bluuebunny/crossref_metadata_2025 huggingface dataset:
A Splicing Variant in RDH8 Is Associated with Autosomal Recessive Stargardt Macular Dystrophy
Authors: Zampatti Stefania , Peconi Cristina , Calvino Giulia , Ferese Rosangela , Gambardella Stefano , Cascella Raffaella , Sebastiani Jacopo , Falsini Benedetto , Cusumano Andrea , Giardina Emiliano
Published: August 2023

Stargardt macular dystrophy is a genetic disorder, but in many cases, the causative gene remains unrevealed. Through a combined approach (whole-exome sequencing and phenotype/family-driven filtering algorithm) and a multilevel validation (international database searching, prediction scores calculation, splicing analysis assay, segregation analyses), a biallelic mutation in the RDH8 gene was identified to be responsible for Stargardt macular dystrophy in a consanguineous Italian family. This paper is a report on the first family in which a biallelic deleterious mutation in RDH8 is detected. The disease phenotype is consistent with the expected phenotype hypothesized in previous studies on murine models. The application of the combined approach to genetic data and the multilevel validation allowed the identification of a splicing mutation in a gene that has never been reported before in human disorders.
A Cross-Sectional Study of Oral Health Status and Behavioral Risk Indicators among Non-Smoking and Currently Smoking Lithuanian Adolescents
Authors: Petrauskienė Sandra , Žemaitienė Miglė , Bendoraitienė Eglė Aida , Saldūnaitė-Mikučionienė Kristina , Vasiliauskienė Ingrida , Zūbienė Jūratė , Andruškevičienė Vilija , Slabšinskienė Eglė
Published: August 2023

The purpose of this study was to evaluate oral health status, behavioral risk indicators, and the impact of smoking on oral health among Lithuanian adolescents. This representative cross-sectional study was conducted among 15-year-old Lithuanian adolescents. The method of multistage cluster sampling was used. A total of 1127 adolescents met the inclusion criteria. Two originally created self-reported questionnaires were used in this study. Dental caries, periodontal status, and oral hygiene status were evaluated by four trained researchers. A p-value ≤ 0.05 was set to indicate statistically significant differences. Statistical analysis included Mann–Whitney, Kruskal–Wallis, and Spearman correlation tests. Out of all the participants, 9.6% self-reported being a current tobacco smoker. The mean PI value was 1.14 ± 0.69 among all the participants. Currently smoking adolescents had more active caries lesions (D-S) than those who did not smoke (13.2 ± 16.4 vs. 9.8 ± 10.7, p = 0.023). Considering periodontal status, non-smoking adolescents had significantly lower mean PSR index scores than current smokers (0.52 ± 0.51 vs. 0.61 ± 0.50, p = 0.0298). Tobacco smoking and the consumption of energy drinks were significantly associated (OR = 3.74, 95% CI 2.66–5.26, p < 0.001) among participants. Currently smoking adolescents tended to have improper dietary habits, especially a higher consumption of energy drinks; thus, they were more likely to have active dental caries lesions, as well as poorer periodontal status, than their non-smoking peers.
From ToyBox Study to eToyBox: Advancing Childhood Obesity Reduction in Malaysian Kindergartens
Authors: Reeves Sue , Poh Bee Koon , Chong Yi Ting , Lee Julia Ai Cheng , Cheah Whye Lian , Hafizah Yatiman Noor , Nelson Georgia , Ruzita Abd Talib , Koh Denise , Summerbell Carolyn , Essau Cecilia A. , Gibson Edward Leigh
Published: August 2023

Prevention and treatment of childhood obesity is a global concern, and in Malaysia, it is considered a national public health priority. Determinants of childhood obesity are multifactorial and include factors that directly and indirectly influence energy balance-related behaviours, including energy intake and energy expenditure. Interventions to address childhood obesity that have multiple components at different levels have been shown to be the most influential. The ToyBox-study is a childhood obesity intervention aimed at preschool-aged children and their families that had been shown to be effective in several European countries and so was chosen for adaption for the Malaysian setting. Materials were translated and adjusted for the Malaysian context and audience and implemented in kindergartens in Peninsular Malaysia and Sarawak. However, during the COVID-19 pandemic and lockdown, teaching transitioned to being online. This brought an opportunity to reach a wider audience and consider the long-term sustainability of the intervention, and thus eToybox was born. eToybox aims to bring support for healthy energy balance behaviours directly to the teachers, into kindergartens and homes, to encourage families to be active and eat healthily, and prevent or reduce obesity. Through online innovation, the Toybox Study Malaysia programme has been expanded to enhance its potential to impact the promotion of healthy lifestyles among preschoolers and their families, highlighting the importance of a holistic approach to preventing and treating childhood obesity in Malaysia.
How People’s COVID-19 Induced-Worries and Multiple Environmental Exposures Are Associated with Their Depression, Anxiety, and Stress during the Pandemic
Authors: Huang Jianwei , Kwan Mei-Po , Tse Lap Ah , He Sylvia Y.
Published: August 2023

This study investigates how people’s perceived COVID-19 risk, worries about financial hardship, job loss, and family conflicts, and exposures to greenspace, PM2.5, and noise (in people’s residential neighborhoods and daily activity locations) are related to their depression, anxiety, and stress during the COVID-19 pandemic. Using a two-day activity-travel diary, a questionnaire, and real-time air pollutant and noise sensors, a survey was conducted to collect data from 221 participants living in two residential neighborhoods of Hong Kong during the COVID-19 pandemic. Linear regression was conducted to explore the relationships. Significant associations between people’s COVID-19-related worries and exposures to grassland and PM2.5 with depression, anxiety, and stress were found in the results. These associations with depression, anxiety, and stress vary depending on people’s demographic attributes. These results can help direct the public authorities’ efforts in dealing with the public mental health crisis during the COVID-19 pandemic.
Fell on Black Days: Analyzing the Song Lyrics of Chris Cornell for Insight into Depression and Suicide
Authors: Conway Kevin P. , McGrain Patrick , Theodory Michelle
Published: August 2023

