bluuebunny/crossref_metadata_2025 huggingface dataset:
clbP Gene, a Potential New Member of the β-Lactamase Family
Authors: Azour Adel , Al-Bayssari Charbel , Pinault Lucile , Azza Saïd , Rolain Jean-Marc , Diene Seydina M.
Published: December 2022

The colibactin island (pks) of Escherichia coli formed by 19 genes (55-Kb), encodes non-ribosomal peptide (NRP) and polyketide (PK) synthases, which allow the synthesis of colibactin, a suspected hybrid PK-NRP compound that causes damage to DNA in eukaryotic cells. The clbP, an unusual essential gene, is found in the operon structure with the clbS gene in the pks-encoded machinery. Interestingly, the clbP gene has been annotated as a β-lactamase but no previous study has reported its β-lactamase characteristics. In this study, we (i) investigated the β-lactamase properties of the clbP gene in silico by analysing its phylogenetic relationship with bacterial β-lactamase and peptidase enzymes, (ii) compared its three-dimensional (3D) protein structure with those of bacterial β-lactamase proteins using the Phyr2 database and PyMOL software, and (iii) evaluated in vitro its putative enzymatic activities, including β-lactamase, nuclease, and ribonuclease using protein expression and purification from an E. coli BL21 strain. In this study, we reveal a structural configuration of toxin/antitoxin systems in this island. Thus, similar to the toxin/antitoxin systems, the role of the clbP gene within the pks-island gene group appears as an antitoxin, insofar as it is responsible for the activation of the toxin, which is colibactin. In silico, our analyses revealed that ClbP belonged to the superfamily of β-lactamase, class C. Furthermore, in vitro we were unable to demonstrate its β-lactamase activity, likely due to the fact that the clbP gene requires co-expression with other genes, such as the genes present in the pks-island (19 genes). More research is needed to better understand its actions, particularly with regards to antibiotics, and to discover whether it has any additional functions due to the importance of this gene and its toxicity.
The Chromatin Structure at the MECP2 Gene and In Silico Prediction of Potential Coding and Non-Coding MECP2 Splice Variants
Authors: Shevkoplyas Danilo , Vuu Yen My , Davie James R. , Rastegar Mojgan
Published: December 2022

Methyl CpG binding protein 2 (MeCP2) is an epigenetic reader that binds to methylated CpG dinucleotides and regulates gene transcription. Mecp2/MECP2 gene has 4 exons, encoding for protein isoforms MeCP2E1 and MeCP2E2. MeCP2 plays key roles in neurodevelopment, therefore, its gain- and loss-of-function mutations lead to neurodevelopmental disorders including Rett Syndrome. Here, we describe the structure, functional domains, and evidence support for potential additional alternatively spliced MECP2 transcripts and protein isoforms. We conclude that NCBI MeCP2 isoforms 3 and 4 contain certain MeCP2 functional domains. Our in silico analysis led to identification of histone modification and accessibility profiles at the MECP2 gene and its cis-regulatory elements. We conclude that the human MECP2 gene associated histone post-translational modifications exhibit high similarity between males and females. Between brain regions, histone modifications were found to be less conserved and enriched within larger genomic segments named as “S1–S11”. We also identified highly conserved DNA accessibility regions in different tissues and brain regions, named as “A1–A9” and “B1–B9”. DNA methylation profile was similar between mid-frontal gyrus of donors 35 days–25 years of age. Based on ATAC-seq data, the identified hypomethylated regions “H1–H8” intersected with most regions of the accessible chromatin (A regions).
microRNAs Associated with Carotid Plaque Development and Vulnerability: The Clinician’s Perspective
Authors: Badacz Rafał , Przewłocki Tadeusz , Legutko Jacek , Żmudka Krzysztof , Kabłak-Ziembicka Anna
Published: December 2022

Ischemic stroke (IS) related to atherosclerosis of large arteries is one of the leading causes of mortality and disability in developed countries. Atherosclerotic internal carotid artery stenosis (ICAS) contributes to 20% of all cerebral ischemia cases. Nowadays, atherosclerosis prevention and treatment measures aim at controlling the atherosclerosis risk factors, or at the interventional (surgical or endovascular) management of mature occlusive lesions. There is a definite lack of the established circulating biomarkers which, once modulated, could prevent development of atherosclerosis, and consequently prevent the carotid-artery-related IS. Recent studies emphasize that microRNA (miRNA) are the emerging particles that could potentially play a pivotal role in this approach. There are some research studies on the association between the expression of small non-coding microRNAs with a carotid plaque development and vulnerability. However, the data remain inconsistent. In addition, all major studies on carotid atherosclerotic plaque were conducted on cell culture or animal models; very few were conducted on humans, whereas the accumulating evidence demonstrates that it cannot be automatically extrapolated to processes in humans. Therefore, this paper aims to review the current knowledge on how miRNA participate in the process of carotid plaque formation and rupture, as well as stroke occurrence. We discuss potential target miRNA that could be used as a prognostic or therapeutic tool.
Inhibition of JAK1,2 Prevents Fibrotic Remodeling of Pulmonary Vascular Bed and Improves Outcomes in the Rat Model of Chronic Thromboembolic Pulmonary Hypertension
Authors: Karpov Andrei A. , Mihailova Aleksandra M. , Shilenko Leonid A. , Vaulina Dariya D. , Sidorova Elizaveta E. , Akhmetova Anna A. , Docshin Pavel M. , Krasichkov Alexander S. , Sanarova Kseniia E. , Moiseeva Olga M. , Galagudza Michael M.
Published: December 2022

