bluuebunny/crossref_metadata_2025 huggingface dataset:
The Role of Extracellular Polymeric Substances in the Toxicity Response of Anaerobic Granule Sludge to Different Metal Oxide Nanoparticles
Authors: Li Huiting , Chang Fang , Li Zhendong , Cui Fuyi
Published: April 2022

Wastewater treatment plants (WWTP) are regarded as the last barriers for the release of incompletely separated and recycled nanoparticles (NPs) into the environment. Despite the importance and ubiquity of microbial extracellular polymeric substances (EPSs) in the complex wastewater matrix, the interaction between NPs and EPSs of anaerobic microflora involved in wastewater treatment and the resultant impact on the biomass metabolomics are unclear. Thus, the impacts of different metal oxide (TiO2, ZnO, and CuO) NPs on functional bacteria in anaerobic granular sludge (AGS) and the possible toxicity mechanisms were investigated. In particular, the binding quality, enhanced resistance mechanism, and chemical fractional contribution of EPSs from AGS against the nanotoxicity of different NPs was assessed. The results showed that CuO NPs caused the most severe inhibition towards acetoclastic and hydrogenotrophic methanogens, followed by ZnO NPs, whereas TiO2 NPs caused no inhibition to methanogenesis. Excessive EPS production, especially the protein-like substances, was an effective strategy for reducing certain NPs’ toxicity by immobilizing NPs away from AGS cells, whereas the metabolism restriction on inner microorganisms of AGS induced by CuO NPs can deteriorate the protective role of EPS, indicating that the roles of EPS may not be amenable to generalizations. Further investigations with lactate dehydrogenase (LDH) and reactive oxygen species (ROS) assays indicated that there are greatly essential differences between the toxicity mechanisms of metal NPs to AGS, which varied depending on the NPs’ type and dosage. In addition, dynamic changes in the responses of EPS content to different NPs can result in a significant shift in methanogenic and acidogenic microbial communities. Thus, the production and composition of EPSs will be a key factor in determining the fate and potential effect of NPs in the complex biological matrix. In conclusion, this study broadens the understanding of the inhibition mechanisms of metal oxide NPs on the AGS process, and the influence of EPSs on the fate, behavior, and toxicity of NPs.
Patient-Nurse Partnerships to Prevent Medication Errors: A Concept Development Using the Hybrid Method
Authors: Jeong Hee-Ja , Park Eun-Young
Published: April 2022

Medication safety is the most patient-centered aspect of nursing, and the medication process needs patients’ active participation to effectively prevent medication errors. The aim of this study was to develop the concept of a patient–nurse partnership for medication safety activities. The study design used the three-phase hybrid model for concept analysis: the theoretical phase, fieldwork phase, and final phase for integration. The results of a study define the concept of patient–nurse partnership for medication safety as “a fair cooperative relationship of mutual responsibility in which patients and nurses share information and communicate with each other through mutual trust.” Seven attributes were derived: mutual trust, mutual respect, mutual sharing, mutual communication, mutual responsibility, fair relationship, and mutual cooperation. The conclusion of the study of patient–nurse partnerships for medication safety was that it is necessary to ensure a balance in power between patient and nurse. This balance can be established through patient-centered nursing by implementing the active transfer of authority from nurses as professionals to patients.
Tailoring Tofacitinib Oral Therapy in Rheumatoid Arthritis: The TuTOR App
Authors: Radin Massimo , Arbrile Marta , Cecchi Irene , Di Nunzio Pierluigi , Buccarano Nicola , Di Gregorio Federico , Milone Valeria , Osella Sara , Crosasso Paola , Favuzzi Marika Denise , Barinotti Alice , Baldovino Simone , Menegatti Elisa , Rossi Daniela , Sciascia Savino , Roccatello Dario
Published: April 2022

To support the management of rheumatoid arthritis (RA) patients treated with tofacitinib, we designed the TuTOR (tailoring tofacitinib oral therapy in rheumatoid arthritis) mobile app. The impact of the app on medical adherence was evaluated using a crossover design alternating a paper-diary and the TuTOR App. Twenty patients with RA (mean age at inclusion, 59 ± 13 years) were included in the study. A statistically significant decrease in DAS28 was observed since the first month of therapy (mean DAS28 at baseline, 3.9 ± 1 vs. 1° month 3.1 ± 1, p = 0.0016). Similarly, the numerical rating scale (NRS) of perceived activity of disease and subjective fatigue progressively decreased. No differences were reported in DAS28 or NRS between the TuTOR app and the paper-diary groups. A significant decrease was observed in HAQ during the follow-up (baseline 1.38 ± 1.11 vs. six months 0.83 ± 0.9; p = 0.01). When filling out the self-reporting questionnaires, most of the patients (82%) preferred the TuTOR App helping them to remember to take the pills. Furthermore, 82% of patients used the app regularly (vs. 53% for the paper diary). Three patients suspended tofacitinib due to gastrointestinal intolerance. Both digital and paper devices can help maximize adherence to therapy; however, the TuTOR app was preferred by the patients for its simplicity and immediacy.
The Daalbirrwirr Gamambigu (Safe Children) Model: Embedding Cultural Safety in Child Protection Responses for Australian Aboriginal Children in Hospital Settings
Authors: Flemington Tara , Fraser Jennifer , Gibbs Clinton , Shipp Joanne , Bryant Joe , Ryan Amanda , Wijetilaka Devika , Marks Susan , Scarcella Mick , Tzioumi Dimitra , Ramanathan Shanthi , Clague Liesa , Hartz Donna , Lonne Bob , Lock (Ngiyampaa) Mark
Published: April 2022

