bluuebunny/crossref_metadata_2025 huggingface dataset:
Can a Multidisciplinary Weight Loss Treatment Improve Motor Performance in Children with Obesity? Results from an Observational Study
Authors: Gallè Francesca , Valerio Giuliana , Muscariello Espedita , Daniele Ornella , Di Mauro Valentina , Forte Simone , Mastantuono Teresa , Ricchiuti Roberta , Liguori Giorgio , Pecoraro Pierluigi
Published: March 2023

In the last two decades, the relationship between weight status and children’s motor skill competence has been receiving increasing attention, given its possible role in the prevention and treatment of obesity. This study aimed to evaluate the effect of a multidisciplinary obesity treatment on motor performance in a sample of Italian children and adolescents. Visual and auditory reaction time (VRT and ART), vertical jump elevation (VJE) and power (VJP), body mass index (BMI) and BMI-standard deviation score (BMI-SDS), waist circumference (WC), body composition, dietary habits and physical activity (PA) levels were assessed at baseline and at 6- and 12-month follow-up. Significant improvements were observed in BMI-SDS and FFM, diet and PA levels. Adolescents showed significant improvements in VRT and ART. Jump elevation and power increased in both children and adolescent subgroups. Girls exhibited greater changes than boys in both VRT and ART and VJP but lower changes in VJE. VRT improvement was related to age (OR = 0.285, 95%CI 0.098–0.830, p = 0.021) and FFM (OR = 0.255, 95%CI 0.070–0.933, p = 0.039). An increase in VJE was associated with BMI-SDS (OR = 0.158, 95%CI 0.036–0.695, p = 0.015) and with PA level (OR = 19.102, 95%CI 4.442–82.142, p < 0.001); the increase in VJP was related with the increase in PA (OR = 5.564, 95%CI 1.812–17.081, p = 0.003). These findings suggest the possible effects of a multidisciplinary obesity treatment on children’s motor competence. Since the improvement in motor skills can increase children’s motivation and adherence to weight loss treatment in the long term, these aspects should be further investigated.
Application of Artificial Intelligence in Assessing the Self-Management Practices of Patients with Type 2 Diabetes
Authors: Ansari Rashid M. , Harris Mark F. , Hosseinzadeh Hassan , Zwar Nicholas
Published: March 2023

The use of Artificial intelligence in healthcare has evolved substantially in recent years. In medical diagnosis, Artificial intelligence algorithms are used to forecast or diagnose a variety of life-threatening illnesses, including breast cancer, diabetes, heart disease, etc. The main objective of this study is to assess self-management practices among patients with type 2 diabetes in rural areas of Pakistan using Artificial intelligence and machine learning algorithms. Of particular note is the assessment of the factors associated with poor self-management activities, such as non-adhering to medications, poor eating habits, lack of physical activities, and poor glycemic control (HbA1c %). The sample of 200 participants was purposefully recruited from the medical clinics in rural areas of Pakistan. The artificial neural network algorithm and logistic regression classification algorithms were used to assess diabetes self-management activities. The diabetes dataset was split 80:20 between training and testing; 80% (160) instances were used for training purposes and 20% (40) instances were used for testing purposes, while the algorithms’ overall performance was measured using a confusion matrix. The current study found that self-management efforts and glycemic control were poor among diabetes patients in rural areas of Pakistan. The logistic regression model performance was evaluated based on the confusion matrix. The accuracy of the training set was 98%, while the test set’s accuracy was 97.5%; each set had a recall rate of 79% and 75%, respectively. The output of the confusion matrix showed that only 11 out of 200 patients were correctly assessed/classified as meeting diabetes self-management targets based on the values of HbA1c < 7%. We added a wide range of neurons (32 to 128) in the hidden layers to train the artificial neural network models. The results showed that the model with three hidden layers and Adam’s optimisation function achieved 98% accuracy on the validation set. This study has assessed the factors associated with poor self-management activities among patients with type 2 diabetes in rural areas of Pakistan. The use of a wide range of neurons in the hidden layers to train the artificial neural network models improved outcomes, confirming the model’s effectiveness and efficiency in assessing diabetes self-management activities from the required data attributes.
Serious Long-Term Effects of Head and Neck Cancer from the Survivors’ Point of View
Authors: Taylor Katherine J. , Amdal Cecilie D. , Bjordal Kristin , Astrup Guro L. , Herlofson Bente B. , Duprez Fréderic , Gama Ricardo R. , Jacinto Alexandre , Hammerlid Eva , Scricciolo Melissa , Jansen Femke , Verdonck-de Leeuw Irma M. , Fanetti Giuseppe , Guntinas-Lichius Orlando , Inhestern Johanna , Dragan Tatiana , Fabian Alexander , Boehm Andreas , Wöhner Ulrike , Kiyota Naomi , Krüger Maximilian , Bonomo Pierluigi , Pinto Monica , Nuyts Sandra , Silva Joaquim C. , Stromberger Carmen , Tramacere Francesco , Bushnak Ayman , Perotti Pietro , Plath Michaela , Paderno Alberto , Stempler Noa , Kouri Maria , Singer Susanne
Published: March 2023

