bluuebunny/crossref_metadata_2025 huggingface dataset:
Neurological Manifestations and Clinical Outcomes of Patients with COVID-19 in the Aseer Region, Saudi Arabia
Authors: Alshehri Nada N. , AlQahtani Maha A. , Riaz Fatima , Mahmood Syed E. , Ahmad Ausaf , AbdelGhaffar Nawal F. , Almakfor Abdulaziz H. Abdullah , Alahmari Fawziah M. , Abdulmutal Hanan , Rudainee Mojahed Hadi A.
Published: February 2023

COVID-19 patients also present with rheumatological problems, cardiac problems, and even neurological manifestations. However, the data are still insufficient at present to fill the gaps in our understanding of the neurological presentations of COVID-19. Therefore, the present study was undertaken to reveal the various neurological manifestations of patients with COVID-19 and to find the association between neurological manifestations and the clinical outcome. This cross-sectional study was conducted in Abha, in the Aseer region of the Kingdom of Saudi Arabia, among COVID-19 patients aged 18 years or older who were admitted with the neurological manifestations of COVID-19 to the Aseer Central Hospital and Heart Center Hospital Abha. Non-probability convenient sampling was used. All the information was gathered by the principal investigator using a questionnaire including sociodemographic information, disease characteristics of COVID-19, neurological manifestations, and other complications. Data were analyzed using the Statistical Package for Social Sciences, version 16.0 (SPSS, Inc., Chicago, IL, USA). A total of 55 patients were included in the present study. About half of the patients were admitted to the ICU, and 18 (62.1%) patients died after 1 month of follow-up. Patients aged over 60 years had a 75% mortality rate. About 66.66% of patients with pre-existing neurological disorders died. Statistically significant associations were found between neurological symptoms such as cranial nerve symptoms and a poor outcome. A statistically significant difference was also found between laboratory parameters such as the absolute neutrophil count (ANC), activated partial thromboplastin time (aPTT), total cholesterol (TC), creatinine, urea, and lactate dehydrogenase (LDH) level and the outcome. A statistically significant difference was also found between the use of medications such as antiplatelets, anticoagulants, and statins at the baseline and after a 1-month follow-up. Neurological symptoms and complications are not uncommon among COVID-19 patients. Most of these patients had poor outcomes. Further studies are required to provide more data and knowledge about this issue, including the possible risk factors and the long-term neurological consequences of COVID-19.
Association between Anemia Severity and Ischemic Stroke Incidence: A Retrospective Cohort Study
Authors: Chen Hui-Fen , Ho Tsing-Fen , Kuo Yu-Hung , Chien Ju-Huei
Published: February 2023

Stroke patients presenting with anemia at the time of stroke onset had a higher risk of mortality and development of other cardiovascular diseases and comorbidities. The association between the severity of anemia and the risk of developing a stroke is still uncertain. This retrospective study aimed to evaluate the association between stroke incidence and anemia severity (by WHO criteria). A total of 71,787 patients were included, of whom 16,708 (23.27%) were identified as anemic and 55,079 patients were anemia-free. Female patients (62.98%) were more likely to have anemia than males (37.02%). The likelihood of having a stroke within eight years after anemia diagnosis was calculated using Cox proportional hazard regression. Patients with moderate anemia had a significant increase in stroke risk compared to the non-anemia group in univariate analyses (hazard ratios [HR] = 2.31, 95% confidence interval [CI], 1.97–2.71, p < 0.001) and in adjusted HRs (adj-HR = 1.20, 95% CI, 1.02–1.43, p = 0.032). The data reveal that patients with severe anemia received more anemia treatment, such as blood transfusion and nutritional supplementation, and maintaining blood homeostasis may be important to preventing stroke. Anemia is an important risk factor, but other risk factors, including diabetes and hyperlipidemia, also affect stroke development. There is a heightened awareness of anemia’s severity and the increasing risk of stroke development.
The Experience of COVID-19 in a Sample of Gynecological Cancer Patients Undergoing Chemotherapy: A Focus on the Psychological Implications
Authors: Perego Gaia , Di Mattei Valentina Elisabetta , Mazzetti Martina , Milano Francesca , Gatti Carola , Rancoita Paola Maria Vittoria , Taranto Paola , Rabaiotti Emanuela , Cioffi Raffaella , Candiani Massimo
Published: February 2023

Cancer patients are at an increased risk of developing severe consequences due to the COVID-19 infection. However, psychological outcomes in this population have been overlooked in the literature. The present study aims to identify significant psychological differences between gynecological cancer patients undergoing chemotherapy before and during the pandemic. Additionally, we explore the correlations between COVID-19-related concerns and anxiety, depression, distress, and quality of life levels. Forty-two patients completed the STAI-Y, the EORTC QLQ-C30, the BDI II, the DT, and an ad-hoc questionnaire that investigated COVID-19-related concerns. The analyses did not show significant differences in the psychometric scales between the two groups, highlighting a considerable resilience against mental health and quality of life deterioration during the COVID-19 pandemic in gynecologic cancer patients. However, COVID-19-related concerns were positively associated with anxiety and inversely related to emotional functioning levels. These results emphasize the importance of a comprehensive patient care and the need to implement a multidisciplinary approach that includes psychological support in the treatment plan. Moreover, it is essential to encourage clear communication to convey comprehensive information about the impact of the pandemic on physical and psychological levels, as well as to offer psychoeducational tools to face the pandemic.
Digital Health Service for Identification of Frailty Risk Factors in Community-Dwelling Older Adults: The SUNFRAIL+ Study Protocol
Authors: De Luca Vincenzo , Femminella Grazia Daniela , Leonardini Lisa , Patumi Lola , Palummeri Ernesto , Roba Isabella , Aronni Walter , Toccoli Stefano , Sforzin Simona , Denisi Fortunata , Basso Anna Maddalena , Ruatta Manuela , Obbia Paola , Rizzo Alessio , Borgioli Moira , Eccher Claudio , Farina Riccardo , Conforti Diego , Mercurio Lorenzo , Salvatore Elena , Gentile Maurizio , Bocchino Marialuisa , Sanduzzi Zamparelli Alessandro , Viceconte Giulio , Gentile Ivan , Ruosi Carlo , Ferrara Nicola , Fabbrocini Gabriella , Colao Annamaria , Triassi Maria , Iaccarino Guido , Liotta Giuseppe , Illario Maddalena
Published: February 2023

