bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of Neighborhood Environment on Pedestrian Route Selection among Elementary Schoolchildren in Korea
Authors: Lee Somin , Lee Myeong-Hun
Published: July 2021

Previous studies on the walking environment of elementary school students have focused on physical factors such as traffic accidents, safety, and the neighborhood environment. However, scholars have yet to consider the behavioral characteristics of elementary school students, particularly in respect to the relationship between environmental factors and behavioral characteristics in pedestrian route selection and safety. Addressing this gap, this study identifies how neighborhood environment factors and behavioral characteristics impact route selection and satisfaction among elementary school students. Accordingly, this study surveyed 251 elementary school students at three elementary schools in Korea and analyzed the spatial forms of the selected sites. In doing so, this study discerns students’ satisfaction with their selection of the shortest or non-shortest route and which environmental factors and behavioral characteristics influenced their selection and satisfaction. Study results have practical implications for policymaking, including valuable insights into the planning of school routes for elementary school students.
Findings on the Central Auditory Functions of Endemic Disease Control Agents
Authors: de Souza Alcarás Patrícia Arruda , Zeigelboim Bianca Simone , Corazza Maria Cristina Alves , Lüders Débora , Marques Jair Mendes , de Lacerda Adriana Bender Moreira
Published: July 2021

This study aimed to assess the central auditory functions of endemic disease control agents. This cross-sectional cohort study comprised two groups: the exposed group, with 38 male endemic disease control agents with simultaneous occupational noise and pesticide exposure; and the control group, with 18 age- and sex-matched workers without occupational noise and/or pesticide exposure. All participants underwent pure-tone audiometry, brainstem auditory evoked potentials, dichotic digits test, and transient-evoked otoacoustic emissions suppression effect. There was a significant inter-group difference in waves III and V absolute latencies, and interpeak I–III and I–V latencies bilaterally, with worse results found in the exposed group. Abnormal dichotic digits test results occurred more often in the exposed group, with a significant association between pesticide- and noise-exposure and the abnormal results (p = 0.0099). The transient-evoked otoacoustic emissions with suppression effect did not yield significant inter-group differences. It was concluded that pesticide and noise exposure induce harmful effects on the central auditory functions, particularly on the brainstem and figure-ground speech-sound auditory skills.
Haemoglobin Levels in Early Life among Infants with and without Retinopathy of Prematurity
Authors: Pheng Edwin , Lim Zi Di , Tai Li Min Evelyn , Rostenberghe Hans Van , Shatriah Ismail
Published: July 2021

Retinopathy of prematurity (ROP) is a proliferative retinal vascular disorder attributed to an ischaemic stimulus in preterm infants. Haemoglobin, the main component for oxygen transportation, may be implicated in ROP development. This retrospective study compared the mean weekly haemoglobin levels between infants with and without ROP over the first six weeks of life. Premature infants of less than 32 weeks gestational age and less than 1.5 kg birth weight were grouped into age and birth weight-matched ROP cases and controls. Weekly mean haemoglobin levels were documented. An independent t-test was used to analyze the difference in mean haemoglobin levels between infants with ROP and infants without ROP. Adjustment for confounders was performed using one-way analysis of covariance. There was a statistically significant difference in adjusted mean haemoglobin levels between the ROP and non-ROP group during the first week of life (p = 0.038). No significant intergroup differences were observed at the other weeks. Haemoglobin monitoring during the first week of postnatal life may be useful to guide ROP screening in premature infants.
Assessing Interactions between PNPLA3 and Dietary Intake on Liver Steatosis in Mexican-Origin Adults
Authors: Morrill Kristin E. , Bland Victoria L. , Klimentidis Yann C. , Hingle Melanie D. , Thomson Cynthia A. , Garcia David O.
Published: July 2021

Mexican-origin (MO) adults have among the highest rates of nonalcoholic fatty liver disease (NAFLD) placing them at increased risk of liver cancer. Evidence suggests that a single nucleotide polymorphism (SNP) in the PNPLA3 gene, rs738409, increases the risk and progression of NAFLD and may modify the relationship between certain dietary factors and liver steatosis. The purpose of this study was to identify whether interactions exist between specific dietary factors and rs738409 genotype status among MO adults in relation to levels of liver steatosis. We analyzed cross-sectional data from a sample of 288 MO adults. Participants completed at least two 24-h dietary recalls. Multiple linear regression was performed assuming an additive genetic model to test the main effects of several dietary variables on levels of hepatic steatosis, adjusting for covariates. To test for effect modification, the product of the genotype and the dietary variable was included as a covariate in the model. No significant association between dietary intake and level of hepatic steatosis was observed, nor any significant gene-diet interactions. Our findings suggest that dietary intake may have the same magnitude of protective or deleterious effect even among MO adults with high genetic risk for NAFLD and NAFLD progression.
Physical Activity among Adults Residing in 11 Countries during the COVID-19 Pandemic Lockdown
Authors: Ding Kele , Yang Jingzhen , Chin Ming-Kai , Sullivan Lindsay , Durstine J. , Violant-Holz Verónica , Demirhan Giyasettin , Oliveira Nara , Popeska Biljana , Kuan Garry , Khan Waheeda , Dai Jianhui , Xu Xia , Mladenova Zornitza , Balasekaran Govindasamy , Smith Gary ,   on behalf of Global Community Health-COVID-19 Collaborative Research Team
Published: July 2021