The long-term problems of head and neck cancer survivors (HNCS) are not well known. In a cross-sectional international study aimed at exploring the long-term quality of life in this population, 1114 HNCS were asked to state their two most serious long-term effects. A clinician recorded the responses during face-to-face appointments. A list of 15 example problems was provided, but a free text field was also available. A total of 1033 survivors responded to the question. The most frequent problems were ‘dry mouth’ (DM) (n = 476; 46%), ‘difficulty swallowing/eating’ (DSE) (n = 408; 40%), ‘hoarseness/difficulty speaking’ (HDS) (n = 169; 16%), and ‘pain in the head and neck’ (PHN) (n = 142; 14%). A total of 5% reported no problems. Logistic regression adjusted for age, gender, treatment, and tumor stage and site showed increased odds of reporting DM and DSE for chemo-radiotherapy (CRT) alone compared to surgery alone (odds ratio (OR): 4.7, 95% confidence interval (CI): 2.5–9.0; OR: 2.1, CI: 1.1–3.9), but decreased odds for HDS and PHN (OR: 0.3, CI: 0.1–0.6; OR: 0.2, CI: 0.1–0.5). Survivors with UICC stage IV at diagnosis compared to stage I had increased odds of reporting HDS (OR: 1.9, CI: 1.2–3.0). Laryngeal cancer survivors had reduced odds compared to oropharynx cancer survivors of reporting DM (OR: 0.4, CI: 0.3–0.6) but increased odds of HDS (OR: 7.2, CI: 4.3–12.3). This study provides evidence of the serious long-term problems among HNCS.
Overview of Materials and Techniques of Paintings by Liu Kang Made between 1927 and 1999 from the National Gallery Singapore and Liu Family Collections
Authors: Lizun Damian , Rogóż Jarosław
Published: March 2023

This article summarises the extensive research conducted in recent years on the paintings by Liu Kang (1911–2004), a renowned modern Singaporean artist. The investigation considered 97 paintings made between 1927 and 1999 from the National Gallery Singapore and Liu family collections. While detailed results of the analytical studies were presented in a series of publications, the scope of this article comprises an overview of the artist’s preferential painting supports and pigments and an outline of the evolution of his working methods. The collected information considerably increases the knowledge about Liu Kang’s painting practice and may assist conservators in the diagnosing, treatment, dating and authentication of artworks of uncertain origin. The results demonstrate the importance of comprehensive multi-analytical studies, which combined with documentary sources and art history research, provide a full understanding of the artist’s painting practice.
Modelling Soil Water Redistribution in Irrigated Japanese Plum (Prunus salicina) Orchards in the Western Cape (South Africa)
Authors: Jovanović Nebojša , Motsei Nonofo , Mashabatu Munashe , Dube Timothy
Published: March 2023

Japanese plum (Prunus salicina) farming in the Western Cape (South Africa) is an important industry for the export market and job creation and is a large water user; however, adequate information on water requirements of this crop is not available in this semi-arid area. The objective of this study was to determine seasonal plum water requirements for the purpose of water use planning and allocation. The study made use of experimental data from four fully bearing, high-yielding plum orchards (cv African Delight and Fortune) in two major plum production regions (Robertson and Wellington). Crop water requirements and the soil water balance were modelled with the physically based HYDRUS-2D model. Seasonal crop water requirements were estimated to be between 524 mm (cv Fortune in Wellington) and 864 mm (cv African Delight in Robertson). Initial basal crop coefficients (Kcb) ranged between 0.98 and 1.01, whilst Kcb for the mid-stage averaged between 1.11 (cv African Delight in Robertson) and 1.18 (cv Fortune in Wellington). Modelling scenarios indicated that soil water redistribution beyond the root zone continues at reduced rates after the soil dries to levels below field capacity. Irrigation management needs to be balanced with other farming practices to reduce leaching and impacts on water resource quality, as well as with the economics of the farm.
Measuring Traffic Congestion with Novel Metrics: A Case Study of Six U.S. Metropolitan Areas
Authors: Seong Jeong , Kim Yunsik , Goh Hyewon , Kim Hyunmin , Stanescu Ana
Published: March 2023

Quantifying traffic congestion is a critical task for transportation planning and research. Numerous metrics have been developed, mainly focusing on changes in vehicle speeds, their extents, and travel time. In this study, new metrics are presented using the Hägerstrand’s space-time cube that has been studied from time geography perspectives since the 1960s. Particularly, the product of distance and time, i.e., distanceTime, is proposed as a base metric to measure traffic congestion amounts. Using the base metric such as mileHours, metrics of weighted congestion and normalized congestion amounts were also developed. New metrics were applied to six metropolitan areas and their vicinities in the United States (Atlanta, Chicago, Washington, D.C. and Baltimore, Dallas and Fort Worth, Los Angeles, and New York), and congestion amounts were calculated and compared. The Google Traffic Layer API was used to obtain traffic congestion datasets for six months (April–September 2022), and GIS (geographic information systems) was used for delineating road features and traffic intensity levels. Among the six areas, New York and its vicinity showed the largest congestion when only heavy congestion was used. Los Angeles and its vicinity showed the largest congestion when all congestion levels were considered. This study shows that the proposed metrics are very effective in summarizing traffic amounts and broadly applicable for further analyses of traffic congestion phenomena by associating various other factors, such as weekdays, months, or gas prices. The new metrics developed in this research may help transportation researchers and practitioners by providing them with a set of metrics applicable to summarizing congestion amounts by synthesizing congestion intensity, extent, and duration.
Modern Microscopic Approaches to Astrocytes
Authors: Morita Mitsuhiro
Published: March 2023

