bluuebunny/crossref_metadata_2025 huggingface dataset:
Public Perceptions of Flavored Waterpipe Smoking on Twitter
Authors: Feliciano Juan Ramon , Li Dongmei , Xie Zidian
Published: March 2023

Waterpipe tobacco smoking has become increasingly popular in recent years, especially among youth. We aimed to understand longitudinal trends in the prevalence and user perception of waterpipes and their flavors on Twitter. We extracted waterpipe-related tweets from March 2021 to May 2022 using the Twitter Streaming API and classified them into promotional tweets and non-promotional tweets. We examined the longitudinal trends regarding the waterpipe flavors mentioned on Twitter and conducted sentiment analysis on each waterpipe flavor-related non-promotional tweet. Among over 1.3 million waterpipe-related tweets, 1,158,884 tweets were classified as non-promotional and 235,132 were classified as promotional. The most frequently mentioned waterpipe flavor groups were fruit (34%), sweets (17%), and beverages (15%) among all flavor-containing non-promotional tweets (17,746 tweets). The least mentioned flavor groups were tobacco (unflavored, 4%) and spices (2%). Sentiment analysis showed that among non-promotional waterpipe-related tweets, 39% were neutral, 36% were positive, and 23% were negative. The most preferred waterpipe flavors were fruit, mixed, and alcohol flavors. The least preferred flavor groups were tobacco and spice flavors. Our study provided valuable information on the prevalence of waterpipe flavors that can be used to support the future regulation of flavored waterpipe tobacco products given the nature of the current regulations on other flavored tobacco products.
Towards the Influence of Media on Suicidality: A Systematic Review of Netflix’s ‘Thirteen Reasons Why’
Authors: Guinovart Martí , Cobo Jesús , González-Rodríguez Alexandre , Parra-Uribe Isabel , Palao Diego
Published: March 2023

Online streaming series ‘Thirteen Reasons Why’ (13RW), released in March 2017, was criticized for its sensationalist portrayal of the main character’s suicide, leading some people to voice fears of a global contagion of self-harm behaviors. The current investigation provides a systematic review of original studies analyzing the role of 13RW as an influencing factor for suicide. Articles were identified through a systematic search of Medline, Web of Science, Scopus, PsycInfo, and a manual search of reference lists from inception until the 16 January 2023. Twenty-seven published articles were identified from an initial search of 496 studies. The positive effects of watching 13RW included a reduction in suicide stigma and a greater likelihood to discuss mental health concerns and seek for help. However, several studies reported negative outcomes, including significant increases in the rate of deaths by suicide in adolescents, the number of admissions for suicidal reasons, and the prevalence and severity of suicidal ideation and self-harm behaviors in vulnerable viewers. Still, due to methodological limitations, no causal relationship could be established. Preventive measures are required to alert of the risk and should be particularly addressed to susceptible subjects. Psychoeducational programs should be focused on this kind of phenomena in vulnerable populations.
Reimagining Healthcare: Human–Animal Bond Support as a Primary, Secondary, and Tertiary Public Health Intervention
Authors: Hoy-Gerlach Janet , Townsend Lisa
Published: March 2023

The emergence of human–animal support services (HASS)—services provided to help keep people and their companion animals together—in the United States has been driven by two global public health crises. Despite such impetuses and an increasing recognition of One Health approaches, HASS are generally not recognized as public health interventions. The Ottawa Charter, defining health as well-being and resources for living and calling for cross-sector action to advance such, provides a clear rationale for locating HASS within a public health framework. Drawing from Ottawa Charter tenets and using the United States as a case study, we: (1) recognize and explicate HASS as public health resources for human and animal well-being and (2) delineate examples of HASS within the three-tiered public health intervention framework. HASS examples situated in the three-tier framework reveal a public health continuum for symbiotic well-being and health. Humans and their respective companion animals may need different levels of intervention to optimize mutual well-being. Tenets of the Ottawa Charter provide a clear rationale for recognizing and promoting HASS as One Health public health interventions; doing so enables cross-sector leveraging of resources and offers a symbiotic strategy for human and animal well-being.
Galectin-9 in Gastroenterological Cancer
Authors: Morishita Asahiro , Oura Kyoko , Tadokoro Tomoko , Shi Tingting , Fujita Koji , Tani Joji , Atsukawa Masanori , Masaki Tsutomu
Published: March 2023

Immunochemotherapy has become popular in recent years. The detailed mechanisms of cancer immunity are being elucidated, and new developments are expected in the future. Apoptosis allows tissues to maintain their form, quantity, and function by eliminating excess or abnormal cells. When apoptosis is inhibited, the balance between cell division and death is disrupted and tissue homeostasis is impaired. This leads to dysfunction and the accumulation of genetically abnormal cells, which can contribute to carcinogenesis. Lectins are neither enzymes nor antibodies but proteins that bind sugar chains. Among soluble endogenous lectins, galectins interact with cell surface sugar chains outside the cell to regulate signal transduction and cell growth. On the other hand, intracellular lectins are present at the plasma membrane and regulate signal transduction by regulating receptor–ligand interactions. Galectin-9 expressed on the surface of thymocytes induces apoptosis of T lymphocytes and plays an essential role in immune self-tolerance by negative selection in the thymus. Furthermore, the administration of extracellular galectin-9 induces apoptosis of human cancer and immunodeficient cells. However, the detailed pharmacokinetics of galectin-9 in vivo have not been elucidated. In addition, the cell surface receptors involved in galectin-9-induced apoptosis of cancer cells have not been identified, and the intracellular pathways involved in apoptosis have not been fully investigated. We have previously reported that galectin-9 induces apoptosis in various gastrointestinal cancers and suppresses tumor growth. However, the mechanism of galectin-9 and apoptosis induction in gastrointestinal cancers and the detailed mechanisms involved in tumor growth inhibition remain unknown. In this article, we review the effects of galectin-9 on gastrointestinal cancers and its mechanisms.
Iron Acquisition and Metabolism as a Promising Target for Antimicrobials (Bottlenecks and Opportunities): Where Do We Stand?
Authors: Stelitano Giovanni , Cocorullo Mario , Mori Matteo , Villa Stefania , Meneghetti Fiorella , Chiarelli Laurent Roberto
Published: March 2023