During the novel coronavirus (COVID-19) pandemic, physical activity (PA) behaviors were altered worldwide due to public health measures such as “lockdown.” This study described PA among adults residing in 11 countries during COVID-19 lockdown and examined factors associated with PA engagement. We conducted a cross-sectional anonymous survey among adults (≥18 years old) in 11 countries (Brazil, Bulgaria, China, India, Ireland, Malaysia, North Macedonia, Singapore, Spain, Turkey, United States). Of 11,775 participants, 63.7% were female and 52.8% were 18–34 years old. More than 40% of participants were insufficiently active (43.9%) and reported a decrease in their PA during lockdown (44.8%). Statistically significant differences were observed in (1) proportions of participants being insufficiently active, (2) level of PA, and (3) decrease in PA across the 11 countries. More stringent governmental policy responses were associated with greater likelihood of being insufficiently active during lockdown (adjusted odds ratio = 1.22, 95% confidence interval = 1.03, 1.45). Higher depression or anxiety scores were associated with greater likelihood of decreased level of PA during lockdown.We found substantial reductions in PA levels during COVID-19 lockdown across countries. Country-specific PA promotion interventions are needed during this and similar global emergencies.
The Role of Deep Hypothermia in Cardiac Surgery
Authors: Gocoł Radosław , Hudziak Damian , Bis Jarosław , Mendrala Konrad , Morkisz Łukasz , Podsiadło Paweł , Kosiński Sylweriusz , Piątek Jacek , Darocha Tomasz
Published: July 2021

Hypothermia is defined as a decrease in body core temperature to below 35 °C. In cardiac surgery, four stages of hypothermia are distinguished: mild, moderate, deep, and profound. The organ protection offered by deep hypothermia (DH) enables safe circulatory arrest as a prerequisite to carrying out cardiac surgical intervention. In adult cardiac surgery, DH is mainly used in aortic arch surgery, surgical treatment of pulmonary embolism, and acute type-A aortic dissection interventions. In surgery treating congenital defects, DH is used to assist aortic arch reconstructions, hypoplastic left heart syndrome interventions, and for multi-stage treatment of infants with a single heart ventricle during the neonatal period. However, it should be noted that a safe duration of circulatory arrest in DH for the central nervous system is 30 to 40 min at most and should not be exceeded to prevent severe neurological adverse events. Personalized therapy for the patient and adequate blood temperature monitoring, glycemia, hematocrit, pH, and cerebral oxygenation is a prerequisite and indispensable part of DH.
Health Issues with Learning to Use Smart Devices in the Digital Age: Using a Grounded Theory Approach
Authors: Chung Myung-Sill , Seomun GyeongAe
Published: July 2021

The Korean government has announced a plan for a national policy to deliver smart education among all students. As a result, many people are worried about the possible health-related adverse effects. This qualitative study aimed at analyzing health issues related to middle school students who learn by using smart devices using the grounded theory approach. We conducted in-depth interviews with 30 students at four middle schools who used smart devices for more than a year. The analysis of this research data was based on the constant comparative method, using grounded theory as a theoretical framework. The data analysis revealed many concepts in 28 subcategories and 13 categories related to smart learning health issues, with the central phenomenon being experience with health problems. Students’ health-related experiences were classified as physical or psychosocial symptoms. Adverse health effects related to smart learning were related to unsafe smart learning behavior and an inefficient smart learning environment. The consequences appeared to be the formation of diverse digital habits through the ambivalent use of smart devices and differences in ability to control health problems. Our findings suggest that students can form ideal habits for using smart devices if their health issues are well monitored and managed.
Disinfection of Neonatal Resuscitation Equipment in Low-Resource Settings: The Importance, the Reality, and Considerations for the Future
Authors: White Anne M. , Mutai Dominic , Cheruiyot David , Rule Amy R. L. , Mortensen Joel E. , Schaffzin Joshua K. , Kamath-Rayne Beena D.
Published: July 2021

Preventable neonatal deaths due to prematurity, perinatal events, and infections are the leading causes of under-five mortality. The vast majority of these deaths are in resource-limited areas. Deaths due to infection have been associated with lack of access to clean water, overcrowded nurseries, and improper disinfection (reprocessing) of equipment, including vital resuscitation equipment. Reprocessing has recently come to heightened attention, with the COVID-19 pandemic bringing this issue to the forefront across all economic levels; however, it is particularly challenging in low-resource settings. In 2015, Eslami et al. published a letter to the editor in Resuscitation, highlighting concerns about the disinfection of equipment being used to resuscitate newborns in Kenya. To address the issue of improper disinfection, the global health nongovernment organization PATH gathered a group of experts and, due to lack of best-practice evidence, published guidelines with recommendations for reprocessing of neonatal resuscitation equipment in low-resource areas. The guidelines follow the gold-standard principle of high-level disinfection; however, there is ongoing concern that the complexity of the guideline would make feasibility and sustainability difficult in the settings for which it was designed. Observations from hospitals in Kenya and Malawi reinforce this concern. The purpose of this review is to discuss why proper disinfection of equipment is important, why this is challenging in low-resource settings, and suggestions for solutions to move forward.
A Tidal Flat Wetlands Delineation and Classification Method for High-Resolution Imagery
Authors: Pan Hong , Jia Yonghong , Zhao Dawei , Xiu Tianyu , Duan Fuzhi
Published: July 2021