This article reports the study protocol of a nationwide multicentric study in seven Italian regions aimed at assessing the effectiveness of a digitally supported approach for the early screening of frailty risk factors in community-dwelling older adults. SUNFRAIL+ is a prospective observational cohort study aimed at carrying out a multidimensional assessment of community-dwelling older adults through an IT platform, which allows to connect the items of the SUNFRAIL frailty assessment tool with a cascading multidimensional in-depth assessment of the bio–psycho–social domains of frailty. Seven centers in seven Italian regions will administer the SUNFRAIL questionnaire to 100 older adults. According to the answers provided by older adults, they will be subjected to one or more validated in-depth scale tests in order to perform further diagnostic or dimensional evaluations. The study aims to contribute to the implementation and validation of a multiprofessional and multistakeholder service model for the screening of frailty in community-dwelling older adult population.
Emergency Medical Service Response Time for Road Traffic Accidents in the Kingdom of Saudi Arabia: Analysis of National Data (2016–2020)
Authors: Alslamah Thamer , Alsofayan Yousef Mohammad , Al Imam Mahmudul Hassan , Almazroa Monerah Abdullah , Abalkhail Adil , Alasqah Ibrahim , Mahmud Ilias
Published: February 2023

Despite preventive measures and initiatives, road traffic accidents are on the rise in the Kingdom of Saudi Arabia. This study aimed to investigate the emergency medical service unit’s response to RTA by socio-demographic and accident-related variables in the Kingdom of Saudi Arabia. This retrospective survey included Saudi Red Crescent Authority data on road traffic accidents between 2016 and 2020. As part of the study, information on sociodemographic characteristics (e.g., age, sex, and nationality), accident-related data (type and place of the accident), and response time to road traffic accidents were extracted. Our study included 95,372 cases of road traffic accidents recorded by the Saudi Red Crescent Authority in the Kingdom of Saudi Arabia between 2016 and 2020. Descriptive analyses were performed to explore the emergency medical service unit’s response time to road traffic accidents, and linear regression analyses were performed to investigate the predictors of response time. Most of the road traffic accident cases were among males (59.1%), and the age group of 25–34 years accounted for about a quarter (24.3%), while the mean age of the road traffic accident cases was 30.13 (±12.86) years. Among the regions, the capital city of Riyadh experienced the highest proportion of road traffic accidents (25.3%). In most road traffic accidents, the mission acceptance time was excellent (0–60 s; 93.7%), movement duration was excellent (<120 s; 91.1%), reaching site duration was excellent (<12 min; 57.9%), treatment start time was excellent (<120 s; 76.4%), duration at the scene was poor (>15 min; 40.8%), reaching hospital duration was good (30–60 min; 52.7%), and in-hospital duration was poor (>15 min; 44.1%). Regions, places and types of accidents, age, gender, and nationality of victims were significantly associated with different parameters of response time. Excellent response time was observed in most of the parameters except the duration at the scene, reaching hospital duration, and in-hospital duration. Apart from the initiatives to prevent road traffic accidents, policymakers should focus on strategies to improve accident response time to save lives.
Analysis of the Spatial Relationship between Ecosystem Regulation Services and Rural Tourism
Authors: Wang Junying , Han Guifeng , You Jing , Zhu Liang , Li Yafei , Zhou Xiang
Published: February 2023

In the context of China’s implementation of the rural revitalization strategy and establishment of a mechanism to realize the value of ecological products, rural tourism as an eco-friendly industry promotes regional social and economic development with high-quality natural and ecological conditions in rural areas and is one of the key patterns to realize regional green development. Existing studies in the field focus on the spatial relationship between rural tourism and traditional factors such as economy, population, and transportation and ignore to some extent the relationship between ecosystem services and rural tourism. However, from the perspective of distribution, rural tourism is popular mainly in areas with high ecological quality, so it can be inferred that there is a relationship between ecosystem services and rural tourism. Therefore, this paper targets the key problem—the spatial relationship between ecosystem regulation services and rural tourism, taking rural tourist spots in six districts and counties in the Wuling Mountains in southeastern Chongqing as the subjects, and using the geo-econometric analysis method and geographic detector model to analyze the spatial-driving and development-support roles of ecosystem services on rural tourism. The results show that: (1) the nearest neighbor index of the distribution of rural tourist spots in the regions of study is 0.28, showing a significant clustering trend as a whole; (2) there are obviously high-value areas among the six types of ecosystem regulation services, which are mainly distributed in forest ecosystems; (3) the driving effects of dual factors are more significant, and the combined driving effects of climate regulation and anion supply services are the most significant, with the q value of these driving effects being 0.1962; (4) from the perspective of the supply–demand relationship of industrial development, ecosystem services play an important role in supporting the development of rural tourism. Based on these results, it is proposed in this paper that, in the next step, a comprehensive analysis of the impact of ecosystem regulation services should be conducted during the special planning of rural tourism and the rational layout of industries should be guided on the premise of compliance with space-use control, as well as economical and intensive land use, to support the scientific formulation of regional rural tourism development strategies with new ideas based on basic analysis and better realize the value of ecological products and boost rural revitalization.
Music Alters Conscious Distance Monitoring without Changing Pacing and Performance during a Cycling Time Trial
Authors: Vasconcelos Gustavo C. , Brietzke Cayque , Franco-Alvarenga Paulo E. , Hettinga Florentina J. , Pires Flávio O.
Published: February 2023