Chris Cornell was a guitarist, singer, songwriter, and pioneer of grunge music. Cornell struggled with mental illness and addiction and incorporated these themes into his song lyrics. At age 52, Cornell died by suicide in his hotel bathroom following a live performance. This mixed-methods study examines Cornell’s song lyrics for references to negative words and themes related to depression and suicide. Two coders independently reviewed lyrical transcripts to identify the primary theme, secondary theme(s), and valence (positive or negative). Sentiment analysis, a natural language processing technique, was used to examine word frequency and valence. Songs (N = 215) were predominantly (79%) negative and contained more negative (N = 3244, 56.1%) than positive (N = 2537, 43.9%) words. Thematic analysis by stage of career shows a narrowing focus on depression, failed relationships, and morbid thoughts. Themes of depressed mood, death, and suicide were common and increased by stage of career. By applying qualitative and quantitative techniques to song lyrics, this study revealed that Cornell’s songs reflect a narrative of negativity consistent with someone experiencing depression and thoughts of death and suicide. Like personal notes and poems, song lyrics may reflect symptoms of depression and suicidal thoughts warranting clinical attention.
Old Mine Map Georeferencing: Case of Marsigli’s 1696 Map of the Smolník Mines
Authors: Hvizdák Ladislav , Tometzová Dana , Iannaccone Barbora , Šoltésová Marieta , Domaracká Lucia , Kyšeľa Kamil
Published: August 2023

Historical maps represent a unique and irreplaceable source of information about the history of a country, be it large (historical) regions, individual geomorphological units or specifically defined sites. Using a methodologically correct, critical historical analysis, old maps provide both the horizontal and vertical analysis of a landscape and its transformation in different time periods. These maps represent some of the oldest, but relatively easily accessible, historical pictorial documents (plausibly) depicting historical landscapes. This study provides the methodology for processing and georeferencing old mine maps with the possibility of their further use for the purposes of mining tourism. The 1696 Marsigli mine map has been chosen for the case study in question. It depicts a cross-section of the copper mines in Smolník and shows in detail the process of cementation water mining. Through an analysis and a detailed study, two-dimensional parts of a georeferenced historical map have been plotted in Google Earth’s three-dimensional space.
SASTGCN: A Self-Adaptive Spatio-Temporal Graph Convolutional Network for Traffic Prediction
Authors: Li Wei , Zhan Xi , Liu Xin , Zhang Lei , Pan Yu , Pan Zhisong
Published: August 2023

Traffic prediction plays a significant part in creating intelligent cities such as traffic management, urban computing, and public safety. Nevertheless, the complex spatio-temporal linkages and dynamically shifting patterns make it somewhat challenging. Existing mainstream traffic prediction approaches heavily rely on graph convolutional networks and sequence prediction methods to extract complicated spatio-temporal patterns statically. However, they neglect to account for dynamic underlying correlations and thus fail to produce satisfactory prediction results. Therefore, we propose a novel Self-Adaptive Spatio-Temporal Graph Convolutional Network (SASTGCN) for traffic prediction. A self-adaptive calibrator, a spatio-temporal feature extractor, and a predictor comprise the bulk of the framework. To extract the distribution bias of the input in the self-adaptive calibrator, we employ a self-supervisor made of an encoder–decoder structure. The concatenation of the bias and the original characteristics are provided as input to the spatio-temporal feature extractor, which leverages a transformer and graph convolution structures to learn the spatio-temporal pattern, and then applies a predictor to produce the final prediction. Extensive trials on two public traffic prediction datasets (METR-LA and PEMS-BAY) demonstrate that SASTGCN surpasses the most recent techniques in several metrics.
The Synergistic Effects of Environmental and Genetic Factors on the Regulation of Anthocyanin Accumulation in Plant Tissues
Authors: Do Van Giap , Lee Youngsuk , Kim Jeong-Hee , Kwon Young-Soon , Park Jong-Taek , Yang Sangjin , Park Juhyeon , Win Nay Myo , Kim Seonae
Published: August 2023

Anthocyanin accumulation is responsible for the coloration of apple fruit, and their accumulation depends on the expression of anthocyanin biosynthesis-related genes. Light is an environmental stimulus that induces fruit color by regulating genes involved in the anthocyanin biosynthesis pathway. In this study, the roles of light and genetic factors on fruit coloration and anthocyanin accumulation in apple fruit were investigated. Three genes in the anthocyanin biosynthesis pathway, MdCHS, MdANS, and MdUFGT1, were synthesized and cloned into a viral-based expression vector system for transient expression in ‘Ruby S’ apple fruits. Apple fruits were agroinfiltrated with expression vectors harboring MdCHS, MdANS, and MdUFGT1. Agroinfiltrated apple fruits were then either kept in the dark (bagged fruits) or exposed to light (exposed fruits). The agroinfiltrated fruits showed significantly different coloration patterns, transcript expression levels, and anthocyanin accumulation compared to the control fruits. Moreover, these parameters were higher in exposed fruits than in bagged fruits. For stable expression, MdCHS was introduced into a binary vector under the control of the rice α-amylase 3D (RAmy3D) promoter. The ectopic overexpression of MdCHS in transgenic rice calli showed a high accumulation of anthocyanin content. Taken together, our findings suggest that light, together with the overexpression of anthocyanin biosynthesis genes, induced the coloration and accumulation of anthocyanin content in apple fruits by upregulating the expression of the genes involved in the anthocyanin biosynthesis pathway.
Structural and Biochemical Analysis of the Recombination Mediator Protein RecR from Campylobacter jejuni
Authors: Lee Su-jin , Ahn Si Yeon , Oh Han Byeol , Kim Seung Yeon , Song Wan Seok , Yoon Sung-il
Published: August 2023