As an important part of coastal wetlands, tidal flat wetlands provide various significant ecological functions. Due to offshore pollution and unreasonable utilization, tidal flats have been increasingly threatened and degraded. Therefore, it is necessary to protect and restore this important wetland by monitoring its distribution. Considering the multiple sizes of research objects, remote sensing images with high resolutions have unique resolution advantages to support the extraction of tidal flat wetlands for subsequent monitoring. The purpose of this study is to propose and evaluate a tidal flat wetland delineation and classification method from high-resolution images. First, remote sensing features and geographical buffers are used to establish a decision tree for initial classification. Next, a natural shoreline prediction algorithm is designed to refine the range of the tidal flat wetland. Then, a range and standard deviation descriptor is constructed to extract the rock marine shore, a category of tidal flat wetlands. A geographical analysis method is considered to distinguish the other two categories of tidal flat wetlands. Finally, a tidal correction strategy is introduced to regulate the borderline of tidal flat wetlands to conform to the actual situation. The performance of each step was evaluated, and the results of the proposed method were compared with existing available methods. The results show that the overall accuracy of the proposed method mostly exceeded 92% (all higher than 88%). Due to the integration and the performance superiority compared to existing available methods, the proposed method is applicable in practice and has already been applied during the construction project of Hengqin Island in China.
A Circuity Temporal Analysis of Urban Street Networks Using Open Data: A Lisbon Case Study
Authors: Costa Miguel , Marques Manuel , Moura Filipe
Published: July 2021

Urban street networks impact urban space usage and movement across a city. Circuity, the ratio of network distances to straight-line distances, is considered a critical measurement in urban network morphology and transportation efficiency as it can measure the attractiveness of routes in terms of distance traveled. Here, we compare circuity measures for drivable, cyclable, and walkable networks to analyze how they evolved and understand whether urban changes have produced meaningful circuity changes. Our analyses rely on Lisbon data from OpenStreetMaps to explore circuity for the period 2013–2020, which we used to simulate 4.8 million routes using OpenRouteService to compute the different modes’ circuity measures. Our findings suggest that it is crucial to analyze each transport network type separately when planning or modeling urban street networks. Their composition and design differ significantly from mode to mode, such as their attractiveness to users. We identify significant changes in modes’ circuity over time, especially in cycling, following Lisbon’s cycling infrastructure expansion. Our paper demonstrates that the circuity indicator is useful when planning and modeling street networks, in particular, to optimize the location choice for interventions required to increase the attractiveness of active modes and promote sustainable mobility. At the same time, we emphasize the lack of information on walking infrastructures required for more detailed analyses.
Role of Multiple Comorbidities and Therapies in Conditioning the Clinical Severity of DRESS: A Mono-Center Retrospective Study of 25 Cases
Authors: Toniato Andrea , Gamba Chiara , Schroeder Jan Walter , Fabbri Valeria , Bernal Ortiz Scarlett Valeria , Borgonovo Linda , Piantanida Marta , Scibilia Joseph , Balossi Luca , Brusamolino Eleonora , Bonoldi Emanuela , Caputo Valentina , Nichelatti Michele , Pastorello Elide Anna
Published: July 2021

DRESS/DiHS is a complex and potentially fatal drug reaction. Little is known about risk factors and elements that can help to identify patients with a severe reaction early. The aim of the study was to investigate those factors favoring the disease and its severity by analyzing the clinical conditions and therapies preceding the reaction. We conducted a retrospective analysis on patients admitted to our center between 2010 and 2020 who were discharged with a diagnosis of DRESS. We used the RegiSCAR diagnostic criteria. We defined the severity of DRESS using the criteria of Mizukawa et al. We included 25 patients (15 females) with a median age of 66 years. Skin involvement, eosinophilia, and liver injury were the most important aspects. Allopurinol was found to be the most involved drug. Reaction severity was significantly associated with the number of daily medications (p = 0.0067) and an age of at least 68 years (p = 0.013). In addition, 75% of severe cases had at least three comorbidities in history, and most of the severe cases were female. In our study the advanced age, the high number of comorbidities and home therapies, and the inflammatory state were found to be predisposing elements to the development of the disease and its severity.
The Enigma of Eosinophil Degranulation
Authors: Fettrelet Timothée , Gigon Lea , Karaulov Alexander , Yousefi Shida , Simon Hans-Uwe
Published: July 2021

Eosinophils are specialized white blood cells, which are involved in the pathology of diverse allergic and nonallergic inflammatory diseases. Eosinophils are traditionally known as cytotoxic effector cells but have been suggested to additionally play a role in immunomodulation and maintenance of homeostasis. The exact role of these granule-containing leukocytes in health and diseases is still a matter of debate. Degranulation is one of the key effector functions of eosinophils in response to diverse stimuli. The different degranulation patterns occurring in eosinophils (piecemeal degranulation, exocytosis and cytolysis) have been extensively studied in the last few years. However, the exact mechanism of the diverse degranulation types remains unknown and is still under investigation. In this review, we focus on recent findings and highlight the diversity of stimulation and methods used to evaluate eosinophil degranulation.
Search for Highly Divergent Tandem Repeats in Amino Acid Sequences
Authors: Rudenko Valentina , Korotkov Eugene
Published: July 2021

