bluuebunny/crossref_metadata_2025 huggingface dataset:
Insights into Molecular Structure of Pterins Suitable for Biomedical Applications
Authors: Buglak Andrey A. , Kapitonova Marina A. , Vechtomova Yulia L. , Telegina Taisiya A.
Published: December 2022

Pterins are an inseparable part of living organisms. Pterins participate in metabolic reactions mostly as tetrahydropterins. Dihydropterins are usually intermediates of these reactions, whereas oxidized pterins can be biomarkers of diseases. In this review, we analyze the available data on the quantum chemistry of unconjugated pterins as well as their photonics. This gives a comprehensive overview about the electronic structure of pterins and offers some benefits for biomedicine applications: (1) one can affect the enzymatic reactions of aromatic amino acid hydroxylases, NO synthases, and alkylglycerol monooxygenase through UV irradiation of H4pterins since UV provokes electron donor reactions of H4pterins; (2) the emission properties of H2pterins and oxidized pterins can be used in fluorescence diagnostics; (3) two-photon absorption (TPA) should be used in such pterin-related infrared therapy because single-photon absorption in the UV range is inefficient and scatters in vivo; (4) one can affect pathogen organisms through TPA excitation of H4pterin cofactors, such as the molybdenum cofactor, leading to its detachment from proteins and subsequent oxidation; (5) metal nanostructures can be used for the UV-vis, fluorescence, and Raman spectroscopy detection of pterin biomarkers. Therefore, we investigated both the biochemistry and physical chemistry of pterins and suggested some potential prospects for pterin-related biomedicine.
Calorie Restriction Provides Kidney Ischemic Tolerance in Senescence-Accelerated OXYS Rats
Authors: Andrianova Nadezda V. , Zorova Ljubava D. , Pevzner Irina B. , Kolosova Nataliya G. , Plotnikov Egor Y. , Zorov Dmitry B.
Published: December 2022

Kidney diseases belong to a group of pathologies, which are most common among elderly people. With age, even outwardly healthy organisms start to exhibit some age-related changes in the renal tissue, which reduce the filtration function of kidneys and increase the susceptibility to injury. The therapy of acute kidney injury (AKI) is aggravated by the absence of targeted pharmacotherapies thus yielding high mortality of patients with AKI. In this study, we analyzed the protective effects of calorie restriction (CR) against ischemic AKI in senescence-accelerated OXYS rats. We observed that CR afforded OXYS rats with significant nephroprotection. To uncover molecular mechanisms of CR beneficial effects, we assessed the levels of anti- and proapoptotic proteins of the Bcl-2 family, COX IV, GAPDH, and mitochondrial deacetylase SIRT-3, as well as alterations in total protein acetylation and carbonylation, mitochondrial dynamics (OPA1, Fis1, Drp1) and kidney regeneration pathways (PCNA, GDF11). The activation of autophagy and mitophagy was analyzed by LC3 II/LC3 I ratio, beclin-1, PINK-1, and total mitochondrial protein ubiquitination. Among all considered protective pathways, the improvement of mitochondrial functioning may be suggested as one of the possible mechanisms for beneficial effects of CR.
Systems Biology in Chronic Heart Failure—Identification of Potential miRNA Regulators
Authors: Vilella-Figuerola Alba , Gallinat Alex , Escate Rafael , Mirabet Sònia , Padró Teresa , Badimon Lina
Published: December 2022

Heart failure (HF) is a complex disease entity with high clinical impact, poorly understood pathophysiology and scantly known miRNA-mediated epigenetic regulation. We have analysed miRNA patterns in patients with chronic HF (cHF) and a sex- and age-matched reference group and pursued an in silico system biology analysis to discern pathways involved in cHF pathophysiology. Twenty-eight miRNAs were identified in cHF that were up-regulated in the reference group, and eight of them were validated by RT-qPCR. In silico analysis of predicted targets by STRING protein-protein interaction networks revealed eight cluster networks (involving seven of the identified miRNAs) enriched in pathways related to cell cycle, Ras, chemokine, PI3K-AKT and TGF-β signaling. By ROC curve analysis, combined probabilities of these seven miRNAs (let-7a-5p, miR-107, miR-125a-5p, miR-139-5p, miR-150-5p, miR-30b-5p and miR-342-3p; clusters 1–4 [C:1–4]), discriminated between HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF), and ischaemic and non-ischaemic aetiology. A combination of miR-107, miR-139-5p and miR-150-5p, involved in clusters 5 and 7 (C:5+7), discriminated HFpEF from HFrEF. Pathway enrichment analysis of miRNAs present in C:1–4 (let-7a-5p, miR-125a-5p, miR-30b-5p and miR-342-3p) revealed pathways related to HF pathogenesis. In conclusion, we have identified a differential signature of down-regulated miRNAs in the plasma of HF patients and propose novel cellular mechanisms involved in cHF pathogenesis.
Different Intermolecular Interactions Drive Nonpathogenic Liquid–Liquid Phase Separation and Potentially Pathogenic Fibril Formation by TDP-43
Authors: Zeng Yu-Teng , Bi Lu-Lu , Zhuo Xiao-Feng , Yang Ling-Yun , Sun Bo , Lu Jun-Xia
Published: December 2022