The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) infections is one of the most crucial challenges currently faced by the scientific community. Developments in the fundamental understanding of their underlying mechanisms may open new perspectives in drug discovery. In this review, we conducted a systematic literature search in PubMed, Web of Science, and Scopus, to collect information on innovative strategies to hinder iron acquisition in bacteria. In detail, we discussed the most interesting targets from iron uptake and metabolism pathways, and examined the main chemical entities that exhibit anti-infective activities by interfering with their function. The mechanism of action of each drug candidate was also reviewed, together with its pharmacodynamic, pharmacokinetic, and toxicological properties. The comprehensive knowledge of such an impactful area of research will hopefully reflect in the discovery of newer antibiotics able to effectively tackle the antimicrobial resistance issue.
Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands
Authors: Shpakov Alexander O.
Published: March 2023

Allosteric regulation is critical for the functioning of G protein-coupled receptors (GPCRs) and their signaling pathways. Endogenous allosteric regulators of GPCRs are simple ions, various biomolecules, and protein components of GPCR signaling (G proteins and β-arrestins). The stability and functional activity of GPCR complexes is also due to multicenter allosteric interactions between protomers. The complexity of allosteric effects caused by numerous regulators differing in structure, availability, and mechanisms of action predetermines the multiplicity and different topology of allosteric sites in GPCRs. These sites can be localized in extracellular loops; inside the transmembrane tunnel and in its upper and lower vestibules; in cytoplasmic loops; and on the outer, membrane-contacting surface of the transmembrane domain. They are involved in the regulation of basal and orthosteric agonist-stimulated receptor activity, biased agonism, GPCR-complex formation, and endocytosis. They are targets for a large number of synthetic allosteric regulators and modulators, including those constructed using molecular docking. The review is devoted to the principles and mechanisms of GPCRs allosteric regulation, the multiplicity of allosteric sites and their topology, and the endogenous and synthetic allosteric regulators, including autoantibodies and pepducins. The allosteric regulation of chemokine receptors, proteinase-activated receptors, thyroid-stimulating and luteinizing hormone receptors, and beta-adrenergic receptors are described in more detail.
Clonal Spreading of ST42 Staphylococcus haemolyticus Strains Occurs Possibly Due to fusB and tetK Resistant Genes and Capsule-Related Genes
Authors: Lin Lee-Chung , Chang Shih-Cheng , Ou Yu-Hsiang , Liu Tsui-Ping , Lu Jang-Jih
Published: March 2023

Multi-drug resistant Staphylococcus haemolyticus is a frequent nosocomial invasive bacteremia pathogen in hospitals. Our previous analysis showed one of the predominant strains, ST42 originated from ST3, had only one multilocus sequence typing (MLST) variation among seven loci in SH1431; yet no significant differences in biofilm formation observed between ST42 and ST3, suggesting that other factors influence clonal lineage change. Whole genome sequencing was conducted on two isolates from ST42 and ST3 to find phenotypic and genotypic variations, and these variations were further validated in 140 clinical isolates. The fusidic acid- and tetracycline-resistant genes (fusB and tetK) were found only in CGMH-SH51 (ST42). Further investigation revealed consistent resistant genotypes in all isolates, with 46% and 70% of ST42 containing fusB and tetK, respectively. In contrast, only 23% and 4.2% ST3 contained these two genes, respectively. The phenotypic analysis also showed that ST42 isolates were highly resistant to fusidic acid (47%) and tetracycline (70%), compared with ST3 (23% and 4%, respectively). Along with drug-resistant genes, three capsule-related genes were found in higher percentage distributions in ST42 than in ST3 isolates. Our findings indicate that ST42 could become endemic in Taiwan, further constitutive surveillance is required to prevent the spread of this bacterium.
Solid Lipid Nanoparticles: Applications and Prospects in Cancer Treatment
Authors: Sivadasan Durgaramani , Ramakrishnan Kalaivanan , Mahendran Janani , Ranganathan Hariprasad , Karuppaiah Arjunan , Rahman Habibur
Published: March 2023

