval training (HIIT) using a 3D-multiple object tracking (3D-MOT) task called Neurotracker (NT). In an experimental design, 42 healthy adults (age M = 23.3 SD = 2.94, VO2max 52.8 ± 5.66 mL·kg−1·min−1) were randomly assigned to an intervention (HIIT + NT, NT, HIIT) or control group. NT performance (20 trials per session) was measured pre-and post-test (at 5, 15, and 25 min while running on the treadmill). The participants trained twice a week for a 4-week intervention period. There was a significant interaction effect between pre/post-test and groups regarding perceptual-cognitive performance, indicating similar enhancements in the HIIT + NT and the NT group during exercise. HIIT influences physical fitness but did not show any impact on perceptual–cognitive performance. Due to the specific NT task characteristics, improved physical abilities may not directly impact sport-specific perceptual-cognitive performance. Our findings suggest that training resulted in substantial task-specific gains. Therefore, combination training may be proposed as a training program to improve perceptual–cognitive, and physical performance in a time-efficient way.
Examination of the Effectiveness of the Healthy Empowered Active Lifestyles (HEAL) Program on Advanced Glycation End Products
Authors: Gregoski Mathew J. , Newton Janis , Blaylock Kathleen , Smith Sheila A. O. , Turner David P.
Published: May 2021

This pilot study investigated the effectiveness of the healthy empowered active lifestyles (HEAL) program to reduce circulatory levels of advanced glycation end products (AGEs) and assess its relationship to BMI, % body fat, fasting glucose, and A1C. The HEAL program was delivered at a local wellness center using a team-based approach and focused on physical activity and dietary education. A sample of twenty primarily European American (19 white, 1 black) participants (i.e., 10 males, 10 females) aged 26 to 71 (m = 48.75 ± 10.26) completed 12 weeks of the HEAL intervention. Pre to post changes in AGEs, BMI, % body fat, fasting glucose, and A1C were examined as primary outcomes. The findings showed participants had the following average reductions: AGEs 36.04 ± 18.48 ug/mL, BMI 2.0 ± 1.2 kg/m2, % body fat 3.18 ± 1.57%, fasting glucose 5.9 ± 17.21 mg/dL, and A1C 0.68 ± 1.11%. All twenty participants successfully completed the entire twelve weeks of the HEAL intervention. The results of this study show that the HEAL intervention provides beneficial reductions of AGEs, BMI, % body fat, fasting glucose, and A1C. In addition, the high adherence shows promise, and demonstrates the potential for HEAL as a behavioral intervention to improve pre-diabetic and other inflammatory related comorbidities. Further replication of results via additional randomized controlled trials is needed.
A Method for Exploring and Analyzing Spatiotemporal Patterns of Traffic Congestion in Expressway Networks Based on Origin–Destination Data
Authors: Gao Hong , Yan Zhenjun , Hu Xu , Yu Zhaoyuan , Luo Wen , Yuan Linwang , Zhang Jiyi
Published: May 2021

Traffic congestion in expressway networks has a strong negative influence on regional development. Understanding the spatiotemporal patterns of traffic congestion in expressway networks is critical for improving the exchange of products in regional production and promoting regional economic development. Nevertheless, existing studies pay less attention to these spatiotemporal patterns of traffic congestion. Considering that Origin–Destination (OD) data are available for the recorded spatial movements of vehicles in expressways, this study proposes a method with which to explore traffic congestion at the level of road segments in the regional expressway network, the mainstream of driving behaviors, and traffic regulations. Methods for analyzing spatial disparity and temporal changes in traffic congestion in expressway networks are also put forward in this paper. The empirical results show that the proposed methods could detect road segments where traffic congestion happens, and then uncover temporal patterns of several congested locations and spatial patterns of road segments with frequent congestion. These spatiotemporal patterns of traffic congestion could be in accord with the actual situation. This study provides a new approach to investigating traffic congestion in expressway networks based on low-cost data, which might be helpful for optimizing expressway network planning and promoting balanced regional development.
Expert Knowledge as Basis for Assessing an Automatic Matching Procedure
Authors: Ruiz-Lendínez Juan José , Ariza-López Francisco Javier , Ureña-Cámara Manuel Antonio
Published: May 2021