We report a Method to Search for Highly Divergent Tandem Repeats (MSHDTR) in protein sequences which considers pairwise correlations between adjacent residues. MSHDTR was compared with some previously developed methods for searching for tandem repeats (TRs) in amino acid sequences, such as T-REKS and XSTREAM, which focus on the identification of TRs with significant sequence similarity, whereas MSHDTR detects repeats that significantly diverged during evolution, accumulating deletions, insertions, and substitutions. The application of MSHDTR to a search of the Swiss-Prot databank revealed over 15 thousand TR-containing amino acid sequences that were difficult to find using the other methods. Among the detected TRs, the most representative were those with consensus lengths of two and seven residues; these TRs were subjected to cluster analysis and the classes of patterns were identified. All TRs detected in this study have been combined into a databank accessible over the WWW.
Lipoproteins Are Responsible for the Pro-Inflammatory Property of Staphylococcus aureus Extracellular Vesicles
Authors: Kopparapu Pradeep Kumar , Deshmukh Meghshree , Hu Zhicheng , Mohammad Majd , Maugeri Marco , Götz Friedrich , Valadi Hadi , Jin Tao
Published: July 2021

Staphylococcal aureus (S. aureus), a Gram-positive bacteria, is known to cause various infections. Extracellular vesicles (EVs) are a heterogeneous array of membranous structures secreted by cells from all three domains of life, i.e., eukaryotes, bacteria, and archaea. Bacterial EVs are implied to be involved in both bacteria–bacteria and bacteria–host interactions during infections. It is still unclear how S. aureus EVs interact with host cells and induce inflammatory responses. In this study, EVs were isolated from S. aureus and mutant strains deficient in either prelipoprotein lipidation (Δlgt) or major surface proteins (ΔsrtAB). Their immunostimulatory capacities were assessed both in vitro and in vivo. We found that S. aureus EVs induced pro-inflammatory responses both in vitro and in vivo. However, this activity was dependent on lipidated lipoproteins (Lpp), since EVs isolated from the Δlgt showed no stimulation. On the other hand, EVs isolated from the ΔsrtAB mutant showed full immune stimulation, indicating the cell wall anchoring of surface proteins did not play a role in immune stimulation. The immune stimulation of S. aureus EVs was mediated mainly by monocytes/macrophages and was TLR2 dependent. In this study, we demonstrated that not only free Lpp but also EV-imbedded Lpp had high pro-inflammatory activity.
Ubiquitylation of ABA Receptors and Protein Phosphatase 2C Coreceptors to Modulate ABA Signaling and Stress Response
Authors: Coego Alberto , Julian Jose , Lozano-Juste Jorge , Pizzio Gaston A. , Alrefaei Abdulwahed F. , Rodriguez Pedro L.
Published: July 2021

Post-translational modifications play a fundamental role in regulating protein function and stability. In particular, protein ubiquitylation is a multifaceted modification involved in numerous aspects of plant biology. Landmark studies connected the ATP-dependent ubiquitylation of substrates to their degradation by the 26S proteasome; however, nonproteolytic functions of the ubiquitin (Ub) code are also crucial to regulate protein interactions, activity, and localization. Regarding proteolytic functions of Ub, Lys-48-linked branched chains are the most common chain type for proteasomal degradation, whereas promotion of endocytosis and vacuolar degradation is triggered through monoubiquitylation or Lys63-linked chains introduced in integral or peripheral plasma membrane proteins. Hormone signaling relies on regulated protein turnover, and specifically the half-life of ABA signaling components is regulated both through the ubiquitin-26S proteasome system and the endocytic/vacuolar degradation pathway. E3 Ub ligases have been reported that target different ABA signaling core components, i.e., ABA receptors, PP2Cs, SnRK2s, and ABFs/ABI5 transcription factors. In this review, we focused specifically on the ubiquitylation of ABA receptors and PP2C coreceptors, as well as other post-translational modifications of ABA receptors (nitration and phosphorylation) that result in their ubiquitination and degradation.
Increased Expression of Thymic Stromal Lymphopoietin in Chronic Constriction Injury of Rat Nerve
Authors: Wu Chieh-Hsin , Lu Chun-Ching , Huang Chao-Lan , Wu Ming-Kung , Lu Ying-Yi
Published: July 2021

Thymic stromal lymphopoietin (TSLP) is a well-known cytokine for T helper 2 inflammatory responses. A nerve injury activates the neuroinflammation cascade and neuron–glia interaction in dorsal root ganglions (DRG)s, leading to neuropathic pain. Therefore, this study was to investigate the role of TSLP after nerve injury. Male Sprague-Dawley rats were divided as an experimental group with chronic constriction injury (CCI) to the sciatic nerve and a control group. The mechanical pain threshold response was determined by calibration forceps. After assessment of mechanical allodynia, the ipsilateral spinal cord, DRG, sciatic nerve and skin were harvested. Immunofluorescence staining was performed to identify cell types with various markers. Western blot analyses were performed to evaluate protein expressions. Mechanical allodynia developed after CCI and persisted for the next 14 days. Astrocyte reactions occurred and continued until day 14, too. After CCI, DRG and the sciatic nerve also had significantly increased expressions of TSLP/TSLP-R/STAT5. The TSLPR was localized to sensory neuronal endings innervating the skin. This study is the first to demonstrate that the TSLP complex and the STAT5 pathway in nerve are potential therapeutic targets because of their roles in pain regulation after nerve injury.
RAAS: A Convergent Player in Ischemic Heart Failure and Cancer
Authors: Garcia-Garduño Texali C. , Padilla-Gutierrez Jorge R. , Cambrón-Mora Diego , Valle Yeminia
Published: July 2021