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare complication of acute pulmonary embolism with poor clinical outcomes. Therapeutic approaches to prevention of fibrotic remodeling of the pulmonary vascular bed in CTEPH are limited. In this work, we tested the hypothesis that Janus kinase 1/2 (JAK1/2) inhibition with ruxolitinib might prevent and attenuate CTEPH in a rat model. CTEPH was induced by repeated embolization of the pulmonary artery with partially biodegradable 180 ± 30 μm alginate microspheres. Two weeks after the last injection of microspheres, ruxolitinib was administered orally at doses of 0.86, 2.58, and 4.28 mg/kg per day for 4 weeks. Prednisolone (1.475 mg/kg, i.m.) was used as a reference drug. Ruxolitinib in all doses as well as prednisolone reduced pulmonary vascular wall hypertrophy. Ruxolitinib at a dose of 2.58 mg/kg and prednisolone reduced vascular wall fibrosis. Prednisolone treatment resulted in decreased right ventricular systolic pressure. Pulmonary vascular resistance was lower in the prednisolone and ruxolitinib (4.28 mg/kg) groups in comparison with the placebo group. The plasma level of brain natriuretic peptide was lower in groups receiving ruxolitinib at doses of 2.58 and 4.28 mg/kg versus placebo. This study demonstrated that JAK1/2 inhibitor ruxolitinib dose-dependently reduced pulmonary vascular remodeling, thereby preventing CTEPH formation in rats.
The Pan-Cancer Multi-Omics Landscape of FOXO Family Relevant to Clinical Outcome and Drug Resistance
Authors: Xie Jindong , Zhang Junsheng , Tian Wenwen , Zou Yutian , Tang Yuhui , Zheng Shaoquan , Wong Chau-Wei , Deng Xinpei , Wu Song , Chen Junxin , Mo Yunxian , Xie Xiaoming
Published: December 2022

The forkhead box O (FOXO) transcription factors (TFs) family are frequently mutated, deleted, or amplified in various human cancers, making them attractive candidates for therapy. However, their roles in pan-cancer remain unclear. Here, we evaluated the expression, prognostic value, mutation, methylation, and clinical features of four FOXO family genes (FOXO1, FOXO3, FOXO4, and FOXO6) in 33 types of cancers based on the Cancer Genome Atlas (TCGA) and Genotype Tissue Expression (GTEx) databases. We used a single sample gene set enrichment analysis (ssGSEA) algorithm to establish a novel index called “FOXOs score”. Moreover, we investigated the association between the FOXOs score and tumor microenvironment (TME), the responses to multiple treatments, along with drug resistance. We found that the FOXO family genes participated in tumor progression and were related to the prognosis in various types of cancer. We calculated the FOXOs score and found that it was significantly correlated with multiple malignant pathways in pan-cancer, including Wnt/beta-catenin signaling, TGF-beta signaling, and hedgehog signaling. In addition, the FOXOs score was also associated with multiple immune-related characteristics. Furthermore, the FOXOs score was sensitive for predicting the efficacy of diverse treatments in multiple cancers, especially immunotherapy. In conclusion, FOXO family genes were vital in pan-cancer and were strongly correlated with the TME. A high FOXOs score indicated an excellent immune-activated TME and sensitivity to multiple treatments. Hence, the FOXOs score might potentially be used as a biomarker in patients with a tumor.
3-Bromopyruvate Suppresses the Malignant Phenotype of Vemurafenib-Resistant Melanoma Cells
Authors: Vital Patrik da Silva , Bonatelli Murilo , Dias Marina Pereira , de Salis Larissa Vedovato Vilela , Pinto Mariana Tomazini , Baltazar Fátima , Maria-Engler Silvya Stuchi , Pinheiro Céline
Published: December 2022

(1) BRAF mutations are associated with high mortality and are a substantial factor in therapeutic decisions. Therapies targeting BRAF-mutated tumors, such as vemurafenib (PLX), have significantly improved the overall survival of melanoma patients. However, patient relapse and low response rates remain challenging, even with contemporary therapeutic alternatives. Highly proliferative tumors often rely on glycolysis to sustain their aggressive phenotype. 3-bromopyruvate (3BP) is a promising glycolysis inhibitor reported to mitigate resistance in tumors. This study aimed to evaluate the potential of 3BP as an antineoplastic agent for PLX-resistant melanoma treatment. (2) The effect of 3BP alone or in combination with PLX on viability, proliferation, colony formation, cell death, migration, invasion, epithelial-mesenchymal marker and metabolic protein expression, extracellular glucose and lactate, and reactive species were evaluated in two PLX-resistant melanoma cell lines. (3) 3BP treatment, which was more effective as monotherapy than combined with PLX, disturbed the metabolic and epithelial-mesenchymal profile of PLX-resistant cells, impairing their proliferation, migration, and invasion and triggering cell death. (4) 3BP monotherapy is a potent metabolic-disrupting agent against PLX-resistant melanomas, supporting the suppression of the malignant phenotype in this type of neoplasia.
XML-CIMT: Explainable Machine Learning (XML) Model for Predicting Chemical-Induced Mitochondrial Toxicity
Authors: Jaganathan Keerthana , Rehman Mobeen Ur , Tayara Hilal , Chong Kil To
Published: December 2022