Recent advancements in drug delivery technologies paved a way for improving cancer therapeutics. Nanotechnology emerged as a potential tool in the field of drug delivery, overcoming the challenges of conventional drug delivery systems. In the field of nanotechnology, solid lipid nanoparticles (SLNs) play a vital role with a wide range of diverse applications, namely drug delivery, clinical medicine, and cancer therapeutics. SLNs establish a significant role owing to their ability to encapsulate hydrophilic and hydrophobic compounds, biocompatibility, ease of surface modification, scale-up feasibility, and possibilities of both active and passive targeting to various organs. In cancer therapy, SLNs have emerged as imminent nanocarriers for overcoming physiological barriers and multidrug resistance pathways. However, there is a need for special attention to be paid to further improving the conceptual understanding of the biological responses of SLNs in cancer therapeutics. Hence, further research exploration needs to be focused on the determination of the structure and strength of SLNs at the cellular level, both in vitro and in vivo, to develop potential therapeutics with reduced side effects. The present review addresses the various modalities of SLN development, SLN mechanisms in cancer therapeutics, and the scale-up potential and regulatory considerations of SLN technology. The review extensively focuses on the applications of SLNs in cancer treatment.
The Alterations of Serum N-glycome in Response to SARS-CoV-2 Vaccination
Authors: Dojcsák Dalma , Kardos Zsófia , Szabó Miklós , Oláh Csaba , Körömi Zsolt , Viskolcz Béla , Váradi Csaba
Published: March 2023

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has caused a global concern since its outbreak in 2019, with one of the main solutions being vaccination. Altered glycosylation has been described in patients after SARS-CoV-2 infection, while the effect of vaccination on serum glycoproteins remained unexplored. In this study, total serum glycosylation was analyzed in patients after SARS-CoV-2 infection and/or mRNA vaccination in order to identify potential glycosylation-based alterations. Enzyme-linked immunosorbent assay was applied to identify post-COVID-19 and post-Vaccinated patients and rule out potential outliers. Serum samples were deglycosylated by PNGase F digestion, and the released glycans were fluorescently derivatized using procainamide labeling. Solid-phase extraction was used to purify the labeled glycans followed by the analysis of hydrophilic-interaction liquid chromatography with fluorescence and mass-spectrometric detection. Alterations of serum N-glycome in response to SARS-CoV-2 infection and mRNA vaccination were revealed by linear discriminant analysis.
Immune Responses to Sequential Binocular Transplantation of Allogeneic Retinal Progenitor Cells to the Vitreous Cavity in Mice
Authors: Chen Lu , Yang Jing , Klassen Henry
Published: March 2023

Intravitreal transplantation of allogeneic human retinal progenitor cells (hRPCs) holds promise as a treatment for blinding retinal degenerations. Prior work has shown that neural progenitors are well-tolerated as allografts following single injections; however, sequential delivery of allogeneic cells raises the potential risk of host sensitization with subsequent immune rejection of grafts. The current study was designed to assess whether an immune response would be induced by repeated intravitreal transplants of allogeneic RPCs utilizing the mouse animal model. We injected murine retinal progenitor cells (gmRPCs), originally derived from donors with a C57BL/6 genetic background, into BALB/c recipient mice in order to provide safety data as to what might be expected following repeated treatment of patients with allogeneic human cell product. Immune responses to gmRPCs were mild, consisting of T cells, B cells, neutrophils, and natural killer cells, with macrophages clearly the predominating. Animals treated with repeat doses of gmRPCs did not show evidence of sensitization, nor was there immune-mediated destruction of the grafts. Despite the absence of immunosuppressive treatments, allogeneic gmRPC grafts survived following repeat dosing, thus providing support for the preliminary observation that repeated injection of allogeneic RPCs to the vitreous cavity is tolerated in patients with retinitis pigmentosa.
Amniotic Membrane Restores Chronic Wound Features to Normal in a Keratinocyte TGF-β-Chronified Cell Model
Authors: Liarte Sergio , Bernabé-García Ángel , Rodríguez-Valiente Mónica , Moraleda José M. , Castellanos Gregorio , Nicolás Francisco J.
Published: March 2023

Unsuccessful wound closure in chronic wounds can be linked to altered keratinocyte activation and their inability to re-epithelize. Suggested mechanisms driving this impairment involve unbalanced cytokine signaling. However, the molecular events leading to these aberrant responses are poorly understood. Among cytokines affecting keratinocyte responses, Transforming Growth Factor-β (TFG-β) is thought to have a great impact. In this study, we have used a previously characterized skin epidermal in vitro model, HaCaT cells continuously exposed to TGF-β1, to study the wound recovery capabilities of chronified/senescent keratinocytes. In this setting, chronified keratinocytes show decreased migration and reduced activation in response to injury. Amniotic membrane (AM) has been used successfully to manage unresponsive complicated wounds. In our in vitro setting, AM treatment of chronified keratinocytes re-enabled migration in the early stages of wound healing, also promoting proliferation at later stages. Interestingly, when checking the gene expression of markers known to be altered in TGF-β chronified cells and involved in cell cycle regulation, early migratory responses, senescence, and chronic inflammation, we discovered that AM treatment seemed to reset back to keratinocyte status. The analysis of the evolution of both the levels of keratinocyte activation marker cytokeratin 17 and the spatial-temporal expression pattern of the proliferation marker Ki-67 in human in vivo biopsy samples suggests that responses to AM recorded in TGF-β chronified HaCaT cells would be homologous to those of resident keratinocytes in chronic wounds. All these results provide further evidence that sustained TGF-β might play a key role in wound chronification and postulate the validity of our TGF-β chronified HaCaT in vitro model for the study of chronic wound physiology.
Bioactive Ingredients in K. pinnata Extract and Synergistic Effects of Combined K. pinnata and Metformin Preparations on Antioxidant Activities in Diabetic and Non-Diabetic Skeletal Muscle Cells
Authors: Ramon Pedro , Bergmann Daniela , Abdulla Hussain , Sparks Jean , Omoruyi Felix
Published: March 2023