The liquid–liquid phase separation (LLPS) of proteins has been found ubiquitously in eukaryotic cells, and is critical in the control of many biological processes by forming a temporary condensed phase with different bimolecular components. TDP-43 is recruited to stress granules in cells and is the main component of TDP-43 granules and proteinaceous amyloid inclusions in patients with amyotrophic lateral sclerosis (ALS). TDP-43 low complexity domain (LCD) is able to de-mix in solution, forming the protein condensed droplets, and amyloid aggregates would form from the droplets after incubation. The molecular interactions regulating TDP-43 LCD LLPS were investigated at the protein fusion equilibrium stage, when the droplets stopped growing after incubation. We found the molecules in the droplet were still liquid-like, but with enhanced intermolecular helix–helix interactions. The protein would only start to aggregate after a lag time and aggregate slower than at the condition when the protein does not phase separately into the droplets, or the molecules have a reduced intermolecular helix–helix interaction. In the protein condensed droplets, a structural transition intermediate toward protein aggregation was discovered involving a decrease in the intermolecular helix–helix interaction and a reduction in the helicity. Our results therefore indicate that different intermolecular interactions drive LLPS and fibril formation. The discovery that TDP-43 LCD aggregation was faster through the pathway without the first protein phase separation supports that LLPS and the intermolecular helical interaction could help maintain the stability of TDP-43 LCD.
Duckweed Is a Promising Feedstock of Biofuels: Advantages and Approaches
Authors: Yang Gui-Li
Published: December 2022

With the growing scarcity of traditional sources of energy and the accompanying acute environmental challenges, biofuels based on biomass are favored as the most promising alternative. As one of the core raw materials for biomass energy, research on its production methods and synthesis mechanisms is emerging. In recent years, duckweed has been used as a high-quality new biomass feedstock for its advantages, including fast biomass accumulation, high starch content, high biomass conversion efficiency, and sewage remediation. This study provides a systematic review of the growth characteristics, starch metabolism pathways, and methods to improve starch accumulation in the new energy plant, duckweed. The study also presents a prospect that might be used as a reference for the development of duckweed as a new energy-providing plant.
EPLIN, a Putative Tumour Suppressor in Colorectal Cancer, Implications in Drug Resistance
Authors: Zeng Jianyuan , Sanders Andrew J. , Ye Lin , Hargest Rachel , Ruge Fiona , Jiang Wen G.
Published: December 2022

Colorectal cancer is a serious threat to human health. Poor prognosis and frequently reported drug resistance urges research into novel biomarkers and mechanisms to aid in the understanding of the development and progression of colorectal cancer and to optimise therapeutic strategies. In the current study, we investigated the roles of a putative tumour suppressor, EPLIN, in colorectal cancer. Our clinical colorectal cancer cohort and online databases revealed a downregulation of EPLIN in colorectal cancer tissues compared with normal tissues. The reduced expression of EPLIN was associated with poor clinical outcomes of patients. In vitro cellular function assays showed that EPLIN elicited an inhibitory effect on cellular growth, adhesion, migration and invasion. Utilising a protein microarray on protein samples from normal and tumour patient tissues suggested HSP60, Her2 and other signalling events were novel potential interacting partners of EPLIN. It was further revealed that EPLIN and HSP60 were negative regulators of Her2 in colorectal cancer cells. The clinical cohort also demonstrated that expression of HSP60 and Her2 affected clinical outcomes, but most interestingly the combination of EPLIN, HSP60 and Her2 was able to identify patients with the most unfavourable clinical outcome by independently predicting patient overall survival and disease free survival. Furthermore, EPLIN and HSP60 exhibited potential to regulate cellular response to chemotherapeutic and EGFR/Her2 targeted therapeutic agents. In conclusion, EPLIN is an important prognostic factor for patients with colon cancer and reduced EPLIN in CRC contributes to aggressive traits of CRC cells and their responses to chemotherapeutic drugs. Collectively, EPLIN is a pivotal factor for the development and progression of colorectal cancer and has important clinical and therapeutic values in this cancer type.
Atrial Fibrillation with Heart Failure in a Case with Resistance to Thyroid Hormone Due to a Rare Thyroid Hormone Receptor β Gene Mutation
Authors: Lai Huei-Pin , Chen Mei-Hsiu
Published: December 2022