Organ toxicity caused by chemicals is a serious problem in the creation and usage of chemicals such as medications, insecticides, chemical products, and cosmetics. In recent decades, the initiation and development of chemical-induced organ damage have been related to mitochondrial dysfunction, among several adverse effects. Recently, many drugs, for example, troglitazone, have been removed from the marketplace because of significant mitochondrial toxicity. As a result, it is an urgent requirement to develop in silico models that can reliably anticipate chemical-induced mitochondrial toxicity. In this paper, we have proposed an explainable machine-learning model to classify mitochondrially toxic and non-toxic compounds. After several experiments, the Mordred feature descriptor was shortlisted to be used after feature selection. The selected features used with the CatBoost learning algorithm achieved a prediction accuracy of 85% in 10-fold cross-validation and 87.1% in independent testing. The proposed model has illustrated improved prediction accuracy when compared with the existing state-of-the-art method available in the literature. The proposed tree-based ensemble model, along with the global model explanation, will aid pharmaceutical chemists in better understanding the prediction of mitochondrial toxicity.
A New Transgenic Tool to Study the Ret Signaling Pathway in the Enteric Nervous System
Authors: Bandla Ashoka , Melancon Ellie , Taylor Charlotte R. , Davidson Ann E. , Eisen Judith S. , Ganz Julia
Published: December 2022

The receptor tyrosine kinase Ret plays a critical role in regulating enteric nervous system (ENS) development. Ret is important for proliferation, migration, and survival of enteric progenitor cells (EPCs). Ret also promotes neuronal fate, but its role during neuronal differentiation and in the adult ENS is less well understood. Inactivating RET mutations are associated with ENS diseases, e.g., Hirschsprung Disease, in which distal bowel lacks ENS cells. Zebrafish is an established model system for studying ENS development and modeling human ENS diseases. One advantage of the zebrafish model system is that their embryos are transparent, allowing visualization of developmental phenotypes in live animals. However, we lack tools to monitor Ret expression in live zebrafish. Here, we developed a new BAC transgenic line that expresses GFP under the ret promoter. We find that EPCs and the majority of ENS neurons express ret:GFP during ENS development. In the adult ENS, GFP+ neurons are equally present in females and males. In homozygous mutants of ret and sox10—another important ENS developmental regulator gene—GFP+ ENS cells are absent. In summary, we characterize a ret:GFP transgenic line as a new tool to visualize and study the Ret signaling pathway from early development through adulthood.
Sex-Specific Multiparameter Blood Test for the Early Diagnosis of Alzheimer’s Disease
Authors: Cho Hyung Joon , Schulz Philip , Venkataraman Lalitha , Caselli Richard J. , Sierks Michael R.
Published: December 2022

Blood-based biomarkers are needed for the early diagnosis of Alzheimer’s disease (AD). We analyzed longitudinal human plasma samples from AD and control cases to identify biomarkers for the early diagnosis of AD. Plasma samples were grouped based on clinical diagnosis at the time of collection: AD, mild cognitive impairment (MCI), and pre-symptomatic (preMCI). Samples were analyzed by ELISA using a panel of reagents against nine different AD-related amyloid-β (Aβ), tau, or TDP-43 variants. Receiver operating characteristic (ROC) curves of different biomarker panels for different diagnostic sample groups were determined. Analysis of all of the samples gave a sensitivity of 92% and specificity of 76% for the diagnosis of AD. Early-stage diagnosis of AD, utilizing only the preMCI and MCI samples, identified 88% of AD cases. Using sex-biased biomarker panels, early diagnosis of AD cases improved to 96%. Using the sex-biased panels, we also identified 6 of the 25 control group cases as being at high risk of AD, which is consistent with what is expected given the advanced age of the control cases. Specific AD-associated protein variants are effective blood-based biomarkers for the early diagnosis of AD. Notably, significant differences were observed in biomarker profiles for the early detection of male and female AD cases.
Identification and Validation of Ferroptosis-Related DNA Methylation Signature for Predicting the Prognosis and Guiding the Treatment in Cutaneous Melanoma
Authors: Guo Wenna , Wang Xue , Wang Yanna , Zhu Shuting , Zhu Rui , Zhu Liucun
Published: December 2022

Cutaneous melanoma (CM) is one of the most aggressive skin tumors with a poor prognosis. Ferroptosis is a newly discovered form of regulated cell death that is closely associated with cancer development and immunotherapy. The aim of this study was to establish and validate a ferroptosis-related gene (FRG) DNA methylation signature to predict the prognosis of CM patients using data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database. A reliable four-FRG DNA methylation prognostic signature was constructed via Cox regression analysis based on TCGA database. Kaplan–Meier analysis showed that patients in the high-risk group tended to have a shorter overall survival (OS) than the low-risk group in both training TCGA and validation GEO cohorts. Time-dependent receiver operating characteristic (ROC) analysis showed the areas under the curve (AUC) at 1, 3, and 5 years were 0.738, 0.730, and 0.770 in TCGA cohort and 0.773, 0.775, and 0.905 in the validation cohort, respectively. Univariate and multivariate Cox regression analyses indicated that the signature was an independent prognostic indicator of OS in patients with CM. Immunogenomic profiling showed the low-risk group of patients had a higher immunophenoscore, and most immune checkpoints were negatively associated with the risk signature. Functional enrichment analysis revealed that immune response and immune-related pathways were enriched in the low-risk group. In conclusion, we established and validated a four-FRG DNA methylation signature that independently predicts prognosis in CM patients. This signature was strongly correlated with the immune landscape, and may serve as a biomarker to guide clinicians in making more precise and personalized treatment decisions for CM patients.
Current and Emerging Approaches for Spine Tumor Treatment
Authors: Costăchescu Bogdan , Niculescu Adelina-Gabriela , Iliescu Bogdan Florin , Dabija Marius Gabriel , Grumezescu Alexandru Mihai , Rotariu Daniel
Published: December 2022

