bluuebunny/crossref_metadata_2025 huggingface dataset:
Impacts of Landscape Type, Viewing Distance, and Permeability on Anxiety, Depression, and Stress
Authors: Shu Yun , Wu Chengzhao , Zhai Yujia
Published: August 2022

Contact with nature is beneficial for mental health, including anxiety and stress. Exposure to virtual nature also has similar restorative traits with real nature. However, previous studies on the restorative environment mostly focus on ordinary people while caring less about patients with depressive disorders. Thus, the restorative impacts of virtual nature on patients with depression warrant examination. This research aims to study the restorative effects of virtual reality (VR) landscape type, viewing distance, and permeability on anxiety, depression, and stress in patients with depression. Study A revealed that the perceived restorative level of landscape type varies greatly: grassland > forest > water > undergrowth > urban square. Additionally, natural environments with higher openness, more green elements, more blue sky, and more sunshine exposure had higher restorative levels on perceived depression, anxiety, and stress relief. Study B found that the grassland landscape with a higher viewing distance and a medium vegetation edge permeability provides more restorative impacts for patients with depression.
Exploring Multivariate Profiles of Psychological Distress and Empathy in Early Adolescent Victims, Bullies, and Bystanders Involved in Cyberbullying Episodes
Authors: Fabris Matteo , Longobardi Claudio , Morese Rosalba , Marengo Davide
Published: August 2022

(1) Background: Adolescents may be involved in cyberbullying as victims, perpetrators, or to a lesser extent, victim–perpetrators simultaneously. The present research investigated differences between participants acting in different bullying roles—namely, bully, victim, or bully/victim—and bystander roles—namely, defending, passive bystander, and passive/defending; (2) Methods: We used multivariate analysis of covariance to determine how, in the same individuals, direct involvement in cyberbullying episodes compares to participating in them as by-standers in relation to both psychological distress and empathy; (3) Results: Both victims and bully/victims were found to be at increased risk for suicidal ideation, internalizing and externalizing symptoms, and emotional dysregulation compared with students who were neither victims nor perpetrators of cyberbullying episodes. Additionally, victims showed higher empathy scores when compared with bullies and bully/victims. All bystander roles showed increased emotional dysregulation compared with uninvolved students, but no differences emerged on other psychological distress measures. Finally, defending bystanders showed increased cognitive empathy. (4) Conclusions: During early adolescence, the direct experience of cyberbullying, as a bully or a victim (or both), show a stronger association with psychological distress than the mere participation in cyberbullying as a witness, regardless of the witness acting defensive toward the victim, or passive. However, both cyberbullying and bystanding roles provide a similar (small) explicative power over empathy variables.
Association between Dental Caries and Handgrip Strength: In a Population-Based Study in Korea (KNHANES 2016–2018)
Authors: Kim Eun-Jeong , Lim Chae-Hee , Eun Min , Yu Su-A , Kwon So-Min , Lee Jeong-Eun , Lee Kyu-Ri , Park Se-Hyun , Lee Hye-Ju
Published: August 2022

This study aimed to verify the relationship between handgrip strength and oral health using data from the Korea National Health and Nutrition Examination Survey, representing Korean adults. Data from the seventh survey (2016–2018) conducted by the Korea Centers for Disease Control and Prevention were utilized, and 10,607 final study participants were recruited according to the selection and exclusion criteria. A complex sample logistic regression analysis was performed to confirm the relationship between handgrip strength and dental caries according to the sex of the study participants. On analyzing the correlation in men, “C1 (DMFT: 11–32),” when compared to “C4 (DMFT: 0–3),” in Model 1 without adjustment for potential confounders, was 2.92 (95% confidence interval [CI]: 2.15–3.97) times more likely to be associated with lower handgrip strength, and a statistically significant result was detected (p < 0.001). Additionally, significant odds ratios (ORs) were confirmed for all adjusted models. In women, the ORs in Model 1 without adjustment for potential confounders were 1.41 times (95% CI: 1.14–1.75) and demonstrated a significant result; however, the results were not significant in all adjusted models 2–4. Resultantly, a significant association was detected between dental caries and handgrip strength in Korean adults.
Correction: Shi et al. Spatio-Temporal Variation Analysis of the Biological Boundary Temperature Index Based on Accumulated Temperature: A Case Study of the Yangtze River Basin. ISPRS Int. J. Geo-Inf. 2021, 10, 675
Authors: Shi Guangxun , Ye Peng , Yang Xianwu
Published: August 2022

The authors wish to make the following corrections to their paper [...]
An Effective Approach to Improve the Thermal Conductivity, Strength, and Stress Relaxation of Carbon Nanotubes/Epoxy Composites Based on Vitrimer Chemistry
Authors: Feng Yang , Nie Zhuguang , Deng Panhong , Luo Liping , Hu Xingman , Su Jie , Li Haiming , Fan Xiaodong , Qi Shuhua
Published: August 2022

An effective method was developed to improve the interfacial interaction between Mutiwalled carbon nanotubes (MWCNTs) and epoxy matrix. The performance of thermal conductivity and strength of the epoxy vitrimer were enhanced by polydopamine (PDA) coating. Polydopamine is a commonly used photothermal agent, which of course, was effective in modifying MWCNTs used in photoresponsive epoxy resin. The surface temperature of the epoxy composite with 3% MWCNTs@PDA fillers added increased from room temperature to 215 °C in 48 s. The metal–catechol coordination interactions formed between the catechol groups of PDA and Zn2+ accelerated the stress relaxation of epoxy vitrimer. Moreover, the shape memory, repairing, and recycling of epoxy vitrimer were investigated. Therefore, dopamine coating is a multifunctional approach to enhance the performance of epoxy vitrimer.
Discovering Biomarkers for Non-Alcoholic Steatohepatitis Patients with and without Hepatocellular Carcinoma Using Fecal Metaproteomics
Authors: Sydor Svenja , Dandyk Christian , Schwerdt Johannes , Manka Paul , Benndorf Dirk , Lehmann Theresa , Schallert Kay , Wolf Maximilian , Reichl Udo , Canbay Ali , Bechmann Lars P. , Heyer Robert
Published: August 2022