The aim of this paper is to describe the development of a model of care to embed cultural safety for Aboriginal children into paediatric hospital settings. The Daalbirrwirr Gamambigu (pronounced “Dahl-beer-weer gum-um-be-goo” in the Gumbaynggirr language means ‘safe children’) model encompasses child protection responses at clinical, managerial and organisational levels of health services. A review of scholarly articles and grey literature followed by qualitative interviews with Aboriginal health professionals formed the evidence base for the model, which then underwent rounds of consultation for cultural suitability and clinical utility. Culturally appropriate communication with children and their families using clinical yarning and a culturally adapted version of ISBAR (a mnemonic for Identify, Situation, Background, Assessment and Recommendation) for interprofessional communication is recommended. The model guides the development of a critical consciousness about cultural safety in health care settings, and privileges the cultural voices of many diverse Aboriginal peoples. When adapted appropriately for local clinical and cultural contexts, it will contribute to a patient journey experience of respect, dignity and empowerment.
Effects of Meteorological Factors on Waterbird Functional Diversity and Community Composition in Liaohe Estuary, China
Authors: Li Xiuzhong , Zeng Qing , Lei Guangchun , Sun Gongqi
Published: April 2022

Functional trait diversity represents ecological differences among species, and the structure of waterbird communities is an important aspect of biodiversity. To understand the effect of meteorological changes on the waterbird functional diversity and provide suggestions for management and conservation, we selected a study area (726 km2) in Liaohe Estuary, located in northeast China. We explored the trends of the waterbird functional diversity changes in response to meteorological factors using fourth corner analysis. Our study demonstrated that temperature was a key factor that impacted waterbird functional diversity in spring, while precipitation had a greater impact in autumn. The population size of goose and duck was positively associated with temperature and negatively with precipitation, while that of the waders (Charadriiformes) showed opposite association trends. Herbivores and species nesting on the bare ground exhibited responses to meteorological factors similar to those of geese and ducks, while benthivores and waterbirds nesting under grass/shrubs exhibited trends similar to those of waterbirds. Waterbirds with smaller bodies, shorter feathers, and lower reproductive rates preferred higher temperatures and less precipitation than other waterbirds. In addition, we observed seasonal variations in waterbird functional diversity. In spring, we should pay attention to waders, herbivores, and waterbirds nesting on the bare ground when the temperature is low. In autumn, waders, benthivores, and omnivores need more attention under extreme precipitation. As the global climate warms in this study area, waterbird functional diversity is expected to decline, and community composition would become simpler, with overlapping niches. Biodiversity management should involve protecting intertidal habitats, supporting benthic macrofaunal communities, preparing bare breeding fields for waterbirds favoring high temperatures to meet their requirements for population increase, and preventing the population decline of geese and ducks, herbivores, and species nesting under grass/shrubs. The findings of our study can aid in developing accurate guidelines for waterbird biodiversity management and conservation.
Research on the Aging-Friendly Kitchen Based on Space Syntax Theory
Authors: Wang Ying , Lin Di , Huang Ze
Published: April 2022

As a result of aging populations globally, a growing number of older adults prefer to age in place; therefore, it is essential to study the spatial adaptability of the house. This study aimed to explore the relationship between the efficiency of daily activities and the spatial layout of home kitchens in the elderly population, and to assess the moderating role of cognitive function. Twenty-one elderly participants completed the experiment, including non-cognitively impaired (n = 12) and cognitively impaired groups (n = 9). Their home kitchen space was partitioned in plan and elevation based on space syntax theory. They were required to complete three tasks (i.e., an easy task, a medium task, and a difficult task) in their respective kitchens. The relationship between the efficiency of different tasks’ completion and the corresponding kitchen space attributes (integration, mean depth) was examined. The results showed a significant association between the home kitchen space layout of homebound older adults and their kitchen activity efficiency. In addition, a positive moderating effect of cognitive ability was found in the association between moderate and difficult tasks (p < 0.05), and its effect appeared to be stronger under challenging tasks (p < 0.01). The results of this study may help provide a basis for future design and optimization of aging-friendly residential spaces.
Effects of Acute Hypobaric Hypoxia Exposure on Cardiovascular Function in Unacclimatized Healthy Subjects: A “Rapid Ascent” Hypobaric Chamber Study
Authors: Theunissen Sigrid , Balestra Costantino , Bolognési Sébastien , Borgers Guy , Vissenaeken Dirk , Obeid Georges , Germonpré Peter , Honoré Patrick M. , De Bels David
Published: April 2022