The continuous development of machine learning procedures and the development of new ways of mapping based on the integration of spatial data from heterogeneous sources have resulted in the automation of many processes associated with cartographic production such as positional accuracy assessment (PAA). The automation of the PAA of spatial data is based on automated matching procedures between corresponding spatial objects (usually building polygons) from two geospatial databases (GDB), which in turn are related to the quantification of the similarity between these objects. Therefore, assessing the capabilities of these automated matching procedures is key to making automation a fully operational solution in PAA processes. The present study has been developed in response to the need to explore the scope of these capabilities by means of a comparison with human capabilities. Thus, using a genetic algorithm (GA) and a group of human experts, two experiments have been carried out: (i) to compare the similarity values between building polygons assigned by both and (ii) to compare the matching procedure developed in both cases. The results obtained showed that the GA—experts agreement was very high, with a mean agreement percentage of 93.3% (for the experiment 1) and 98.8% (for the experiment 2). These results confirm the capability of the machine-based procedures, and specifically of GAs, to carry out matching tasks.
Synthesis and Photobehavior of a New Dehydrobenzoannulene-Based HOF with Fluorine Atoms: From Solution to Single Crystals Observation
Authors: Gomez Eduardo , Hisaki Ichiro , Douhal Abderrazzak
Published: May 2021

Hydrogen-bonded organic frameworks (HOFs) are the focus of intense scientific research due their potential applications in science and technology. Here, we report on the synthesis, characterization, and photobehavior of a new HOF (T12F-1(124TCB)) based on a dehydrobenzoannulene derivative containing fluorine atoms (T12F-COOH). This HOF exhibits a 2D porous sheet, which is hexagonally networked via H-bonds between the carboxylic groups, and has an interlayers distance (4.3 Å) that is longer than that of a typical π–π interaction. The presence of the fluorine atoms in the DBA molecular units largely increases the emission quantum yield in DMF (0.33, T12F-COOH) when compared to the parent compound (0.02, T12-COOH). The time-resolved dynamics of T12F-COOH in DMF is governed by the emission from a locally excited state (S1, ~0.4 ns), a charge-transfer state (S1(CT), ~2 ns), and a room temperature emissive triplet state (T1, ~20 ns), in addition to a non-emissive triplet structure with a charge-transfer character (T1(CT), τ = 0.75 µs). We also report on the results using T12F-ester. Interestingly, FLIM experiments on single crystals unravel that the emission lifetimes of the crystalline HOF are almost twice those of the amorphous ones or the solid T12F-ester sample. This shows the relevance of the H-bonds in the photodynamics of the HOF and provides a strong basis for further development and study of HOFs based on DBAs for potential applications in photonics.
Multidrug Resistance in Mammals and Fungi—From MDR to PDR: A Rocky Road from Atomic Structures to Transport Mechanisms
Authors: Khunweeraphong Narakorn , Kuchler Karl
Published: May 2021

Multidrug resistance (MDR) can be a serious complication for the treatment of cancer as well as for microbial and parasitic infections. Dysregulated overexpression of several members of the ATP-binding cassette transporter families have been intimately linked to MDR phenomena. Three paradigm ABC transporter members, ABCB1 (P-gp), ABCC1 (MRP1) and ABCG2 (BCRP) appear to act as brothers in arms in promoting or causing MDR in a variety of therapeutic cancer settings. However, their molecular mechanisms of action, the basis for their broad and overlapping substrate selectivity, remains ill-posed. The rapidly increasing numbers of high-resolution atomic structures from X-ray crystallography or cryo-EM of mammalian ABC multidrug transporters initiated a new era towards a better understanding of structure–function relationships, and for the dynamics and mechanisms driving their transport cycles. In addition, the atomic structures offered new evolutionary perspectives in cases where transport systems have been structurally conserved from bacteria to humans, including the pleiotropic drug resistance (PDR) family in fungal pathogens for which high resolution structures are as yet unavailable. In this review, we will focus the discussion on comparative mechanisms of mammalian ABCG and fungal PDR transporters, owing to their close evolutionary relationships. In fact, the atomic structures of ABCG2 offer excellent models for a better understanding of fungal PDR transporters. Based on comparative structural models of ABCG transporters and fungal PDRs, we propose closely related or even conserved catalytic cycles, thus offering new therapeutic perspectives for preventing MDR in infectious disease settings.
Role of Endocrine-Disrupting Chemicals in the Pathogenesis of Non-Alcoholic Fatty Liver Disease: A Comprehensive Review
Authors: Cano Raquel , Pérez José , Dávila Lissé , Ortega Ángel , Gómez Yosselin , Valero-Cedeño Nereida , Parra Heliana , Manzano Alexander , Véliz Castro Teresa , Albornoz María , Cano Gabriel , Rojas-Quintero Joselyn , Chacín Maricarmen , Bermúdez Valmore
Published: May 2021