With healthcare costs rising, many affected by ailments are turning to alternative medicine for treatment. More people are choosing to complement their pharmacological regimen with dietary supplements from natural products. In this study, the compound composition of Kalanchoe Pinnata (K. pinnata) and the effects of combined preparations of K. pinnata and metformin on antioxidant activity in human skeletal muscle myoblasts (HSMMs) and human diabetic skeletal muscle myoblasts (DHSMMs) were investigated. Ultraperformance liquid chromatography fusion orbitrap mass spectrometry (UPLC-OT-FTMS) identified biologically active flavanols in K. pinnata. The main compounds identified in locally grown K. pinnata were quercetin, kaempferol, apigenin, epigallocatechin gallate (EGCG), and avicularin. Antioxidant results indicated that a combinatorial preparation of K. pinnata with metformin may modulate antioxidant responses by increasing the enzymatic activity of superoxide dismutase and increasing levels of reduced glutathione. A combination of 50 μM and 150 μg/mL of metformin and K. pinnata, respectively, resulted in a significant increase in reduced glutathione levels in non-diabetic and diabetic human skeletal muscle myoblasts and H2O2-stress-induced human skeletal muscle myoblasts. Additionally, a K. pinnata treatment (400 µg/mL) alone significantly increased catalase (CAT) activity for non-diabetic and diabetic human skeletal muscle myoblasts and a H2O2-stress-induced human skeletal muscle myoblast cell line, while significantly lowering malondialdehyde (MDA) levels. However, the treatment options were more effective at promoting cell viability after 24 h versus 72 h and did not promote cell viability after 72 h in H2O2-stress-induced HSMM cells. These treatment options show promise for treating oxidative-stress-mediated pathophysiological complications associated with type II diabetes.
A PCOS Paradox: Does Inositol Therapy Find a Rationale in All the Different Phenotypes?
Authors: Unfer Vittorio , Dinicola Simona , Russo Michele
Published: March 2023

A recent evaluation of the published data regarding the PCOS topic has highlighted a paradox in the definition of this condition. Even though the name of the syndrome refers to ovarian dysfunction, it seems that patients diagnosed with PCOS are more likely affected by an endocrine and metabolic issue. The term PCOS might not be appropriate to indicate the phenotypes described by the Rotterdam criteria, since the only phenotype with a gynecological issue alone is PCOS phenotype D. This novel perspective regarding how PCOS is currently defined leads the way to a reinterpretation of the entire pathological context and the treatment prescribed, such as inositols. A new point of view on the etiopathogenesis of the disease completely changes the current meaning of PCOS and consequently the therapeutic rationale evaluated to date.
The Role of MicroRNA in the Pathogenesis of Diabetic Nephropathy
Authors: Szostak Joanna , Gorący Anna , Durys Damian , Dec Paweł , Modrzejewski Andrzej , Pawlik Andrzej
Published: March 2023

Diabetic nephropathy is one of the most common and severe complications of diabetes mellitus, affecting one in every five patients suffering from diabetes. Despite extensive research, the exact pathogenesis of diabetic nephropathy is still unclear. Several factors and pathways are known to be involved in the development of the disease, such as reactive oxygen species or the activation of the renin–angiotensin–aldosterone system. The expression of those proteins might be extensively regulated by microRNA. Recent research suggests that in diabetic nephropathy patients, the profile of miRNA is significantly changed. In this review, we focus on the actions of miRNA in various pathways involved in the pathogenesis of diabetic nephropathy and the clinical usage of miRNAs as biomarkers and therapeutic targets.
Antidiabetic Drugs Can Reduce the Harmful Impact of Chronic Smoking on Post-Traumatic Brain Injuries
Authors: Sivandzade Farzane , Alqahtani Faleh , Dhaibar Hemangini , Cruz-Topete Diana , Cucullo Luca
Published: March 2023

Traumatic Brain Injury (TBI) is a primary cause of cerebrovascular and neurological disorders worldwide. The current scientific researchers believe that premorbid conditions such as tobacco smoking (TS) can exacerbate post-TBI brain injury and negatively affect recovery. This is related to vascular endothelial dysfunction resulting from the exposure to TS-released reactive oxygen species (ROS), nicotine, and oxidative stress (OS) stimuli impacting the blood–brain barrier (BBB) endothelium. Interestingly, these pathogenic modulators of BBB impairment are similar to those associated with hyperglycemia. Antidiabetic drugs such as metformin (MF) and rosiglitazone (RSG) were shown to prevent/reduce BBB damage promoted by chronic TS exposure. Thus, using in vivo approaches, we evaluated the effectiveness of post-TBI treatment with MF or RSG to reduce the TS-enhancement of BBB damage and brain injury after TBI. For this purpose, we employed an in vivo weight-drop TBI model using male C57BL/6J mice chronically exposed to TS with and without post-traumatic treatment with MF or RSG. Our results revealed that these antidiabetic drugs counteracted TS-promoted downregulation of nuclear factor erythroid 2-related factor 2 (NRF2) expression and concomitantly dampened TS-enhanced OS, inflammation, and loss of BBB integrity following TBI. In conclusion, our findings suggest that MF and RSG could reduce the harmful impact of chronic smoking on post-traumatic brain injuries.
Potential Roles of m6A and FTO in Synaptic Connectivity and Major Depressive Disorder
Authors: Mitsuhashi Haruka , Nagy Corina
Published: March 2023