Spine tumors represent a significant social and medical problem, affecting the quality of life of thousands of patients and imposing a burden on healthcare systems worldwide. Encompassing a wide range of diseases, spine tumors require prompt multidisciplinary treatment strategies, being mainly approached through chemotherapy, radiotherapy, and surgical interventions, either alone or in various combinations. However, these conventional tactics exhibit a series of drawbacks (e.g., multidrug resistance, tumor recurrence, systemic adverse effects, invasiveness, formation of large bone defects) which limit their application and efficacy. Therefore, recent research focused on finding better treatment alternatives by utilizing modern technologies to overcome the challenges associated with conventional treatments. In this context, the present paper aims to describe the types of spine tumors and the most common current treatment alternatives, further detailing the recent developments in anticancer nanoformulations, personalized implants, and enhanced surgical techniques.
Oligonucleotide Insecticides for Green Agriculture: Regulatory Role of Contact DNA in Plant–Insect Interactions
Authors: Oberemok Volodymyr V. , Useinov Refat Z. , Skorokhod Oleksii A. , Gal’chinsky Nikita V. , Novikov Ilya A. , Makalish Tatyana P. , Yatskova Ekaterina V. , Sharmagiy Alexander K. , Golovkin Ilya O. , Gninenko Yuri I. , Puzanova Yelizaveta V. , Andreeva Oksana A. , Alieva Edie E. , Eken Emre , Laikova Kateryna V. , Plugatar Yuri V.
Published: December 2022

Insects vastly outnumber us in terms of species and total biomass, and are among the most efficient and voracious consumers of plants on the planet. As a result, to preserve crops, one of the primary tasks in agriculture has always been the need to control and reduce the number of insect pests. The current use of chemical insecticides leads to the accumulation of xenobiotics in ecosystems and a decreased number of species in those ecosystems, including insects. Sustainable development of human society is impossible without useful insects, so the control of insect pests must be effective and selective at the same time. In this article, we show for the first time a natural way to regulate the number of insect pests based on the use of extracellular double-stranded DNA secreted by the plant Pittosporum tobira. Using a principle similar to one found in nature, we show that the topical application of artificially synthesized short antisense oligonucleotide insecticides (olinscides, DNA insecticides) is an effective and selective way to control the insect Coccus hesperidum. Using contact oligonucleotide insecticide Coccus-11 at a concentration of 100 ng/μL on C. hesperidum larvae resulted in a mortality of 95.59 ± 1.63% within 12 days. Green oligonucleotide insecticides, created by nature and later discovered by humans, demonstrate a new method to control insect pests that is beneficial and safe for macromolecular insect pest management.
Shrunken Pore Syndrome Is Frequently Occurring in Severe COVID-19
Authors: Larsson Anders O. , Hultström Michael , Frithiof Robert , Lipcsey Miklos , Eriksson Mats B.
Published: December 2022

A selective decrease in the renal filtration of larger molecules is attributed to the shrinkage of glomerular pores, a condition termed Shrunken Pore Syndrome (SPS). SPS is associated with poor long-term prognosis. We studied SPS as a risk marker in a cohort of patients with COVID-19 treated in an intensive care unit. SPS was defined as a ratio < 0.7 when the estimated glomerular filtration rate (eGFR), determined by cystatin C, calculated by the Cystatin C Caucasian-Asian-Pediatric-Adult equation (CAPA), was divided by the eGFR determined by creatinine, calculated by the revised Lund–Malmö creatinine equation (LMR). Clinical data were prospectively collected. In total, SPS was present in 86 (24%) of 352 patients with COVID-19 on ICU admission. Patients with SPS had a higher BMI, Simplified Physiology Score (SAPS3), and had diabetes and/or hypertension more frequently than patients without SPS. Ninety-nine patients in the total cohort were women, 50 of whom had SPS. In dexamethasone-naïve patients, C-reactive protein (CRP ), TNF-alpha, and interleukin-6 did not differ between SPS and non-SPS patients. Demographic factors (gender, BMI) and illness severity (SAPS3) were independent predictors of SPS. Age and dexamethasone treatment did not affect the frequency of SPS after adjustments for age, sex, BMI, and acute severity. SPS is frequent in severely ill COVID-19 patients. Female gender was associated with a higher proportion of SPS. Demographic factors and illness severity were independent predictors of SPS.
Sodium Butyrate Supplementation Modulates Neuroinflammatory Response Aggravated by Antibiotic Treatment in a Mouse Model of Binge-like Ethanol Drinking
Authors: Gao Lei , Davies Daryl L. , Asatryan Liana
Published: December 2022

Growing evidence supports the pivotal role of the bidirectional interplay between the gut microbiota and the central nervous system during the progression of alcohol use disorder (AUD). In our previous study, supplementation with sodium butyrate (SB) in C57BL/6J mice prevented increased ethanol consumption in a binge-like drinking paradigm (DID) as a result of treatment with a non-absorbable antibiotic cocktail (ABX). In this study, we tested the hypothesis that SB protection against enhanced ABX-induced ethanol consumption in mice is partially due to modulation of neuroinflammatory responses. Pro- and anti-inflammatory cytokines, as well as changes in microglia and astrocytes were analyzed in hippocampus tissues from ABX-, SB-, ABX+SB-treated mice subjected to 4-week DID. We found that ethanol without or with ABX treatment increased mRNA levels of key brain cytokines (MCP-1, TNF-α, IL-1β, IL-6 and IL-10) while SB supplementation prevented these changes. Additionally, SB supplementation prevented changes in microglia, i.e., increase in Iba-1 positive cell number and morphology, and in astrocytes, i.e., decrease in GFAP-positive cell number, induced by combination of ethanol and ABX treatments. Our results suggest that gut microbiota metabolites can influence drinking behavior by modulation of neuroinflammation, highlighting the potential for microbiome-targeting strategies for treatment or prevention of AUD.
Rbm20ΔRRM Mice, Expressing a Titin Isoform with Lower Stiffness, Are Protected from Mechanical Ventilation-Induced Diaphragm Weakness
Authors: van den Berg Marloes , Peters Eva L. , van der Pijl Robbert J. , Shen Shengyi , Heunks Leo M. A. , Granzier Henk L. , Ottenheijm Coen A. C.
Published: December 2022