Non-alcoholic fatty liver disease (NAFLD) is considered the most common liver disorder, affecting around 25% of the population worldwide. It is a complex disease spectrum, closely linked with other conditions such as obesity, insulin resistance, type 2 diabetes mellitus, and metabolic syndrome, which may increase liver-related mortality. In light of this, numerous efforts have been carried out in recent years in order to clarify its pathogenesis and create new prevention strategies. Currently, the essential role of environmental pollutants in NAFLD development is recognized. Particularly, endocrine-disrupting chemicals (EDCs) have a notable influence. EDCs can be classified as natural (phytoestrogens, genistein, and coumestrol) or synthetic, and the latter ones can be further subdivided into industrial (dioxins, polychlorinated biphenyls, and alkylphenols), agricultural (pesticides, insecticides, herbicides, and fungicides), residential (phthalates, polybrominated biphenyls, and bisphenol A), and pharmaceutical (parabens). Several experimental models have proposed a mechanism involving this group of substances with the disruption of hepatic metabolism, which promotes NAFLD. These include an imbalance between lipid influx/efflux in the liver, mitochondrial dysfunction, liver inflammation, and epigenetic reprogramming. It can be concluded that exposure to EDCs might play a crucial role in NAFLD initiation and evolution. However, further investigations supporting these effects in humans are required.
Synthesis and Biological Activity of New Brassinosteroid Analogs of Type 24-Nor-5β-Cholane and 23-Benzoate Function in the Side Chain
Authors: Soto Nitza , Ferrer Karoll , Díaz Katy , González César , Taborga Lautaro , Olea Andrés F. , Carrasco Héctor , Espinoza Luis
Published: May 2021

Brassinosteroids are polyhydroxysteroids that are involved in different plants’ biological functions, such as growth, development and resistance to biotic and external stresses. Because of its low abundance in plants, much effort has been dedicated to the synthesis and characterization of brassinosteroids analogs. Herein, we report the synthesis of brassinosteroid 24-nor-5β-cholane type analogs with 23-benzoate function and 22,23-benzoate groups. The synthesis was accomplished with high reaction yields in a four-step synthesis route and using hyodeoxycholic acid as starting material. All synthesized analogs were tested using the rice lamina inclination test to assess their growth-promoting activity and compare it with those obtained for brassinolide, which was used as a positive control. The results indicate that the diasteroisomeric mixture of monobenzoylated derivatives exhibit the highest activity at the lowest tested concentrations (1 × 10−8 and 1 × 10−7 M), being even more active than brassinolide. Therefore, a simple synthetic procedure with high reaction yields that use a very accessible starting material provides brassinosteroid synthetic analogs with promising effects on plant growth. This exploratory study suggests that brassinosteroid analogs with similar chemical structures could be a good alternative to natural brassinosteroids.
Concurrent Physiological and Pathological Angiogenesis in Retinopathy of Prematurity and Emerging Therapies
Authors: Dai Chang , Webster Keith A. , Bhatt Amit , Tian Hong , Su Guanfang , Li Wei
Published: May 2021

Retinopathy of prematurity (ROP) is an ocular vascular disease affecting premature infants, characterized by pathological retinal neovascularization (RNV), dilated and tortuous retinal blood vessels, and retinal or vitreous hemorrhages that may lead to retinal detachment, vision impairment and blindness. Compared with other neovascular diseases, ROP is unique because of ongoing and concurrent physiological and pathological angiogenesis in the developing retina. While the disease is currently treated by laser or cryotherapy, anti-vascular endothelial growth factor (VEGF) agents have been extensively investigated but are not approved in the U.S. because of safety concerns that they negatively interfere with physiological angiogenesis of the developing retina. An ideal therapeutic strategy would selectively inhibit pathological but not physiological angiogenesis. Our group recently described a novel strategy that selectively and safely alleviates pathological RNV in animal models of ROP by targeting secretogranin III (Scg3), a disease-restricted angiogenic factor. The preclinical profile of anti-Scg3 therapy presents a high potential for next-generation disease-targeted anti-angiogenic therapy for the ROP indication. This review focuses on retinal vessel development in neonates, the pathogenesis of ROP and its underlying molecular mechanisms, including different animal models, and provides a summary of current and emerging therapies.
Acid-Sensing Ion Channels and Mechanosensation
Authors: Ruan Nina , Tribble Jacob , Peterson Andrew M. , Jiang Qian , Wang John Q. , Chu Xiang-Ping
Published: May 2021