The current global prevalence of heart failure is estimated at 64.34 million cases, and it is expected to increase in the coming years, especially in countries with a medium-low sociodemographic index where the prevalence of risk factors is increasing alarmingly. Heart failure is associated with many comorbidities and among them, cancer has stood out as a contributor of death in these patients. This connection points out new challenges both in the context of the pathophysiological mechanisms involved, as well as in the quality of life of affected individuals. A hallmark of heart failure is chronic activation of the renin-angiotensin-aldosterone system, especially marked by a systemic increase in levels of angiotensin-II, a peptide with pleiotropic activities. Drugs that target the renin-angiotensin-aldosterone system have shown promising results both in the prevention of secondary cardiovascular events in myocardial infarction and heart failure, including a lower risk of certain cancers in these patients, as well as in current cancer therapies; therefore, understanding the mechanisms involved in this complex relationship will provide tools for a better diagnosis and treatment and to improve the prognosis and quality of life of people suffering from these two deadly diseases.
Overlap Arrhythmia Syndromes Resulting from Multiple Genetic Variations Studied in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes
Authors: Treat Jacqueline A. , Pfeiffer Ryan , Barajas-Martinez Hector , Goodrow Robert J. , Bot Corina , Haedo Rodolfo J. , Knox Ronald , Cordeiro Jonathan M.
Published: July 2021

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are used for genetic models of cardiac diseases. We report an arrhythmia syndrome consisting of Early Repolarization Syndrome (ERS) and Short QT Syndrome (SQTS). The index patient (MMRL1215) developed arrhythmia-mediated syncope after electrocution and was found to carry six mutations. Functional alterations resulting from these mutations were examined in patient-derived hiPSC-CMs. Electrophysiological recordings were made in hiPSC-CMs from MMRL1215 and healthy controls. ECG analysis of the index patient showed slurring of the QRS complex and QTc = 326 ms. Action potential (AP) recordings from MMRL1215 myocytes showed slower spontaneous activity and AP duration was shorter. Field potential recordings from MMRL1215 hiPSC-CMs lack a “pseudo” QRS complex suggesting reduced inward current(s). Voltage clamp analysis of ICa showed no difference in the magnitude of current. Measurements of INa reveal a 60% reduction in INa density in MMRL1215 hiPSC-CMs. Steady inactivation and recovery of INa was unaffected. mRNA analysis revealed ANK2 and SCN5A are significantly reduced in hiPSC-CM derived from MMRL1215, consistent with electrophysiological recordings. The polygenic cause of ERS/SQTS phenotype is likely due to a loss of INa due to a mutation in PKP2 coupled with and a gain of function in IK,ATP due to a mutation in ABCC9.
STAT5 as a Key Protein of Erythropoietin Signalization
Authors: Tóthová Zuzana , Tomc Jana , Debeljak Nataša , Solár Peter
Published: July 2021

Erythropoietin (EPO) acts on multiple tissues through its receptor EPOR, a member of a cytokine class I receptor superfamily with pleiotropic effects. The interaction of EPO and EPOR triggers the activation of several signaling pathways that induce erythropoiesis, including JAK2/STAT5, PI3K/AKT, and MAPK. The canonical EPOR/JAK2/STAT5 pathway is a known regulator of differentiation, proliferation, and cell survival of erythroid progenitors. In addition, its role in the protection of other cells, including cancer cells, is under intense investigation. The involvement of EPOR/JAK2/STAT5 in other processes such as mRNA splicing, cytoskeleton reorganization, and cell metabolism has been recently described. The transcriptomics, proteomics, and epigenetic studies reviewed in this article provide a detailed understanding of EPO signalization. Advances in this area of research may be useful for improving the efficacy of EPO therapy in hematologic disorders, as well as in cancer treatment.
The P2X7 Receptor: A Promising Pharmacological Target in Diabetic Retinopathy
Authors: Tassetto Matteo , Scialdone Anna , Solini Anna , Di Virgilio Francesco
Published: July 2021

Diabetes is a worldwide emergency. Its chronic complications impose a heavy burden on patients, health systems, and on society as a whole. Diabetic retinopathy is one of the most common and serious complications of diabetes, and an established risk factor for blindness in adults. Over 15 years of investigation led to the identification of vascular endothelial growth factor (VEGF) as a main pathogenic factor in diabetic retinopathy and to the introduction of highly effective anti-VEGF-based therapies, such as the monoclonal antibody bevacizumab or its fragment ranibizumab, which helped to prevent diabetes-related blindness in millions of patients. Recently, a pathogenic role for uncontrolled increases in the extracellular ATP concentration (eATP) and for overactivation of the purinergic receptor P2X7 (P2X7R) has been suggested. The P2X7R is an eATP-gated plasma membrane channel expressed in multiple tissues and organs, with a pleiotropic function in inflammation, immunity, cancer, and hormone and growth factor release. P2X7R stimulation or overexpression positively regulate the secretion and buildup of VEGF, thus promoting neo-angiogenesis in a wide variety of disease processes. In this review, we explore current evidence that supports the role of P2X7R receptor signaling in the pathogenesis of diabetic retinopathy, as well as the most appealing current therapeutical options for P2X7R targeting.
Deciphering the Epigenetic Alphabet Involved in Transgenerational Stress Memory in Crops
Authors: Mladenov Velimir , Fotopoulos Vasileios , Kaiserli Eirini , Karalija Erna , Maury Stephane , Baranek Miroslav , Segal Na'ama , Testillano Pilar , Vassileva Valya , Pinto Glória , Nagel Manuela , Hoenicka Hans , Miladinović Dragana , Gallusci Philippe , Vergata Chiara , Kapazoglou Aliki , Abraham Eleni , Tani Eleni , Gerakari Maria , Sarri Efi , Avramidou Evangelia , Gašparović Mateo , Martinelli Federico
Published: July 2021