Background: This study aimed to observe the effects of a fast acute ascent to simulated high altitudes on cardiovascular function both in the main arteries and in peripheral circulation. Methods: We examined 17 healthy volunteers, between 18 and 50 years old, at sea level, at 3842 m of hypobaric hypoxia and after return to sea level. Cardiac output (CO) was measured with Doppler transthoracic echocardiography. Oxygen delivery was estimated as the product of CO and peripheral oxygen saturation (SpO2). The brachial artery’s flow-mediated dilation (FMD) was measured with the ultrasound method. Post-occlusion reactive hyperemia (PORH) was assessed by digital plethysmography. Results: During altitude stay, peripheral oxygen saturation decreased (84.9 ± 4.2% of pre-ascent values; p < 0.001). None of the volunteers presented any hypoxia-related symptoms. Nevertheless, an increase in cardiac output (143.2 ± 36.2% of pre-ascent values, p < 0.001) and oxygen delivery index (120.6 ± 28.4% of pre-ascent values; p > 0.05) was observed. FMD decreased (97.3 ± 4.5% of pre-ascent values; p < 0.05) and PORH did not change throughout the whole experiment. Τhe observed changes disappeared after return to sea level, and normoxia re-ensued. Conclusions: Acute exposure to hypobaric hypoxia resulted in decreased oxygen saturation and increased compensatory heart rate, cardiac output and oxygen delivery. Pre-occlusion vascular diameters increase probably due to the reduction in systemic vascular resistance preventing flow-mediated dilation from increasing. Mean Arterial Pressure possibly decrease for the same reason without altering post-occlusive reactive hyperemia throughout the whole experiment, which shows that compensation mechanisms that increase oxygen delivery are effective.
Assessing Street Space Quality Using Street View Imagery and Function-Driven Method: The Case of Xiamen, China
Authors: Wang Moyang , He Yijun , Meng Huan , Zhang Ye , Zhu Bao , Mango Joseph , Li Xiang
Published: April 2022

Street space quality assessment refers to the extraction and appropriate evaluation of the space quality information of urban streets, which is usually employed to improve the quality of urban planning and management. Compared to traditional approaches relying on expert knowledge, the advances of big data collection and analysis technologies provide an alternative for assessing street space more precisely. With street view imagery (SVI), points of interest (POI) and comment data from social media, this study evaluates street space quality from the perspective of exploring and discussing the relationship among street vitality, service facilities and built environment. Firstly, a transfer-learning-based framework is employed for SVI semantic segmentation to quantify the street built environment. Then, we use POI data to identify different urban functions that streets serve, and comment data are utilized to investigate urban vitality composition and integrate it with different urban functions associated with streets. Finally, a function-driven street space quality assessment approach is established. To examine its applicability and performance, the proposed method is experimented with data from part area in Xiamen, China. The output is compared to results based on expert opinion using the correlation analysis method. Results show that the proposed assessment approach designed in this study is in accordance with the validation data, with the overall R2 value being greater than 0.6. In particular, the proposed method shows better performance in scenic land and mixed functional streets with R2 value being greater than 0.8. This method is expected to be an efficient tool for discovering problems and optimizing urban planning and management.
Identifying Multiple Scales of Spatial Heterogeneity in Housing Prices Based on Eigenvector Spatial Filtering Approaches
Authors: Peng Zhan , Inoue Ryo
Published: April 2022

Interest in studying the urban real estate market, especially in investigating the relationship between house prices and related housing characteristics, is rapidly growing. However, this increasing attention is handicapped by a limited consideration of the multi-scale spatial heterogeneity in these relationships. This study uses the rental price data of 72,466 apartments in the Tokyo metropolitan area to examine spatial heterogeneity in the real estate market at multiple spatial scales. Within the framework of spatially varying coefficient (SVC) modeling, we utilized a random effect eigenvector spatial filtering-based SVC (RE-ESF-SVC) model, an approach not previously employed in real estate studies, and compared it with the traditional ESF-SVC model, which has no random effects. Our results show that: (1) except for one housing characteristic that impacts prices consistently throughout the Tokyo metropolitan area, relationships between other characteristics and prices vary from local to global spatial scales; (2) because of the utilization of random effects, RE-ESF-SVC has the unique advantage of making estimations flexibly while maintaining a high performance.
GIScience and Historical Visual Sources: A Promising Look at Past Scenarios and Sceneries
Authors: Zohar Motti
Published: April 2022

The discipline of historical geography evolved rapidly in the 20th century [...]
Changes in Astroglial K+ upon Brief Periods of Energy Deprivation in the Mouse Neocortex
Authors: Eitelmann Sara , Stephan Jonathan , Everaerts Katharina , Durry Simone , Pape Nils , Gerkau Niklas J. , Rose Christine R.
Published: April 2022

Malfunction of astrocytic K+ regulation contributes to the breakdown of extracellular K+ homeostasis during ischemia and spreading depolarization events. Studying astroglial K+ changes is, however, hampered by a lack of suitable techniques. Here, we combined results from fluorescence imaging, ion-selective microelectrodes, and patch-clamp recordings in murine neocortical slices with the calculation of astrocytic [K+]. Brief chemical ischemia caused a reversible ATP reduction and a transient depolarization of astrocytes. Moreover, astrocytic [Na+] increased by 24 mM and extracellular [Na+] decreased. Extracellular [K+] increased, followed by an undershoot during recovery. Feeding these data into the Goldman–Hodgkin–Katz equation revealed a baseline astroglial [K+] of 146 mM, an initial K+ loss by 43 mM upon chemical ischemia, and a transient K+ overshoot of 16 mM during recovery. It also disclosed a biphasic mismatch in astrocytic Na+/K+ balance, which was initially ameliorated, but later aggravated by accompanying changes in pH and bicarbonate, respectively. Altogether, our study predicts a loss of K+ from astrocytes upon chemical ischemia followed by a net gain. The overshooting K+ uptake will promote low extracellular K+ during recovery, likely exerting a neuroprotective effect. The resulting late cation/anion imbalance requires additional efflux of cations and/or influx of anions, the latter eventually driving delayed astrocyte swelling.
The Utility of Nasal Challenges to Phenotype Asthma Patients
Authors: Bentabol-Ramos Guillermo , Saenz de Santa Maria-Garcia Rocio , Vidal-Diaz Monica , Eguiluz-Gracia Ibon , Testera-Montes Almudena
Published: April 2022