RNA modifications known as epitranscriptomics have emerged as a novel layer of transcriptomic regulation. Like the well-studied epigenetic modifications characterized in DNA and on histone-tails, they have been shown to regulate activity-dependent gene expression and play a vital role in shaping synaptic connections in response to external stimuli. Among the hundreds of known RNA modifications, N6-methyladenosine (m6A) is the most abundant mRNA modification in eukaryotes. Through recognition of its binding proteins, m6A can regulate various aspects of mRNA metabolism and is essential for maintaining higher brain functions. Indeed, m6A is highly enriched in synapses and is involved in neuronal plasticity, learning and memory, and adult neurogenesis. m6A can also respond to environmental stimuli, suggesting an important role in linking molecular and behavioral stress. This review summarizes key findings from fields related to major depressive disorder (MDD) including stress and learning and memory, which suggest that activity-dependent m6A changes may, directly and indirectly, contribute to synaptic connectivity changes underlying MDD. Furthermore, we will highlight the roles of m6A and FTO, a m6A eraser, in the context of depressive-like behaviors. Although we have only begun to explore m6A in the context of MDD and psychiatry, elucidating a link between m6A and MDD presents a novel molecular mechanism underlying MDD pathogenesis.
Exploiting the Integrated Valorization of Eucalyptus globulus Leaves: Chemical Composition and Biological Potential of the Lipophilic Fraction before and after Hydrodistillation
Authors: Oliveira Cátia. S. D. , Moreira Patrícia , Cruz Maria T. , Pereira Cláudia M. F. , Silva Artur M. S. , Santos Sónia A. O. , Silvestre Armando J. D.
Published: March 2023

E. globulus leaves have been mainly exploited for essential oil recovery or for energy generation in industrial pulp mills, neglecting the abundance of valuable families of extractives, namely, triterpenic acids, that might open new ways for the integrated valorization of this biomass. Therefore, this study highlights the lipophilic characterization of E. globulus leaves before and after hydrodistillation, aiming at the integrated valorization of both essential oils and triterpenic acids. The lipophilic composition of E. globulus leaves after hydrodistillation is reported for the first time. Extracts were obtained by dichloromethane Soxhlet extraction and analyzed by gas chromatography-mass spectrometry. In addition, their cytotoxicity on different cell lines representative of the innate immune system, skin, liver, and intestine were evaluated. Triterpenic acids, such as betulonic, oleanolic, betulinic and ursolic acids, were found to be the main components of these lipophilic extracts, ranging from 30.63–37.14 g kg−1 of dry weight (dw), and representing 87.7–89.0% w/w of the total content of the identified compounds. In particular, ursolic acid was the major constituent of all extracts, representing 46.8–50.7% w/w of the total content of the identified compounds. Other constituents, such as fatty acids, long-chain aliphatic alcohols and β-sitosterol were also found in smaller amounts in the studied extracts. This study also demonstrates that the hydrodistillation process does not affect the recovery of compounds of greatest interest, namely, triterpenic acids. Therefore, the results establish that this biomass residue can be considered as a promising source of value-added bioactive compounds, opening new strategies for upgrading pulp industry residues within an integrated biorefinery context.
Epi-Impute: Single-Cell RNA-seq Imputation via Integration with Single-Cell ATAC-seq
Authors: Raevskiy Mikhail , Yanvarev Vladislav , Jung Sascha , Del Sol Antonio , Medvedeva Yulia A.
Published: March 2023

Single-cell RNA-seq data contains a lot of dropouts hampering downstream analyses due to the low number and inefficient capture of mRNAs in individual cells. Here, we present Epi-Impute, a computational method for dropout imputation by reconciling expression and epigenomic data. Epi-Impute leverages single-cell ATAC-seq data as an additional source of information about gene activity to reduce the number of dropouts. We demonstrate that Epi-Impute outperforms existing methods, especially for very sparse single-cell RNA-seq data sets, significantly reducing imputation error. At the same time, Epi-Impute accurately captures the primary distribution of gene expression across cells while preserving the gene-gene and cell-cell relationship in the data. Moreover, Epi-Impute allows for the discovery of functionally relevant cell clusters as a result of the increased resolution of scRNA-seq data due to imputation.
Thiosulfinate-Enriched Allium sativum Extract Exhibits Differential Effects between Healthy and Sepsis Patients: The Implication of HIF-1α
Authors: Avendaño-Ortiz José , Redondo-Calvo Francisco Javier , Lozano-Rodríguez Roberto , Terrón-Arcos Verónica , Bergón-Gutiérrez Marta , Rodríguez-Jiménez Concepción , Rodríguez Juan Francisco , del Campo Rosa , Gómez Luis Antonio , Bejarano-Ramírez Natalia , Pérez-Ortiz José Manuel , López-Collazo Eduardo
Published: March 2023