Athletes use their own perception to monitor distance and regulate their pace during exercise, avoiding premature fatigue before the endpoint. On the other hand, they may also listen to music while training and exercising. Given the potential role of music as a distractor, we verified if music influenced the athletes’ ability to monitor the distance covered during a 20-km cycling time trial (TT20km). We hypothesized that music would elongate cyclists’ perceived distance due to reduced attentional focus on exercise-derived signals, which would also change their ratings of perceived exertion (RPE). We also expected that the motivational role of music would also be beneficial in pacing and performance. After familiarization sessions, ten recreational cyclists performed an in-laboratory TT20km while either listening to music or not (control). They reported their RPE, associative thoughts to exercise (ATE), and motivation when they each perceived they had completed 2-km. Power output and heart rate (HR) were continuously recorded. Cyclists elongated their distance perception with music, increasing the distance covered for each perceived 2 km (p = 0.003). However, music reduced the error of conscious distance monitoring (p = 0.021), pushing the perceived distance towards the actual distance. Music increased the actual distance–RPE relationship (p = 0.004) and reduced ATE (p < 0.001). However, music affected neither performance assessed as mean power output (p = 0.564) and time (p = 0.524) nor psychophysiological responses such as HR (p = 0.066), RPE (p = 0.069), and motivation (p = 0.515). Cyclists elongated their distance perception during the TT20km and changed the actual distance–RPE relationship, which is likely due to a music-distractive effect. Although there was a reduced error of conscious distance monitoring, music affected neither pacing nor performance.
Geostatistics on Real-Time Geodata Streams—An Extended Spatiotemporal Moran’s I Index with Distributed Stream Processing Technologies
Authors: Lemmerz Thomas , Herlé Stefan , Blankenbach Jörg
Published: February 2023

The availability of geodata with high spatial and temporal resolution is increasing steadily. Often, these data are continuously generated by distributed sensor networks and provided as geodata streams. Geostatistical analysis methods, such as spatiotemporal autocorrelation, have thus far been applied primarily to historized data. As such, the advantages of continuous and up-to-date acquisition of geodata have not yet been transferred to the analysis phase. At the same time, open-source frameworks for distributed stream processing have been developed into powerful real-time data processing tools. In this paper a methodology is developed to apply analyses of spatiotemporal autocorrelation directly to geodata streams through a distributed streaming process using open-source software frameworks. For this purpose, we adapt the extended Moran’s I index for continuous and up-to-date computation, then apply it to simulated geospatial data streams of recorded taxi trip data. Various application scenarios for the developed methodology are tested and compared on a distributed computing cluster. The results show that the developed methodology can provide geostatistical analysis results in real time. This research demonstrates how modern datastream processing technologies have the potential to significantly advance the way geostatistical analysis can be performed and used in the future.
Dominant Factors Affecting Rheological Properties of Cellulose Derivatives Forming Thermotropic Cholesteric Liquid Crystals with Visible Reflection
Authors: Ogiwara Yuki , Iwata Naoto , Furumi Seiichi
Published: February 2023

Hydroxypropyl cellulose (HPC) derivatives with alkanoyl side chains are known to form thermotropic cholesteric liquid crystals (CLCs) with visible reflection. Although the widely investigated CLCs are requisite for tedious syntheses of chiral and mesogenic compounds from precious petroleum resources, the HPC derivatives easily prepared from biomass resources would contribute to the realization of environment-friendly CLC devices. In this study, we report the linear rheological behavior of thermotropic CLCs of HPC derivatives possessing alkanoyl side chains of different lengths. In addition, the HPC derivatives have been synthesized by the complete esterification of hydroxy groups in HPC. The master curves of these HPC derivatives were almost identical at reference temperatures, with their light reflection at 405 nm. The relaxation peaks appeared at an angular frequency of ~102 rad/s, suggesting the motion of the CLC helical axis. Moreover, the dominant factors affecting the rheological properties of HPC derivatives were strongly dependent on the CLC helical structures. Further, this study provides one of the most promising fabrication strategies for the highly oriented CLC helix by shearing force, which is indispensable to the development of advanced photonic devices with eco-friendliness.
Clinical-Scale Mesenchymal Stem Cell-Derived Extracellular Vesicle Therapy for Wound Healing
Authors: Kim Jieun , Kim Eun Hee , Lee Hanbee , Sung Ji Hee , Bang Oh Young
Published: February 2023