The recombination mediator complex RecFOR, consisting of the RecF, RecO, and RecR proteins, is needed to initiate homologous recombination in bacteria by positioning the recombinase protein RecA on damaged DNA. Bacteria from the phylum Campylobacterota, such as the pathogen Campylobacter jejuni, lack the recF gene and trigger homologous recombination using only RecR and RecO. To elucidate the functional properties of C. jejuni RecR (cjRecR) in recombination initiation that differ from or are similar to those in RecF-expressing bacteria, we determined the crystal structure of cjRecR and performed structure-based binding analyses. cjRecR forms a rectangular ring-like tetrameric structure and coordinates a zinc ion using four cysteine residues, as observed for RecR proteins from RecF-expressing bacteria. However, the loop of RecR that has been shown to recognize RecO and RecF in RecF-expressing bacteria is substantially shorter in cjRecR as a canonical feature of Campylobacterota RecR proteins, indicating that cjRecR lost a part of the loop in evolution due to the lack of RecF and has a low RecO-binding affinity. Furthermore, cjRecR features a larger positive patch and exhibits substantially higher ssDNA-binding affinity than RecR from RecF-expressing bacteria. Our study provides a framework for a deeper understanding of the RecOR-mediated recombination pathway.
Effect of T-DNA Integration on Growth of Transgenic Populus × euramericana cv. Neva Underlying Field Stands
Authors: Zhang Zijie , Huang Yali , Dong Yan , Ren Yachao , Du Kejiu , Wang Jinmao , Yang Minsheng
Published: August 2023

Multigene cotransformation has been widely used in the study of genetic improvement in crops and trees. However, little is known about the unintended effects and causes of multigene cotransformation in poplars. To gain insight into the unintended effects of T-DNA integration during multigene cotransformation in field stands, here, three lines (A1–A3) of Populus × euramericana cv. Neva (PEN) carrying Cry1Ac-Cry3A-BADH genes and three lines (B1–B3) of PEN carrying Cry1Ac-Cry3A-NTHK1 genes were used as research objects, with non-transgenic PEN as the control. Experimental stands were established at three common gardens in three locations and next generation sequencing (NGS) was used to identify the insertion sites of exogenous genes in six transgenic lines. We compared the growth data of the transgenic and control lines for four consecutive years. The results demonstrated that the tree height and diameter at breast height (DBH) of transgenic lines were significantly lower than those of the control, and the adaptability of transgenic lines in different locations varied significantly. The genotype and the experimental environment showed an interaction effect. A total of seven insertion sites were detected in the six transgenic lines, with B3 having a double-site insertion and the other lines having single copies. There are four insertion sites in the gene region and three insertion sites in the intergenic region. Analysis of the bases near the insertion sites showed that AT content was higher than the average chromosome content in four of the seven insertion sites within 1000 bp. Transcriptome analysis suggested that the differential expression of genes related to plant hormone transduction and lignin synthesis might be responsible for the slow development of plant height and DBH in transgenic lines. This study provides an integrated analysis of the unintended effects of transgenic poplar, which will benefit the safety assessment and reasonable application of genetically modified trees.
Suicide-Gene-Modified Extracellular Vesicles of Human Primary Uveal Melanoma in Future Therapies
Authors: Jakubechova Jana , Smolkova Bozena , Furdova Alena , Demkova Lucia , Altanerova Ursula , Nicodemou Andreas , Zeleznikova Tatiana , Klimova Daniela , Altaner Cestmir
Published: August 2023

Extracellular vesicles secreted from uveal melanoma (UM) cells are involved in the establishment of the premetastatic niche and display transforming potential for the formation of metastases, preferentially in the liver. In this study, we cultivated human primary UM cells and uveal melanoma-associated fibroblasts in vitro to be transduced by infection with a retrovirus containing the suicide gene—fused yeast cytosine deaminase::uracil phospho-ribosyl transferase (yCD::UPRT). A homogenous population of yCD::UPRT-UM cells with the integrated provirus expressed the gene, and we found it to continuously secrete small extracellular vesicles (sEVs) possessing mRNA of the suicide gene. The yCD::UPRT-UM-sEVs were internalized by tumor cells to the intracellular conversion of the prodrug 5-fluorocytosine (5-FC) to the cytotoxic drug 5-fluorouracil (5-FU). The host range of the yCD::UPRT-UM-sEVs was not limited to UMs only. The yCD::UPRT-UM-sEVs inhibited the growth of the human cutaneous melanoma cell line A375 and uveal melanoma cell line MP38, as well as other primary UMs, to various extents in vitro. The yCD::UPRT-UM-sEVs hold the therapeutic and prophylactic potential to become a therapeutic drug for UM. However, the use of yCD::UPRT-UM-sEVs must first be tested in animal preclinical studies.
Allicin, an Emerging Treatment for Pulmonary Arterial Hypertension: An Experimental Study
Authors: Sánchez-Gloria José L. , Martínez-Olivares Constanza E. , Del Valle-Mondragón Leonardo , Cortés-Camacho Fernando , Zambrano-Vásquez Oscar R. , Hernández-Pando Rogelio , Sánchez-Muñoz Fausto , Sánchez-Lozada Laura G. , Osorio-Alonso Horacio
Published: August 2023