Garlic (Allium sativum) has historically been associated with antioxidant, immunomodulatory, and microbiocidal properties, mainly due to its richness in thiosulfates and sulfur-containing phytoconstituents. Sepsis patients could benefit from these properties because it involves both inflammatory and refractory processes. We evaluated the effects of thiosulfinate-enriched Allium sativum extract (TASE) on the immune response to bacterial lipopolysaccharide (LPS) by monocytes from healthy volunteers (HVs) and patients with sepsis. We also explored the TASE effects in HIF-1α, described as the key transcription factor leading to endotoxin tolerance in sepsis monocytes through IRAK-M expression. Our results showed TASE reduced the LPS-triggered reactive oxygen species (ROS) production in monocytes from both patients with sepsis and HVs. Moreover, this extract significantly reduced tumor necrosis factor (TNF)-α, interleukin-1β, and interleukin-6 production in LPS-stimulated monocytes from HVs. However, TASE enhanced the inflammatory response in monocytes from patients with sepsis along with increased expression of human leukocyte antigen-DR. Curiously, these dual effects of TASE on immune response were also found when the HV cohort was divided into low- and high-LPS responders. Although TASE enhanced TNFα production in the LPS-low responders, it decreased the inflammatory response in the LPS-high responders. Furthermore, TASE decreased the HIF-1α pathway-associated genes IRAK-M, VEGFA and PD-L1 in sepsis cells, suggesting HIF-1α inhibition by TASE leads to higher cytokine production in these cells as a consequence of IRAK-M downregulation. The suppression of this pathway by TASE was confirmed in vitro with the prolyl hydroxylase inhibitor dimethyloxalylglycine. Our data revealed TASE’s dual effect on monocyte response according to status/phenotype and suggested the HIF-1α suppression as the possible underlying mechanism.
Profiling and Cellular Analyses of Obesity-Related circRNAs in Neurons and Glia under Obesity-like In Vitro Conditions
Authors: Jo Danbi , Yoon Gwangho , Lim Yeonghwan , Kim Youngkook , Song Juhyun
Published: March 2023

Recent evidence indicates that the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease, is associated with metabolic disorders such as diabetes and obesity. Various circular RNAs (circRNAs) have been found in brain tissues and recent studies have suggested that circRNAs are related to neuropathological mechanisms in the brain. However, there is a lack of interest in the involvement of circRNAs in metabolic imbalance-related neuropathological problems until now. Herein we profiled and analyzed diverse circRNAs in mouse brain cell lines (Neuro-2A neurons, BV-2 microglia, and C8-D1a astrocytes) exposed to obesity-related in vitro conditions (high glucose, high insulin, and high levels of tumor necrosis factor-alpha, interleukin 6, palmitic acid, linoleic acid, and cholesterol). We observed that various circRNAs were differentially expressed according to cell types with many of these circRNAs conserved in humans. After suppressing the expression of these circRNAs using siRNAs, we observed that these circRNAs regulate genes related to inflammatory responses, formation of synaptic vesicles, synaptic density, and fatty acid oxidation in neurons; scavenger receptors in microglia; and fatty acid signaling, inflammatory signaling cyto that may play important roles in metabolic disorders associated with neurodegenerative diseases.
Recent Advances in Generation of In Vitro Cardiac Organoids
Authors: Sahara Makoto
Published: March 2023

Cardiac organoids are in vitro self-organizing and three-dimensional structures composed of multiple cardiac cells (i.e., cardiomyocytes, endothelial cells, cardiac fibroblasts, etc.) with or without biological scaffolds. Since cardiac organoids recapitulate structural and functional characteristics of the native heart to a higher degree compared to the conventional two-dimensional culture systems, their applications, in combination with pluripotent stem cell technologies, are being widely expanded for the investigation of cardiogenesis, cardiac disease modeling, drug screening and development, and regenerative medicine. In this mini-review, recent advances in cardiac organoid technologies are summarized in chronological order, with a focus on the methodological points for each organoid formation. Further, the current limitations and the future perspectives in these promising systems are also discussed.
Integrating AI/ML Models for Patient Stratification Leveraging Omics Dataset and Clinical Biomarkers from COVID-19 Patients: A Promising Approach to Personalized Medicine
Authors: Bello Babatunde , Bundey Yogesh N. , Bhave Roshan , Khotimchenko Maksim , Baran Szczepan W. , Chakravarty Kaushik , Varshney Jyotika
Published: March 2023

The COVID-19 pandemic has presented an unprecedented challenge to the healthcare system. Identifying the genomics and clinical biomarkers for effective patient stratification and management is critical to controlling the spread of the disease. Omics datasets provide a wealth of information that can aid in understanding the underlying molecular mechanisms of COVID-19 and identifying potential biomarkers for patient stratification. Artificial intelligence (AI) and machine learning (ML) algorithms have been increasingly used to analyze large-scale omics and clinical datasets for patient stratification. In this manuscript, we demonstrate the recent advances and predictive accuracies in AI- and ML-based patient stratification modeling linking omics and clinical biomarker datasets, focusing on COVID-19 patients. Our ML model not only demonstrates that clinical features are enough of an indicator of COVID-19 severity and survival, but also infers what clinical features are more impactful, which makes our approach a useful guide for clinicians for prioritization best-fit therapeutics for a given cohort of patients. Moreover, with weighted gene network analysis, we are able to provide insights into gene networks that have a significant association with COVID-19 severity and clinical features. Finally, we have demonstrated the importance of clinical biomarkers in identifying high-risk patients and predicting disease progression.
Exogenous Kinetin Modulates ROS Homeostasis to Affect Heat Tolerance in Rice Seedlings
Authors: Mei Wentao , Chen Wenjuan , Wang Yingfeng , Liu Zeyun , Dong Yating , Zhang Guilian , Deng Huabing , Liu Xiong , Lu Xuedan , Wang Feng , Chen Guihua , Tang Wenbang , Xiao Yunhua
Published: March 2023