We developed an extracellular vesicle (EV) bioprocessing platform for the scalable production of human Wharton’s jelly mesenchymal stem cell (MSC)-derived EVs. The effects of clinical-scale MSC-EV products on wound healing were tested in two different wound models: subcutaneous injection of EVs in a conventional full-thickness rat model and topical application of EVs using a sterile re-absorbable gelatin sponge in the chamber mouse model that was developed to prevent the contraction of wound areas. In vivo efficacy tests showed that treatment with MSC-EVs improved the recovery following wound injury, regardless of the type of wound model or mode of treatment. In vitro mechanistic studies using multiple cell lines involved in wound healing showed that EV therapy contributed to all stages of wound healing, such as anti-inflammation and proliferation/migration of keratinocytes, fibroblasts, and endothelial cells, to enhance wound re-epithelialization, extracellular matrix remodeling, and angiogenesis.
Does Reproductive Success in Natural and Anthropogenic Populations of Generalist Epipactis helleborine Depend on Flower Morphology and Nectar Composition?
Authors: Brzosko Emilia , Bajguz Andrzej , Burzyńska Justyna , Chmur Magdalena
Published: February 2023

The purpose of our study was to determine the role of flower structure and nectar composition in shaping the reproductive success (RS) of the generalist orchid Epipactis helleborine in natural and anthropogenic populations. We supposed that the distinct character of two groups of habitats creates different conditions for plant–pollinator relationships, thus influencing reproductive success in E. helleborine populations. Both pollinaria removal (PR) and fruiting (FRS) were differentiated between the populations. On average, FRS was almost two times higher in the anthropogenic than in the natural populations. The difference between the two population groups in PR was smaller but still statistically significant. RS parameters were correlated with some floral display and flower traits. Floral display influenced RS only in three anthropogenic populations. Flower traits had a weak influence on RS (10 of the 192 cases analyzed). The more important trait in shaping RS was nectar chemistry. The nectar of E. helleborine is relatively diluted with a lower sugar concentration in the anthropogenic than in the natural populations. In the natural populations, domination of sucrose over hexoses was found, while in the anthropogenic populations, hexoses were more abundant and the participation of sugars was balanced. In some populations, sugars influenced RS. In E. helleborine nectar, 20 proteogenic and 7 non-proteogenic amino acids (AAs) were found with a clear domination of glutamic acid. We noted relationships between some AAs and RS, but distinct AAs shaped RS in different populations, and their impact was independent of their participation. Our results indicate that the flower structure and nectar composition of E. helleborine reflect its generalistic character and meet the requirements of a wide range of pollinators. Simultaneously, the differentiation of flower traits suggests a variation in pollinator assemblages in particular populations. Knowledge about the factors influencing RS in distinct habitats helps to understand the evolutionary potential of species and to understand mechanisms and processes crucial for shaping interactions between plants and pollinators.
Quantification and Characterization of CTCs and Clusters in Pancreatic Cancer by Means of the Hough Transform Algorithm
Authors: Calero-Castro Francisco José , Pereira Sheila , Laga Imán , Villanueva Paula , Suárez-Artacho Gonzalo , Cepeda-Franco Carmen , de la Cruz-Ojeda Patricia , Navarro-Villarán Elena , Dios-Barbeito Sandra , Serrano María José , Fresno Cristóbal , Padillo-Ruiz Javier
Published: February 2023

Circulating Tumor Cells (CTCs) are considered a prognostic marker in pancreatic cancer. In this study we present a new approach for counting CTCs and CTC clusters in patients with pancreatic cancer using the IsofluxTM System with the Hough transform algorithm (Hough-IsofluxTM). The Hough-IsofluxTM approach is based on the counting of an array of pixels with a nucleus and cytokeratin expression excluding the CD45 signal. Total CTCs including free and CTC clusters were evaluated in healthy donor samples mixed with pancreatic cancer cells (PCCs) and in samples from patients with pancreatic ductal adenocarcinoma (PDAC). The IsofluxTM System with manual counting was used in a blinded manner by three technicians who used Manual-IsofluxTM as a reference. The accuracy of the Hough-IsofluxTM approach for detecting PCC based on counted events was 91.00% [84.50, 93.50] with a PCC recovery rate of 80.75 ± 16.41%. A high correlation between the Hough-IsofluxTM and Manual-IsofluxTM was observed for both free CTCs and for clusters in experimental PCC (R2 = 0.993 and R2 = 0.902 respectively). However, the correlation rate was better for free CTCs than for clusters in PDAC patient samples (R2 = 0.974 and R2 = 0.790 respectively). In conclusion, the Hough-IsofluxTM approach showed high accuracy for the detection of circulating pancreatic cancer cells. A better correlation rate was observed between Hough-IsofluxTM approach and with the Manual-IsofluxTM for isolated CTCs than for clusters in PDAC patient samples.
Oxidized Low-Density Lipoproteins Trigger Hepatocellular Oxidative Stress with the Formation of Cholesteryl Ester Hydroperoxide-Enriched Lipid Droplets
Authors: Sazaki Iku , Sakurai Toshihiro , Yamahata Arisa , Mogi Sumire , Inoue Nao , Ishida Koutaro , Kikkai Ami , Takeshita Hana , Sakurai Akiko , Takahashi Yuji , Chiba Hitoshi , Hui Shu-Ping
Published: February 2023