Microscopy started as the histological analysis based on intrinsic optical properties of tissues such as the refractive index and light absorption, and is expanding to include the visualization of organelles by chemical staining, localization of molecules by immunostaining, physiological measurements such as Ca2+ imaging, functional manipulation by optogenetics, and comprehensive analysis of chemical composition by Raman spectra. The microscope is one of the most important tools in neuroscience, which aims to reveal the complex intercellular communications underlying brain function and pathology. Many aspects of astrocytes, including the structures of their fine processes and physiological activities in concert with neurons and blood vessels, were revealed in the course of innovations in modern microscopy. The evolution of modern microscopy is a consequence of breakthroughs in spatiotemporal resolutions and expansions in molecular and physiological targets due to the progress in optics and information technology, as well as the inventions of probes using organic chemistry and molecular biology. This review overviews the modern microscopic approach to astrocytes.
Characterization and Application of the Sugar Transporter Zmo0293 from Zymomonas mobilis
Authors: Zhang Kun , Zhang Wenwen , Qin Mengxing , Li Yi , Wang Hailei
Published: March 2023

Zymomonas mobilis is a natural ethanologen with many desirable characteristics, which makes it an ideal industrial microbial biocatalyst for the commercial production of desirable bioproducts. Sugar transporters are responsible for the import of substrate sugars and the conversion of ethanol and other products. Glucose-facilitated diffusion protein Glf is responsible for facilitating the diffusion of glucose uptake in Z. mobilis. However, another sugar transporter-encoded gene, ZMO0293, is poorly characterized. We employed gene deletion and heterologous expression mediated by the CRISPR/Cas method to investigate the role of ZMO0293. The results showed that deletion of the ZMO0293 gene slowed growth and reduced ethanol production and the activities of key enzymes involved in glucose metabolism in the presence of high concentrations of glucose. Moreover, ZMO0293 deletion caused different transcriptional changes in some genes of the Entner Doudoroff (ED) pathway in the ZM4-ΔZM0293 strain but not in ZM4 cells. The integrated expression of ZMO0293 restored the growth of the glucose uptake-defective strain Escherichia coli BL21(DE3)-ΔptsG. This study reveals the function of the ZMO0293 gene in Z. mobilis in response to high concentrations of glucose and provides a new biological part for synthetic biology.
Sperm RNA Payload: Implications for Intergenerational Epigenetic Inheritance
Authors: Liu Simeiyun , Sharma Upasna
Published: March 2023

There is mounting evidence that ancestral life experiences and environment can influence phenotypes in descendants. The parental environment regulates offspring phenotypes potentially via modulating epigenetic marks in the gametes. Here, we review examples of across-generational inheritance of paternal environmental effects and the current understanding of the role of small RNAs in such inheritance. We discuss recent advances in revealing the small RNA payload of sperm and how environmental conditions modulate sperm small RNAs. Further, we discuss the potential mechanism of inheritance of paternal environmental effects by focusing on sperm small RNA-mediated regulation of early embryonic gene expression and its role in influencing offspring phenotypes.
Impaired Integrated Stress Response and Mitochondrial Integrity Modulate Genotoxic Stress Impact and Lower the Threshold for Immune Signalling
Authors: Temelie Mihaela , Talpur Rubab , Dominguez-Prieto Marta , Dantas Silva Ayanda , Cenusa Constantin , Craciun Liviu , Savu Diana Iulia , Moisoi Nicoleta
Published: March 2023

Mitochondria–nucleus communication during stress dictates cellular fate with consequences on the etiopathology of multiple age-related diseases. Impaired mitochondrial quality control through loss of function of the mitochondrial protease HtrA2 associates with accumulation of damaged mitochondria and triggers the integrated stress response, implicating the transcription factor CHOP. Here we have employed a combined model of impaired mitochondria quality control, namely HtrA2 loss of function, and/or integrated stress response, namely CHOP loss of function, and genotoxicity to address the distinctive roles of these cellular components in modulating intracellular and intercellular responses. The genotoxic agents employed were cancer therapeutic agents such as irradiation with X-ray and protons or treatment with the radiomimetic bleomycin. The irradiation had an enhanced effect in inducing DNA damage in cells with CHOP loss of function, while the bleomycin treatment induced more DNA damage in all the transgenic cells as compared to the control. The genetic modifications impaired the transmission of DNA damage signalling intercellularly. Furthermore, we have dissected the signalling pathways modulated by irradiation in selected genotypes with RNA sequencing analysis. We identified that loss of HtrA2 and CHOP function, respectively, lowers the threshold where irradiation may induce the activation of innate immune responses via cGAS-STING; this may have a significant impact on decisions for combined therapeutic approaches for various diseases.
The Integrity of the Blood–Brain Barrier as a Critical Factor for Regulating Glutamate Levels in Traumatic Brain Injury
Authors: Boyko Matthew , Gruenbaum Benjamin F. , Frank Dmitry , Natanel Dmitry , Negev Shahar , Azab Abed N. , Barsky Guy , Knyazer Boris , Kofman Ora , Zlotnik Alexander
Published: March 2023

A healthy blood–brain barrier (BBB) shields the brain from high concentrations of blood glutamate, which can cause neurotoxicity and neurodegeneration. It is believed that traumatic brain injury (TBI) causes long-term BBB disruption, subsequently increasing brain glutamate in the blood, in addition to increased glutamate resulting from the neuronal injury. Here, we investigate the relationship between blood and brain glutamate levels in the context of BBB permeability. Rats exposed to BBB disruption through an osmotic model or TBI and treated with intravenous glutamate or saline were compared to control rats with an intact BBB treated with intravenous glutamate or saline. After BBB disruption and glutamate administration, the concentrations of glutamate in the cerebrospinal fluid and blood and brain tissue were analyzed. The results showed a strong correlation between the brain and blood glutamate concentrations in the groups with BBB disruption. We conclude that a healthy BBB protects the brain from high levels of blood glutamate, and the permeability of the BBB is a vital component in regulating levels of glutamate in the brain. These findings bring a new approach to treating the consequences of TBI and other diseases where long-term disruption of the BBB is the central mechanism of their development.
Genome-Wide Identification and Expression Analysis of the Cytochrome P450 Gene Family in Bemisia tabaci MED and Their Roles in the Insecticide Resistance
Authors: Qin Penghao , Zheng Haoyuan , Tao Yunli , Zhang Youjun , Chu Dong
Published: March 2023