We assessed whether allicin, through its antihypertensive and antioxidant effects, relieves vascular remodeling, endothelial function, and oxidative stress (OS), thereby improving experimental pulmonary arterial hypertension (PAH). Allicin (16 mg/kg) was administered to rats with PAH (monocrotaline 60 mg/kg). Allicin encouraged body weight gain and survival rate, and medial wall thickness and the right ventricle (RV) hypertrophy were prevented. Also, angiotensin II concentrations in the lung (0.37 ± 0.01 vs. 0.47 ± 0.06 pmoles/mL, allicin and control, respectively) and plasma (0.57 ± 0.05 vs. 0.75 ± 0.064, allicin and control respectively) and the expressions of angiotensin-converting enzyme II and angiotensin II type 1 receptor in lung tissue were maintained at normal control levels with allicin. In PAH rats treated with allicin, nitric oxide (NO) (31.72 ± 1.22 and 51.4 ± 3.45 pmoles/mL), tetrahydrobiopterin (8.43 ± 0.33 and 10.14 ± 0.70 pmoles/mL), cyclic guanosine monophosphate (5.54 ± 0.42 and 5.64 ± 0.73 pmoles/mL), and Ang-(1-7) (0.88 ± 0.23 and 0.83 ± 0.056 pmoles/mL) concentrations increased in lung tissue and plasma, respectively. In contrast, dihydrobiopterin increase was prevented in both lung tissue and plasma (5.75 ± 0.3 and 5.64 ± 0.73 pmoles/mL); meanwhile, phosphodiesterase-5 was maintained at normal levels in lung tissue. OS in PAH was prevented with allicin through the increased expression of Nrf2 in the lung. Allicin prevented the lung response to hypoxia, preventing the overexpression of HIF-1α and VEGF. Allicin attenuated the vascular remodeling and RV hypertrophy in PAH through its effects on NO-dependent vasodilation, modulation of RAS, and amelioration of OS. Also, these effects could be associated with the modulation of HIF-1α and improved lung oxygenation. The global effects of allicin contribute to preventing endothelial dysfunction, remodeling of the pulmonary arteries, and RV hypertrophy, preventing heart failure, thus favoring survival. Although human studies are needed, the data suggest that, alone or in combination therapy, allicin may be an alternative in treating PAH if we consider that, similarly to current treatments, it improves lung vasodilation and increase survival. Allicin may be considered an option when there is a lack of efficacy, and where drug intolerance is observed, to enhance the efficacy of drugs, or when more than one pathogenic mechanism must be addressed.
The Fate and Functionality of Alien tRNA Fragments in Culturing Medium and Cells of Escherichia coli
Authors: Shavkunov Konstantin S. , Markelova Natalia Yu. , Glazunova Olga A. , Kolzhetsov Nikolay P. , Panyukov Valery V. , Ozoline Olga N.
Published: August 2023

Numerous observations have supported the idea that various types of noncoding RNAs, including tRNA fragments (tRFs), are involved in communications between the host and its microbial community. The possibility of using their signaling function has stimulated the study of secreted RNAs, potentially involved in the interspecies interaction of bacteria. This work aimed at identifying such RNAs and characterizing their maturation during transport. We applied an approach that allowed us to detect oligoribonucleotides secreted by Prevotella copri (Segatella copri) or Rhodospirillum rubrum inside Escherichia coli cells. Four tRFs imported by E. coli cells co-cultured with these bacteria were obtained via chemical synthesis, and all of them affected the growth of E. coli. Their successive modifications in the culture medium and recipient cells were studied by high-throughput cDNA sequencing. Instead of the expected accidental exonucleolysis, in the milieu, we observed nonrandom cleavage by endonucleases continued in recipient cells. We also found intramolecular rearrangements of synthetic oligonucleotides, which may be considered traces of intermediate RNA circular isomerization. Using custom software, we estimated the frequency of such events in transcriptomes and secretomes of E. coli and observed surprising reproducibility in positions of such rare events, assuming the functionality of ring isoforms or their permuted derivatives in bacteria.
SARS-CoV-2 Reinfections and Long COVID in the Post-Omicron Phase of the Pandemic
Authors: Boufidou Fotini , Medić Snežana , Lampropoulou Vicky , Siafakas Nikolaos , Tsakris Athanasios , Anastassopoulou Cleo
Published: August 2023

We are reviewing the current state of knowledge on the virological and immunological correlates of long COVID, focusing on recent evidence for the possible association between the increasing number of SARS-CoV-2 reinfections and the parallel pandemic of long COVID. The severity of reinfections largely depends on the severity of the initial episode; in turn, this is determined both by a combination of genetic factors, particularly related to the innate immune response, and by the pathogenicity of the specific variant, especially its ability to infect and induce syncytia formation at the lower respiratory tract. The cumulative risk of long COVID as well as of various cardiac, pulmonary, or neurological complications increases proportionally to the number of SARS-CoV-2 infections, primarily in the elderly. Therefore, the number of long COVID cases is expected to remain high in the future. Reinfections apparently increase the likelihood of long COVID, but less so if they are mild or asymptomatic as in children and adolescents. Strategies to prevent SARS-CoV-2 reinfections are urgently needed, primarily among older adults who have a higher burden of comorbidities. Follow-up studies using an established case definition and precise diagnostic criteria of long COVID in people with or without reinfection may further elucidate the contribution of SARS-CoV-2 reinfections to the long COVID burden. Although accumulating evidence supports vaccination, both before and after the SARS-CoV-2 infection, as a preventive strategy to reduce the risk of long COVID, more robust comparative observational studies, including randomized trials, are needed to provide conclusive evidence of the effectiveness of vaccination in preventing or mitigating long COVID in all age groups. Thankfully, answers not only on the prevention, but also on treatment options and rates of recovery from long COVID are gradually starting to emerge.
Virus-like Particle (VLP) Vaccines for Cancer Immunotherapy
Authors: Ruzzi Francesca , Semprini Maria Sofia , Scalambra Laura , Palladini Arianna , Angelicola Stefania , Cappello Chiara , Pittino Olga Maria , Nanni Patrizia , Lollini Pier-Luigi
Published: August 2023