Oxidized low-density lipoproteins (oxLDLs) induce oxidative stress in the liver tissue, leading to hepatic steatosis, inflammation, and fibrosis. Precise information on the role of oxLDL in this process is needed to establish strategies for the prevention and management of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Here, we report the effects of native LDL (nLDL) and oxLDL on lipid metabolism, lipid droplet formation, and gene expression in a human liver-derived C3A cell line. The results showed that nLDL induced lipid droplets enriched with cholesteryl ester (CE) and promoted triglyceride hydrolysis and inhibited oxidative degeneration of CE in association with the altered expression of LIPE, FASN, SCD1, ATGL, and CAT genes. In contrast, oxLDL showed a striking increase in lipid droplets enriched with CE hydroperoxides (CE-OOH) in association with the altered expression of SREBP1, FASN, and DGAT1. Phosphatidylcholine (PC)-OOH/PC was increased in oxLDL-supplemented cells as compared with other groups, suggesting that oxidative stress increased hepatocellular damage. Thus, intracellular lipid droplets enriched with CE-OOH appear to play a crucial role in NAFLD and NASH, triggered by oxLDL. We propose oxLDL as a novel therapeutic target and candidate biomarker for NAFLD and NASH.
Multiple Roles of the Stress Sensor GCN2 in Immune Cells
Authors: Zhao Chenxu , Guo Han , Hou Yangxiao , Lei Tong , Wei Dong , Zhao Yong
Published: February 2023

The serine/threonine-protein kinase general control nonderepressible 2 (GCN2) is a well-known stress sensor that responds to amino acid starvation and other stresses, making it critical to the maintenance of cellular and organismal homeostasis. More than 20 years of research has revealed the molecular structure/complex, inducers/regulators, intracellular signaling pathways and bio-functions of GCN2 in various biological processes, across an organism’s lifespan, and in many diseases. Accumulated studies have demonstrated that the GCN2 kinase is also closely involved in the immune system and in various immune-related diseases, such as GCN2 acts as an important regulatory molecule to control macrophage functional polarization and CD4+ T cell subset differentiation. Herein, we comprehensively summarize the biological functions of GCN2 and discuss its roles in the immune system, including innate and adaptive immune cells. We also discuss the antagonism of GCN2 and mTOR pathways in immune cells. A better understanding of GCN2′s functions and signaling pathways in the immune system under physiological, stressful, and pathological situations will be beneficial to the development of potential therapies for many immune-relevant diseases.
Pathogenesis of Hypertension in Metabolic Syndrome: The Role of Fructose and Salt
Authors: Soleimani Manoocher , Barone Sharon , Luo Henry , Zahedi Kamyar
Published: February 2023

Metabolic syndrome is manifested by visceral obesity, hypertension, glucose intolerance, hyperinsulinism, and dyslipidemia. According to the CDC, metabolic syndrome in the US has increased drastically since the 1960s leading to chronic diseases and rising healthcare costs. Hypertension is a key component of metabolic syndrome and is associated with an increase in morbidity and mortality due to stroke, cardiovascular ailments, and kidney disease. The pathogenesis of hypertension in metabolic syndrome, however, remains poorly understood. Metabolic syndrome results primarily from increased caloric intake and decreased physical activity. Epidemiologic studies show that an enhanced consumption of sugars, in the form of fructose and sucrose, correlates with the amplified prevalence of metabolic syndrome. Diets with a high fat content, in conjunction with elevated fructose and salt intake, accelerate the development of metabolic syndrome. This review article discusses the latest literature in the pathogenesis of hypertension in metabolic syndrome, with a specific emphasis on the role of fructose and its stimulatory effect on salt absorption in the small intestine and kidney tubules.
Characteristics of the (Auto)Reactive T Cells in Rheumatoid Arthritis According to the Immune Epitope Database
Authors: Carlé Caroline , Degboe Yannick , Ruyssen-Witrand Adeline , Arleevskaya Marina I. , Clavel Cyril , Renaudineau Yves
Published: February 2023

T cells are known to be involved in the pathogenesis of rheumatoid arthritis (RA). Accordingly, and to better understand T cells’ contribution to RA, a comprehensive review based on an analysis of the Immune Epitope Database (IEDB) was conducted. An immune CD8+ T cell senescence response is reported in RA and inflammatory diseases, which is driven by active viral antigens from latent viruses and cryptic self-apoptotic peptides. RA-associated pro-inflammatory CD4+ T cells are selected by MHC class II and immunodominant peptides, which are derived from molecular chaperones, host extra-cellular and cellular peptides that could be post-translationally modified (PTM), and bacterial cross-reactive peptides. A large panel of techniques have been used to characterize (auto)reactive T cells and RA-associated peptides with regards to their interaction with the MHC and TCR, capacity to enter the docking site of the shared epitope (DRB1-SE), capacity to induce T cell proliferation, capacity to select T cell subsets (Th1/Th17, Treg), and clinical contribution. Among docking DRB1-SE peptides, those with PTM expand autoreactive and high-affinity CD4+ memory T cells in RA patients with an active disease. Considering original therapeutic options in RA, mutated, or altered peptide ligands (APL) have been developed and are tested in clinical trials.
Whole-Exome Sequencing and cfDNA Analysis Uncover Genetic Determinants of Melanoma Therapy Response in a Real-World Setting
Authors: Vanni Irene , Pastorino Lorenza , Tanda Enrica Teresa , Andreotti Virginia , Dalmasso Bruna , Solari Nicola , Mascherini Matteo , Cabiddu Francesco , Guadagno Antonio , Coco Simona , Allavena Eleonora , Bruno William , Pietra Gabriella , Croce Michela , Gangemi Rosaria , Piana Michele , Zoppoli Gabriele , Ferrando Lorenzo , Spagnolo Francesco , Queirolo Paola , Ghiorzo Paola
Published: February 2023