The whitefly, Bemisia tabaci MED (Hemiptera: Aleyrodidae), is an omnivorous agricultural pest, which causes huge economic losses to agriculture and is highly resistant to many pesticides. The overexpression of cytochrome P450 may play an important role in host adaptation and insecticide resistance in B. tabaci MED. Therefore, the present study systematically analyzed the cytochrome P450 gene family at the genome-wide level to understand its function in B. tabaci MED. Our analysis identified 58 cytochrome P450 genes in B. tabaci MED, among which 24 were novel. Phylogenetic analysis revealed broad functional and species-specific diversification in B. tabaci MED P450, suggesting the role of multiple P450 genes in detoxifying. Reverse transcription-real time quantitative PCR (RT-qPCR) showed that CYP4CS2, CYP4CS5, CYP4CS6, CYP4CS8, CYP6DW4, CYP6DW5, CYP6DW6, CYP6DZ8, and CYP6EN1 genes increased significantly after two days of exposure to imidacloprid. Interestingly, all nine genes belonged to the CYP4 and CYP6 families. A decrease in the expression of five genes (CYP6DW4, CYP6DW5, CYP6DW6, CYP6DZ8, and CYP4CS6) via RNA interference (RNAi) resulted in a significant increase in the mortalities of whiteflies when exposed to imidacloprid. These results indicate that the overexpression of the P450 genes may play an essential role in imidacloprid tolerance of B. tabaci MED. Thus, the present study provides basic information on P450 genes in B. tabaci MED, which will further help elucidate the insecticide resistance mechanism in the agricultural pest whitefly.
Lactate Dehydrogenase Superfamily in Rice and Arabidopsis: Understanding the Molecular Evolution and Structural Diversity
Authors: Chatterjee Yajnaseni , Bhowal Bidisha , Gupta Kapuganti Jagadis , Pareek Ashwani , Singla-Pareek Sneh Lata
Published: March 2023

Lactate/malate dehydrogenases (Ldh/Maldh) are ubiquitous enzymes involved in the central metabolic pathway of plants and animals. The role of malate dehydrogenases in the plant system is very well documented. However, the role of its homolog L-lactate dehydrogenases still remains elusive. Though its occurrence is experimentally proven in a few plant species, not much is known about its role in rice. Therefore, a comprehensive genome-wide in silico investigation was carried out to identify all Ldh genes in model plants, rice and Arabidopsis, which revealed Ldh to be a multigene family encoding multiple proteins. Publicly available data suggest its role in a wide range of abiotic stresses such as anoxia, salinity, heat, submergence, cold and heavy metal stress, as also confirmed by our qRT-PCR analysis, especially in salinity and heavy metal mediated stresses. A detailed protein modelling and docking analysis using Schrodinger Suite reveals the presence of three putatively functional L-lactate dehydrogenases in rice, namely OsLdh3, OsLdh7 and OsLdh9. The analysis also highlights the important role of Ser-219, Gly-220 and His-251 in the active site geometry of OsLdh3, OsLdh7 and OsLdh9, respectively. In fact, these three genes have also been found to be highly upregulated under salinity, hypoxia and heavy metal mediated stresses in rice.
Alteration of Gut Microbes in Benign Prostatic Hyperplasia Model and Finasteride Treatment Model
Authors: An Jinho , Song Youngcheon , Kim Sangbum , Kong Hyunseok , Kim Kyungjae
Published: March 2023

Gut microbes are closely associated with disease onset and improvement. However, the effects of gut microbes on the occurrence, prevention, and treatment of benign prostatic hyperplasia (BPH) are still unclear. We investigated the alteration of gut microbiota with implications for the diagnosis, prevention, and treatment of BPH and identified correlations among various indicators, including hormone indicators, apoptosis markers in BPH, and finasteride treatment models. BPH induction altered the abundance of Lactobacillus, Flavonifractor, Acetatifactor, Oscillibacter, Pseudoflavonifractor, Intestinimonas, and Butyricimonas genera, which are related to BPH indicators. Among these, the altered abundance of Lactobacillus and Acetatifactor was associated with the promotion and inhibition of prostate apoptosis, respectively. Finasteride treatment altered the abundance of Barnesiella, Acetatifactor, Butyricimonas, Desulfovibrio, Anaerobacterium, and Robinsoniella genera, which are related to BPH indicators. Among these, altered abundances of Desulfovibrio and Acetatifactor were associated with the promotion and inhibition of prostate apoptosis, respectively. In addition, the abundances of Lactobacillus and Acetatifactor were normalized after finasteride treatment. In conclusion, the association between apoptosis and altered abundances of Lactobacillus and Acetatifactor, among other gut microbes, suggests their potential utility in the diagnosis, prevention, and treatment of BPH.
Antiretroviral Treatment of HIV-2 Infection: Available Drugs, Resistance Pathways, and Promising New Compounds
Authors: Moranguinho Inês , Taveira Nuno , Bártolo Inês
Published: March 2023