Although epigenetic modifications have been intensely investigated over the last decade due to their role in crop adaptation to rapid climate change, it is unclear which epigenetic changes are heritable and therefore transmitted to their progeny. The identification of epigenetic marks that are transmitted to the next generations is of primary importance for their use in breeding and for the development of new cultivars with a broad-spectrum of tolerance/resistance to abiotic and biotic stresses. In this review, we discuss general aspects of plant responses to environmental stresses and provide an overview of recent findings on the role of transgenerational epigenetic modifications in crops. In addition, we take the opportunity to describe the aims of EPI-CATCH, an international COST action consortium composed by researchers from 28 countries. The aim of this COST action launched in 2020 is: (1) to define standardized pipelines and methods used in the study of epigenetic mechanisms in plants, (2) update, share, and exchange findings in epigenetic responses to environmental stresses in plants, (3) develop new concepts and frontiers in plant epigenetics and epigenomics, (4) enhance dissemination, communication, and transfer of knowledge in plant epigenetics and epigenomics.
Single Copy Oligonucleotide Fluorescence In Situ Hybridization Probe Design Platforms: Development, Application and Evaluation
Authors: Liu Guanqing , Zhang Tao
Published: July 2021

Oligonucleotides fluorescence in situ hybridization (Oligo-FISH) is an emerging technology and is an important tool in research areas such as detection of chromosome variation, identification of allopolyploid, and deciphering of three-dimensional (3D) genome structures. Based on the demand for highly efficient oligo probes for oligo-FISH experiments, increasing numbers of tools have been developed for probe design in recent years. Obsolete oligonucleotide design tools have been adapted for oligo-FISH probe design because of their similar considerations. With the development of DNA sequencing and large-scale synthesis, novel tools have been designed to increase the specificity of designed oligo probes and enable genome-scale oligo probe design, which has greatly improved the application of single copy oligo-FISH. Despite this, few studies have introduced the development of the oligo-FISH probe design tools and their application in FISH experiments systematically. Besides, a comprehensive comparison and evaluation is lacking for the available tools. In this review, we provide an overview of the oligo-FISH probe design process, summarize the development and application of the available tools, evaluate several state-of-art tools, and eventually provide guidance for single copy oligo-FISH probe design.
Access to New Cytotoxic Triterpene and Steroidal Acid-TEMPO Conjugates by Ugi Multicomponent-Reactions
Authors: Sultani Haider N. , Morgan Ibrahim , Hussain Hidayat , Roos Andreas H. , Haeri Haleh H. , Kaluđerović Goran N. , Hinderberger Dariush , Westermann Bernhard
Published: July 2021

Multicomponent reactions, especially the Ugi-four component reaction (U-4CR), provide powerful protocols to efficiently access compounds having potent biological and pharmacological effects. Thus, a diverse library of betulinic acid (BA), fusidic acid (FA), cholic acid (CA) conjugates with TEMPO (nitroxide) have been prepared using this approach, which also makes them applicable in electron paramagnetic resonance (EPR) spectroscopy. Moreover, convertible amide modified spin-labelled fusidic acid derivatives were selected for post-Ugi modification utilizing a wide range of reaction conditions which kept the paramagnetic center intact. The nitroxide labelled betulinic acid analogue 6 possesses cytotoxic effects towards two investigated cell lines: prostate cancer PC3 (IC50 7.4 ± 0.7 μM) and colon cancer HT29 (IC50 9.0 ± 0.4 μM). Notably, spin-labelled fusidic acid derivative 8 acts strongly against these two cancer cell lines (PC3: IC50 6.0 ± 1.1 μM; HT29: IC50 7.4 ± 0.6 μM). Additionally, another fusidic acid analogue 9 was also found to be active towards HT29 with IC50 7.0 ± 0.3 μM (CV). Studies on the mode of action revealed that compound 8 increased the level of caspase-3 significantly which clearly indicates induction of apoptosis by activation of the caspase pathway. Furthermore, the exclusive mitochondria targeting of compound 18 was successfully achieved, since mitochondria are the major source of ROS generation.
Comprehensive Molecular Dissection of Dermatophilus congolensis Genome and First Observation of tet(Z) Tetracycline Resistance
Authors: Branford Ian , Johnson Shevaun , Chapwanya Aspinas , Zayas Samantha , Boyen Filip , Mielcarska Matylda Barbara , Szulc-Dąbrowska Lidia , Butaye Patrick , Toka Felix Ngosa
Published: July 2021