High-calorie diets lead to hepatic steatosis and to the development of non-alcoholic fatty liver disease (NAFLD), which can evolve over many years into the inflammatory form of non-alcoholic steatohepatitis (NASH), posing a risk for the development of hepatocellular carcinoma (HCC). Due to diet and liver alteration, the axis between liver and gut is disturbed, resulting in gut microbiome alterations. Consequently, detecting these gut microbiome alterations represents a promising strategy for early NASH and HCC detection. We analyzed medical parameters and the fecal metaproteome of 19 healthy controls, 32 NASH patients, and 29 HCC patients, targeting the discovery of diagnostic biomarkers. Here, NASH and HCC resulted in increased inflammation status and shifts within the composition of the gut microbiome. An increased abundance of kielin/chordin, E3 ubiquitin ligase, and nucleophosmin 1 represented valuable fecal biomarkers, indicating disease-related changes in the liver. Although a single biomarker failed to separate NASH and HCC, machine learning-based classification algorithms provided an 86% accuracy in distinguishing between controls, NASH, and HCC. Fecal metaproteomics enables early detection of NASH and HCC by providing single biomarkers and machine learning-based metaprotein panels.
Adaptation to Hypoxia May Promote Therapeutic Resistance to Androgen Receptor Inhibition in Triple-Negative Breast Cancer
Authors: Jinna Nikita , Rida Padmashree , Smart Max , LaBarge Mark , Jovanovic-Talisman Tijana , Natarajan Rama , Seewaldt Victoria
Published: August 2022

Triple-negative breast cancer (TNBC) surpasses other BC subtypes as the most challenging to treat due to its lack of traditional BC biomarkers. Nearly 30% of TNBC patients express the androgen receptor (AR), and the blockade of androgen production and AR signaling have been the cornerstones of therapies for AR-positive TNBC. However, the majority of women are resistant to AR-targeted therapy, which is a major impediment to improving outcomes for the AR-positive TNBC subpopulation. The hypoxia signaling cascade is frequently activated in the tumor microenvironment in response to low oxygen levels; activation of the hypoxia signaling cascade allows tumors to survive despite hypoxia-mediated interference with cellular metabolism. The activation of hypoxia signaling networks in TNBC promotes resistance to most anticancer drugs including AR inhibitors. The activation of hypoxia network signaling occurs more frequently in TNBC compared to other BC subtypes. Herein, we examine the (1) interplay between hypoxia signaling networks and AR and (2) whether hypoxia and hypoxic stress adaptive pathways promote the emergence of resistance to therapies that target AR. We also pose the well-supported question, “Can the efficacy of androgen-/AR-targeted treatments be enhanced by co-targeting hypoxia?” By critically examining the evidence and the complex entwinement of these two oncogenic pathways, we argue that the simultaneous targeting of androgen biosynthesis/AR signaling and hypoxia may enhance the sensitivity of AR-positive TNBCs to AR-targeted treatments, derail the emergence of therapy resistance, and improve patient outcomes.
A Scoping Analysis of Cathelicidin in Response to Organic Dust Exposure and Related Chronic Lung Illnesses
Authors: Golec Marcin , Lemieszek Marta Kinga , Dutkiewicz Jacek , Milanowski Janusz , Barteit Sandra
Published: August 2022

Over two billion people worldwide are exposed to organic dust, which can cause respiratory disorders. The discovery of the cathelicidin peptide provides novel insights into the lung’s response to organic dust; however, its role in the lung’s response to organic dust exposure and chronic lung diseases remains limited. We conducted a scoping review to map the current evidence on the role of cathelicidin LL-37/CRAMP in response to organic dust exposure and related chronic lung diseases: hypersensitivity pneumonitis (HP), chronic obstructive pulmonary disease (COPD) and asthma. We included a total of n = 53 peer-reviewed articles in this review, following the process of (i) a preliminary screening; (ii) a systematic MEDLINE/PubMed database search; (iii) title, abstract and full-text screening; (iv) data extraction and charting. Cathelicidin levels were shown to be altered in all clinical settings investigated; its pleiotropic function was confirmed. It was found that cathelicidin contributes to maintaining homeostasis and participates in lung injury response and repair, in addition to exerting a positive effect against microbial load and infections. In addition, LL-37 was found to sustain continuous inflammation, increase mucus formation and inhibit microorganisms and corticosteroids. In addition, studies investigated cathelicidin as a treatment modality, such as cathelicidin inhalation in experimental HP, which had positive effects. However, the primary focus of the included articles was on LL-37’s antibacterial effect, leading to the conclusion that the beneficial LL-37 activity has not been adequately examined and that further research is required.
Phenol/Chloroform-Free TiO2-Based miRNA Extraction from Cell Lysate
Authors: Smela Denisa , Zelinkova Eliska , Rehulka Pavel , Bilkova Zuzana , Kupcik Rudolf
Published: August 2022