Cancer vaccines are increasingly being studied as a possible strategy to prevent and treat cancers. While several prophylactic vaccines for virus-caused cancers are approved and efficiently used worldwide, the development of therapeutic cancer vaccines needs to be further implemented. Virus-like particles (VLPs) are self-assembled protein structures that mimic native viruses or bacteriophages but lack the replicative material. VLP platforms are designed to display single or multiple antigens with a high-density pattern, which can trigger both cellular and humoral responses. The aim of this review is to provide a comprehensive overview of preventive VLP-based vaccines currently approved worldwide against HBV and HPV infections or under evaluation to prevent virus-caused cancers. Furthermore, preclinical and early clinical data on prophylactic and therapeutic VLP-based cancer vaccines were summarized with a focus on HER-2-positive breast cancer.
The Association of Selected GWAS Reported AD Risk Loci with CSF Biomarker Levels and Cognitive Decline in Slovenian Patients
Authors: Vogrinc David , Gregorič Kramberger Milica , Emeršič Andreja , Čučnik Saša , Goričar Katja , Dolžan Vita
Published: August 2023

Alzheimer’s disease (AD) is the most common neurodegenerative disease, with a complex genetic background. Apart from rare, familial cases, a combination of multiple risk loci contributes to the susceptibility of the disease. Genome-wide association studies (GWAS) have identified numerous AD risk loci. Changes in cerebrospinal fluid (CSF) biomarkers and imaging techniques can detect AD-related brain changes before the onset of clinical symptoms, even in the presence of preclinical mild cognitive impairment. In this study, we aimed to assess the associations between SNPs in well-established GWAS AD risk loci and CSF biomarker levels or cognitive test results in Slovenian patients with cognitive decline. The study included 82 AD patients, 28 MCI patients with pathological CSF biomarker levels and 35 MCI patients with normal CSF biomarker levels. Carriers of at least one polymorphic TOMM40 rs157581 C allele had lower Aβ42 (p = 0.033) and higher total tau (p = 0.032) and p-tau181 levels (p = 0.034). Carriers of at least one polymorphic T allele in SORCS1 rs1358030 had lower total tau (p = 0.019), while polymorphic SORCS1 rs1416406 allele was associated with lower total tau (p = 0.013) and p-tau181 (p = 0.036). In addition, carriers of at least one polymorphic T allele in BCHE rs1803274 had lower cognitive test scores (p = 0.029). The study findings may contribute to the identification of genetic markers associated with AD and MCI and provide insights into early disease diagnostics.
The Induction of Long-Term Potentiation by Medial Septum Activation under Urethane Anesthesia Can Alter Gene Expression in the Hippocampus
Authors: Dobryakova Yulia V. , Gerasimov Konstantin , Spivak Yulia S. , Korotkova Tinna , Koryagina Alena , Deryabina Angelina , Markevich Vladimir A. , Bolshakov Alexey P.
Published: August 2023

We studied changes in the expression of early genes in hippocampal cells in response to stimulation of the dorsal medial septal area (dMSA), leading to long-term potentiation in the hippocampus. Rats under urethane anesthesia were implanted with stimulating electrodes in the ventral hippocampal commissure and dMSA and a recording electrode in the CA1 area of the hippocampus. We found that high-frequency stimulation (HFS) of the dMSA led to the induction of long-term potentiation in the synapses formed by the ventral hippocampal commissure on the hippocampal CA1 neurons. One hour after dMSA HFS, we collected the dorsal and ventral hippocampi on both the ipsilateral (damaged by the implanted electrode) and contralateral (intact) sides and analyzed the expression of genes by qPCR. The dMSA HFS led to an increase in the expression of bdnf and cyr61 in the ipsilateral hippocampi and egr1 in the ventral contralateral hippocampus. Thus, dMSA HFS under the conditions of degeneration of the cholinergic neurons in the medial septal area prevented the described increase in gene expression. The changes in cyr61 expression appeared to be dependent on the muscarinic M1 receptors. Our data suggest that the induction of long-term potentiation by dMSA activation enhances the expression of select early genes in the hippocampus.
Specific Proton-Donor Properties of Glycine Betaine. Metric Parameters and Enthalpy of Noncovalent Interactions in its Dimer, Water Complexes and Crystalline Hydrate
Authors: Frolov Nikita E. , Shishkina Anastasia V. , Vener Mikhail V.
Published: August 2023