Diaphragm weakness frequently develops in mechanically ventilated critically ill patients and is associated with increased morbidity, including ventilator weaning failure, mortality, and health care costs. The mechanisms underlying diaphragm weakness are incompletely understood but may include the elastic properties of titin, a giant protein whose layout in the muscle’s sarcomeres makes it an ideal candidate to sense ventilation-induced diaphragm unloading, resulting in downstream signaling through titin-binding proteins. In the current study, we investigated whether modulating titin stiffness affects the development of diaphragm weakness during mechanical ventilation. To this end, we ventilated genetically engineered mice with reduced titin stiffness (Rbm20ΔRRM), and robust (TtnΔIAjxn) or severely (TtnΔ112–158) increased titin stiffness for 8 h, and assessed diaphragm contractility and protein expression of titin-binding proteins. Mechanical ventilation reduced the maximum active tension of the diaphragm in WT, TtnΔIAjxn and TtnΔ112–158 mice. However, in Rbm20ΔRRM mice maximum active tension was preserved after ventilation. Analyses of titin binding proteins suggest that muscle ankyrin repeat proteins (MARPs) 1 and 2 may play a role in the adaptation of the diaphragm to mechanical ventilation, and the preservation of diaphragm contractility in Rbm20ΔRRM mice. Thus, Rbm20ΔRRM mice, expressing titin isoforms with lower stiffness, are protected from mechanical ventilation-induced diaphragm weakness, suggesting that titin elasticity may modulate the diaphragm’s response to unloading during mechanical ventilation.
Integrated Analysis of Bulk RNA-Seq and Single-Cell RNA-Seq Unravels the Influences of SARS-CoV-2 Infections to Cancer Patients
Authors: Chen Yu , Qin Yujia , Fu Yuanyuan , Gao Zitong , Deng Youping
Published: December 2022

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly contagious and pathogenic coronavirus that emerged in late 2019 and caused a pandemic of respiratory illness termed as coronavirus disease 2019 (COVID-19). Cancer patients are more susceptible to SARS-CoV-2 infection. The treatment of cancer patients infected with SARS-CoV-2 is more complicated, and the patients are at risk of poor prognosis compared to other populations. Patients infected with SARS-CoV-2 are prone to rapid development of acute respiratory distress syndrome (ARDS) of which pulmonary fibrosis (PF) is considered a sequelae. Both ARDS and PF are factors that contribute to poor prognosis in COVID-19 patients. However, the molecular mechanisms among COVID-19, ARDS and PF in COVID-19 patients with cancer are not well-understood. In this study, the common differentially expressed genes (DEGs) between COVID-19 patients with and without cancer were identified. Based on the common DEGs, a series of analyses were performed, including Gene Ontology (GO) and pathway analysis, protein–protein interaction (PPI) network construction and hub gene extraction, transcription factor (TF)–DEG regulatory network construction, TF–DEG–miRNA coregulatory network construction and drug molecule identification. The candidate drug molecules (e.g., Tamibarotene CTD 00002527) obtained by this study might be helpful for effective therapeutic targets in COVID-19 patients with cancer. In addition, the common DEGs among ARDS, PF and COVID-19 patients with and without cancer are TNFSF10 and IFITM2. These two genes may serve as potential therapeutic targets in the treatment of COVID-19 patients with cancer. Changes in the expression levels of TNFSF10 and IFITM2 in CD14+/CD16+ monocytes may affect the immune response of COVID-19 patients. Specifically, changes in the expression level of TNFSF10 in monocytes can be considered as an immune signature in COVID-19 patients with hematologic cancer. Targeting N6-methyladenosine (m6A) pathways (e.g., METTL3/SERPINA1 axis) to restrict SARS-CoV-2 reproduction has therapeutic potential for COVID-19 patients.
Development of a Chemically Modified Sensor Based on a Pentapeptide and Its Application for Sensitive Detection of Verbascoside in Extra Virgin Olive Oil
Authors: Munteanu Irina Georgiana , Grădinaru Vasile Robert , Apetrei Constantin
Published: December 2022

In addition to their antioxidant and antimicrobial action in functional foods, beverages, and in some dermato-cosmetic products, olive phenolic compounds are also recognized for their role in the prevention of diabetes and inflammation, treatment of heart disease and, consequently, of the numerous chronic diseases mediated by the free radicals. In recent years, attention has increased, in particular, regarding one of the most important compound in extra virgin olive oil (EVOO) having glycosidic structure, namely verbocoside, due to the existence in the literature of numerous studies demonstrating its remarkable contribution to the prophylaxis and treatment of various disorders of the human body. The purpose of this study was the qualitative and quantitative determination of verbascoside in commercial EVOOs from different regions by means of a newly developed sensor based on a screen-printed carbon electrode (SPCE) modified with graphene oxide (GPHOX), on the surface of which a pentapeptide was immobilized by means of glutaraldehyde as cross-linking agent. The modified electrode surface was investigated using both Fourier-transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM) methods. This newly developed sensor has shown a high sensibility compared to the unmodified electrode, a low detection limit (LOD) of up to 9.38 × 10−8 M, and a wide linearity range between 0.1 µM and 10.55 µM. The applicability of the modified sensor was confirmed by detecting verbascoside in ten different EVOOs samples using the cyclic voltammetry (CV) method, with very good results. The validation of the electroanalytical method was performed by using the standard addition method with very good recoveries in the range of 97.48–103.77%.
Plasma Calprotectin Levels Associate with Suspected Metabolic-Associated Fatty Liver Disease and All-Cause Mortality in the General Population
Authors: Bourgonje Arno R. , van den Berg Eline H. , Kieneker Lyanne M. , Nilsen Tom , Hidden Clara , Bakker Stephan J. L. , Blokzijl Hans , Dullaart Robin P. F. , van Goor Harry , Abdulle Amaal E.
Published: December 2022