While microRNAs are considered as excellent biomarkers of various diseases, there are still several remaining challenges regarding their isolation. In this study, we aimed to design a novel RNA isolation method that would help to overcome those challenges. Therefore, we present a novel phenol/chloroform-free, low-cost method for miRNA extraction. Within this method, RNA is extracted from cell lysate with an isopropanol/water/NaCl system, followed by solid-phase extraction using TiO2 microspheres to effectively separate short RNAs from long RNA molecules. We also demonstrated the pH-dependent selectivity of TiO2 microspheres towards different sizes of RNA. We were able to regulate the size range of extracted RNAs with simple adjustments in binding conditions used during the solid-phase extraction.
Influence of Gender in Diabetes Mellitus and Its Complication
Authors: Ciarambino Tiziana , Crispino Pietro , Leto Gaetano , Mastrolorenzo Erika , Para Ombretta , Giordano Mauro
Published: August 2022

In medicine, there is growing evidence that gender differences are important and lead to variations in the pathophysiology and treatment of many diseases with traits that appear to be particularly relevant in influencing the outcomes of many morbid forms. Today, the inclusion of gender in biomedical research, to improve the scientific quality and scientific relevance of knowledge, of technology is an increasingly present element precisely due to the practical implications that derive from it. Gender differences describe the biological variability between women and men, which is, in turn, related to differences in the information contained in sex chromosomes, the specific gene expression of autosomes linked to sex, the different number and quality of sex hormones, and their different effects on systems and organs, without neglecting the fact that each of the sexes has different target organs on which these hormones act. Additionally, both genders undergo metabolic changes throughout their lives, and this is especially true for women who show more dramatic changes due to their role in reproduction. Gender differences are not only the result of our genetic makeup but are also mixed with socio-cultural habits, behaviors, and lifestyles, differences between women and men, exposure to specific environmental influences, different food and lifestyle styles or stress, or different attitude in compliance with treatments and disease prevention campaigns. Gender differences also affect behavior throughout life, and physical changes can have implications for lifestyle, social roles, and mental health. Therefore, determinism and therapeutic outcome in chronic diseases are influenced by a complex combination of biological and environmental factors, not forgetting that there are many interactions of social and biological factors in women and men. This review will address the role of gender differences in the management of various forms of diabetes and its complications considering the different biological functions of hormones, the difference in body composition, physiological differences in glucose and fat metabolism, also considering the role of the microbiota. intestinal, as well as the description of gestational diabetes linked to possible pathophysiological events typical of reproduction.
Transcriptome Analysis Reveals Contrasting Plant Responses of Sorghum bicolor upon Colonization by Two Formae Speciales of Sporisorium reilianum
Authors: Poloni Alana , Garde Ravindra , Dittiger Lukas Dorian , Heidrich Theresa , Müller Christian , Drechsler Frank , Zhao Yulei , Mazumdar Tilottama , Schirawski Jan
Published: August 2022

The biotrophic fungus Sporisorium reilianum exists in two host-adapted formae speciales that cause head smut in maize (S. reilianum f. sp. zeae; SRZ) and sorghum (S. reilianum f. sp. reilianum; SRS). In sorghum, the spread of SRZ is limited to the leaves. To understand the plant responses to each forma specialis, we determined the transcriptome of sorghum leaves inoculated either with SRS or SRZ. Fungal inoculation led to gene expression rather than suppression in sorghum. SRZ induced a much greater number of genes than SRS. Each forma specialis induced a distinct set of plant genes. The SRZ-induced genes were involved in plant defense mainly at the plasma membrane and were associated with the Molecular Function Gene Ontology terms chitin binding, abscisic acid binding, protein phosphatase inhibitor activity, terpene synthase activity, chitinase activity, transmembrane transporter activity and signaling receptor activity. Specifically, we found an upregulation of the genes involved in phospholipid degradation and sphingolipid biosynthesis, suggesting that the lipid content of the plant plasma membrane may contribute to preventing the systemic spread of SRZ. In contrast, the colonization of sorghum with SRS increased the expression of the genes involved in the detoxification of cellular oxidants and in the unfolded protein response at the endoplasmic reticulum, as well as of the genes modifying the cuticle wax and lipid composition through the generation of alkanes and phytosterols. These results identified plant compartments that may have a function in resistance against SRZ (plasma membrane) and susceptibility towards SRS (endoplasmic reticulum) that need more attention in the future.
Identification of Key Functions Required for Production and Utilization of the Siderophore Piscibactin Encoded by the High-Pathogenicity Island irp-HPI in Vibrionaceae
Authors: Lages Marta A. , Ageitos Lucía , Rodríguez Jaime , Jiménez Carlos , Lemos Manuel L. , Balado Miguel
Published: August 2022

Piscibactin is a widespread siderophore system present in many different bacteria, especially within the Vibrionaceae family. Previous works showed that most functions required for biosynthesis and transport of this siderophore are encoded by the high-pathogenicity island irp-HPI. In the present work, using Vibrio anguillarum as a model, we could identify additional key functions encoded by irp-HPI that are necessary for piscibactin production and transport and that have remained unknown. Allelic exchange mutagenesis, combined with cross-feeding bioassays and LC-MS analysis, were used to demonstrate that Irp4 protein is an essential component for piscibactin synthesis since it is the thioesterase required for nascent piscibactin be released from the NRPS Irp1. We also show that Irp8 is a MFS-type protein essential for piscibactin secretion. In addition, after passage through the outer membrane transporter FrpA, the completion of ferri-piscibactin internalization through the inner membrane would be achieved by the ABC-type transporter FrpBC. The expression of this transporter is coordinated with the expression of FrpA and with the genes encoding biosynthetic functions. Since piscibactin is a major virulence factor of some pathogenic vibrios, the elements of biosynthesis and transport described here could be additional interesting targets for the design of novel antimicrobials against these bacterial pathogens.
Transcript-Targeted Therapy Based on RNA Interference and Antisense Oligonucleotides: Current Applications and Novel Molecular Targets
Authors: Barresi Vincenza , Musmeci Camillo , Rinaldi Alessandro , Condorelli Daniele Filippo
Published: August 2022