Asthma is a heterogeneous disease in terms of both phenotype and response to therapy. Therefore, there is a great need for clinically applicable tools allowing for improved patient classification, and selection for specific management approaches. Some interventions are highly helpful in selected patients (e.g., allergen immunotherapy or aspirin desensitization), but they are costly and/or difficult to implement. Currently available biomarkers measurable in peripheral blood or exhaled air display many limitations for asthma phenotyping and cannot identify properly the specific triggers of the disease (e.g., aeroallergens or NSAID). The united airway concept illustrates the relevant epidemiological and pathophysiological links between the upper and lower airways. This concept has been largely applied to patient management and treatment, but its diagnostic implications have been less often explored. Of note, a recent document by the European Academy of Allergy and Clinical Immunology proposes the use of nasal allergen challenge to confirm the diagnosis of allergic asthma. Similarly, the nasal challenge with lysine acetylsalicylate (L-ASA) can be used to identify aspirin-sensitive asthma patients. In this review, we will summarize the main features of allergic asthma and aspirin-exacerbated respiratory disease and will discuss the methodology of nasal allergen and L-ASA challenges with a focus on their capacity to phenotype the inflammatory disease affecting both the upper and lower airways.
Current Understanding in the Clinical Characteristics and Molecular Mechanisms in Different Subtypes of Biliary Atresia
Authors: He Lin , Chung Patrick Ho Yu , Lui Vincent Chi Hang , Tang Clara Sze Man , Tam Paul Kwong Hang
Published: April 2022

Biliary atresia is a severe obliterative cholangiopathy in early infancy that is by far the most common cause of surgical jaundice and the most common indicator for liver transplantation in children. With the advanced knowledge gained from different clinical trials and the development of research models, a more precise clinical classification of BA (i.e., isolated BA (IBA), cystic BA (CBA), syndromic BA (SBA), and cytomegalovirus-associated BA (CMVBA)) is proposed. Different BA subtypes have similar yet distinguishable clinical manifestations. The clinical and etiological heterogeneity leads to dramatically different prognoses; hence, treatment needs to be specific. In this study, we reviewed the clinical characteristics of different BA subtypes and revealed the molecular mechanisms of their developmental contributors. We aimed to highlight the differences among these various subtypes of BA which ultimately contribute to the development of a specific management protocol for each subtype.
Transcriptome Analysis of the Cf-13-Mediated Hypersensitive Response of Tomato to Cladosporium fulvum Infection
Authors: Jiang Xiuming , Li Yang , Li Ran , Gao Yijie , Liu Zengbing , Yang Huanhuan , Li Jingfu , Jiang Jingbin , Zhao Tingting , Xu Xiangyang
Published: April 2022

Tomato leaf mold disease caused by Cladosporium fulvum (C. fulvum) is one of the most common diseases affecting greenhouse tomato production. Cf proteins can recognize corresponding AVR proteins produced by C. fulvum, and Cf genes are associated with leaf mold resistance. Given that there are many physiological races of C. fulvum and that these races rapidly mutate, resistance to common Cf genes (such as Cf-2, Cf-4, Cf-5, and Cf-9) has decreased. In the field, Ont7813 plants (carrying the Cf-13 gene) show effective resistance to C. fulvum; thus, these plants could be used as new, disease-resistant materials. To explore the mechanism of the Cf-13-mediated resistance response, transcriptome sequencing was performed on three replicates each of Ont7813 (Cf-13) and Moneymaker (MM; carrying the Cf-0 gene) at 0, 9, and 15 days after inoculation (dai) for a total of 18 samples. In total, 943 genes were differentially expressed, specifically in the Ont7813 response process as compared to the Moneymaker response process. Gene ontology (GO) classification of these 943 differentially expressed genes (DEGs) showed that GO terms, including “hydrogen peroxide metabolic process (GO_Process)”, “secondary active transmembrane transporter activity (GO_Function)”, and “mismatch repair complex (GO_Component)”, which were the same as 11 other GO terms, were significantly enriched. An analysis of the Kyoto Encyclopedia of Genes and Genomes (KEGG) revealed that many key regulatory genes of the Cf-13-mediated resistance response processes were involved in the “plant hormone signal transduction” pathway, the “plant–pathogen interaction” pathway, and the “MAPK signaling pathway–plant” pathway. Moreover, during C. fulvum infection, jasmonic acid (JA) and salicylic acid (SA) contents significantly increased in Ont7813 at the early stage. These results lay a vital foundation for further understanding the molecular mechanism of the Cf-13 gene in response to C. fulvum infection.
Identification of ATP2B4 Regulatory Element Containing Functional Genetic Variants Associated with Severe Malaria
Authors: Nisar Samia , Torres Magali , Thiam Alassane , Pouvelle Bruno , Rosier Florian , Gallardo Frederic , Ka Oumar , Mbengue Babacar , Diallo Rokhaya Ndiaye , Brosseau Laura , Spicuglia Salvatore , Dieye Alioune , Marquet Sandrine , Rihet Pascal
Published: April 2022