Metabolic-associated fatty liver disease (MAFLD) is characterized by hepatic steatosis, metabolic dysregulation, and neutrophilic inflammation. In this study, we hypothesized that systemic levels of plasma calprotectin, as a biomarker of neutrophilic inflammation, may be associated with suspected MAFLD. Plasma calprotectin levels were measured in subjects (n = 5446) participating in the Prevention of Renal and Vascular ENd-stage Disease (PREVEND) cohort study. Suspected MAFLD was defined by the fatty liver index (FLI ≥ 60) and hepatic steatosis index (HSI ≥ 36) as proxies. Plasma calprotectin levels were significantly higher in subjects with FLI ≥ 60 (0.57 [IQR: 0.42–0.79] mg/L, n = 1592) (p < 0.001) compared to subjects with FLI < 60 (0.46 [0.34–0.65] mg/L, n = 3854). Multivariable logistic regression analyses revealed that plasma calprotectin levels were significantly associated with suspected MAFLD (FLI ≥ 60), even after adjustment for potential confounding factors, including current smoking, alcohol consumption, hypertension, diabetes, cardiovascular diseases, insulin resistance (HOMA-IR), hs-CRP, eGFR, and total cholesterol levels (OR 1.19 [95% CI: 1.06–1.33], p = 0.003). Interaction analyses revealed significant effect modifications for the association between plasma calprotectin and suspected MAFLD by BMI (p < 0.001) and hypertension (p = 0.003), with the strongest associations in subjects with normal BMI and without hypertension. Prospectively, plasma calprotectin levels were significantly associated with all-cause mortality after adjustment for potential confounding factors, particularly in subjects without suspected MAFLD (FLI < 60) (hazard ratio (HR) per doubling: 1.34 (1.05–1.72), p < 0.05). In conclusion, higher plasma calprotectin levels are associated with suspected MAFLD and with the risk of all-cause mortality, the latter especially in subjects without suspected MAFLD.
A Tea Plant (Camellia sinensis) FLOWERING LOCUS C-like Gene, CsFLC1, Is Correlated to Bud Dormancy and Triggers Early Flowering in Arabidopsis
Authors: Liu Ying , Dreni Ludovico , Zhang Haojie , Zhang Xinzhong , Li Nana , Zhang Kexin , Di Taimei , Wang Lu , Yang Yajun , Hao Xinyuan , Wang Xinchao
Published: December 2022

Flowering and bud dormancy are crucial stages in the life cycle of perennial angiosperms in temperate climates. MADS-box family genes are involved in many plant growth and development processes. Here, we identified three MADS-box genes in tea plant belonging to the FLOWERING LOCUS C (CsFLC) family. We monitored CsFLC1 transcription throughout the year and found that CsFLC1 was expressed at a higher level during the winter bud dormancy and flowering phases. To clarify the function of CsFLC1, we developed transgenic Arabidopsis thaliana plants heterologously expressing 35S::CsFLC1. These lines bolted and bloomed earlier than the WT (Col-0), and the seed germination rate was inversely proportional to the increased CsFLC1 expression level. The RNA-seq of 35S::CsFLC1 transgenic Arabidopsis showed that many genes responding to ageing, flower development and leaf senescence were affected, and phytohormone-related pathways were especially enriched. According to the results of hormone content detection and RNA transcript level analysis, CsFLC1 controls flowering time possibly by regulating SOC1, AGL42, SEP3 and AP3 and hormone signaling, accumulation and metabolism. This is the first time a study has identified FLC-like genes and characterized CsFLC1 in tea plant. Our results suggest that CsFLC1 might play dual roles in flowering and winter bud dormancy and provide new insight into the molecular mechanisms of FLC in tea plants as well as other plant species.
Immunotherapy for Melanoma: The Significance of Immune Checkpoint Inhibitors for the Treatment of Advanced Melanoma
Authors: Fujimura Taku , Muto Yusuke , Asano Yoshihide
Published: December 2022

Therapeutic options for treating advanced melanoma have progressed rapidly in recent decades. Until 6 years ago, the regimen for treating advanced melanoma consisted mainly of cytotoxic agents such as dacarbazine and type I interferons. Since 2014, anti-programmed cell death 1 (PD1) antibodies have been recognized as anchor drugs for treating advanced melanoma, with or without additional combination drugs such as ipilimumab, but the efficacies of these immunotherapies are not fully satisfactory. In this review, we describe the development of the currently available anti-PD1 Abs-based immunotherapies for advanced melanoma, focusing on their efficacy and immune-related adverse events (AEs), as well as clinical trials still ongoing for the future treatment of advanced melanoma.
The In Vitro Effect of Laser Irradiation (Er:YAG and CO2) and Chemical Reagents (Hydrogen Peroxide, Sodium Hypochlorite, Chlorhexidine, or Sodium Fluoride) Alone or in Combination on Reducing Root Caries Bacteria
Authors: Reddy Nitya , Golob Deeb Janina , Kitten Todd , Carrico Caroline K. , Grzech-Leśniak Kinga
Published: December 2022