Although several studies have explored the molecular landscape of metastatic melanoma, the genetic determinants of therapy resistance are still largely unknown. Here, we aimed to determine the contribution of whole-exome sequencing and circulating free DNA (cfDNA) analysis in predicting response to therapy in a consecutive real-world cohort of 36 patients, undergoing fresh tissue biopsy and followed during treatment. Although the underpowered sample size limited statistical analysis, samples from non-responders had higher copy number variations and mutations in melanoma driver genes compared to responders in the BRAF V600+ subset. In the BRAF V600− subset, Tumor Mutational Burden (TMB) was twice that in responders vs. non-responders. Genomic layout revealed commonly known and novel potential intrinsic/acquired resistance driver gene variants. Among these, RAC1, FBXW7, GNAQ mutations, and BRAF/PTEN amplification/deletion were present in 42% and 67% of patients, respectively. Both Loss of Heterozygosity (LOH) load and tumor ploidy were inversely associated with TMB. In immunotherapy-treated patients, samples from responders showed higher TMB and lower LOH and were more frequently diploid compared to non-responders. Secondary germline testing and cfDNA analysis proved their efficacy in finding germline predisposing variants carriers (8.3%) and following dynamic changes during treatment as a surrogate of tissue biopsy, respectively.
Research Progresses and Applications of Fluorescent Protein Antibodies: A Review Focusing on Nanobodies
Authors: Chen Yu-Lei , Xie Xin-Xin , Zhong Ning , Sun Le-Chang , Lin Duanquan , Zhang Ling-Jing , Weng Ling , Jin Tengchuan , Cao Min-Jie
Published: February 2023

Since the discovery of fluorescent proteins (FPs), their rich fluorescence spectra and photochemical properties have promoted widespread biological research applications. FPs can be classified into green fluorescent protein (GFP) and its derivates, red fluorescent protein (RFP) and its derivates, and near-infrared FPs. With the continuous development of FPs, antibodies targeting FPs have emerged. The antibody, a class of immunoglobulin, is the main component of humoral immunity that explicitly recognizes and binds antigens. Monoclonal antibody, originating from a single B cell, has been widely applied in immunoassay, in vitro diagnostics, and drug development. The nanobody is a new type of antibody entirely composed of the variable domain of a heavy-chain antibody. Compared with conventional antibodies, these small and stable nanobodies can be expressed and functional in living cells. In addition, they can easily access grooves, seams, or hidden antigenic epitopes on the surface of the target. This review provides an overview of various FPs, the research progress of their antibodies, particularly nanobodies, and advanced applications of nanobodies targeting FPs. This review will be helpful for further research on nanobodies targeting FPs, making FPs more valuable in biological research.
Lacrimal Gland Epithelial Cells Shape Immune Responses through the Modulation of Inflammasomes and Lipid Metabolism
Authors: Delcroix Vanessa , Mauduit Olivier , Yang Menglu , Srivastava Amrita , Umazume Takeshi , de Paiva Cintia S. , Shestopalov Valery I. , Dartt Darlene A. , Makarenkova Helen P.
Published: February 2023

Lacrimal gland inflammation triggers dry eye disease through impaired tear secretion by the epithelium. As aberrant inflammasome activation occurs in autoimmune disorders including Sjögren’s syndrome, we analyzed the inflammasome pathway during acute and chronic inflammation and investigated its potential regulators. Bacterial infection was mimicked by the intraglandular injection of lipopolysaccharide (LPS) and nigericin, known to activate the NLRP3 inflammasome. Acute injury of the lacrimal gland was induced by interleukin (IL)-1α injection. Chronic inflammation was studied using two Sjögren’s syndrome models: diseased NOD.H2b compared to healthy BALBc mice and Thrombospondin-1-null (TSP-1-/-) compared to TSP-1WT C57BL/6J mice. Inflammasome activation was investigated by immunostaining using the R26ASC-citrine reporter mouse, by Western blotting, and by RNAseq. LPS/Nigericin, IL-1α and chronic inflammation induced inflammasomes in lacrimal gland epithelial cells. Acute and chronic inflammation of the lacrimal gland upregulated multiple inflammasome sensors, caspases 1/4, and interleukins Il1b and Il18. We also found increased IL-1β maturation in Sjögren’s syndrome models compared with healthy control lacrimal glands. Using RNA-seq data of regenerating lacrimal glands, we found that lipogenic genes were upregulated during the resolution of inflammation following acute injury. In chronically inflamed NOD.H2b lacrimal glands, an altered lipid metabolism was associated with disease progression: genes for cholesterol metabolism were upregulated, while genes involved in mitochondrial metabolism and fatty acid synthesis were downregulated, including peroxisome proliferator-activated receptor alpha (PPARα)/sterol regulatory element-binding 1 (SREBP-1)-dependent signaling. We conclude that epithelial cells can promote immune responses by forming inflammasomes, and that sustained inflammasome activation, together with an altered lipid metabolism, are key players of Sjögren’s syndrome-like pathogenesis in the NOD.H2b mouse lacrimal gland by promoting epithelial dysfunction and inflammation.
Effect of Newly Synthesized Structures of Peptides on the Stability of the Monolayers Formed
Authors: Golonka Iwona , Greber Katarzyna E. , Szyja Bartłomiej M. , Petrus Patrycja P. , Pucułek Jakub E. , Musiał Witold
Published: February 2023