Genome-wide association studies for severe malaria (SM) have identified 30 genetic variants mostly located in non-coding regions. Here, we aimed to identify potential causal genetic variants located in these loci and demonstrate their functional activity. We systematically investigated the regulatory effect of the SNPs in linkage disequilibrium (LD) with the malaria-associated genetic variants. Annotating and prioritizing genetic variants led to the identification of a regulatory region containing five ATP2B4 SNPs in LD with rs10900585. We found significant associations between SM and rs10900585 and our candidate SNPs (rs11240734, rs1541252, rs1541253, rs1541254, and rs1541255) in a Senegalese population. Then, we demonstrated that both individual SNPs and the combination of SNPs had regulatory effects. Moreover, CRISPR/Cas9-mediated deletion of this region decreased ATP2B4 transcript and protein levels and increased Ca2+ intracellular concentration in the K562 cell line. Our data demonstrate that severe malaria-associated genetic variants alter the expression of ATP2B4 encoding a plasma membrane calcium-transporting ATPase 4 (PMCA4) expressed on red blood cells. Altering the activity of this regulatory element affects the risk of SM, likely through calcium concentration effect on parasitaemia.
Molecular and Histological Effects of Glyphosate on Testicular Tissue of the Lizard Podarcis siculus
Authors: Verderame Mariailaria , Chianese Teresa , Rosati Luigi , Scudiero Rosaria
Published: April 2022

The expansion of agriculture produces a steady increase in habitat fragmentation and degradation due to the increased use of pesticides and herbicides. Habitat loss and alteration associated with crop production play an important role in reptile decline, among which lizards are particularly endangered. In this study, we evaluated testicular structure, steroidogenesis, and estrogen receptor expression/localization after three weeks of oral exposure to glyphosate at 0.05 and 0.5 μg/kg body weight every other day in the field lizard Podarcis siculus. Our results show that glyphosate affected testicular morphology, reduced spermatogenesis, altered gap junctions and changed the localization of estrogen receptors in germ cells, increasing their expression; the effects were mostly dose-dependent. The result also demonstrates that glyphosate, at least at these concentrations, did not influence steroidogenesis. Overall, the data indicate that this herbicide can disturb the morphophysiology of the male lizard’s reproductive system, with obviously detrimental effects on their reproductive fitness. The effects of glyphosate must be considered biologically relevant and could endanger the reproductive capacity not only of lizards but also of other vertebrates, including humans; a more controlled and less intensive use of glyphosate in areas devoted to crop production would therefore be advisable.
Current and Future Treatment of Mucopolysaccharidosis (MPS) Type II: Is Brain-Targeted Stem Cell Gene Therapy the Solution for This Devastating Disorder?
Authors: Horgan Claire , Jones Simon A. , Bigger Brian W. , Wynn Robert
Published: April 2022

Mucopolysaccharidosis type II (Hunter Syndrome) is a rare, x-linked recessive, progressive, multi-system, lysosomal storage disease caused by the deficiency of iduronate-2-sulfatase (IDS), which leads to the pathological storage of glycosaminoglycans in nearly all cell types, tissues and organs. The condition is clinically heterogeneous, and most patients present with a progressive, multi-system disease in their early years. This article outlines the pathology of the disorder and current treatment strategies, including a detailed review of haematopoietic stem cell transplant outcomes for MPSII. We then discuss haematopoietic stem cell gene therapy and how this can be employed for treatment of the disorder. We consider how preclinical innovations, including novel brain-targeted techniques, can be incorporated into stem cell gene therapy approaches to mitigate the neuropathological consequences of the condition.
Saikosaponin A and Saikosaponin C Reduce TNF-α-Induced TSLP Expression through Inhibition of MAPK-Mediated EGR1 Expression in HaCaT Keratinocytes
Authors: Ahn Sung Shin , Lee Young Han , Yeo Hyunjin , Jung Euitaek , Lim Yoongho , Shin Soon Young
Published: April 2022

Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases worldwide, characterized by intense pruritus and eczematous lesions. Aberrant expression of thymic stromal lymphopoietin (TSLP) in keratinocytes is associated with the pathogenesis of AD and is considered a therapeutic target for the treatment of this disease. Saikosaponin A (SSA) and saikosaponin C (SSC), identified from Radix Bupleuri, exert anti-inflammatory effects. However, the topical effects of SSA and SSC on chronic inflammatory skin diseases are unclear. In this study, we investigated the effects of SSA and SSC on TSLP suppression in an AD-like inflammatory environment. We observed that SSA and SSC suppressed tumor necrosis factor-α-induced TSLP expression by downregulating the expression of the transcription factor early growth response 1 (EGR1) via inhibition of the extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase 1/2, and p38 mitogen-activated protein kinase pathways. We also confirmed that topical application of SSA or SSC reduced AD-like skin lesions in BALB/c mice challenged with 2,4-dinitrochlorobenzene. Our findings suggest that suppression of EGR1-regulated TSLP expression in keratinocytes might be attributable to the anti-inflammatory effects of SSA and SSC in AD-like skin lesions.
The Distribution of Glucosinolates in Different Phenotypes of Lepidium peruvianum and Their Role as Acetyl- and Butyrylcholinesterase Inhibitors—In Silico and In Vitro Studies
Authors: Tarabasz Dominik , Szczeblewski Paweł , Laskowski Tomasz , Płaziński Wojciech , Baranowska-Wójcik Ewa , Szwajgier Dominik , Kukula-Koch Wirginia , Meissner Henry O.
Published: April 2022