Acid-sensing ion channels (ASICs) are mainly proton-gated cation channels that are activated by pH drops and nonproton ligands. They are part of the degenerin/epithelial sodium channel superfamily due to their sodium permeability. Predominantly expressed in the central nervous system, ASICs are involved in synaptic plasticity, learning/memory, and fear conditioning. These channels have also been implicated in multiple disease conditions, including ischemic brain injury, multiple sclerosis, Alzheimer’s disease, and drug addiction. Recent research has illustrated the involvement of ASICs in mechanosensation. Mechanosensation is a form of signal transduction in which mechanical forces are converted into neuronal signals. Specific mechanosensitive functions have been elucidated in functional ASIC1a, ASIC1b, ASIC2a, and ASIC3. The implications of mechanosensation in ASICs indicate their subsequent involvement in functions such as maintaining blood pressure, modulating the gastrointestinal function, and bladder micturition, and contributing to nociception. The underlying mechanism of ASIC mechanosensation is the tether-gate model, which uses a gating-spring mechanism to activate ASIC responses. Further understanding of the mechanism of ASICs will help in treatments for ASIC-related pathologies. Along with the well-known chemosensitive functions of ASICs, emerging evidence has revealed that mechanosensitive functions of ASICs are important for maintaining homeostasis and contribute to various disease conditions.
Laccase and Tyrosinase Biosensors Used in the Determination of Hydroxycinnamic Acids
Authors: Bounegru Alexandra Virginia , Apetrei Constantin
Published: May 2021

In recent years, researchers have focused on developing simple and efficient methods based on electrochemical biosensors to determine hydroxycinnamic acids from various real samples (wine, beer, propolis, tea, and coffee). Enzymatic biosensors represent a promising, low-cost technology for the direct monitoring of these biologically important compounds, which implies a fast response and simple sample processing procedures. The present review aims at highlighting the structural features of this class of compounds and the importance of hydroxycinnamic acids for the human body, as well as presenting a series of enzymatic biosensors commonly used to quantify these phenolic compounds. Enzyme immobilization techniques on support electrodes are very important for their stability and for obtaining adequate results. The following sections of this review will briefly describe some of the laccase (Lac) and tyrosinase (Tyr) biosensors used for determining the main hydroxycinnamic acids of interest in the food or cosmetics industry. Considering relevant studies in the field, the fact has been noticed that there is a greater number of studies on laccase-based biosensors as compared to those based on tyrosinase for the detection of hydroxycinnamic acids. Significant progress has been made in relation to using the synergy of nanomaterials and nanocomposites for more stable and efficient enzyme immobilization. These nanomaterials are mainly carbon- and/or polymer-based nanostructures and metallic nanoparticles which provide a suitable environment for maintaining the biocatalytic activity of the enzyme and for increasing the rate of electron transport.
Analysis of the Oxidative Burst and Its Relevant Signaling Pathways in Leptosphaeria maculans—Brassica napus Pathosystem
Authors: Yang Cunchun , Fernando W. G. Dilantha
Published: May 2021

An oxidative burst is an early response of plants to various biotic/abiotic stresses. In plant-microbe interactions, the plant body can induce oxidative burst to activate various defense mechanisms to combat phytopathogens. A localized oxidative burst is also one of the typical behaviors during hypersensitive response (HR) caused by gene-for-gene interaction. In this study, the occurrence of oxidative burst and its signaling pathways was studied from different levels of disease severity (i.e., susceptible, intermediate, and resistant) in the B. napus–L. maculans pathosystem. Canola cotyledons with distinct levels of resistance exhibited differential regulation of the genes involved in reactive oxygen species (ROS) accumulation and responses. Histochemical assays were carried out to understand the patterns of H2O2 accumulation and cell death. Intermediate and resistant genotypes exhibited earlier accumulation of H2O2 and emergence of cell death around the inoculation origins. The observations also suggested that the cotyledons with stronger resistance were able to form a protective region of intensive oxidative bursts between the areas with and without hyphal intrusions to block further fungal advancement to the uninfected regions. The qPCR analysis suggested that different onset patterns of some marker genes in ROS accumulation/programmed cell death (PCD) such as RBOHD, MPK3 were associated with distinct levels of resistance from B. napus cultivars against L. maculans. The observations and datasets from this article indicated the distinct differences in ROS-related cellular behaviors and signaling between compatible and incompatible interactions.
Multivariate Optimization of the FLC-dc-APGD-Based Reaction-Discharge System for Continuous Production of a Plasma-Activated Liquid of Defined Physicochemical and Anti-Phytopathogenic Properties
Authors: Dzimitrowicz Anna , Jamroz Piotr , Pohl Pawel , Babinska Weronika , Terefinko Dominik , Sledz Wojciech , Motyka-Pomagruk Agata
Published: May 2021