Resistance to thyroid hormone (RTH) is a rare disease typically associated with elevated levels of thyroid hormones and non-suppressed thyroid stimulating hormones. The most common cause of RTH is thyroid hormone receptor β (THRβ) gene mutation. Most individuals with RTH are considered clinical euthyroid. We report a family with a rare heterozygous point mutation, c.959G>T, (p.R320L) of the THRβ gene. The proband developed atrial fibrillation and life-threatening heart failure with pulmonary edema, which was quite different from previously reported THRβ gene mutations. Considering the rareness of RTH and the heterogeneity of its phenotypes, our report allows for a better understanding of the manifestation and management of patients with RTH and THRβ gene mutation.
Sustainable Plant-Based Biopolymer Membranes for PEM Fuel Cells
Authors: Li Songtao , Cai George , Wu Songze , Raut Aniket , Borges William , Sharma Priyanka R. , Sharma Sunil K. , Hsiao Benjamin S. , Rafailovich Miriam
Published: December 2022

Carboxycellulose nanofibers (CNFs) promise to be a sustainable and inexpensive alternative material for polymer electrolyte membranes compared to the expensive commercial Nafion membrane. However, its practical applications have been limited by its relatively low performance and reduced mechanical properties under typical operating conditions. In this study, carboxycellulose nanofibers were derived from wood pulp by TEMPO oxidation of the hydroxyl group present on the C6 position of the cellulose chain. Then, citric acid cross-linked CNF membranes were prepared by a solvent casting method to enhance performance. Results from FT-IR spectroscopy, 13C NMR spectroscopy, and XRD reveal a chemical cross-link between the citric acid and CNF, and the optimal fuel cell performance was obtained by cross-linking 70 mL of 0.20 wt % CNF suspension with 300 µL of 1.0 M citric acid solution. The membrane electrode assemblies (MEAs), operated in an oxygen atmosphere, exhibited the maximum power density of 27.7 mW cm−2 and the maximum current density of 111.8 mA cm−2 at 80 °C and 100% relative humidity (RH) for the citric acid cross-linked CNF membrane with 0.1 mg cm−2 Pt loading on the anode and cathode, which is approximately 30 times and 22 times better, respectively, than the uncross-linked CNF film. A minimum activation energy of 0.27 eV is achieved with the best-performing citric acid cross-linked CNF membrane, and a proton conductivity of 9.4 mS cm−1 is obtained at 80 °C. The surface morphology of carboxycellulose nanofibers and corresponding membranes were characterized by FIB/SEM, SEM/EDX, TEM, and AFM techniques. The effect of citric acid on the mechanical properties of the membrane was assessed by tensile strength DMA.
Effect of High Viscosity on Energy Metabolism and Kinematics of Spermatozoa from Three Mouse Species Incubated under Capacitating Conditions
Authors: Sanchez-Rodriguez Ana , Sansegundo Ester , Tourmente Maximiliano , Roldan Eduardo R. S.
Published: December 2022

In order to sustain motility and prepare for fertilization, sperm require energy. The characterization of sperm ATP production and usage in mouse species revealed substantial differences in metabolic pathways that can be differentially affected by capacitation. Moreover, spermatozoa encounter different environments with varying viscoelastic properties in the female reproductive tract. Here, we examine whether viscosity affects sperm ATP levels and kinematics during capacitation in vitro. Sperm from three mouse species (Mus musculus, M. spretus, M. spicilegus) were incubated under capacitating conditions in a modified Tyrode’s medium containing bicarbonate, glucose, pyruvate, lactate, and bovine serum albumin (mT-BH) or in a bicarbonate-free medium as a non-capacitating control. Viscosity was increased with the inclusion of polyvinylpyrrolidone. ATP was measured with a bioluminescence kit, and kinematics were examined with a computer-aided sperm analysis system. In M. musculus sperm, ATP declined during capacitation, but no differences were found between non-capacitating and capacitating sperm. In contrast, in M. spretus and M. spicilegus, ATP levels decreased in capacitating sperm. Increasing viscosity in the medium did not modify the timing or proportion of cells undergoing capacitation but did result in additional time- and concentration-dependent decreases in ATP in M. spretus and M. spicilegus under capacitating conditions. Additionally, increased viscosity altered both velocity and trajectory descriptors. The limited impact of capacitation and higher viscosity on M. musculus sperm ATP and kinematics could be related to the low intensity of postcopulatory sexual selection in this species. Responses seen in the other two species could be linked to the ability of their sperm to perform better under enhanced selective pressures.
Study of Degradation Kinetics and Structural Analysis of Related Substances of Ceftobiprole by HPLC with UV and MS/MS Detection
Authors: Boczar Dariusz , Bus Katarzyna , Michalska Katarzyna
Published: December 2022