The aim of the study was to present the fingerprint of different Lepidium peruvianum tuber extracts showing glucosinolates-containing substances possibly playing an important role in preventinting dementia and other memory disorders. Different phenotypes of Lepidium peruvianum (Brassicaceae) tubers were analysed for their glucosinolate profile using a liquid chromatograph coupled with mass spectrometer (HPLC-ESI-QTOF-MS/MS platform). Qualitative analysis in 50% ethanolic extracts confirmed the presence of ten compounds: aliphatic, indolyl, and aromatic glucosinolates, with glucotropaeolin being the leading one, detected at levels between 0–1.57% depending on phenotype, size, processing, and collection site. The PCA analysis showed important variations in glucosinolate content between the samples and different ratios of the detected compounds. Applied in vitro activity tests confirmed inhibitory properties of extracts and single glucosinolates against acetylcholinesterase (AChE) (15.3–28.9% for the extracts and 55.95–57.60% for individual compounds) and butyrylcholinesterase (BuChE) (71.3–77.2% for the extracts and 36.2–39.9% for individual compounds). The molecular basis for the activity of glucosinolates was explained through molecular docking studies showing that the tested metabolites interacted with tryptophan and histidine residues of the enzymes, most likely blocking their active catalytic side. Based on the obtained results and described mechanism of action, it could be concluded that glucosinolates exhibit inhibitory properties against two cholinesterases present in the synaptic cleft, which indicates that selected phenotypes of L. peruvianum tubers cultivated under well-defined environmental and ecological conditions may present a valuable plant material to be considered for the development of therapeutic products with memory-stimulating properties.
Oxidative Stress and Chemoradiation-Induced Oral Mucositis: A Scoping Review of In Vitro, In Vivo and Clinical Studies
Authors: Nguyen Huynh , Sangha Simran , Pan Michelle , Shin Dong Ha , Park Hayoung , Mohammed Ali I. , Cirillo Nicola
Published: April 2022

Chemoradiation-induced mucositis is a debilitating condition of the gastrointestinal tract eventuating from antineoplastic treatment. It is believed to occur primarily due to oxidative stress mechanisms, which generate Reactive Oxygen Species (ROS). The aim of this scoping review was to assess the role of oxidative stress in the development of Oral Mucositis (OM). Studies from the literature, published in MEDLINE and SCOPUS, that evaluated the oxidative stress pathways or antioxidant interventions for OM, were retrieved to elucidate the current understanding of their relationship. Studies failing inclusion criteria were excluded, and those suitable underwent data extraction, using a predefined data extraction table. Eighty-nine articles fulfilled criteria, and these were sub-stratified into models of study (in vitro, in vivo, or clinical) for evaluation. Thirty-five clinical studies evaluated antioxidant interventions on OM’s severity, duration, and pain, amongst other attributes. A number of clinical studies sought to elucidate the protective or therapeutic effects of compounds that had been pre-determined to have antioxidant properties, without directly assessing oxidative stress parameters (these were deemed “indirect evidence”). Forty-seven in vivo studies assessed the capacity of various compounds to prevent OM. Findings were mostly consistent, reporting reduced OM severity associated with a reduction in ROS, malondialdehyde (MDA), myeloperoxidase (MPO), but higher glutathione (GSH) and superoxide dismutase (SOD) activity or expression. Twenty-one in vitro studies assessed potential OM therapeutic interventions. The majority demonstrated successful a reduction in ROS, and in select studies, secondary molecules were assessed to identify the mechanism. In summary, this review highlighted numerous oxidative stress pathways involved in OM pathogenesis, which may inform the development of novel therapeutic targets.
Oncolytic Herpes Simplex Virus Type 1 Induces Immunogenic Cell Death Resulting in Maturation of BDCA-1+ Myeloid Dendritic Cells
Authors: Kalus Philipp , De Munck Jolien , Vanbellingen Sarah , Carreer Laura , Laeremans Thessa , Broos Katrijn , Dufait Inès , Schwarze Julia K. , Van Riet Ivan , Neyns Bart , Breckpot Karine , Aerts Joeri L.
Published: April 2022

Recently, a paradigm shift has been established for oncolytic viruses (OVs) as it was shown that the immune system plays an important role in the specific killing of tumor cells by OVs. OVs have the intrinsic capacity to provide the right signals to trigger anti-tumor immune responses, on the one hand by delivering virus-derived innate signals and on the other hand by inducing immunogenic cell death (ICD), which is accompanied by the release of various damage-associated molecules from infected tumor cells. Here, we determined the ICD-inducing capacity of Talimogene laherparepvec (T-VEC), a herpes simplex virus type 1 based OV, and benchmarked this to other previously described ICD (e.g., doxorubicin) and non-ICD inducing agents (cisplatin). Furthermore, we studied the capability of T-VEC to induce the maturation of human BDCA-1+ myeloid dendritic cells (myDCs). We found that T-VEC treatment exerts direct and indirect anti-tumor effects as it induces tumor cell death that coincides with the release of hallmark mediators of ICD, while simultaneously contributing to the maturation of BDCA-1+ myDCs. These results unequivocally cement OVs in the category of cancer immunotherapy.
Selective Inhibition of PDE4B Reduces Methamphetamine Reinforcement in Two C57BL/6 Substrains
Authors: Honeywell Kevin M. , Doren Eliyana Van , Szumlinski Karen K.
Published: April 2022