To the present day, no efficient plant protection method against economically important bacterial phytopathogens from the Pectobacteriaceae family has been implemented into agricultural practice. In this view, we have performed a multivariate optimization of the operating parameters of the reaction-discharge system, employing direct current atmospheric pressure glow discharge, generated in contact with a flowing liquid cathode (FLC-dc-APGD), for the production of a plasma-activated liquid (PAL) of defined physicochemical and anti-phytopathogenic properties. As a result, the effect of the operating parameters on the conductivity of PAL acquired under these conditions was assessed. The revealed optimal operating conditions, under which the PAL of the highest conductivity was obtained, were as follows: flow rate of the solution equaled 2.0 mL min−1, the discharge current was 30 mA, and the inorganic salt concentration (ammonium nitrate, NH4NO3) in the solution turned out to be 0.50% (m/w). The developed PAL exhibited bacteriostatic and bactericidal properties toward Dickeya solani IFB0099 and Pectobacterium atrosepticum IFB5103 strains, with minimal inhibitory and minimal bactericidal concentrations equaling 25%. After 24 h exposure to 25% PAL, 100% (1−2 × 106) of D. solani and P. atrosepticum cells lost viability. We attributed the antibacterial properties of PAL to the presence of deeply penetrating, reactive oxygen and nitrogen species (RONS), which were, in this case, OH, O, O3, H2O2, HO2, NH, N2, N2+, NO2−, NO3−, and NH4+. Putatively, the generated low-cost, eco-friendly, easy-to-store, and transport PAL, exhibiting the required antibacterial and physicochemical properties, may find numerous applications in the plant protection sector.
Cellular Mechanisms of the Anti-Arrhythmic Effect of Cardiac PDE2 Overexpression
Authors: Wagner Michael , Sadek Mirna S. , Dybkova Nataliya , Mason Fleur E. , Klehr Johann , Firneburg Rebecca , Cachorro Eleder , Richter Kurt , Klapproth Erik , Kuenzel Stephan R. , Lorenz Kristina , Heijman Jordi , Dobrev Dobromir , El-Armouche Ali , Sossalla Samuel , Kämmerer Susanne
Published: May 2021

Background: Phosphodiesterases (PDE) critically regulate myocardial cAMP and cGMP levels. PDE2 is stimulated by cGMP to hydrolyze cAMP, mediating a negative crosstalk between both pathways. PDE2 upregulation in heart failure contributes to desensitization to β-adrenergic overstimulation. After isoprenaline (ISO) injections, PDE2 overexpressing mice (PDE2 OE) were protected against ventricular arrhythmia. Here, we investigate the mechanisms underlying the effects of PDE2 OE on susceptibility to arrhythmias. Methods: Cellular arrhythmia, ion currents, and Ca2+-sparks were assessed in ventricular cardiomyocytes from PDE2 OE and WT littermates. Results: Under basal conditions, action potential (AP) morphology were similar in PDE2 OE and WT. ISO stimulation significantly increased the incidence of afterdepolarizations and spontaneous APs in WT, which was markedly reduced in PDE2 OE. The ISO-induced increase in ICaL seen in WT was prevented in PDE2 OE. Moreover, the ISO-induced, Epac- and CaMKII-dependent increase in INaL and Ca2+-spark frequency was blunted in PDE2 OE, while the effect of direct Epac activation was similar in both groups. Finally, PDE2 inhibition facilitated arrhythmic events in ex vivo perfused WT hearts after reperfusion injury. Conclusion: Higher PDE2 abundance protects against ISO-induced cardiac arrhythmia by preventing the Epac- and CaMKII-mediated increases of cellular triggers. Thus, activating myocardial PDE2 may represent a novel intracellular anti-arrhythmic therapeutic strategy in HF.
Antidepressants Differentially Regulate Intracellular Signaling from α1-Adrenergic Receptor Subtypes In Vitro
Authors: Chmielarz Piotr , Kuśmierczyk Justyna , Rafa-Zabłocka Katarzyna , Chorązka Katarzyna , Kowalska Marta , Satała Grzegorz , Nalepa Irena
Published: May 2021