The development of novel target therapies based on the use of RNA interference (RNAi) and antisense oligonucleotides (ASOs) is growing in an exponential way, challenging the chance for the treatment of the genetic diseases and cancer by hitting selectively targeted RNA in a sequence-dependent manner. Multiple opportunities are taking shape, able to remove defective protein by silencing RNA (e.g., Inclisiran targets mRNA of protein PCSK9, permitting a longer half-life of LDL receptors in heterozygous familial hypercholesteremia), by arresting mRNA translation (i.e., Fomivirsen that binds to UL123-RNA and blocks the translation into IE2 protein in CMV-retinitis), or by reactivating modified functional protein (e.g., Eteplirsen able to restore a functional shorter dystrophin by skipping the exon 51 in Duchenne muscular dystrophy) or a not very functional protein. In this last case, the use of ASOs permits modifying the expression of specific proteins by modulating splicing of specific pre-RNAs (e.g., Nusinersen acts on the splicing of exon 7 in SMN2 mRNA normally not expressed; it is used for spinal muscular atrophy) or by downregulation of transcript levels (e.g., Inotersen acts on the transthryretin mRNA to reduce its expression; it is prescribed for the treatment of hereditary transthyretin amyloidosis) in order to restore the biochemical/physiological condition and ameliorate quality of life. In the era of precision medicine, recently, an experimental splice-modulating antisense oligonucleotide, Milasen, was designed and used to treat an 8-year-old girl affected by a rare, fatal, progressive form of neurodegenerative disease leading to death during adolescence. In this review, we summarize the main transcriptional therapeutic drugs approved to date for the treatment of genetic diseases by principal regulatory government agencies and recent clinical trials aimed at the treatment of cancer. Their mechanism of action, chemical structure, administration, and biomedical performance are predominantly discussed.
Standing Genetic Diversity and Transmission Bottleneck Size Drive Adaptation in Bacteriophage Qβ
Authors: Somovilla Pilar , Rodríguez-Moreno Alicia , Arribas María , Manrubia Susanna , Lázaro Ester
Published: August 2022

A critical issue to understanding how populations adapt to new selective pressures is the relative contribution of the initial standing genetic diversity versus that generated de novo. RNA viruses are an excellent model to study this question, as they form highly heterogeneous populations whose genetic diversity can be modulated by factors such as the number of generations, the size of population bottlenecks, or exposure to new environment conditions. In this work, we propagated at nonoptimal temperature (43 °C) two bacteriophage Qβ populations differing in their degree of heterogeneity. Deep sequencing analysis showed that, prior to the temperature change, the most heterogeneous population contained some low-frequency mutations that had previously been detected in the consensus sequences of other Qβ populations adapted to 43 °C. Evolved populations with origin in this ancestor reached similar growth rates, but the adaptive pathways depended on the frequency of these standing mutations and the transmission bottleneck size. In contrast, the growth rate achieved by populations with origin in the less heterogeneous ancestor did depend on the transmission bottleneck size. The conclusion is that viral diversification in a particular environment may lead to the emergence of mutants capable of accelerating adaptation when the environment changes.
Cytokine Storm Signature in Patients with Moderate and Severe COVID-19
Authors: Kalinina Olga , Golovkin Alexey , Zaikova Ekaterina , Aquino Arthur , Bezrukikh Vadim , Melnik Olesya , Vasilieva Elena , Karonova Tatiana , Kudryavtsev Igor , Shlyakhto Evgeny
Published: August 2022

Hypercytokinemia, found in SARS-CoV-2 infection, contributes to multiple organ dysfunctions with acute respiratory distress syndrome, shock etc. The aim of this study was to describe cytokine storm signatures in patients with acute COVID-19 and to investigate their influence on severity of the infection. Plasma levels of 47 cytokines were investigated in 73 patients with moderate and severe COVID-19 (41 and 32, respectively) and 11 healthy donors (HD). The most elevated levels comparing patients and the HD were observed for seven pro-inflammatory cytokines (IL-6, IL-8, IL-15, IL-18, IL-27, IFNγ, TNFα), three chemokines (GROα, IP-10, MIG), two anti-inflammatory cytokines (IL-1RA, IL-10), and two growth factors (G-CSF, M-CSF). The patients with severe disease had significantly higher levels of FGF-2/FGF-basic, IL-1β, and IL-7 compared to the HD. The two groups of patients differed from each other only based on the levels of EGF, eotaxin, and IL-12 p40. Pneumonia lung injury, characterized by computer tomography, positively correlated with levels of EGF, IP-10, MCP-3 levels and negatively with IL-12 p40. Pro-inflammatory factors including IL-6, TNFα, and IP-10 negatively correlated with the frequency of the circulating T-helper17-like cells (Th17-like) and follicular Th cells that are crucial to develop SARS-CoV-2-specific plasma cells and memory B cells. Obtained data on the cytokine levels illustrate their influence on progression and severity of COVID-19.
ACBD3 Bioinformatic Analysis and Protein Expression in Breast Cancer Cells
Authors: Houghton-Gisby Jack , Kerslake Rachel , Karteris Emmanouil , Mokbel Kefah , Harvey Amanda J.
Published: August 2022