Dermatophilus congolensis is a bacterial pathogen mostly of ruminant livestock in the tropics/subtropics and certain temperate climate areas. It causes dermatophilosis, a skin disease that threatens food security by lowering animal productivity and compromising animal health and welfare. Since it is a prevalent infection in ruminants, dermatophilosis warrants more research. There is limited understanding of its pathogenicity, and as such, there is no registered vaccine against D. congolensis. To better understanding the genomics of D. congolensis, the primary aim of this work was to investigate this bacterium using whole-genome sequencing and bioinformatic analysis. D. congolensis is a high GC member of the Actinobacteria and encodes approximately 2527 genes. It has an open pan-genome, contains many potential virulence factors, secondary metabolites and encodes at least 23 housekeeping genes associated with antimicrobial susceptibility mechanisms and some isolates have an acquired antimicrobial resistance gene. Our isolates contain a single CRISPR array Cas type IE with classical 8 Cas genes. Although the isolates originate from the same geographical location there is some genomic diversity among them. In conclusion, we present the first detailed genomic study on D. congolensis, including the first observation of tet(Z), a tetracycline resistance-conferring gene.
Comparative Transcriptome Analysis Reveals Genetic Mechanisms of Sugarcane Aphid Resistance in Grain Sorghum
Authors: Serba Desalegn D. , Meng Xiaoxi , Schnable James , Bashir Elfadil , Michaud J. P. , Vara Prasad P. V. , Perumal Ramasamy
Published: July 2021

The sugarcane aphid, Melanaphis sacchari (Zehntner) (Hemiptera: Aphididae) (SCA), has become a major pest of grain sorghum since its appearance in the USA. Several grain sorghum parental lines are moderately resistant to the SCA. However, the molecular and genetic mechanisms underlying this resistance are poorly understood, which has constrained breeding for improved resistance. RNA-Seq was used to conduct transcriptomics analysis on a moderately resistant genotype (TAM428) and a susceptible genotype (Tx2737) to elucidate the molecular mechanisms underlying resistance. Differential expression analysis revealed differences in transcriptomic profile between the two genotypes at multiple time points after infestation by SCA. Six gene clusters had differential expression during SCA infestation. Gene ontology enrichment and cluster analysis of genes differentially expressed after SCA infestation revealed consistent upregulation of genes controlling protein and lipid binding, cellular catabolic processes, transcription initiation, and autophagy in the resistant genotype. Genes regulating responses to external stimuli and stress, cell communication, and transferase activities, were all upregulated in later stages of infestation. On the other hand, expression of genes controlling cell cycle and nuclear division were reduced after SCA infestation in the resistant genotype. These results indicate that different classes of genes, including stress response genes and transcription factors, are responsible for countering the physiological effects of SCA infestation in resistant sorghum plants.
Best Practices and Progress in Precision-Cut Liver Slice Cultures
Authors: Dewyse Liza , Reynaert Hendrik , van Grunsven Leo A.
Published: July 2021

Thirty-five years ago, precision-cut liver slices (PCLS) were described as a promising tool and were expected to become the standard in vitro model to study liver disease as they tick off all characteristics of a good in vitro model. In contrast to most in vitro models, PCLS retain the complex 3D liver structures found in vivo, including cell–cell and cell–matrix interactions, and therefore should constitute the most reliable tool to model and to investigate pathways underlying chronic liver disease in vitro. Nevertheless, the biggest disadvantage of the model is the initiation of a procedure-induced fibrotic response. In this review, we describe the parameters and potential of PCLS cultures and discuss whether the initially described limitations and pitfalls have been overcome. We summarize the latest advances in PCLS research and critically evaluate PCLS use and progress since its invention in 1985.
Can Endometriosis-Related Oxidative Stress Pave the Way for New Treatment Targets?
Authors: Cacciottola Luciana , Donnez Jacques , Dolmans Marie-Madeleine
Published: July 2021

Endometriosis is a disease of reproductive age characterized by chronic pelvic pain and infertility. Its pathogenesis is complex and still partially unexplained. However, there is increasing evidence of the role of chronic inflammation, immune system dysregulation, and oxidative stress in its development and progression. The latter appears to be involved in multiple aspects of the disease. Indeed, disease progression sustained by a hyperproliferative phenotype can be related to reactive oxygen species (ROS) imbalance, as numerous experiments using drugs to counteract hyperproliferation have shown in recent years. Chronic pelvic pain is also associated with cell function dysregulation favoring chronic inflammation and oxidative stress, specifically involving macrophages and mast cell activation. Moreover, there is increasing evidence of a role for ROS and impaired mitochondrial function not only as deleterious effectors of the ovarian reserve in patients with endometriomas but also in terms of oocyte quality and, hence, embryo development impairment. Targeting oxidative stress looks to be a promising strategy to both curb endometriotic lesion progression and alleviate endometriosis-associated symptoms of chronic pain and infertility. More investigations are nevertheless needed to develop effective therapeutic strategies for clinical application.
Plasticity in Intrinsic Excitability of Hypothalamic Magnocellular Neurosecretory Neurons in Late-Pregnant and Lactating Rats
Authors: Perkinson Michael R. , Augustine Rachael A. , Bouwer Gregory T. , Brown Emily F. , Cheong Isaiah , Seymour Alexander J. , Fronius Martin , Brown Colin H.
Published: July 2021