Currently, it is estimated that 1–2 million people worldwide are infected with HIV-2, accounting for 3–5% of the global burden of HIV. The course of HIV-2 infection is longer compared to HIV-1 infection, but without effective antiretroviral therapy (ART), a substantial proportion of infected patients will progress to AIDS and die. Antiretroviral drugs in clinical use were designed for HIV-1 and, unfortunately, some do not work as well, or do not work at all, for HIV-2. This is the case for non-nucleoside reverse transcriptase inhibitors (NNRTIs), the fusion inhibitor enfuvirtide (T-20), most protease inhibitors (PIs), the attachment inhibitor fostemsavir and most broadly neutralizing antibodies. Integrase inhibitors work well against HIV-2 and are included in first-line therapeutic regimens for HIV-2-infected patients. However, rapid emergence of drug resistance and cross-resistance within each drug class dramatically reduces second-line treatment options. New drugs are needed to treat infection with drug-resistant isolates. Here, we review the therapeutic armamentarium available to treat HIV-2-infected patients, as well as promising drugs in development. We also review HIV-2 drug resistance mutations and resistance pathways that develop in HIV-2-infected patients under treatment.
Ovarian Stimulation in Mice Resulted in Abnormal Placentation through Its Effects on Proliferation and Cytokine Production of Uterine NK Cells
Authors: Ma Rong , Jin Ni , Lei Hui , Dong Jie , Xiong Yujing , Qian Chenxi , Chen Shuqiang , Wang Xiaohong
Published: March 2023

Ovarian stimulation is associated with an increased incidence of abnormal placentation. Uterine natural killer (uNK) cells are the major subpopulation of decidual immune cells, which are crucial for placentation. In a previous study, we found that ovarian stimulation impairs uNK cell density on gestation day (GD) 8.5 in mice. However, it was not clear how ovarian stimulation led to a reduction in the density of uNK cells. In this study, we constructed two mouse models, an in vitro mouse embryo transfer model and an estrogen-stimulated mouse model. We used HE and PAS glycogen staining, immunohistochemical techniques, q-PCR, Western blot, and flow cytometry to analyze the mouse decidua and placenta, and the results showed that SO resulted in a fetal weight reduction, abnormal placental morphology, decreased placental vascular density, and abnormal density and function of uNK cells. Our results suggest that ovarian stimulation resulted in aberrant estrogen signaling and may contribute to the disorder of uNK cells caused by ovarian stimulation. Together, these results provide new insights into the mechanisms of aberrant maternal endocrine environments and abnormal placentation.
Computational Approaches Drive Developments in Immune-Oncology Therapies for PD-1/PD-L1 Immune Checkpoint Inhibitors
Authors: Sobral Patrícia S. , Luz Vanessa C. C. , Almeida João M. G. C. F. , Videira Paula A. , Pereira Florbela
Published: March 2023

Computational approaches in immune-oncology therapies focus on using data-driven methods to identify potential immune targets and develop novel drug candidates. In particular, the search for PD-1/PD-L1 immune checkpoint inhibitors (ICIs) has enlivened the field, leveraging the use of cheminformatics and bioinformatics tools to analyze large datasets of molecules, gene expression and protein–protein interactions. Up to now, there is still an unmet clinical need for improved ICIs and reliable predictive biomarkers. In this review, we highlight the computational methodologies applied to discovering and developing PD-1/PD-L1 ICIs for improved cancer immunotherapies with a greater focus in the last five years. The use of computer-aided drug design structure- and ligand-based virtual screening processes, molecular docking, homology modeling and molecular dynamics simulations methodologies essential for successful drug discovery campaigns focusing on antibodies, peptides or small-molecule ICIs are addressed. A list of recent databases and web tools used in the context of cancer and immunotherapy has been compilated and made available, namely regarding a general scope, cancer and immunology. In summary, computational approaches have become valuable tools for discovering and developing ICIs. Despite significant progress, there is still a need for improved ICIs and biomarkers, and recent databases and web tools have been compiled to aid in this pursuit.
Glioblastoma-Derived Small Extracellular Vesicles: Nanoparticles for Glioma Treatment
Authors: Araujo-Abad Salomé , Manresa-Manresa Antonio , Rodríguez-Cañas Enrique , Fuentes-Baile María , García-Morales Pilar , Mallavia Ricardo , Saceda Miguel , de Juan Romero Camino
Published: March 2023

Glioblastoma (GBM), characterized by fast growth and invasion into adjacent tissue, is the most aggressive cancer of brain origin. Current protocols, which include cytotoxic chemotherapeutic agents, effectively treat localized disease; however, these aggressive therapies present side effects due to the high doses administered. Therefore, more efficient ways of drug delivery have been studied to reduce the therapeutic exposure of the patients. We have isolated and fully characterized small extracellular vesicles (EVs) from seven patient-derived GBM cell lines. After loading them with two different drugs, Temozolomide (TMZ) and EPZ015666, we observed a reduction in the total amount of drugs needed to trigger an effect on tumor cells. Moreover, we observed that GBM-derived small EVs, although with lower target specificity, can induce an effect on pancreatic cancer cell death. These results suggest that GBM-derived small EVs represent a promising drug delivery tool for further preclinical studies and potentially for the clinical development of GBM treatments.
Retinal Organoids from an AIPL1 CRISPR/Cas9 Knockout Cell Line Successfully Recapitulate the Molecular Features of LCA4 Disease
Authors: Perdigão Pedro R. L. , Ollington Bethany , Sai Hali , Leung Amy , Sacristan-Reviriego Almudena , van der Spuy Jacqueline
Published: March 2023

Aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1) is expressed in photoreceptors where it facilitates the assembly of phosphodiesterase 6 (PDE6) which hydrolyses cGMP within the phototransduction cascade. Genetic variations in AIPL1 cause type 4 Leber congenital amaurosis (LCA4), which presents as rapid loss of vision in early childhood. Limited in vitro LCA4 models are available, and these rely on patient-derived cells harbouring patient-specific AIPL1 mutations. While valuable, the use and scalability of individual patient-derived LCA4 models may be limited by ethical considerations, access to patient samples and prohibitive costs. To model the functional consequences of patient-independent AIPL1 mutations, CRISPR/Cas9 was implemented to produce an isogenic induced pluripotent stem cell line harbouring a frameshift mutation in the first exon of AIPL1. Retinal organoids were generated using these cells, which retained AIPL1 gene transcription, but AIPL1 protein was undetectable. AIPL1 knockout resulted in a decrease in rod photoreceptor-specific PDE6α and β, and increased cGMP levels, suggesting downstream dysregulation of the phototransduction cascade. The retinal model described here provides a novel platform to assess functional consequences of AIPL1 silencing and measure the rescue of molecular features by potential therapeutic approaches targeting mutation-independent pathogenesis.
Editorial of Special Issue “Molecular Mechanisms of Natural Products and Phytochemicals in Immune Cells and Asthma”
Authors: Lee Young-Cheol
Published: March 2023

The Special Issue “Molecular Mechanisms of Natural Products and Phytochemicals in Immune Cells and Asthma” in the International Journal of Molecular Sciences includes original research and reviews on the molecular mechanisms of active, natural products (medicinal plants and animal ones) and phytochemicals in vitro and in vivo [...]
Alpha Synuclein: Neurodegeneration and Inflammation
Authors: Forloni Gianluigi
Published: March 2023

Alpha-Synuclein (α-Syn) is one of the most important molecules involved in the pathogenesis of Parkinson’s disease and related disorders, synucleinopathies, but also in several other neurodegenerative disorders with a more elusive role. This review analyzes the activities of α-Syn, in different conformational states, monomeric, oligomeric and fibrils, in relation to neuronal dysfunction. The neuronal damage induced by α-Syn in various conformers will be analyzed in relation to its capacity to spread the intracellular aggregation seeds with a prion-like mechanism. In view of the prominent role of inflammation in virtually all neurodegenerative disorders, the activity of α-Syn will also be illustrated considering its influence on glial reactivity. We and others have described the interaction between general inflammation and cerebral dysfunctional activity of α-Syn. Differences in microglia and astrocyte activation have also been observed when in vivo the presence of α-Syn oligomers has been combined with a lasting peripheral inflammatory effect. The reactivity of microglia was amplified, while astrocytes were damaged by the double stimulus, opening new perspectives for the control of inflammation in synucleinopathies. Starting from our studies in experimental models, we extended the perspective to find useful pointers to orient future research and potential therapeutic strategies in neurodegenerative disorders.
Investigation of the Presence of DNA in Human Blood Plasma Small Extracellular Vesicles
Authors: Lichá Kristína , Pastorek Michal , Repiská Gabriela , Celec Peter , Konečná Barbora
Published: March 2023

Extracellular DNA (ecDNA) is DNA outside of cells, which is a result of various mechanisms. EcDNA is believed to be a cause of various pathogeneses as well as their potential biomarker. EcDNA is believed to also be part of small extracellular vesicles (sEVs) from cell cultures. If ecDNA is present in sEVs in plasma, their membrane may protect it from degradation by deoxyribonucleases. Moreover, sEVs play a role in the intercellular communication, and they can therefore transfer ecDNA between cells. The aim of this study was to investigate the presence of ecDNA in sEVs isolated from fresh human plasma by the ultracentrifugation and density gradient, which serves to exclude the co-isolation of non-sEVs compartments. The novelty of the current study is the investigation of the localization and subcellular origin of the ecDNA associated with sEVs in plasma, as well as the estimation of the approximate concentration. The cup-shaped sEVs were confirmed by transmission electron microscopy. The highest concentration of particles was in the size of 123 nm. The presence of the sEVs markers CD9 and TSG101 was confirmed by western blot. It was found that 60–75% of DNA is on the surface of sEVs, but a part of the DNA is localized inside the sEVs. Moreover, both nuclear and mitochondrial DNA were present in plasma EVs. Further studies should focus on the potential harmful autoimmune effect of DNA carried by plasma EVs or specifically sEVs.
Hypophysitis: Defining Histopathologic Variants and a Review of Emerging Clinical Causative Entities
Authors: Rawanduzy Cameron A. , Winkler-Schwartz Alexander , Couldwell William T.
Published: March 2023

Inflammatory disease of the pituitary gland is known as hypophysitis. There are multiple histological subtypes, the most common being lymphocytic, and the pathogenesis is variable and diverse. Hypophysitis can be primary and idiopathic or autoimmune related, or secondary to local lesions, systemic disease, medications, and more. Although hypophysitis was previously accepted as an exceedingly rare diagnosis, a greater understanding of the disease process and new insights into possible etiologic sources have contributed to an increased frequency of recognition. This review provides an overview of hypophysitis, its causes, and detection strategies and management.
Dietary Protection against Cognitive Impairment, Neuroinflammation and Oxidative Stress in Alzheimer’s Disease Animal Models of Lipopolysaccharide-Induced Inflammation
Authors: Decandia Davide , Gelfo Francesca , Landolfo Eugenia , Balsamo Francesca , Petrosini Laura , Cutuli Debora
Published: March 2023