ACBD3 overexpression has previously been found to correlate with worse prognosis for breast cancer patients and, as an incredibly diverse protein in both function and cellular localisation, ACBD3 may have a larger role in breast cancer than previously thought. This study further investigated ACBD3′s role in breast cancer. Bioinformatic databases were queried to characterise ACBD3 expression and mutation in breast cancer and to investigate how overexpression affects breast cancer patient outcomes. Immunohistochemistry was carried out to examine ACBD3 location within cells and tissue structures. ACBD3 was more highly expressed in breast cancer than in any other cancer or matched normal tissue, and expression over the median level resulted in reduced relapse-free, overall, and distant metastasis-free survival for breast cancer patients as a whole, with some differences observed between subtypes. IHC analysis found that ACBD3 levels varied based on hormone receptor status, indicating that ACBD3 could be a candidate biomarker for poor patient prognosis in breast cancer and may possibly be a biomarker for ER signal reprogramming of precancerous breast tissue.
Increased Expression of Interferon-Induced Transmembrane 3 (IFITM3) in Stroke and Other Inflammatory Conditions in the Brain
Authors: Harmon Elisabeth , Doan Andrea , Bautista-Garrido Jesus , Jung Joo Eun , Marrelli Sean P. , Kim Gab Seok
Published: August 2022

Microglia, the resident innate immune cells of the brain, become more highly reactive with aging and diseased conditions. In collaboration with other cell types in brains, microglia can contribute both to worsened outcome following stroke or other neurodegenerative diseases and to the recovery process by changing their phenotype toward reparative microglia. Recently, IFITM3 (a member of the “interferon-inducible transmembrane” family) has been revealed as a molecular mediator between amyloid pathology and neuroinflammation. Expression of IFITM3 in glial cells, especially microglia following stroke, is not well described. Here, we present evidence that ischemic stroke causes an increase in IFITM3 expression along with increased microglial activation marker genes in aged brains. To further validate the induction of IFITM3 in post-stroke brains, primary microglia and microglial-like cells were exposed to a variety of inflammatory conditions, which significantly induced IFITM3 as well as other inflammatory markers. These findings suggest the critical role of IFITM3 in inducing inflammation. Our findings on the expression of IFITM3 in microglia and in aged brains following stroke could establish the basic foundations for the role of IFITM3 in a variety of neurodegenerative diseases, particularly those that are prevalent or enhanced in the aged brain.
Chaperone-Mediated Autophagy in Pericytes: A Key Target for the Development of New Treatments against Glioblastoma Progression
Authors: Salinas María Dolores , Valdor Rut
Published: August 2022

Glioblastoma (GB) cells physically interact with peritumoral pericytes (PCs) present in the brain microvasculature. These interactions facilitate tumor cells to aberrantly increase and benefit from chaperone-mediated autophagy (CMA) in the PC. GB-induced CMA leads to major changes in PC immunomodulatory phenotypes, which, in turn, support cancer progression. In this review, we focus on the consequences of the GB-induced up-regulation of CMA activity in PCs and evaluate how manipulation of this process could offer new strategies to fight glioblastoma, increasing the availability of treatments for this cancer that escapes conventional therapies. We finally discuss the use of modified PCs unable to increase CMA in response to GB as a cell therapy alternative to minimize undesired off-target effects associated with a generalized CMA inhibition.
Ex Vivo Feedback Control of Neurotransmission Using a Photocaged Adenosine A1 Receptor Agonist
Authors: Craey Erine , Hulpia Fabian , Spanoghe Jeroen , Manzella Simona , Larsen Lars E. , Sprengers Mathieu , De Bundel Dimitri , Smolders Ilse , Carrette Evelien , Delbeke Jean , Vonck Kristl , Boon Paul , Van Calenbergh Serge , Wadman Wytse J. , Raedt Robrecht
Published: August 2022

We report the design, synthesis, and validation of the novel compound photocaged N6-cyclopentyladenosine (cCPA) to achieve precisely localized and timed release of the parent adenosine A1 receptor agonist CPA using 405 nm light. Gi protein-coupled A1 receptors (A1Rs) modulate neurotransmission via pre- and post-synaptic routes. The dynamics of the CPA-mediated effect on neurotransmission, characterized by fast activation and slow recovery, make it possible to implement a closed-loop control paradigm. The strength of neurotransmission is monitored as the amplitude of stimulus-evoked local field potentials. It is used for feedback control of light to release CPA. This system makes it possible to regulate neurotransmission to a pre-defined level in acute hippocampal brain slices incubated with 3 µM cCPA. This novel approach of closed-loop photopharmacology holds therapeutic potential for fine-tuned control of neurotransmission in diseases associated with neuronal hyperexcitability.
Thermodynamic Swings: How Ideal Complex of Cas9–RNA/DNA Forms
Authors: Zhdanova Polina V. , Lomzov Alexander A. , Prokhorova Daria V. , Stepanov Grigory A. , Chernonosov Alexander A. , Koval Vladimir V.
Published: August 2022