Trimethylglycine (glycine betaine, GB) is an important organic osmolyte that accumulates in various plant species in response to environmental stresses and has significant potential as a bioactive agent with low environmental impact. It is assumed that the hydration of GB is playing an important role in the protective mechanism. The hydration and aggregation properties of GB have not yet been studied in detail at the atomistic level. In this work, noncovalent interactions in the GB dimer and its complexes with water and crystalline monohydrate are studied. Depending on the object, periodic and non-periodic DFT calculations are used. Particular attention is paid to the metric parameters and enthalpies of intermolecular hydrogen bonds. The identification of noncovalent interactions is carried out by means of the Bader analysis of periodic or non-periodic electron density. The enthalpy of hydrogen bonds is estimated using the Rosenberg formula (PCCP 2 (2000) 2699). The specific proton donor properties of glycine betaine are due to its ability to form intermolecular C–H∙∙∙O bonds with the oxygen atom of a water molecule or the carboxylate group of a neighboring GB. The enthalpy of these bonds can be significantly greater than 10 kJ/mol. The water molecule that forms a hydrogen bond with the carboxylate group of GB also interacts with its CH groups through lone pairs of electrons. The C–H∙∙∙O bonds contribute up to 40% of the total entropy of the GB–water interaction, which is about 45 kJ/mol. The possibility of identifying C–H∙∙∙O bonds by the proton nuclear magnetic resonance method is discussed.
Partial Reversible Inhibition of Enzymes and Its Metabolic and Pharmaco-Toxicological Implications
Authors: Masson Patrick , Mukhametgalieva Aliya R.
Published: August 2023

Partial reversible inhibition of enzymes, also called hyperbolic inhibition, is an uncommon mechanism of reversible inhibition, resulting from a productive enzyme–inhibitor complex. This type of inhibition can involve competitive, mixed, non-competitive and uncompetitive inhibitors. While full reversible inhibitors show linear plots for reciprocal enzyme initial velocity versus inhibitor concentration, partial inhibitors produce hyperbolic plots. Similarly, dose–response curves show residual fractional activity of enzymes at high doses. This article reviews the theory and methods of analysis and discusses the significance of this type of reversible enzyme inhibition in metabolic processes, and its implications in pharmacology and toxicology.
Possible Compensatory Role of ASICs in Glutamatergic Synapses
Authors: Evlanenkov Konstantin K. , Zhigulin Arseniy S. , Tikhonov Denis B.
Published: August 2023

Proton-gated channels of the ASIC family are widely distributed in central neurons, suggesting their role in common neurophysiological functions. They are involved in glutamatergic neurotransmission and synaptic plasticity; however, the exact function of these channels remains unclear. One problem is that acidification of the synaptic cleft due to the acidic content of synaptic vesicles has opposite effects on ionotropic glutamate receptors and ASICs. Thus, the pH values required to activate ASICs strongly inhibit AMPA receptors and almost completely inhibit NMDA receptors. This, in turn, suggests that ASICs can provide compensation for post-synaptic responses in the case of significant acidifications. We tested this hypothesis by patch-clamp recordings of rat brain neuron responses to acidifications and glutamate receptor agonists at different pH values. Hippocampal pyramidal neurons have much lower ASICs than glutamate receptor responses, whereas striatal interneurons show the opposite ratio. Cortical pyramidal neurons and hippocampal interneurons show similar amplitudes in their responses to acidification and glutamate. Consequently, the total response to glutamate agonists at different pH levels remains rather stable up to pH 6.2. Besides these pH effects, the relationship between the responses mediated by glutamate receptors and ASICs depends on the presence of Mg2+ and the membrane voltage. Together, these factors create a complex picture that provides a framework for understanding the role of ASICs in synaptic transmission and synaptic plasticity.
Role of Innate Immunity in Allergic Contact Dermatitis: An Update
Authors: Yamaguchi Hiroki L. , Yamaguchi Yuji , Peeva Elena
Published: August 2023

Our understanding of allergic contact dermatitis mechanisms has progressed over the past decade. Innate immune cells that are involved in the pathogenesis of allergic contact dermatitis include Langerhans cells, dermal dendritic cells, macrophages, mast cells, innate lymphoid cells (ILCs), neutrophils, eosinophils, and basophils. ILCs can be subcategorized as group 1 (natural killer cells; ILC1) in association with Th1, group 2 (ILC2) in association with Th2, and group 3 (lymphoid tissue-inducer cells; ILC3) in association with Th17. Pattern recognition receptors (PRRs) including toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) in innate immune cells recognize damage-associated molecular patterns (DAMPs) and cascade the signal to produce several cytokines and chemokines including tumor necrosis factor (TNF)-α, interferon (IFN)-α, IFN-γ, interleukin (IL)-1β, IL-4, IL-6, IL-12, IL-13, IL-17, IL-18, and IL-23. Here we discuss the recent findings showing the roles of the innate immune system in allergic contact dermatitis during the sensitization and elicitation phases.
Biodegradable Polymer-Based Drug-Delivery Systems for Ocular Diseases
Authors: Tsung Ta-Hsin , Tsai Yu-Chien , Lee Hsin-Pei , Chen Yi-Hao , Lu Da-Wen
Published: August 2023

Ocular drug delivery is a challenging field due to the unique anatomical and physiological barriers of the eye. Biodegradable polymers have emerged as promising tools for efficient and controlled drug delivery in ocular diseases. This review provides an overview of biodegradable polymer-based drug-delivery systems for ocular diseases with emphasis on the potential for biodegradable polymers to overcome the limitations of conventional methods, allowing for sustained drug release, improved bioavailability, and targeted therapy. Natural and synthetic polymers are both discussed, highlighting their biodegradability and biocompatibility. Various formulation strategies, such as nanoparticles, hydrogels, and microemulsions, among others, are investigated, detailing preparation methods, drug encapsulation, and clinical applications. The focus is on anterior and posterior segment drug delivery, covering glaucoma, corneal disorders, ocular inflammation, retinal diseases, age-related macular degeneration, and diabetic retinopathy. Safety considerations, such as biocompatibility evaluations, in vivo toxicity studies, and clinical safety, are addressed. Future perspectives encompass advancements, regulatory considerations, and clinical translation challenges. In conclusion, biodegradable polymers offer potential for efficient and targeted ocular drug delivery, improving therapeutic outcomes while reducing side effects. Further research is needed to optimize formulation strategies and address regulatory requirements for successful clinical implementation.
Parp Inhibitors and Radiotherapy: A New Combination for Prostate Cancer (Systematic Review)
Authors: Rivero Belenchón Inés , Congregado Ruiz Carmen Belen , Saez Carmen , Osman García Ignacio , Medina López Rafael Antonio
Published: August 2023