Currently utilized antidepressants have limited effectiveness and frequently incur undesired effects. Most antidepressants are thought to act via the inhibition of monoamine reuptake; however, direct binding to monoaminergic receptors has been proposed to contribute to both their clinical effectiveness and their side effects, or lack thereof. Among the target receptors of antidepressants, α1‑adrenergic receptors (ARs) have been implicated in depression etiology, antidepressant action, and side effects. However, differences in the direct effects of antidepressants on signaling from the three subtypes of α1-ARs, namely, α1A-, α1B- and α1D‑ARs, have been little explored. We utilized cell lines overexpressing α1A-, α1B- or α1D-ARs to investigate the effects of the antidepressants imipramine (IMI), desipramine (DMI), mianserin (MIA), reboxetine (REB), citalopram (CIT) and fluoxetine (FLU) on noradrenaline-induced second messenger generation by those receptors. We found similar orders of inhibition at α1A-AR (IMI < DMI < CIT < MIA < REB) and α1D‑AR (IMI = DMI < CIT < MIA), while the α1B-AR subtype was the least engaged subtype and was inhibited with low potency by three drugs (MIA < IMI = DMI). In contrast to their direct antagonistic effects, prolonged incubation with IMI and DMI increased the maximal response of the α1B-AR subtype, and the CIT of both the α1A- and the α1B-ARs. Our data demonstrate a complex, subtype-specific modulation of α1-ARs by antidepressants of different groups.
GeromiRs Are Downregulated in the Tumor Microenvironment during Colon Cancer Colonization of the Liver in a Murine Metastasis Model
Authors: Gerovska Daniela , Garcia-Gallastegi Patricia , Crende Olatz , Márquez Joana , Larrinaga Gorka , Unzurrunzaga Maite , Araúzo-Bravo Marcos J. , Badiola Iker
Published: May 2021

Cancer is a phenomenon broadly related to ageing in various ways such as cell cycle deregulation, metabolic defects or telomerases dysfunction as principal processes. Although the tumor cell is the main actor in cancer progression, it is not the only element of the disease. Cells and the matrix surrounding the tumor, called the tumor microenvironment (TME), play key roles in cancer progression. Phenotypic changes of the TME are indispensable for disease progression and a few of these transformations are produced by epigenetic changes including miRNA dysregulation. In this study, we found that a specific group of miRNAs in the liver TME produced by colon cancer called geromiRs, which are miRNAs related to the ageing process, are significantly downregulated. The three principal cell types involved in the liver TME, namely, liver sinusoidal endothelial cells, hepatic stellate (Ito) cells and Kupffer cells, were isolated from a murine hepatic metastasis model, and the miRNA and gene expression profiles were studied. From the 115 geromiRs and their associated hallmarks of aging, which we compiled from the literature, 75 were represented in the used microarrays, 26 out of them were downregulated in the TME cells during colon cancer colonization of the liver, and none of them were upregulated. The histone modification hallmark of the downregulated geromiRs is significantly enriched with the geromiRs miR-15a, miR-16, miR-26a, miR-29a, miR-29b and miR-29c. We built a network of all of the geromiRs downregulated in the TME cells and their gene targets from the MirTarBase database, and we analyzed the expression of these geromiR gene targets in the TME. We found that Cercam and Spsb4, identified as prognostic markers in a few cancer types, are associated with downregulated geromiRs and are upregulated in the TME cells.
Omics Data and Their Integrative Analysis to Support Stratified Medicine in Neurodegenerative Diseases
Authors: La Cognata Valentina , Morello Giovanna , Cavallaro Sebastiano
Published: May 2021

Molecular and clinical heterogeneity is increasingly recognized as a common characteristic of neurodegenerative diseases (NDs), such as Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. This heterogeneity makes difficult the development of early diagnosis and effective treatment approaches, as well as the design and testing of new drugs. As such, the stratification of patients into meaningful disease subgroups, with clinical and biological relevance, may improve disease management and the development of effective treatments. To this end, omics technologies—such as genomics, transcriptomics, proteomics and metabolomics—are contributing to offer a more comprehensive view of molecular pathways underlying the development of NDs, helping to differentiate subtypes of patients based on their specific molecular signatures. In this article, we discuss how omics technologies and their integration have provided new insights into the molecular heterogeneity underlying the most prevalent NDs, aiding to define early diagnosis and progression markers as well as therapeutic targets that can translate into stratified treatment approaches, bringing us closer to the goal of personalized medicine in neurology.
The Kynurenic Acid Analog SZR72 Enhances Neuronal Activity after Asphyxia but Is Not Neuroprotective in a Translational Model of Neonatal Hypoxic Ischemic Encephalopathy
Authors: Kovács Viktória , Remzső Gábor , Körmöczi Tímea , Berkecz Róbert , Tóth-Szűki Valéria , Pénzes Andrea , Vécsei László , Domoki Ferenc
Published: May 2021