Most processes of the recognition and formation of specific complexes in living systems begin with collisions in solutions or quasi-solutions. Then, the thermodynamic regulation of complex formation and fine tuning of complexes come into play. Precise regulation is very important in all cellular processes, including genome editing using the CRISPR–Cas9 tool. The Cas9 endonuclease is an essential component of the CRISPR–Cas-based genome editing systems. The attainment of high-specificity and -efficiency Cas9 during targeted DNA cleavage is the main problem that limits the practical application of the CRISPR–Cas9 system. In this study, we analyzed the thermodynamics of interaction of a complex’s components of Cas9–RNA/DNA through experimental and computer simulation methods. We found that there is a small energetic preference during Cas9–RNA/DNA formation from the Cas9–RNA and DNA/DNA duplex. The small difference in binding energy is relevant for biological interactions and could be part of the sequence-specific recognition of double-stranded DNA by the CRISPR–Cas9 system.
Nervous System-Driven Osseointegration
Authors: Sun Ruoyue , Bai Long , Yang Yaru , Ding Yanshu , Zhuang Jingwen , Cui Jingyuan
Published: August 2022

Implants are essential therapeutic tools for treating bone fractures and joint replacements. Despite the in-depth study of osseointegration for more than fifty years, poor osseointegration caused by aseptic loosening remains one of the leading causes of late implant failures. Osseointegration is a highly sophisticated and spatiotemporal process in vivo involving the immune response, angiogenesis, and osteogenesis. It has been unraveled that the nervous system plays a pivotal role in skeletal health via manipulating neurotrophins, neuropeptides, and nerve cells. Herein, the research related to nervous system-driven osseointegration was systematically analyzed and reviewed, aiming to demonstrate the prominent role of neuromodulation in osseointegration. Additionally, it is indicated that the implant design considering the role of neuromodulation might be a promising way to prevent aseptic loosening.
Highly Stretchable and Sensitive Flexible Strain Sensor Based on Fe NWs/Graphene/PEDOT:PSS with a Porous Structure
Authors: Yang Ping’an , Xiang Sha , Li Rui , Ruan Haibo , Chen Dachao , Zhou Zhihao , Huang Xin , Liu Zhongbang
Published: August 2022

With the rapid development of wearable smart electronic products, high-performance wearable flexible strain sensors are urgently needed. In this paper, a flexible strain sensor device with Fe NWs/Graphene/PEDOT:PSS material added under a porous structure was designed and prepared. The effects of adding different sensing materials and a different number of dips with PEDOT:PSS on the device performance were investigated. The experiments show that the flexible strain sensor obtained by using Fe NWs, graphene, and PEDOT:PSS composite is dipped in polyurethane foam once and vacuum dried in turn with a local linearity of 98.8%, and the device was stable up to 3500 times at 80% strain. The high linearity and good stability are based on the three-dimensional network structure of polyurethane foam, combined with the excellent electrical conductivity of Fe NWs, the bridging and passivation effects of graphene, and the stabilization effect of PEDOT:PSS, which force the graphene-coated Fe NWs to adhere to the porous skeleton under the action of PEDOT:PSS to form a stable three-dimensional conductive network. Flexible strain sensor devices can be applied to smart robots and other fields and show broad application prospects in intelligent wearable devices.
Recent Advances Regarding the Molecular Mechanisms of Triterpenic Acids: A Review (Part II)
Authors: Mioc Marius , Prodea Alexandra , Racoviceanu Roxana , Mioc Alexandra , Ghiulai Roxana , Milan Andreea , Voicu Mirela , Mardale Gabriel , Șoica Codruța
Published: August 2022

Triterpenic acids are a widespread class of phytocompounds which have been found to possess valuable therapeutic properties such as anticancer, anti-inflammatory, hepatoprotective, cardioprotective, antidiabetic, neuroprotective, lipolytic, antiviral, and antiparasitic effects. They are a subclass of triterpenes bearing a characteristic lipophilic structure that imprints unfavorable in vivo properties which subsequently limit their applications. The early investigation of the mechanism of action (MOA) of a drug candidate can provide valuable information regarding the possible side effects and drug interactions that may occur after administration. The current paper aimed to summarize the most recent (last 5 years) studies regarding the MOA of betulinic acid, boswellic acid, glycyrrhetinic acid, madecassic acid, moronic acid, and pomolic acid in order to provide scientists with updated and accessible material on the topic that could contribute to the development of future studies; the paper stands as the sequel of our previously published paper regarding the MOA of triterpenic acids with therapeutic value. The recent literature published on the topic has highlighted the role of triterpenic acids in several signaling pathways including PI3/AKT/mTOR, TNF-alpha/NF-kappa B, JNK-p38, HIF-α/AMPK, and Grb2/Sos/Ras/MAPK, which trigger their various biological activities.
Recombinant FGF21 Attenuates Polychlorinated Biphenyl-Induced NAFLD/NASH by Modulating Hepatic Lipocalin-2 Expression
Authors: Kim Hye Young , Yoo Young Hyun
Published: August 2022

Although recent studies have demonstrated that polychlorinated biphenyls (PCB) exposure leads to toxicant-associated steatohepatitis, the underlying mechanism of this condition remains unsolved. Male C57Bl/6 mice fed a standard diet (SD) or 60% high fat diet (HFD) were exposed to the nondioxin-like PCB mixture Aroclor1260 or dioxin-like PCB congener PCB126 by intraperitoneal injection for a total of four times for six weeks. We observed hepatic injury, steatosis, inflammation, and fibrosis in not only the Aroclor1260-treated mice fed a HFD but the PCB126-treated mice fed either a SD or a HFD. We also observed that both types of PCB exposure induced hepatic iron overload (HIO). Noticeably, the expression of hepatic lipocalin-2 (LCN2) was significantly increased in the PCB-induced nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) models. The knockdown of LCN2 resulted in improvement of PCB-induced lipid and iron accumulation in vitro, suggesting that LCN2 plays a pivotal role in PCB-induced NAFLD/NASH. We observed that recombinant FGF21 improved hepatic steatosis and HIO in the PCB-induced NAFLD/NASH models. Importantly, recombinant FGF21 reduced the PCB-induced overexpression of hepatic LCN2 in vivo and in vitro. Our findings indicate that recombinant FGF21 attenuates PCB-induced NAFLD/NASH by modulating hepatic lipocalin-2 expression. Our data suggest that hepatic LCN2 might represent a suitable therapeutic target for improving PCB-induced NAFLD/NASH accompanying HIO.
IL11 Stimulates IL33 Expression and Proinflammatory Fibroblast Activation across Tissues
Authors: Widjaja Anissa A. , Chothani Sonia , Viswanathan Sivakumar , Goh Joyce Wei Ting , Lim Wei-Wen , Cook Stuart A.
Published: August 2022