Alzheimer’s disease (AD) is a rapidly growing epidemic with a heavy social and economic burden. Evidence suggests that systemic inflammation, dysregulation of the immune response and the resulting neuroinflammation and neurodegeneration play a significant role in AD pathogenesis. Currently, given that there is no fully convincing cure for AD, the interest in lifestyle factors (such as diet), which potentially delay onset and reduce the severity of symptoms, is increasing. This review is aimed at summarizing the effects of dietary supplementation on cognitive decline, neuroinflammation and oxidative stress in AD-like animal models with a focus on neuroinflammation induced by lipopolysaccharide (LPS) injection, which mimics systemic inflammation in animals. The compounds reviewed include curcumin, krill oil, chicoric acid, plasmalogens, lycopene, tryptophan-related dipeptides, hesperetin and selenium peptides. Despite the heterogeneity of these compounds, there is a strong consensus on their counteracting action on LPS-induced cognitive deficits and neuroinflammatory responses in rodents by modulating cell-signaling processes, such as the NF-κB pathway. Overall, dietary interventions could represent an important resource to oppose AD due to their influence in neuroprotection and immune regulation.
Starvation Induces Extracellular Accumulation of Polyphosphate in Dictyostelium discoideum to Inhibit Macropinocytosis, Phagocytosis, and Exocytosis
Authors: Rijal Ramesh , Ismail Issam , Jing Shiyu , Gomer Richard H.
Published: March 2023

Dictyostelium discoideum is a soil-dwelling unicellular eukaryote that accumulates extracellular polyphosphate (polyP). At high cell densities, when the cells are about to overgrow their food supply and starve, the corresponding high extracellular concentrations of polyP allow the cells to preemptively anticipate starvation, inhibit proliferation, and prime themselves to begin development. In this report, we show that starved D. discoideum cells accumulate cell surface and extracellular polyP. Starvation reduces macropinocytosis, exocytosis, and phagocytosis, and we find that these effects require the G protein-coupled polyP receptor (GrlD) and two enzymes, Polyphosphate kinase 1 (Ppk1), which is required for synthesizing intracellular polyP, cell surface polyP, and some of the extracellular polyP, and Inositol hexakisphosphate kinase (I6kA), which is required for cell surface polyP and polyP binding to cells, and some of the extracellular polyP. PolyP reduces membrane fluidity, and we find that starvation reduces membrane fluidity; this effect requires GrlD and Ppk1, but not I6kA. Together, these data suggest that in starved cells, extracellular polyP decreases membrane fluidity, possibly as a protective measure. In the starved cells, sensing polyP appears to decrease energy expenditure from ingestion, and decrease exocytosis, and to both decrease energy expenditures and retain nutrients.
A Systematic Review on the Risk Modulators of Myocardial Infarction in the “Young”—Implications of Lipoprotein (a)
Authors: Stătescu Cristian , Anghel Larisa , Benchea Laura-Cătălina , Tudurachi Bogdan-Sorin , Leonte Andreea , Zăvoi Alexandra , Zota Ioana Mădălina , Prisacariu Cristina , Radu Rodica , Șerban Ionela-Lăcrămioara , Sascău Radu Andy
Published: March 2023

The presence of a myocardial infarction at a younger age is of special interest, considering the psychological and socioeconomic impact, as well as long-term morbidity and mortality. However, this group has a unique risk profile, with less traditional cardiovascular risk factors that are not well studied. This systematic review aims to evaluate traditional risk factors of myocardial infarction in the “young”, highlighting the clinical implications of lipoprotein (a). We performed a comprehensive search using Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) standards; we systematically searched the PubMed, EMBASE, and Science Direct Scopus databases, using the terms: “myocardial infarction”, “young”, “lipoprotein (a)”, “low-density lipoprotein”, “risk factors”. The search identified 334 articles which were screened, and, at the end, 9 original research articles regarding the implications of lipoprotein (a) in myocardial infarction in the “young” were included in the qualitative synthesis. Elevated lipoprotein (a) levels were independently associated with an increased risk of coronary artery disease, especially in young patients, where this risk increased by threefold. Thus, it is recommended to measure the lipoprotein (a) levels in individuals with suspected familial hypercholesterolaemia or with premature atherosclerotic cardiovascular disease and no other identifiable risk factors, in order to identify patients who might benefit from a more intensive therapeutic approach and follow-up.
Exploring the Role of a Novel Interleukin-17 Homolog from Invertebrate Marine Mussel Mytilus coruscus in Innate Immune Response: Is Negative Regulation by Mc-Novel_miR_145 the Key?
Authors: Chen Xinglu , Qiu Longmei , Si Xirui , Zhang Xiaolin , Guo Baoying , Liao Zhi , Yan Xiaojun , Qi Pengzhi
Published: March 2023