The aim of the study was to evaluate the effect of the peptide structure (WKWK)2-KWKWK-NH2, P4 (C12)2-KKKK-NH2, P5 (KWK)2-KWWW-NH2, P6 (KK)2-KWWW-NH2 on their physicochemical properties. The thermogravimetric method (TG/DTG) was used, which made it possible to observe the course of chemical reactions and phase transformations occurring during the heating of solid samples. Based on the DSC curves, the enthalpy of the processes occurring in the peptides was determined. The influence of the chemical structure of this group of compounds on their film-forming properties was determined using the Langmuir–Wilhelmy trough method and was followed by molecular dynamics simulation. Evaluated peptides showed high thermal stability and the first significant mass loss occurred only at about 230 °C and 350 °C. The analysis of the compressibility coefficient of individual peptides indicates that all formed peptide monolayers were in the expanded liquid phase. Their maximum compressibility factor was less than 50.0 mN/m. Its highest value of 42.7 mN/m was achieved in a monolayer made of P4. The results obtained in molecular dynamic simulation indicate that non-polar side chains played an important role in the properties of the P4 monolayer, and the same applies to P5, except that a spherical effect was observed here. A slightly different behavior was observed for the P6 and P2 peptide systems, where the type of amino acids present had an influence. The obtained results indicate that the structure of the peptide affected its physicochemical and layer-forming properties.
The Challenge of Periprosthetic Joint Infection Diagnosis: From Current Methods to Emerging Biomarkers
Authors: Vrancianu Corneliu Ovidiu , Serban Bogdan , Gheorghe-Barbu Irina , Czobor Barbu Ilda , Cristian Roxana Elena , Chifiriuc Mariana Carmen , Cirstoiu Catalin
Published: February 2023

Due to the increase in the life span and mobility at older ages, the number of implanted prosthetic joints is constantly increasing. However, the number of periprosthetic joint infections (PJIs), one of the most severe complications after total joint arthroplasty, also shows an increasing trend. PJI has an incidence of 1–2% in the case of primary arthroplasties and up to 4% in the case of revision operations. The development of efficient protocols for managing periprosthetic infections can lead to the establishment of preventive measures and effective diagnostic methods based on the results obtained after the laboratory tests. In this review, we will briefly present the current methods used in PJI diagnosis and the current and emerging synovial biomarkers used for the prognosis, prophylaxis, and early diagnosis of periprosthetic infections. We will discuss treatment failure that may result from patient factors, microbiological factors, or factors related to errors during diagnosis.
The miR-20a/miR-92b Profile Is Associated with Circulating γδ T-Cell Perturbations in Mild Psoriasis
Authors: Tokić Stana , Jirouš Maja , Plužarić Vera , Mihalj Martina , Šola Marija , Tolušić Levak Maja , Glavaš Kristina , Balogh Peter , Štefanić Mario
Published: February 2023

Psoriasis vulgaris (PV) is an autoinflammatory dermatosis of unknown etiology. Current evidence suggests a pathogenic role of γδT cells, but the growing complexity of this population has made the offending subset difficult to pinpoint. The work on γδTCRint and γδTCRhi subsets, which express intermediate and high levels of γδTCR at their surface, respectively, is particularly scarce, leaving their inner workings in PV essentially unresolved. We have shown here that the γδTCRint/γδTCRhi cell composition and their transcriptom are related to the differential miRNA expression by performing a targeted miRNA and mRNA quantification (RT-qPCR) in multiplexed, flow-sorted γδ blood T cells from healthy controls (n = 14) and patients with PV (n = 13). A significant loss of miR-20a in bulk γδT cells (~fourfold decrease, PV vs. controls) largely mirrored increasing Vδ1-Vδ2- and γδintVδ1-Vδ2- cell densities in the bloodstream, culminating in a relative excess of γδintVδ1-Vδ2- cells for PV. Transcripts encoding DNA-binding factors (ZBTB16), cytokine receptors (IL18R1), and cell adhesion molecules (SELPLG) were depleted in the process, closely tracking miR-20a availability in bulk γδ T-cell RNA. Compared to controls, PV was also associated with enhanced miR-92b expression (~13-fold) in bulk γδT cells that lacked association with the γδT cell composition. The miR-29a and let-7c expressions remained unaltered in case–control comparisons. Overall, our data expand the current landscape of the peripheral γδT cell composition, underlining changes in its mRNA/miRNA transcriptional circuits that may inform PV pathogenesis.
Editorial of Special Issue “The Role of Vitamin D in Human Health and Diseases 2.0”
Authors: Silvagno Francesca , Bergandi Loredana
Published: February 2023

Vitamin D performs a differentiating, metabolic and anti-inflammatory function, through genomic, non-genomic and mitochondrial mechanisms of action [...]
The Threat Posed by Environmental Contaminants on Neurodevelopment: What Can We Learn from Neural Stem Cells?
Authors: Bose Raj , Spulber Stefan , Ceccatelli Sandra
Published: February 2023