Interleukin 11 (IL11) is upregulated in inflammatory conditions, where it is mostly believed to have anti-inflammatory activity. However, recent studies suggest instead that IL11 promotes inflammation by activating fibroblasts. Here, we assessed whether IL11 is pro- or anti-inflammatory in fibroblasts. Primary cultures of human kidney, lung or skin fibroblasts were stimulated with IL11 that resulted in the transient phosphorylation of signal transducer and activator of transcription 3 (STAT3) and the sustained activation of extracellular signal-regulated protein kinases (ERK). RNA sequencing over a time course of IL11 stimulation revealed a robust but short-lived transcriptional response that was enriched for gene set hallmarks of inflammation and characterized by the upregulation of SERPINB2, TNFRSF18, Interleukin 33 (IL33), CCL20, IL1RL1, CXCL3/5/8, ICAM1 and IL11 itself. IL33 was the most upregulated signaling factor (38-fold, p = 9.8 × 10−5), and IL1RL1, its cognate receptor, was similarly increased (18-fold, p = 1.1 × 10−34). In proteomic studies, IL11 triggered a proinflammatory secretome with the notable upregulation of IL8, IL6, MCP1, CCL20 and CXCL1/5/6, which are important chemotaxins for neutrophils, monocytes, and lymphocytes. IL11 induced IL33 expression across fibroblast types, and the inhibition of STAT3 but not of MEK/ERK prevented this. These data establish IL11 as pro-inflammatory with specific importance for priming the IL33 alarmin response in inflammatory fibroblasts across tissues.
Cellular Electrical Impedance as a Method to Decipher CCR7 Signalling and Biased Agonism
Authors: Vanalken Nathan , Boon Katrijn , Doijen Jordi , Schols Dominique , Van Loy Tom
Published: August 2022

The human C-C chemokine receptor type 7 (CCR7) has two endogenous ligands, C-C chemokine ligand 19 (CCL19) and CCL21, displaying biased agonism reflected by a pronounced difference in the level of β-arrestin recruitment. Detecting this preferential activation generally requires the use of separate, pathway-specific label-based assays. In this study, we evaluated an alternative methodology to study CCR7 signalling. Cellular electrical impedance (CEI) is a label-free technology which yields a readout that reflects an integrated cellular response to ligand stimulation. CCR7-expressing HEK293 cells were stimulated with CCL19 or CCL21, which induced distinct impedance profiles with an apparent bias during the desensitisation phase of the response. This discrepancy was mainly modulated by differential β-arrestin recruitment, which shaped the impedance profile but did not seem to contribute to it directly. Pathway deconvolution revealed that Gαi-mediated signalling contributed most to the impedance profile, but Gαq- and Gα12/13-mediated pathways were also involved. To corroborate these results, label-based pathway-specific assays were performed. While CCL19 more potently induced β-arrestin2 recruitment and receptor internalisation than CCL21, both chemokines showed a similar level of Gαi protein activation. Altogether, these findings indicate that CEI is a powerful method to analyse receptor signalling and biased agonism.
Externalization of Mitochondrial PDCE2 on Irradiated Endothelium as a Target for Radiation-Guided Drug Delivery and Precision Thrombosis of Pathological Vasculature
Authors: Faqihi Fahimeh , Stoodley Marcus A. , McRobb Lucinda S.
Published: August 2022

Endothelial cells are highly sensitive to ionizing radiation, and exposure leads to multiple adaptive changes. Remarkably, part of this response is the translocation of normally intracellular proteins to the cell surface. It is unclear whether this ectopic expression has a protective or deleterious function, but, regardless, these surface-exposed proteins may provide unique discriminatory targets for radiation-guided drug delivery to vascular malformations or tumor vasculature. We investigated the ability of an antibody–thrombin conjugate targeting mitochondrial PDCE2 (E2 subunit of pyruvate dehydrogenase) to induce precision thrombosis on irradiated endothelial cells in a parallel-plate flow system. Click-chemistry was used to create antibody–thrombin conjugates targeting PDCE2 as the vascular targeting agent (VTA). VTAs were injected into the parallel-plate flow system with whole human blood circulating over irradiated cells. The efficacy and specificity of fibrin-thrombus formation was assessed relative to non-irradiated controls. The PDCE2-targeting VTA dose-dependently increased thrombus formation: minimal thrombosis was induced in response to 5 Gy radiation; doses of 15 and 25 Gy induced significant thrombosis with equivalent efficacy. Negligible VTA binding or thrombosis was demonstrated in the absence of radiation or with non-targeted thrombin. PDCE2 represents a unique discriminatory target for radiation-guided drug delivery and precision thrombosis in pathological vasculature.
Ectodysplasin A (EDA) Signaling: From Skin Appendage to Multiple Diseases
Authors: Yang Ruihan , Mei Yilan , Jiang Yuhan , Li Huiling , Zhao Ruixi , Sima Jian , Yao Yuyuan
Published: August 2022