Oxytocin and vasopressin secretion from the posterior pituitary gland are required for normal pregnancy and lactation. Oxytocin secretion is relatively low and constant under basal conditions but becomes pulsatile during birth and lactation to stimulate episodic contraction of the uterus for delivery of the fetus and milk ejection during suckling. Vasopressin secretion is maintained in pregnancy and lactation despite reduced osmolality (the principal stimulus for vasopressin secretion) to increase water retention to cope with the cardiovascular demands of pregnancy and lactation. Oxytocin and vasopressin secretion are determined by the action potential (spike) firing of magnocellular neurosecretory neurons of the hypothalamic supraoptic and paraventricular nuclei. In addition to synaptic input activity, spike firing depends on intrinsic excitability conferred by the suite of channels expressed by the neurons. Therefore, we analysed oxytocin and vasopressin neuron activity in anaesthetised non-pregnant, late-pregnant, and lactating rats to test the hypothesis that intrinsic excitability of oxytocin and vasopressin neurons is increased in late pregnancy and lactation to promote oxytocin and vasopressin secretion required for successful pregnancy and lactation. Hazard analysis of spike firing revealed a higher incidence of post-spike hyperexcitability immediately following each spike in oxytocin neurons, but not in vasopressin neurons, in late pregnancy and lactation, which is expected to facilitate high frequency firing during bursts. Despite lower osmolality in late-pregnant and lactating rats, vasopressin neuron activity was not different between non-pregnant, late-pregnant, and lactating rats, and blockade of osmosensitive ΔN-TRPV1 channels inhibited vasopressin neurons to a similar extent in non-pregnant, late-pregnant, and lactating rats. Furthermore, supraoptic nucleus ΔN-TRPV1 mRNA expression was not different between non-pregnant and late-pregnant rats, suggesting that sustained activity of ΔN-TRPV1 channels might maintain vasopressin neuron activity to increase water retention during pregnancy and lactation.
Immune-Related Urine Biomarkers for the Diagnosis of Lupus Nephritis
Authors: Morell María , Pérez-Cózar Francisco , Marañón Concepción
Published: July 2021

The kidney is one of the main organs affected by the autoimmune disease systemic lupus erythematosus. Lupus nephritis (LN) concerns 30–60% of adult SLE patients and it is significantly associated with an increase in the morbidity and mortality. The definitive diagnosis of LN can only be achieved by histological analysis of renal biopsies, but the invasiveness of this technique is an obstacle for early diagnosis of renal involvement and a proper follow-up of LN patients under treatment. The use of urine for the discovery of non-invasive biomarkers for renal disease in SLE patients is an attractive alternative to repeated renal biopsies, as several studies have described surrogate urinary cells or analytes reflecting the inflammatory state of the kidney, and/or the severity of the disease. Herein, we review the main findings in the field of urine immune-related biomarkers for LN patients, and discuss their prognostic and diagnostic value. This manuscript is focused on the complement system, antibodies and autoantibodies, chemokines, cytokines, and leukocytes, as they are the main effectors of LN pathogenesis.
Regenerative Effects of Hypoxia Primed Flowable Placental Formulation in Muscle and Dermal Injury
Authors: Dhall Sandeep , Park Min Sung , Li Chaoyang , Sathyamoorthy Malathi
Published: July 2021

The placental tissue, due to its angiogenic, anti-inflammatory, antioxidative, antimicrobial, and anti-fibrotic properties, has become a compelling source towards a solution for several indications in regenerative medicine. However, methods to enhance and capture the therapeutic properties with formulations that can further the applications of viable placental tissue have not been explored. In this study, we investigated the regenerative effects of a hypoxia primed flowable placental formulation (FPF), composed of amnion/chorion and umbilical tissue, in two in vivo injury models. Laser Doppler data from rodent ischemia hindlimbs treated with FPF revealed significant tissue perfusion improvements compared to control ischemic hindlimbs. To further corroborate FPF’s effects, we used a rodent ischemic bipedicle skin flap wound model. FPF treatment significantly increased the rate of wound closure and the quality of wound healing. FPF-treated wounds displayed reduced inflammation and an increase in angiogenesis. Furthermore, quantitative PCR and next-generation sequencing analysis confirmed these changes in the FPF-treated group at both the gene and transcriptional level. The observed modulation in miRNAs was associated with angiogenesis, regulation of inflammatory microenvironment, cell migration and apoptosis, reactive oxygen species generation, and restoring epithelial barrier function, all processes involved in impaired tissue healing. Taken together, these data validate the tissue regenerative properties of the flowable placental formulation configuration tested.
Basic Helix-Loop-Helix (bHLH) Transcription Factors Regulate a Wide Range of Functions in Arabidopsis
Authors: Hao Yaqi , Zong Xiumei , Ren Pan , Qian Yuqi , Fu Aigen
Published: July 2021

The basic helix-loop-helix (bHLH) transcription factor family is one of the largest transcription factor gene families in Arabidopsis thaliana, and contains a bHLH motif that is highly conserved throughout eukaryotic organisms. Members of this family have two conserved motifs, a basic DNA binding region and a helix-loop-helix (HLH) region. These proteins containing bHLH domain usually act as homo- or heterodimers to regulate the expression of their target genes, which are involved in many physiological processes and have a broad range of functions in biosynthesis, metabolism and transduction of plant hormones. Although there are a number of articles on different aspects to provide detailed information on this family in plants, an overall summary is not available. In this review, we summarize various aspects of related studies that provide an overview of insights into the pleiotropic regulatory roles of these transcription factors in plant growth and development, stress response, biochemical functions and the web of signaling networks. We then provide an overview of the functional profile of the bHLH family and the regulatory mechanisms of other proteins.