Methamphetamine (MA) is a highly addictive psychostimulant drug, and the number of MA-related overdose deaths has reached epidemic proportions. Repeated MA exposure induces a robust and persistent neuroinflammatory response, and the evidence supports the potential utility of targeting neuroimmune function using non-selective phosphodiesterase 4 (PDE4) inhibitors as a therapeutic strategy for attenuating addiction-related behavior. Off-target, emetic effects associated with non-selective PDE4 blockade led to the development of isozyme-selective inhibitors, of which the PDE4B-selective inhibitor A33 was demonstrated recently to reduce binge drinking in two genetically related C57BL/6 (B6) substrains (C57BL/6NJ (B6NJ) and C57BL/6J (B6J)) that differ in their innate neuroimmune response. Herein, we determined the efficacy of A33 for reducing MA self-administration and MA-seeking behavior in these two B6 substrains. Female and male mice of both substrains were first trained to nose poke for a 100 mg/L MA solution followed by a characterization of the dose–response function for oral MA reinforcement (20 mg/L–3.2 g/L), the demand-response function for 400 mg/L MA, and cue-elicited MA seeking following a period of forced abstinence. During this substrain comparison of MA self-administration, we also determined the dose–response function for A33 pretreatment (0–1 mg/kg) on the maintenance of MA self-administration and cue-elicited MA seeking. Relative to B6NJ mice, B6J mice earned fewer reinforcers, consumed less MA, and took longer to reach acquisition criterion with males of both substrains exhibiting some signs of lower MA reinforcement than their female counterparts during the acquisition phase of the study. A33 pretreatment reduced MA reinforcement at all doses tested. These findings provide the first evidence that pretreatment with a selective PDE4B inhibitor effectively reduces MA self-administration in both male and female mice of two genetically distinct substrains but does not impact cue-elicited MA seeking following abstinence. If relevant to humans, these results posit the potential clinical utility of A33 or other selective PDE4B inhibitors for curbing active drug-taking in MA use disorder.
Epigenetic Mechanisms of Epidermal Differentiation
Authors: Moltrasio Chiara , Romagnuolo Maurizio , Marzano Angelo Valerio
Published: April 2022

Keratinocyte differentiation is an essential process for epidermal stratification and stratum corneum formation. Keratinocytes proliferate in the basal layer of the epidermis and start their differentiation by changing their functional or phenotypical type; this process is regulated via induction or repression of epidermal differentiation complex (EDC) genes that play a pivotal role in epidermal development. Epidermal development and the keratinocyte differentiation program are orchestrated by several transcription factors, signaling pathways, and epigenetic regulators. The latter exhibits both activating and repressive effects on chromatin in keratinocytes via the ATP-dependent chromatin remodelers, histone demethylases, and genome organizers that promote terminal keratinocyte differentiation, and the DNA methyltransferases, histone deacetylases, and Polycomb components that stimulate proliferation of progenitor cells and inhibit premature activation of terminal differentiation-associated genes. In addition, microRNAs are involved in different processes between proliferation and differentiation during the program of epidermal development. Here, we bring together current knowledge of the mechanisms controlling gene expression during keratinocyte differentiation. An awareness of epigenetic mechanisms and their alterations in health and disease will help to bridge the gap between our current knowledge and potential applications for epigenetic regulators in clinical practice to pave the way for promising target therapies.
Modulation of Aptamer–Ligand-Binding by Complementary Oligonucleotides: A G-Quadruplex Anti-Ochratoxin A Aptamer Case Study
Authors: Samokhvalov Alexey V. , Safenkova Irina V. , Eremin Sergei A. , Bonchuk Artem N. , Maksimenko Oksana G. , Sluchanko Nikolai N. , Zherdev Anatoly V. , Dzantiev Boris B.
Published: April 2022

Short oligonucleotides are widely used for the construction of aptamer-based sensors and logical bioelements to modulate aptamer–ligand binding. However, relationships between the parameters (length, location of the complementary region) of oligonucleotides and their influence on aptamer–ligand interactions remain unclear. Here, we addressed this task by comparing the effects of short complementary oligonucleotides (ssDNAs) on the structure and ligand-binding ability of an aptamer and identifying ssDNAs’ features that determine these effects. Within this, the interactions between the OTA-specific G-quadruplex aptamer 1.12.2 (5′-GATCGGGTGTGGGTGGCGTAAAGGGA GCATCGGACA-3′) and 21 single-stranded DNA (ssDNA) oligonucleotides complementary to different regions of the aptamer were studied. Two sets of aptamer–ssDNA dissociation constants were obtained in the absence and in the presence of OTA by isothermal calorimetry and fluorescence anisotropy, respectively. In both sets, the binding constants depend on the number of hydrogen bonds formed in the aptamer–ssDNA complex. The ssDNAs’ having more than 23 hydrogen bonds with the aptamer have a lower aptamer dissociation constant than for aptamer–OTA interactions. The ssDNAs’ having less than 18 hydrogen bonds did not affect the aptamer–OTA affinity. The location of ssDNA’s complementary site in the aptamer affeced the kinetics of the interaction and retention of OTA-binding in aptamer–ssDNA complexes. The location of the ssDNA site in the aptamer G-quadruplex led to its unfolding. In the presence of OTA, the unfolding process was longer and takes from 20 to 70 min. The refolding in the presence of OTA was possible and depends on the length and location of the ssDNA’s complementary site. The location of the ssDNA site in the tail region led to its rapid displacement and wasn’t affecting the G-qaudruplex’s integrity. It makes the tail region more perspective for the development of ssDNA-based tools using this aptamer.
Molecular Insights in Psychiatry
Authors: Traina Giovanna , Tuszynski Jack Adam , Cocchi Massimo
Published: April 2022

This Special Issue included articles discussing several important psychiatric phenomena whose elucidation can be provided by cellular and subcellular molecular mechanisms [...]
Neurogenesis of Subventricular Zone Progenitors in the Premature Cortex of Ferrets Facilitated by Neonatal Valproic Acid Exposure
Authors: Sawada Kazuhiko
Published: April 2022