Ectodysplasin A (EDA) signaling is initially identified as morphogenic signaling regulating the formation of skin appendages including teeth, hair follicles, exocrine glands in mammals, feathers in birds and scales in fish. Gene mutation in EDA signaling causes hypohidrotic ectodermal dysplasia (HED), a congenital hereditary disease with malformation of skin appendages. Interestingly, emerging evidence suggests that EDA and its receptors can modulate the proliferation, apoptosis, differentiation and migration of cancer cells, and thus may regulate tumorigenesis and cancer progression. More recently, as a newly discovered hepatocyte factor, EDA pathway has been demonstrated to be involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and type II diabetes by regulating glucose and lipid metabolism. In this review, we summarize the function of EDA signaling from skin appendage development to multiple other diseases, and discuss the clinical application of recombinant EDA protein as well as other potential targets for disease intervention.
Biochemical Hazards during Three Phases of Assisted Reproductive Technology: Repercussions Associated with Epigenesis and Imprinting
Authors: Menezo Yves , Elder Kay , Clement Patrice , Clement Arthur , Patrizio Pasquale
Published: August 2022

Medically assisted reproduction, now considered a routine, successful treatment for infertility worldwide, has produced at least 8 million live births. However, a growing body of evidence is pointing toward an increased incidence of epigenetic/imprinting disorders in the offspring, raising concern that the techniques involved may have an impact on crucial stages of early embryo and fetal development highly vulnerable to epigenetic influence. In this paper, the key role of methylation processes in epigenesis, namely the essential biochemical/metabolic pathways involving folates and one-carbon cycles necessary for correct DNA/histone methylation, is discussed. Furthermore, potential contributors to epigenetics dysregulation during the three phases of assisted reproduction: preparation for and controlled ovarian hyperstimulation (COH); methylation processes during the preimplantation embryo culture stages; the effects of unmetabolized folic acid (UMFA) during embryogenesis on imprinting methyl “tags”, are described. Advances in technology have opened a window into developmental processes that were previously inaccessible to research: it is now clear that ART procedures have the potential to influence DNA methylation in embryonic and fetal life, with an impact on health and disease risk in future generations. Critical re-evaluation of protocols and procedures is now an urgent priority, with a focus on interventions targeted toward improving ART procedures, with special attention to in vitro culture protocols and the effects of excessive folic acid intake.
Human Umbilical Cord Lining-Derived Epithelial Cells: A Potential Source of Non-Native Epithelial Cells That Accelerate Healing in a Porcine Cutaneous Wound Model
Authors: Kua Jonah Ee Hsiang , Siow Chun Wei , Lim Wee Keng , Masilamani Jeyakumar , Tjin Monica Suryana , Yeong Joe , Lim Tony Kiat Hon , Phan Toan Thang , Chua Alvin Wen Choong
Published: August 2022

Human umbilical cord lining epithelial cells [CLECs) are naïve in nature and can be ethically recovered from cords that are routinely discarded. The success of using oral mucosal epithelial cells for cornea defects hints at the feasibility of treating cutaneous wounds using non-native CLECs. Herein, we characterized CLECs using flow cytometry (FC) and skin organotypic cultures in direct comparison with skin keratinocytes (KCs). This was followed by wound healing study to compare the effects of CLEC application and the traditional use of human skin allografts (HSGs) in a porcine wound model. While CLECs were found to express all the epidermal cell markers probed, the major difference between CLECs and KCs lies in the level of expression (in FC analysis) as well as in the location of expression (of the epithelium in organotypic cultures) of some of the basal cell markers probed. On the pig wounds, CLEC application promoted accelerated healing with no adverse reaction compared to HSG use. Though CLECs, like HSGs, elicited high levels of local and systemic immune responses in the animals during the first week, these effects were tapered off more quickly in the CLEC-treated group. Overall, the in vivo porcine data point to the potential of CLECs as a non-native and safe source of cells to treat cutaneous wounds.
Low-Density Lipoprotein Receptor-Related Protein 8 at the Crossroad between Cancer and Neurodegeneration
Authors: Passarella Daniela , Ciampi Silvia , Di Liberto Valentina , Zuccarini Mariachiara , Ronci Maurizio , Medoro Alessandro , Foderà Emanuele , Frinchi Monica , Mignogna Donatella , Russo Claudio , Porcile Carola
Published: August 2022

The low-density-lipoprotein receptors represent a family of pleiotropic cell surface receptors involved in lipid homeostasis, cell migration, proliferation and differentiation. The family shares common structural features but also has significant differences mainly due to tissue-specific interactors and to peculiar proteolytic processing. Among the receptors in the family, recent studies place low-density lipoprotein receptor-related protein 8 (LRP8) at the center of both neurodegenerative and cancer-related pathways. From one side, its overexpression has been highlighted in many types of cancer including breast, gastric, prostate, lung and melanoma; from the other side, LRP8 has a potential role in neurodegeneration as apolipoprotein E (ApoE) and reelin receptor, which are, respectively, the major risk factor for developing Alzheimer’s disease (AD) and the main driver of neuronal migration, and as a γ-secretase substrate, the main enzyme responsible for amyloid formation in AD. The present review analyzes the contributions of LDL receptors, specifically of LRP8, in both cancer and neurodegeneration, pointing out that depending on various interactions and peculiar processing, the receptor can contribute to both proliferative and neurodegenerative processes.