(1) Lasers have been used for the treatment of dentinal hypersensitivity and bacterial reductions in periodontology. The purpose of this in vitro study was to evaluate the effect of Carbon Dioxide (CO2) and Erbium-doped Yttrium Aluminum Garnet (Er:YAG) lasers with chlorhexidine (CHX), hydrogen peroxide (H2O2), sodium hypochlorite (NaOCl), or sodium fluoride (NaF) on the viability of oral bacteria associated with root caries. (2) Streptococcus mutans, Streptococcus sanguinis, and Enterococcus faecalis were grown in Brain Heart Infusion (BHI) broth, diluted to an OD660 of 0.5, and treated with antiseptics with or without simultaneous irradiation with the Er:YAG and CO2 lasers for 30 s repeated three times. The treatment groups consisted of 1: no treatment, 2: 0.5% H2O2 alone, 3: 0.5% NaOCl alone, 4: 0.12% CHX alone, 5: 2% NaF alone, 6: laser alone, 7: laser with 0.5% H2O2, 8: laser with 0.5% NaOCl, 9: laser with 0.12% CHX, and 10: laser with 2% NaF for both lasers. The microbial viability was determined through plating and viable colonies were counted, converted into CFU/mL, and transformed into log form. The statistical analysis was performed using a two-tailed paired t-test. (3) The use of CO2 and Er:YAG lasers alone failed to show statistically significant antibacterial activity against any of the bacteria. The only effective monotreatment was CHX for S. mutans. The combined treatment of 0.5% NaOCl with Er:YAG produced the greatest reduction in overall viability. (4) The combination of the Er:YAG laser with 0.5% NaOCl resulted in the largest reduction in bacterial survival when compared to monotherapies with antimicrobial solutions or lasers.
High Dose Pharmaceutical Grade Biotin (MD1003) Accelerates Differentiation of Murine and Grafted Human Oligodendrocyte Progenitor Cells In Vivo
Authors: Levy Marion J. F. , Garcia-Diaz Beatriz , Sedel Frédéric , Baron-Van Evercooren Anne , Mozafari Sabah
Published: December 2022

Accumulating evidences suggest a strong correlation between metabolic changes and neurodegeneration in CNS demyelinating diseases such as multiple sclerosis (MS). Biotin, an essential cofactor for five carboxylases, is expressed by oligodendrocytes and involved in fatty acid synthesis and energy production. The metabolic effect of biotin or high-dose-biotin (MD1003) has been reported on rodent oligodendrocytes in vitro, and in neurodegenerative or demyelinating animal models. However, clinical studies, showed mild or no beneficial effect of MD1003 in amyotrophic lateral sclerosis (ALS) or MS. Here, we took advantage of a mouse model of myelin deficiency to study the effects of MD1003 on the behavior of murine and grafted human oligodendrocytes in vivo. We show that MD1003 increases the number and the differentiation potential of endogenous murine oligodendroglia over time. Moreover, the levels of MD1003 are increased in the plasma and brain of pups born to treated mothers, indicating that MD1003 can pass through the mother’s milk. The histological analysis of the grafted animals shows that MD1003 increased proliferation and accelerates differentiation of human oligodendroglia, but without enhancing their myelination potential. These findings provide important insights into the role of MD1003 on murine and human oligodendrocyte maturation/myelination that may explain the mitigated outcome of ALS/MS clinical trials.
New Gd3+ and Mn2+-Co-Doped Scheelite-Type Ceramics—Their Structural, Optical and Magnetic Properties
Authors: Fuks Hubert , Kochmański Paweł , Tomaszewicz Elżbieta
Published: December 2022

New Gd3+- and Mn2+-co-doped calcium molybdato-tungstates with the chemical formula of Ca1−3x−yMny▯xGd2x(MoO4)1−3x(WO4)3x (labeled later as CaMnGdMoWO), where ▯ denotes vacant sites in the crystal lattice, 0 < x ≤ 0.2500 and y = 0.0200 as well as 0 < y ≤ 0.0667 and x = 0.1667 were successfully synthesized by high-temperature solid-state reaction method and combustion route. Obtained ceramic materials crystallize in scheelite-type structure with space group I41/a. Morphological features and grain sizes of powders under study were investigated by SEM technique. Spectroscopic studies within the UV-vis spectral range were carried out to estimate the direct band gap (Eg) and Urbach energy (EU) of obtained powders. EPR studies confirmed the existence of two types of magnetic objects, i.e., Mn2+ and Gd3+ ions, and significant antiferromagnetic (AFM) interactions among them.
TDP-43 Proteinopathy and Tauopathy: Do They Have Pathomechanistic Links?
Authors: Riku Yuichi , Yoshida Mari , Iwasaki Yasushi , Sobue Gen , Katsuno Masahisa , Ishigaki Shinsuke
Published: December 2022

Transactivation response DNA binding protein 43 kDa (TDP-43) and tau are major pathological proteins of neurodegenerative disorders, of which neuronal and glial aggregates are pathological hallmarks. Interestingly, accumulating evidence from neuropathological studies has shown that comorbid TDP-43 pathology is observed in a subset of patients with tauopathies, and vice versa. The concomitant pathology often spreads in a disease-specific manner and has morphological characteristics in each primary disorder. The findings from translational studies have suggested that comorbid TDP-43 or tau pathology has clinical impacts and that the comorbid pathology is not a bystander, but a part of the disease process. Shared genetic risk factors or molecular abnormalities between TDP-43 proteinopathies and tauopathies, and direct interactions between TDP-43 and tau aggregates, have been reported. Further investigations to clarify the pathogenetic factors that are shared by a broad spectrum of neurodegenerative disorders will establish key therapeutic targets.
Educator Feedback Skill Assessment: An Educational Survey Design Study
Authors: Moroz Alex , Stone Jennifer , Lopez Francis , Racine Cynthia , Carmody Kristin
Published: December 2022