The present study evaluated the neurogenesis of neonatal valproic acid (VPA) exposure on subventricular zone progenitors of the developing cerebral cortex in ferrets. VPA was injected at a dose of 200 µg/g of body weight into ferret infants on postnatal days 6 and 7. Two different thymidine analogues, 5-ethynyl-2′-deoxyuridine (EdU) and 5-bromo-2′-deoxyuridine (BrdU), were injected with a 48 h interval to label proliferating cells before and after VPA exposure. Two hours after BrdU injection, BrdU single- and EdU/BrdU double-labeled cells, but not EdU single-labeled cells, were significantly denser in both the inner and outer subventricular zones of VPA-exposed infants than in control infants. Notably, more than 97% of BrdU single- and EdU/BrdU double-labeled cells were immunopositive for Pax6, a stable marker for basal radial glia (bRG), in both groups. In contrast, the percentage of cells positively immunostained for Cux1, a postmitotic marker for upper-layer cortical neurons, in both EdU single- and BrdU single-labeled cells, was significantly higher in VPA-exposed infants than in control infants. These findings suggest that neonatal VPA exposure facilitates bRG proliferation, including self-renewal, followed by their differentiation into upper layer cortical neurons in the premature cortex of ferrets.
Retinitis Pigmentosa: Progress in Molecular Pathology and Biotherapeutical Strategies
Authors: Liu Wanqin , Liu Shanshan , Li Ping , Yao Kai
Published: April 2022

Retinitis pigmentosa (RP) is genetically heterogeneous retinopathy caused by photoreceptor cell death and retinal pigment epithelial atrophy that eventually results in blindness in bilateral eyes. Various photoreceptor cell death types and pathological phenotypic changes that have been disclosed in RP demand in-depth research of its pathogenic mechanism that may account for inter-patient heterogeneous responses to mainstream drug treatment. As the primary method for studying the genetic characteristics of RP, molecular biology has been widely used in disease diagnosis and clinical trials. Current technology iterations, such as gene therapy, stem cell therapy, and optogenetics, are advancing towards precise diagnosis and clinical applications. Specifically, technologies, such as effective delivery vectors, CRISPR/Cas9 technology, and iPSC-based cell transplantation, hasten the pace of personalized precision medicine in RP. The combination of conventional therapy and state-of-the-art medication is promising in revolutionizing RP treatment strategies. This article provides an overview of the latest research on the pathogenesis, diagnosis, and treatment of retinitis pigmentosa, aiming for a convenient reference of what has been achieved so far.
Dendritic Cells and Their Immunotherapeutic Potential for Treating Type 1 Diabetes
Authors: Khan Farhan Ullah , Khongorzul Puregmaa , Raki Ahmed Aziz , Rajasekaran Ashwini , Gris Denis , Amrani Abdelaziz
Published: April 2022

Type 1 diabetes (T1D) results from the destruction of pancreatic beta cells through a process that is primarily mediated by T cells. Emerging evidence suggests that dendritic cells (DCs) play a crucial role in initiating and developing this debilitating disease. DCs are professional antigen-presenting cells with the ability to integrate signals arising from tissue infection or injury that present processed antigens from these sites to naïve T cells in secondary lymphoid organs, thereby triggering naïve T cells to differentiate and modulate adaptive immune responses. Recent advancements in our knowledge of the various subsets of DCs and their cellular structures and methods of orchestration over time have resulted in a better understanding of how the T cell response is shaped. DCs employ various arsenal to maintain their tolerance, including the induction of effector T cell deletion or unresponsiveness and the generation and expansion of regulatory T cell populations. Therapies that suppress the immunogenic effects of dendritic cells by blocking T cell costimulatory pathways and proinflammatory cytokine production are currently being sought. Moreover, new strategies are being developed that can regulate DC differentiation and development and harness the tolerogenic capacity of these cells. Here, in this report, we focus on recent advances in the field of DC immunology and evaluate the prospects of DC-based therapeutic strategies to treat T1D.
Inhibition of Human Urokinase-Type Plasminogen Activator (uPA) Enzyme Activity and Receptor Binding by DNA Aptamers as Potential Therapeutics through Binding to the Different Forms of uPA
Authors: Dreymann Nico , Wuensche Julia , Sabrowski Wiebke , Moeller Anja , Czepluch Denise , Vu Van Dana , Fuessel Susanne , Menger Marcus M.
Published: April 2022

Urokinase-type plasminogen activator is widely discussed as a marker for cancer prognosis and diagnosis and as a target for cancer therapies. Together with its receptor, uPA plays an important role in tumorigenesis, tumor progression and metastasis. In the present study, systematic evolution of ligands by exponential enrichment (SELEX) was used to select single-stranded DNA aptamers targeting different forms of human uPA. Selected aptamers allowed the distinction between HMW-uPA and LMW-uPA, and therefore, presumably, have different binding regions. Here, uPAapt-02-FR showed highly affine binding with a KD of 0.7 nM for HMW-uPA and 21 nM for LMW-uPA and was also able to bind to pro-uPA with a KD of 14 nM. Furthermore, no cross-reactivity to mouse uPA or tissue-type plasminogen activator (tPA) was measured, demonstrating high specificity. Suppression of the catalytic activity of uPA and inhibition of uPAR-binding could be demonstrated through binding with different aptamers and several of their truncated variants. Since RNA aptamers are already known to inhibit uPA-uPAR binding and other pathological functions of the uPA system, these aptamers represent a novel, promising tool not only for detection of uPA but also for interfering with the pathological functions of the uPA system by additionally inhibiting uPA activity.