Exposure to chemicals may pose a greater risk to vulnerable groups, including pregnant women, fetuses, and children, that may lead to diseases linked to the toxicants’ target organs. Among chemical contaminants, methylmercury (MeHg), present in aquatic food, is one of the most harmful to the developing nervous system depending on time and level of exposure. Moreover, certain man-made PFAS, such as PFOS and PFOA, used in commercial and industrial products including liquid repellants for paper, packaging, textile, leather, and carpets, are developmental neurotoxicants. There is vast knowledge about the detrimental neurotoxic effects induced by high levels of exposure to these chemicals. Less is known about the consequences that low-level exposures may have on neurodevelopment, although an increasing number of studies link neurotoxic chemical exposures to neurodevelopmental disorders. Still, the mechanisms of toxicity are not identified. Here we review in vitro mechanistic studies using neural stem cells (NSCs) from rodents and humans to dissect the cellular and molecular processes changed by exposure to environmentally relevant levels of MeHg or PFOS/PFOA. All studies show that even low concentrations dysregulate critical neurodevelopmental steps supporting the idea that neurotoxic chemicals may play a role in the onset of neurodevelopmental disorders.
Certificateless Public Key Authenticated Encryption with Keyword Search Achieving Stronger Security
Authors: Lu Jingwei , Li Hongbo , Huang Jianye , Ma Sha , Au Man Ho Allen , Huang Qiong
Published: February 2023

Transforming data into ciphertexts and storing them in the cloud database is a secure way to simplify data management. Public key encryption with keyword search (PEKS) is an important cryptographic primitive as it provides the ability to search for the desired files among ciphertexts. As a variant of PEKS, certificateless public key authenticated encryption with keyword search (CLPAEKS) not only simplifies certificate management but also could resist keyword guessing attacks (KGA). In this paper, we analyze the security models of two recent CLPAEKS schemes and find that they ignore the threat that, upon capturing two trapdoors, the adversary could directly compare them and distinguish whether they are generated using the same keyword. To cope with this threat, we propose an improved security model and define the notion of strong trapdoor indistinguishability. We then propose a new CLPAEKS scheme and prove it to be secure under the improved security model based on the intractability of the DBDH problem and the DDH problem in the targeted bilinear group.
Adaptive Fault Diagnosis for Simultaneous Sensor Faults in Structural Health Monitoring Systems
Authors: Al-Zuriqat Thamer , Chillón Geck Carlos , Dragos Kosmas , Smarsly Kay
Published: February 2023

Structural health monitoring (SHM) is a non-destructive testing method that supports the condition assessment and lifetime estimation of civil infrastructure. Sensor faults may result in the loss of valuable data and erroneous structural condition assessments and lifetime estimations, in the worst case with structural damage remaining undetected. As a result, the concepts of fault diagnosis (FD) have been increasingly adopted by the SHM community. However, most FD concepts for SHM consider only single-fault occurrence, which may oversimplify actual fault occurrences in real-world SHM systems. This paper presents an adaptive FD approach for SHM systems that addresses simultaneous faults occurring in multiple sensors. The adaptive FD approach encompasses fault detection, isolation, and accommodation, and it builds upon analytical redundancy, which uses correlated data from multiple sensors of an SHM system. Specifically, faults are detected using the predictive capabilities of artificial neural network (ANN) models that leverage correlations within sensor data. Upon defining time instances of fault occurrences in the sensor data, faults are isolated by analyzing the moving average of individual sensor data around the time instances. For fault accommodation, the ANN models are adapted by removing faulty sensors and by using sensor data prior to the occurrence of faults to produce virtual outputs that substitute the faulty sensor data. The proposed adaptive FD approach is validated via two tests using sensor data recorded by an SHM system installed on a railway bridge. The results demonstrate that the proposed approach is capable of ensuring the accuracy, reliability, and performance of real-world SHM systems, in which faults in multiple sensors occur simultaneously.
Appropriateness of Percutaneous Coronary Interventions: A Systematic Review and Meta-Analysis
Authors: Liu Yijie , Chen Yuxiong , Chang Zhen’ge , Han Yitao , Tang Siqi , Zhao Yakun , Fu Jia , Liu Yanbo , Fan Zhongjie
Published: February 2023

Background: Since the foundation of appropriate use criteria (AUC) for coronary revascularization, the proportion of inappropriate (later revised as “rarely inappropriate”) percutaneous coronary interventions (PCIs) varied in different populations. However, the pooled inappropriate PCI rate remains unknown. Methods: We searched the PubMed, Cochrane, Embase, and Sinomed databases for studies related to AUC and PCIs. Studies that reported inappropriate/rarely appropriate PCI rates were included. A random effects model was employed in the meta-analysis because of the high statistical heterogeneity. Results: Thirty-seven studies were included in our study, of which eight studies reported the appropriateness of acute PCIs or PCIs in acute coronary syndrome (ACS) patients, 25 studies reported the appropriateness of non-acute/elective PCIs or PCIs in non-ACS/stable ischemic heart disease (SIHD) patients, and 15 studies reported both acute and non-acute PCIs or did not distinguish the urgency of PCI. The pooled inappropriate PCI rate was 4.3% (95% CI: 2.6–6.4%) in acute scenarios, 8.9% (95% CI: 6.7–11.0%) in non-acute scenarios, and 6.1% (95% CI: 4.9–7.3%) overall. The inappropriate/rarely appropriate PCI rate was significantly higher in non-acute than acute scenarios. No difference in the inappropriate PCI rate was detected based on the study location, the country’s level of development, or the presence of chronic total occlusion (CTO). Conclusions: The worldwide inappropriate PCI rate is generally identical but comparatively high, especially under non-acute scenarios.