Hypoxic–ischemic encephalopathy (HIE) remains to be a major cause of long-term neurodevelopmental deficits in term neonates. Hypothermia offers partial neuroprotection warranting research for additional therapies. Kynurenic acid (KYNA), an endogenous product of tryptophan metabolism, was previously shown to be beneficial in rat HIE models. We sought to determine if the KYNA analog SZR72 would afford neuroprotection in piglets. After severe asphyxia (pHa = 6.83 ± 0.02, ΔBE = −17.6 ± 1.2 mmol/L, mean ± SEM), anesthetized piglets were assigned to vehicle-treated (VEH), SZR72-treated (SZR72), or hypothermia-treated (HT) groups (n = 6, 6, 6; Tcore = 38.5, 38.5, 33.5 °C, respectively). Compared to VEH, serum KYNA levels were elevated, recovery of EEG was faster, and EEG power spectral density values were higher at 24 h in the SZR72 group. However, instantaneous entropy indicating EEG signal complexity, depression of the visual evoked potential (VEP), and the significant neuronal damage observed in the neocortex, the putamen, and the CA1 hippocampal field were similar in these groups. In the caudate nucleus and the CA3 hippocampal field, neuronal damage was even more severe in the SZR72 group. The HT group showed the best preservation of EEG complexity, VEP, and neuronal integrity in all examined brain regions. In summary, SZR72 appears to enhance neuronal activity after asphyxia but does not ameliorate early neuronal damage in this HIE model.
Helicobacter pylori Outer Membrane Vesicles and Extracellular Vesicles from Helicobacter pylori-Infected Cells in Gastric Disease Development
Authors: González María Fernanda , Díaz Paula , Sandoval-Bórquez Alejandra , Herrera Daniela , Quest Andrew F. G.
Published: May 2021

Extracellular vesicles (EVs) are cell-derived vesicles important in intercellular communication that play an essential role in host-pathogen interactions, spreading pathogen-derived as well as host-derived molecules during infection. Pathogens can induce changes in the composition of EVs derived from the infected cells and use them to manipulate their microenvironment and, for instance, modulate innate and adaptive inflammatory immune responses, both in a stimulatory or suppressive manner. Gastric cancer is one of the leading causes of cancer-related deaths worldwide and infection with Helicobacter pylori (H. pylori) is considered the main risk factor for developing this disease, which is characterized by a strong inflammatory component. EVs released by host cells infected with H. pylori contribute significantly to inflammation, and in doing so promote the development of disease. Additionally, H. pylori liberates vesicles, called outer membrane vesicles (H. pylori-OMVs), which contribute to atrophia and cell transformation in the gastric epithelium. In this review, the participation of both EVs from cells infected with H. pylori and H. pylori-OMVs associated with the development of gastric cancer will be discussed. By deciphering which functions of these external vesicles during H. pylori infection benefit the host or the pathogen, novel treatment strategies may become available to prevent disease.
Kidney Disease in Diabetic Patients: From Pathophysiology to Pharmacological Aspects with a Focus on Therapeutic Inertia
Authors: Gembillo Guido , Ingrasciotta Ylenia , Crisafulli Salvatore , Luxi Nicoletta , Siligato Rossella , Santoro Domenico , Trifirò Gianluca
Published: May 2021

Diabetes mellitus represents a growing concern, both for public economy and global health. In fact, it can lead to insidious macrovascular and microvascular complications, impacting negatively on patients’ quality of life. Diabetic patients often present diabetic kidney disease (DKD), a burdensome complication that can be silent for years. The average time of onset of kidney impairment in diabetic patients is about 7–10 years. The clinical impact of DKD is dangerous not only for the risk of progression to end-stage renal disease and therefore to renal replacement therapies, but also because of the associated increase in cardiovascular events. An early recognition of risk factors for DKD progression can be decisive in decreasing morbidity and mortality. DKD presents patient-related, clinician-related, and system-related issues. All these problems are translated into therapeutic inertia, which is defined as the failure to initiate or intensify therapy on time according to evidence-based clinical guidelines. Therapeutic inertia can be resolved by a multidisciplinary pool of healthcare experts. The timing of intensification of treatment, the transition to the best therapy, and dietetic strategies must be provided by a multidisciplinary team, driving the patients to the glycemic target and delaying or overcoming DKD-related complications. A timely nephrological evaluation can also guarantee adequate information to choose the right renal replacement therapy at the right time in case of renal impairment progression.
Glucocerebrosidase Gene Therapy Induces Alpha-Synuclein Clearance and Neuroprotection of Midbrain Dopaminergic Neurons in Mice and Macaques
Authors: Sucunza Diego , Rico Alberto J. , Roda Elvira , Collantes María , González-Aseguinolaza Gloria , Rodríguez-Pérez Ana I. , Peñuelas Iván , Vázquez Alfonso , Labandeira-García José L. , Broccoli Vania , Lanciego José L.
Published: May 2021