Heat stress caused by rapidly changing climate warming has become a serious threat to crop growth worldwide. Exogenous cytokinin (CK) kinetin (KT) has been shown to have positive effects in improving salt and drought tolerance in plants. However, the mechanism of KT in heat tolerance in rice is poorly understood. Here, we found that exogenously adequate application of KT improved the heat stress tolerance of rice seedlings, with the best effect observed when the application concentration was 10−9 M. In addition, exogenous application of 10−9 M KT promoted the expression of CK-responsive OsRR genes, reduced membrane damage and reactive oxygen species (ROS) accumulation in rice, and increased the activity of antioxidant enzymes. Meanwhile, exogenous 10−9 M KT treatment significantly enhanced the expression of antioxidant enzymes, heat activation, and defense-related genes. In conclusion, exogenous KT treatment regulates heat tolerance in rice seedlings by modulating the dynamic balance of ROS in plants under heat stress.
Receptors and Cofactors That Contribute to SARS-CoV-2 Entry: Can Skin Be an Alternative Route of Entry?
Authors: Barthe Manon , Hertereau Leslie , Lamghari Noura , Osman-Ponchet Hanan , Braud Véronique M.
Published: March 2023

To prevent the spread of SARS-CoV-2, all routes of entry of the virus into the host must be mapped. The skin is in contact with the external environment and thus may be an alternative route of entry to transmission via the upper respiratory tract. SARS-CoV-2 cell entry is primarily dependent on ACE2 and the proteases TMPRSS2 or cathepsin L but other cofactors and attachment receptors have been identified that may play a more important role in specific tissues such as the skin. The continued emergence of new variants may also alter the tropism of the virus. In this review, we summarize current knowledge on these receptors and cofactors, their expression profile, factors modulating their expression and their role in facilitating SARS-CoV-2 infection. We discuss their expression in the skin and their possible involvement in percutaneous infection since the presence of the virus has been detected in the skin.
Hydrogel-Inducing Graphene-Oxide-Derived Core–Shell Fiber Composite for Antibacterial Wound Dressing
Authors: Kan Yuliya , Bondareva Julia V. , Statnik Eugene S. , Koudan Elizaveta V. , Ippolitov Evgeniy V. , Podporin Mikhail S. , Kovaleva Polina A. , Kapaev Roman R. , Gordeeva Alexandra M. , Cvjetinovic Julijana , Gorin Dmitry A. , Evlashin Stanislav A. , Salimon Alexey I. , Senatov Fedor S. , Korsunsky Alexander M.
Published: March 2023

The study reveals the polymer–crosslinker interactions and functionality of hydrophilic nanofibers for antibacterial wound coatings. Coaxial electrospinning leverages a drug encapsulation protocol for a core–shell fiber composite with a core derived from polyvinyl alcohol and polyethylene glycol with amorphous silica (PVA-PEG-SiO2), and a shell originating from polyvinyl alcohol and graphene oxide (PVA-GO). Crosslinking with GO and SiO2 initiates the hydrogel transition for the fiber composite upon contact with moisture, which aims to optimize the drug release. The effect of hydrogel-inducing additives on the drug kinetics is evaluated in the case of chlorhexidine digluconate (CHX) encapsulation in the core of core–shell fiber composite PVA-PEG-SiO2-1x-CHX@PVA-GO. The release rate is assessed with the zero, first-order, Higuchi, and Korsmeyer–Peppas kinetic models, where the inclusion of crosslinking silica provides a longer degradation and release rate. CHX medicated core–shell composite provides sustainable antibacterial activity against Staphylococcus aureus.
Decreased Gas6 and sAxl Plasma Levels Are Associated with Hair Loss in COVID-19 Survivors
Authors: Apostolo Daria , D’Onghia Davide , Tonello Stelvio , Minisini Rosalba , Baricich Alessio , Gramaglia Carla , Patrucco Filippo , Zeppegno Patrizia , Acquaviva Antonio , Balbo Piero Emilio , Castello Luigi Mario , Cappellano Giuseppe , Chiocchetti Annalisa , Gerevini Chiara , Giordano Mara , Laaguid Fatiha , Manfredi Marcello , Raineri Davide , Rigamonti Cristina , Rolla Roberta , Romano Valentina , Confalonieri Marco , Savoia Paola , Zavattaro Elisa , Pirisi Mario , Ruaro Barbara , Sainaghi Pier Paolo , Bellan Mattia
Published: March 2023