Interleukin-17 (IL-17) represents a class of proinflammatory cytokines involved in chronic inflammatory and degenerative disorders. Prior to this study, it was predicted that an IL-17 homolog could be targeted by Mc-novel_miR_145 to participate in the immune response of Mytilus coruscus. This study employed a variety of molecular and cell biology research methods to explore the association between Mc-novel_miR_145 and IL-17 homolog and their immunomodulatory effects. The bioinformatics prediction confirmed the affiliation of the IL-17 homolog with the mussel IL-17 family, followed by quantitative real-time PCR assays (qPCR) to demonstrate that McIL-17-3 was highly expressed in immune-associated tissues and responded to bacterial challenges. Results from luciferase reporter assays confirmed the potential of McIL-17-3 to activate downstream NF-κb and its targeting by Mc-novel_miR_145 in HEK293 cells. The study also produced McIL-17-3 antiserum and found that Mc-novel_miR_145 negatively regulates McIL-17-3 via western blotting and qPCR assays. Furthermore, flow cytometry analysis indicated that Mc-novel_miR_145 negatively regulated McIL-17-3 to alleviate LPS-induced apoptosis. Collectively, the current results showed that McIL-17-3 played an important role in molluscan immune defense against bacterial attack. Furthermore, McIL-17-3 was negatively regulated by Mc-novel_miR_145 to participate in LPS-induced apoptosis. Our findings provide new insights into noncoding RNA regulation in invertebrate models.
The Concordant Disruption of B7/CD28 Immune Regulators Predicts the Prognosis of Oral Carcinomas
Authors: Chang Shi-Rou , Chou Chung-Hsien , Liu Chung-Ji , Lin Yu-Cheng , Tu Hsi-Feng , Chang Kuo-Wei , Lin Shu-Chun
Published: March 2023

Immune modulation is a critical factor in determining the survival of patients with malignancies, including those with oral squamous cell carcinoma (OSCC) and head and neck SCC (HNSCC). Immune escape or stimulation may be driven by the B7/CD28 family and other checkpoint molecules, forming ligand–receptor complexes with immune cells in the tumor microenvironment. Since the members of B7/CD28 can functionally compensate for or counteract each other, the concomitant disruption of multiple members of B7/CD28 in OSCC or HNSCC pathogenesis remains elusive. Transcriptome analysis was performed on 54 OSCC tumors and 28 paired normal oral tissue samples. Upregulation of CD80, CD86, PD-L1, PD-L2, CD276, VTCN1, and CTLA4 and downregulation of L-ICOS in OSCC relative to the control were noted. Concordance in the expression of CD80, CD86, PD-L1, PD-L2, and L-ICOS with CD28 members was observed across tumors. Lower ICOS expression indicated a worse prognosis in late-stage tumors. Moreover, tumors harboring higher PD-L1/ICOS, PD-L2/ICOS, or CD276/ICOS expression ratios had a worse prognosis. The survival of node-positive patients was further worsened in tumors exhibiting higher ratios between PD-L1, PD-L2, or CD276 and ICOS. Alterations in T cell, macrophage, myeloid dendritic cell, and mast cell populations in tumors relative to controls were found. Decreased memory B cells, CD8+ T cells, and Tregs, together with increased resting NK cells and M0 macrophages, occurred in tumors with a worse prognosis. This study confirmed frequent upregulation and eminent co-disruption of B7/CD28 members in OSCC tumors. The ratio between PD-L2 and ICOS is a promising survival predictor in node-positive HNSCC patients.
Human Factors in Leveraging Systems Science to Shape Public Policy for Obesity: A Usability Study
Authors: Giabbanelli Philippe J. , Vesuvala Chirag X.
Published: March 2023

Background: despite a broad consensus on their importance, applications of systems thinking in policymaking and practice have been limited. This is partly caused by the longstanding practice of developing systems maps and software in the intention of supporting policymakers, but without knowing their needs and practices. Objective: we aim to ensure the effective use of a systems mapping software by policymakers seeking to understand and manage the complex system around obesity, physical, and mental well-being. Methods: we performed a usability study with eight policymakers in British Columbia based on a software tool (ActionableSystems) that supports interactions with a map of obesity. Our tasks examine different aspects of systems thinking (e.g., unintended consequences, loops) at several levels of mastery and cover common policymaking needs (identification, evaluation, understanding). Video recordings provided quantitative usability metrics (correctness, time to completion) individually and for the group, while pre- and post-usability interviews yielded qualitative data for thematic analysis. Results: users knew the many different factors that contribute to mental and physical well-being in obesity; however, most were only familiar with lower-level systems thinking concepts (e.g., interconnectedness) rather than higher-level ones (e.g., feedback loops). Most struggles happened at the lowest level of the mastery taxonomy, and predominantly on network representation. Although participants completed tasks on loops and multiple pathways mostly correctly, this was at the detriment of spending significant time on these aspects. Results did not depend on the participant, as their experiences with the software were similar. The thematic analysis revealed that policymakers did not have a typical workflow and did not use any special software or tools in their policy work; hence, the integration of a new tool would heavily depend on individual practices. Conclusions: there is an important discrepancy between what constitutes systems thinking to policymakers and what parts of systems thinking are supported by software. Tools may be more successfully integrated when they include tutorials (e.g., case studies), facilitate access to evidence, and can be linked to a policymaker’s portfolio.
A Reference Architecture for Enabling Interoperability and Data Sovereignty in the Agricultural Data Space
Authors: Falcão Rodrigo , Matar Raghad , Rauch Bernd , Elberzhager Frank , Koch Matthias
Published: March 2023

Agriculture is one of the major sectors of the global economy and also a software-intensive domain. The digital landscape of agriculture is composed of multiple digital ecosystems, which together constitute an agricultural domain ecosystem, also referred to as the “Agricultural Data Space’’ (ADS). As the domain is so huge, there are several sub-domains and specialized solutions, and each of them poses challenges to interoperability. Additionally, farmers have increasing concerns about data sovereignty. In the context of the research project COGNAC, we elicited architecture drivers for interoperability and data sovereignty in agriculture and designed a reference architecture of a platform that aims to address these qualities in the ADS. In this paper, we present the solution concepts and design decisions that characterize the reference architecture. Early prototypes have been developed and made available to support the validation of the concept.