Background: Delivering impactful feedback is a skill that is difficult to measure. To date there is no generalizable assessment instrument which measures the quality of medical education feedback. The purpose of the present study was to create an instrument for measuring educator feedback skills. Methods: Building on pilot work, we refined an assessment instrument and addressed content and construct validity using expert validation (qualitative and quantitative). This was followed by cognitive interviews of faculty from several clinical departments, which were transcribed and analyzed using ATLAS.ti qualitative software. A research team revised and improved the assessment instrument. Results: Expert validation and cognitive interviews resulted in the Educator Feedback Skills Assessment, a scale with 10 items and three response options for each. Conclusions: Building on the contemporary medical education literature and empiric pilot work, we created and refined an assessment instrument for measuring educator feedback skills. We also started the argument on validity and addressed content validity.
Decrease in the Starting Temperature of the Reaction for Fabricating Carbides of Refractory Metals When Using Carbon Nanoparticles as Precursors
Authors: Popov Vladimir , Borunova Anna , Shelekhov Evgeny , Koplak Oksana , Dvoretskaya Elizaveta , Matveev Danila , Prosviryakov Alexey , Vershinina Ekaterina , Cheverikin Vladimir
Published: December 2022

Metal matrix composites with a matrix of refractory metals (niobium, tungsten) and reinforcing nanodiamond particles were prepared for studying the possibility of decreasing the starting temperature of carbide synthesis. The size of primary nanodiamond particles was 4–6 nm, but they were combined in large-sized agglomerates. Mechanical alloying was used for producing the composites by crushing agglomerates and distributing nanodiamonds evenly in the metal matrix. The initial and fabricated materials were investigated by X-ray diffraction, differential scanning calorimetry, and transmission and scanning electron microscopy. Thermal processing leads to the reaction for carbide synthesis. Studies have found that the usage of carbon nanoparticles (nanodiamonds) as precursors for fabricating carbides of refractory metals leads to a dramatic decrease in the synthesis temperature in comparison with macro-precursors: lower than 200 °C for tungsten and lower than 350 °C for niobium.
Remnant-Like Particle Cholesterol and the Risk of Major Adverse Cardiovascular Events: A Systematic Review and Meta-Analysis
Authors: Yang Jie , Wang Yuangengshuo , Xi Ziwei , Ma Yue , Shao Chunli , Wang Wenyao , Tang Yi-Da
Published: December 2022

Background: The remnant-like particle cholesterol (RLP-C) has been demonstrated to be associated with residual cardiovascular risk. The meta-analysis aimed to evaluate the impact of baseline RLP-C on the incidence of major cardiovascular adverse events (MACEs) in patients with coronary artery disease (CAD). Methods: A systematic literature search was performed in PubMed and Embase electronic databases from the inception of the databases through 1 October 2022. Studies evaluating the association between baseline RLP-C and the risk of MACEs in patients with CAD were included. Hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled by a random-effect method (RLP-C analyzed as a categorical variable) and a fixed-effects model (RLP-C analyzed as a continuous variable). Results: Ten studies including 18,053 subjects were finally included in this meta-analysis. In our pooled analysis, compared to CAD patients with the lowest RLP-C category, the CAD patients with the highest RLP-C category had a significantly higher risk of future MACEs during follow-up (HR 1.79, 95% CI, 1.42–2.26, I2 = 60.31%, p < 0.01), which was consistent with outcomes of meta-analysis with the RLP-C analyzed as a continuous variable (HR 1.40, 95% CI, 1.28–1.53, I2 = 38.20%, p < 0.01). The sensitivity analysis confirmed the robustness of the results, and no significant publication bias was identified. Conclusion: The present meta-analysis suggests that the RLP-C was associated with an increased risk of long-term MACEs in patients with CAD at baseline. It is necessary to conduct randomized controlled trials to explore whether reducing the RLP-C level is conducive to reducing residual cardiovascular risk, even coronary plaque regression.
The Value of Open Banking Data for Application Credit Scoring: Case Study of a Norwegian Bank
Authors: Hjelkrem Lars Ole , de Lange Petter Eilif , Nesset Erik
Published: December 2022

Banks generally use credit scoring models to assess the creditworthiness of customers when they apply for loans or credit. These models perform significantly worse when used on potential new customers than existing customers, due to the lack of financial behavioral data for new bank customers. Access to such data could therefore increase banks’ profitability when recruiting new customers. If allowed by the customer, Open Banking APIs can provide access to balances and transactions from the past 90 days before the score date. In this study, we compare the performance of conventional application credit scoring models currently in use by a Norwegian bank with a deep learning model trained solely on transaction data available through Open Banking APIs. We evaluate the performance in terms of the AUC and Brier score and find that the models based on Open Banking data alone are surprisingly effective in predicting default compared to the conventional credit scoring models. Furthermore, an ensemble model trained on both traditional credit scoring data and features extracted from the deep learning model further outperforms the conventional application credit scoring model for new customers and narrows the performance gap between application credit scoring models for existing and new customers. Therefore, we argue that banks can increase their profitability by utilizing data available through Open Banking APIs when recruiting new customers.