Post-acute conditions after coronavirus disease 2019 (COVID-19) are quite common, although the underlying pathogenetic mechanisms leading to these conditions are not yet completely understood. In this prospective observational study, we aimed to test the hypothesis that Growth Arrest-Specific 6 (Gas6) and its soluble receptors, Axl (sAxl) and MerTK (sMer), might be implicated. A total of 263 subjects underwent a structured clinical evaluation one year after their hospital discharge for COVID-19, and they consented to donate a blood sample to measure their circulating Gas6, sAxl, and sMer levels. A total of 98 (37.3%) post-COVID-19 subjects complained of at least one residual physical symptom one year after their hospital discharge. Univariate analysis revealed that sAxl was marginally associated with residual symptoms, but at the level of logistic regression analysis, only the diffusing capacity of the lungs for carbon monoxide (DLCO) (OR 0.98, CI 95%: 0.96–0.99; p = 0.007) and the female sex (OR 2.49, CI 95%: 1.45–4.28; p = 0.001) were independently associated with long-lasting symptoms. A total of 69 (26.2%) subjects had hair loss. At the level of univariate analysis, Gas6, sAxl, DLCO, and the female gender were associated with its development. In a logistic regression analysis model, Gas6 (OR 0.96, CI 95%: 0.92–0.99; p = 0.015) and sAxl (OR 0.98, CI 95%; 0.97–1.0; p = 0.014), along with the female sex (OR 6.58, CI 95%: 3.39–12.78; p = 0.0001), were independent predictors of hair loss. Decreased levels of Gas6 and sAxl were associated with a history of hair loss following COVID-19. This was resolved spontaneously in most patients, although 23.7% complained of persistent hair loss one year after hospital discharge.
TRRAP Enhances Cancer Stem Cell Characteristics by Regulating NANOG Protein Stability in Colon Cancer Cells
Authors: Kang Kyung-Taek , Shin Min-Joo , Moon Hye-Ji , Choi Kyung-Un , Suh Dong-Soo , Kim Jae-Ho
Published: March 2023

NANOG, a stemness-associated transcription factor, is highly expressed in many cancers and plays a critical role in regulating tumorigenicity. Transformation/transcription domain-associated protein (TRRAP) has been reported to stimulate the tumorigenic potential of cancer cells and induce the gene transcription of NANOG. This study aimed to investigate the role of the TRRAP-NANOG signaling pathway in the tumorigenicity of cancer stem cells. We found that TRRAP overexpression specifically increases NANOG protein stability by interfering with NANOG ubiquitination mediated by FBXW8, an E3 ubiquitin ligase. Mapping of NANOG-binding sites using deletion mutants of TRRAP revealed that a domain of TRRAP (amino acids 1898–2400) is responsible for binding to NANOG and that the overexpression of this TRRAP domain abrogated the FBXW8-mediated ubiquitination of NANOG. TRRAP knockdown decreased the expression of CD44, a cancer stem cell marker, and increased the expression of P53, a tumor suppressor gene, in HCT-15 colon cancer cells. TRRAP depletion attenuated spheroid-forming ability and cisplatin resistance in HCT-15 cells, which could be rescued by NANOG overexpression. Furthermore, TRRAP knockdown significantly reduced tumor growth in a murine xenograft transplantation model, which could be reversed by NANOG overexpression. Together, these results suggest that TRRAP plays a pivotal role in the regulation of the tumorigenic potential of colon cancer cells by modulating NANOG protein stability.
Muscle Mechanics and Thick Filament Activation: An Emerging Two-Way Interaction for the Vertebrate Striated Muscle Fine Regulation
Authors: Marcucci Lorenzo
Published: March 2023

Contraction in striated muscle is classically described as regulated by calcium-mediated structural changes in the actin-containing thin filaments, which release the binding sites for the interaction with myosin motors to produce force. In this view, myosin motors, arranged in the thick filaments, are basically always ready to interact with the thin filaments, which ultimately regulate the contraction. However, a new “dual-filament” activation paradigm is emerging, where both filaments must be activated to generate force. Growing evidence from the literature shows that the thick filament activation has a role on the striated muscle fine regulation, and its impairment is associated with severe pathologies. This review is focused on the proposed mechanical feedback that activates the inactive motors depending on the level of tension generated by the active ones, the so-called mechanosensing mechanism. Since the main muscle function is to generate mechanical work, the implications on muscle mechanics will be highlighted, showing: (i) how non-mechanical modulation of the thick filament activation influences the contraction, (ii) how the contraction influences the activation of the thick filament and (iii) how muscle, through the mechanical modulation of the thick filament activation, can regulate its own mechanics. This description highlights the crucial role of the emerging bi-directional feedback on muscle mechanical performance.
Variability, Expression, and Methylation of IL-6 and IL-8 Genes in Bladder Cancer Pathophysiology
Authors: Grębowski Radosław , Saluk Joanna , Bijak Michał , Szemraj Janusz , Wigner Paulina
Published: March 2023

Bladder cancer (BC) is the 10th most common form of cancer globally, but its complete aetiology is still unknown. Nevertheless, there is evidence that chronic inflammation plays a role in the development and progression of BC. Therefore, the presented study aimed to detect a potential association between selected single nucleotide polymorphisms (SNPs)—rs1800797 and rs2069845 in IL-6 and rs2227307 in IL-8—and BC development, as well as to identify the impact of BC on the level of expression and methylation of IL-6 and IL-8 promoters in PBMCs with the use of the TaqMan SNP genotyping assay, TaqMan gene expression assay, and methylation-sensitive high-resolution melting techniques. We did not find any association between the genotypes and combined genotypes of all studied polymorphisms and the occurrence of BC. However, we found that BC patients were characterised by decreased IL-6 and IL-8 mRNA expression levels compared to the controls. Additionally, the methylation status of the IL-6 promoter was higher in controls than in BC patients. Our findings suggest that inflammation may be involved in the development and progression of BC.