PARPi, in combination with ionizing radiation, has demonstrated the ability to enhance cellular radiosensitivity in different tumors. The rationale is that the exposure to radiation leads to both physical and biochemical damage to DNA, prompting cells to initiate three primary mechanisms for DNA repair. Two double-stranded DNA breaks (DSB) repair pathways: (1) non-homologous end-joining (NHEJ) and (2) homologous recombination (HR); and (3) a single-stranded DNA break (SSB) repair pathway (base excision repair, BER). In this scenario, PARPi can serve as radiosensitizers by leveraging the BER pathway. This mechanism heightens the likelihood of replication forks collapsing, consequently leading to the formation of persistent DSBs. Together, the combination of PARPi and radiotherapy is a potent oncological strategy. This combination has proven its efficacy in different tumors. However, in prostate cancer, there are only preclinical studies to support it and, recently, an ongoing clinical trial. The objective of this paper is to perform a review of the current evidence regarding the use of PARPi and radiotherapy (RT) in PCa and to give future insight on this topic.
A Novel Multi-Component Formulation Reduces Inflammation In Vitro and Clinically Lessens the Symptoms of Chronic Eczematous Skin
Authors: Kim Jihee , Jung Eunjoong , Yang Wonmi , Kim Chun-Kang , Durnaoglu Serpen , Oh In-Rok , Kim Chan-Wha , Sinskey Anthony J. , Mihm Martin C. , Lee Ju Hee
Published: August 2023

Long-term treatments for inflammatory skin diseases like atopic dermatitis or eczema can cause adverse effects. Super Protein Multifunction (SPM) was investigated as a potential treatment for managing skin inflammation by monitoring the expression of pro-inflammatory cytokines induced using LPS and poly(I:C)/TNFα in HaCaT keratinocytes and Hs27 fibroblasts as measured via RT-PCR. SPM solution was also assessed for its effect on cytokine release, measured using ELISA, in a UVB-irradiated 3D human skin model. To evaluate the efficiency of SPM, 20 patients with mild eczematous skin were randomized to receive SPM or vehicle twice a day for three weeks in a double-blind controlled trial. In vitro studies showed SPM inhibited inflammation-induced IL-1β, IL-6, IL-33, IL-1α, TSLP, and TNFα expression or release. In the clinical study, the SPM group showed significant improvements in the IGA, PA, and DLQI scores compared to the vehicle group. Neither group showed significant differences in VAS (pruritus). Histological analysis showed reduced stratum corneum thickness and inflammatory cell infiltration. The results suggest that SPM may reduce inflammation in individuals with chronic eczematous skin.
Interleukin 6 (IL-6) Regulates GABAA Receptors in the Dorsomedial Hypothalamus Nucleus (DMH) through Activation of the JAK/STAT Pathway to Affect Heart Rate Variability in Stressed Rats
Authors: Zhang Lihua , Shi Weibo , Liu Jingmin , Chen Ke , Zhang Guowei , Zhang Shengnan , Cong Bin , Li Yingmin
Published: August 2023

The dorsomedial hypothalamus nucleus (DMH) is an important component of the autonomic nervous system and plays a critical role in regulating the sympathetic outputs of the heart. Stress alters the neuronal activity of the DMH, affecting sympathetic outputs and triggering heart rate variability. However, the specific molecular mechanisms behind stress leading to abnormal DMH neuronal activity have still not been fully elucidated. Therefore, in the present study, we successfully constructed a stressed rat model and used it to investigate the potential molecular mechanisms by which IL-6 regulates GABAA receptors in the DMH through activation of the JAK/STAT pathway and thus affects heart rate variability in rats. By detecting the c-Fos expression of neurons in the DMH and electrocardiogram (ECG) changes in rats, we clarified the relationship between abnormal DMH neuronal activity and heart rate variability in stressed rats. Then, using ELISA, immunohistochemical staining, Western blotting, RT-qPCR, and RNAscope, we further explored the correlation between the IL-6/JAK/STAT signaling pathway and GABAA receptors. The data showed that an increase in IL-6 induced by stress inhibited GABAA receptors in DMH neurons by activating the JAK/STAT signaling pathway, while specific inhibition of the JAK/STAT signaling pathway using AG490 obviously reduced DMH neuronal activity and improved heart rate variability in rats. These findings suggest that IL-6 regulates the expression of GABAA receptors via the activation of the JAK/STAT pathway in the DMH, which may be an important cause of heart rate variability in stressed rats.
Tumor Suppressor Properties of Small C-Terminal Domain Phosphatases in Clear Cell Renal Cell Carcinoma
Authors: Krasnov George S. , Puzanov Grigory A. , Dashinimaev Erdem B. , Vishnyakova Khava S. , Kondratieva Tatiana T. , Chegodaev Yegor S. , Postnov Anton Y. , Senchenko Vera N. , Yegorov Yegor E.
Published: August 2023