Mutations in the GBA1 gene coding for glucocerebrosidase (GCase) are the main genetic risk factor for Parkinson’s disease (PD). Indeed, identifying reduced GCase activity as a common feature underlying the typical neuropathological signatures of PD—even when considering idiopathic forms of PD—has recently paved the way for designing novel strategies focused on enhancing GCase activity to reduce alpha-synuclein burden and preventing dopaminergic cell death. Here we have performed bilateral injections of a viral vector coding for the mutated form of alpha-synuclein (rAAV9-SynA53T) for disease modeling purposes, both in mice as well as in nonhuman primates (NHPs), further inducing a progressive neuronal death in the substantia nigra pars compacta (SNpc). Next, another vector coding for the GBA1 gene (rAAV9-GBA1) was unilaterally delivered in the SNpc of mice and NHPs one month after the initial insult, together with the contralateral delivery of an empty/null rAAV9 for control purposes. Obtained results showed that GCase enhancement reduced alpha-synuclein burden, leading to improved survival of dopaminergic neurons. Data reported here support using GCase gene therapy as a disease-modifying treatment for PD and related synucleinopathies, including idiopathic forms of these disorders.
Potassium Fertilization Stimulates Sucrose-to-Starch Conversion and Root Formation in Sweet Potato (Ipomoea batatas (L.) Lam.)
Authors: Gao Yang , Tang Zhonghou , Xia Houqiang , Sheng Minfei , Liu Ming , Pan Shenyuan , Li Zongyun , Liu Jingran
Published: May 2021

A field experiment was established to study sweet potato growth, starch dynamic accumulation, key enzymes and gene transcription in the sucrose-to-starch conversion and their relationships under six K2O rates using Ningzishu 1 (sensitive to low-K) and Xushu 32 (tolerant to low-K). The results indicated that K application significantly improved the biomass accumulation of plant and storage root, although treatments at high levels of K, i.e., 300–375 kg K2O ha−1, significantly decreased plant biomass and storage root yield. Compared with the no-K treatment, K application enhanced the biomass accumulation of plant and storage root by 3–47% and 13–45%, respectively, through promoting the biomass accumulation rate. Additionally, K application also enhanced the photosynthetic capacity of sweet potato. In this study, low stomatal conductance and net photosynthetic rate (Pn) accompanied with decreased intercellular CO2 concentration were observed in the no-K treatment at 35 DAT, indicating that Pn was reduced mainly due to stomatal limitation; at 55 DAT, reduced Pn in the no-K treatment was caused by non-stomatal factors. Compared with the no-K treatment, the content of sucrose, amylose and amylopectin decreased by 9–34%, 9–23% and 6–19%, respectively, but starch accumulation increased by 11–21% under K supply. The activities of sucrose synthetase (SuSy), adenosine-diphosphate-glucose pyrophosphorylase (AGPase), starch synthase (SSS) and the transcription of Susy, AGP, SSS34 and SSS67 were enhanced by K application and had positive relationships with starch accumulation. Therefore, K application promoted starch accumulation and storage root yield through regulating the activities and genes transcription of SuSy, AGPase and SSS in the sucrose-to-starch conversion.
Mitochondrial Dysfunction in Podocytes Caused by CRIF1 Deficiency Leads to Progressive Albuminuria and Glomerular Sclerosis in Mice
Authors: Na Ki Ryang , Jeong Jin Young , Shin Jin Ah , Chang Yoon-Kyung , Suh Kwang-Sun , Lee Kang Wook , Choi Dae Eun
Published: May 2021

Recent studies have implicated mitochondrial disruption in podocyte dysfunction, which is a characteristic feature of primary and diabetic glomerular diseases. However, the mechanisms by which primary mitochondrial dysfunction in podocytes affects glomerular renal diseases are currently unknown. To investigate the role of mitochondrial oxidative phosphorylation (OxPhos) in podocyte dysfunction, glomerular function was examined in mice carrying a loss of function mutation of the gene encoding CR6-interacting factor-1 (CRIF1), which is essential for intramitochondrial production and the subsequent insertion of OxPhos polypeptides into the inner mitochondrial membrane. Homozygotic deficiency of CRIF1 in podocytes resulted in profound and progressive albuminuria from 3 weeks of age; the CRIF1-deficient mice also developed glomerular and tubulointerstitial lesions by 10 weeks of age. Furthermore, marked glomerular sclerosis and interstitial fibrosis were observed in homozygous CRIF1-deficient mice at 20 weeks of age. In cultured mouse podocytes, loss of CRIF1 resulted in OxPhos dysfunction and marked loss or abnormal aggregation of F-actin. These findings indicate that the OxPhos status determines the integrity of podocytes and their ability to maintain a tight barrier and control albuminuria. Analyses of the glomerular function of the podocyte-specific primary OxPhos dysfunction model mice demonstrate a link between podocyte mitochondrial dysfunction, progressive glomerular sclerosis, and tubulointerstitial diseases.