Clear cell renal cell carcinoma (ccRCC) accounts for 80–90% of kidney cancers worldwide. Small C-terminal domain phosphatases CTDSP1, CTDSP2, and CTDSPL (also known as SCP1, 2, 3) are involved in the regulation of several important pathways associated with carcinogenesis. In various cancer types, these phosphatases may demonstrate either antitumor or oncogenic activity. Tumor-suppressive activity of these phosphatases in kidney cancer has been shown previously, but in general case, the antitumor activity may be dependent on the choice of cell line. In the present work, transfection of the Caki-1 cell line (ccRCC morphologic phenotype) with expression constructs containing the coding regions of these genes resulted in inhibition of cell growth in vitro in the case of CTDSP1 (p < 0.001) and CTDSPL (p < 0.05) but not CTDSP2. The analysis of The Cancer Genome Atlas (TCGA) data showed differential expression of some of CTDSP genes and of their target, RB1. These results were confirmed by quantitative RT-PCR using an independent sample of primary ccRCC tumors (n = 52). We observed CTDSPL downregulation and found a positive correlation of expression for two gene pairs: CTDSP1 and CTDSP2 (rs = 0.76; p < 0.001) and CTDSPL and RB1 (rs = 0.38; p < 0.05). Survival analysis based on TCGA data demonstrated a strong association of lower expression of CTDSP1, CTDSP2, CTDSPL, and RB1 with poor survival of ccRCC patients (p < 0.001). In addition, according to TCGA, CTDSP1, CTDSP2, and RB1 were differently expressed in two subtypes of ccRCC—ccA and ccB, characterized by different survival rates. These results confirm that CTDSP1 and CTDSPL have tumor suppressor properties in ccRCC and reflect their association with the more aggressive ccRCC phenotype.
Cardiomyocyte-Restricted Expression of IL11 Causes Cardiac Fibrosis, Inflammation, and Dysfunction
Authors: Sweeney Mark , O’Fee Katie , Villanueva-Hayes Chelsie , Rahman Ekhlas , Lee Michael , Vanezis Konstantinos , Andrew Ivan , Lim Wei-Wen , Widjaja Anissa , Barton Paul J. R. , Cook Stuart A.
Published: August 2023

Cardiac fibrosis is a common pathological process in heart disease, representing a therapeutic target. Transforming growth factor β (TGFβ) is the canonical driver of cardiac fibrosis and was recently shown to be dependent on interleukin 11 (IL11) for its profibrotic effects in fibroblasts. In the opposite direction, recombinant human IL11 has been reported as anti-fibrotic and anti-inflammatory in the mouse heart. In this study, we determined the effects of IL11 expression in cardiomyocytes on cardiac pathobiology and function. We used the Cre-loxP system to generate a tamoxifen-inducible mouse with cardiomyocyte-restricted murine Il11 expression. Using protein assays, bulk RNA-sequencing, and in vivo imaging, we analyzed the effects of IL11 on myocardial fibrosis, inflammation, and cardiac function, challenging previous reports suggesting the cardioprotective potential of IL11. TGFβ stimulation of cardiomyocytes caused Il11 upregulation. Compared to wild-type controls, Il11-expressing hearts demonstrated severe cardiac fibrosis and inflammation that was associated with the upregulation of cytokines, chemokines, complement factors, and increased inflammatory cells. IL11 expression also activated a program of endothelial-to-mesenchymal transition and resulted in left ventricular dysfunction. Our data define species-matched IL11 as strongly profibrotic and proinflammatory when secreted from cardiomyocytes and further establish IL11 as a disease factor.
Effect of Siponimod on Brain and Spinal Cord Imaging Markers of Neurodegeneration in the Theiler’s Murine Encephalomyelitis Virus Model of Demyelination
Authors: Pol Suyog , Dhanraj Ravendra , Taher Anissa , Crever Mateo , Charbonneau Taylor , Schweser Ferdinand , Dwyer Michael , Zivadinov Robert
Published: August 2023

Siponimod (Sp) is a Sphingosine 1-phosphate (S1P) receptor modulator, and it suppresses S1P- mediated autoimmune lymphocyte transport and inflammation. Theiler’s murine encephalomyelitis virus (TMEV) infection mouse model of multiple sclerosis (MS) exhibits inflammation-driven acute and chronic phases, spinal cord lesions, brain and spinal cord atrophy, and white matter injury. The objective of the study was to investigate whether Sp treatment could attenuate inflammation-induced pathology in the TMEV model by inhibiting microglial activation and preventing the atrophy of central nervous tissue associated with neurodegeneration. Clinical disability score (CDS), body weight (BW), and rotarod retention time measures were used to assess Sp’s impact on neurodegeneration and disease progression in 4 study groups of 102 animals, including 44 Sp-treated (SpT), 44 vehicle-treated, 6 saline-injected, and 8 age-matched healthy controls (HC). Next, 58 (22 SpT, 22 vehicle, 6 saline injected, and 8 HC) out of the 102 animals were further evaluated to assess the effect of Sp on brain region-specific and spinal cord volume changes, as well as microglial activation. Sp increased CDS and decreased BW and rotarod retention time in TMEV mice, but did not significantly affect most brain region volumes, except for lateral ventricle volume. Sp suppressed ventricular enlargement, suggesting reduced TMEV-induced inflammation in LV. No significant differences in spine volume changes were observed between Sp- and vehicle-treated animals, but there were differences between HC and TMEV groups, indicating TMEV-induced inflammation contributed to increased spine volume. Spine histology revealed no significant microglial density differences between groups in gray matter, but HC animals had higher type 1 morphology and lower type 2 morphology percentages in gray and white matter regions. This suggests that Sp did not significantly affect microglial density but may have modulated neuroinflammation in the spinal cord. Sp may have some effects on neuroinflammation and ventricular enlargement. However, it did not demonstrate a significant impact on neurodegeneration, spinal volume, or lesion volume in the TMEV mouse model. Further investigation is required to fully understand Sp’s effect on microglial activation and its relevance to the pathophysiology of MS. The differences between the current study and previous research using other MS models, such as EAE, highlight the differences in pathological processes in these two disease models.