Ceftobiprole is a novel β-lactam antibiotic, active against methicillin-resistant Staphylococcus aureus, vancomycin-resistant S. aureus and penicillin-resistant Streptococcus pneumoniae. To artificially generate potential degradation products (DPs) of ceftobiprole that may be formed under relevant storage conditions, acidic, alkaline, oxidative, photolytic and thermolytic stress tests were performed in both solution and solid state. A novel selective HPLC method was developed for the separation of ceftobiprole from its DPs and synthesis by-products (SBPs) using Kinetex Biphenyl column, ammonium acetate buffer pH 5.8 and acetonitrile. The kinetic studies demonstrated the low stability of ceftobiprole in alkaline solution, in the presence of an oxidising agent and under irradiation with near UV. In the solid state, ceftobiprole underwent oxidation when the powder was irradiated with visible light and UV. Based on mass spectroscopic analysis, 13 new structural formulas of SBPs and DPs were proposed, along with molecular formulas for three other DPs obtained in solution and four oxidative DPs characteristic of solid-state degradation.
Modifying Effect of the Interleukin-18 Level on the Association between BDNF Methylation and Long-Term Cardiovascular Outcomes in Patients with Acute Coronary Syndrome
Authors: Choi Wonsuk , Kang Hee-Ju , Kim Ju-Wan , Kim Hee Kyung , Kang Ho-Cheol , Kim Sung-Wan , Kim Jung-Chul , Ahn Youngkeun , Jeong Myung Ho , Kim Jae-Min
Published: December 2022

This study investigated the potential modifying effects of the level of the serum interleukin-18 (IL-18) on the association between BDNF methylation status and long-term cardiovascular outcomes in patients with acute coronary syndrome (ACS). Hospitalized ACS patients were recruited sequentially from 2006 to 2012. At baseline, the IL-18 level and BDNF methylation status were evaluated in 969 patients who were followed for major adverse cardiac events (MACEs) for 5–12 years, until 2017 or death. The time to first composite or individual MACE was compared between individuals with lower and higher average BDNF methylation levels (in the low- and high-IL-18 groups, respectively) using a Cox proportional hazards model. After adjusting for potential covariates, the modifying effects of IL-18 and average BDNF methylation levels on the initial composite and individual MACEs were examined. In the high-IL-18 group, but not in the low-IL-18 group, a higher average BDNF methylation level was associated with increases in composite MACEs (HR (95% CI) = 2.15 (1.42–3.26)), all-cause mortality (HR (95% CI) = 1.89 (1.11–3.22)), myocardial infarction (HR (95% CI) = 1.98 (1.07–3.67)), and percutaneous coronary intervention (HR (95% CI) = 1.81 (1.01–3.23)), independent of confounding variables. The interaction effect between the IL-18 and average BDNF methylation levels on composite MACEs (p = 0.019) and myocardial infarction (p = 0.027) was significant after adjusting for covariates. Analysis of BDNF methylation status and IL-18 levels may help identify ACS patients who are most likely to have adverse clinical outcomes.
Ferulic Acid and P-Coumaric Acid Synergistically Attenuate Non-Alcoholic Fatty Liver Disease through HDAC1/PPARG-Mediated Free Fatty Acid Uptake
Authors: Cui Kaili , Zhang Lichao , La Xiaoqin , Wu Haili , Yang Ruipeng , Li Hanqing , Li Zhuoyu
Published: December 2022

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease and has become a growing public health concern worldwide. Polyphenols may improve high-fat diet (HFD)-related NAFLD. Our previous study found that ferulic acid (FA) and p-coumaric acid (p-CA) were the polyphenols with the highest content in foxtail millet. In this study, we investigated the mechanism underlying the impact of ferulic acid and p-coumaric acid (FA/p-CA) on non-alcoholic fatty liver (NAFLD). The association of FA and p-CA with fatty liver was first analyzed by network pharmacology. Synergistic ameliorating of NAFLD by FA and p-CA was verified in oleic acid (OA) and palmitic acid (PA) (FFA)-treated hepatocytes. Meanwhile, FA/p-CA suppressed final body weight and TG content and improved liver dysfunction in HFD-induced NAFLD mice. Mechanistically, our data indicated that FA and p-CA bind to histone deacetylase 1 (HDAC1) to inhibit its expression. The results showed that peroxisome proliferator activated receptor gamma (PPARG), which is positively related to HDAC1, was inhibited by FA/p-CA, and further suppressed fatty acid binding protein (FABP) and fatty acid translocase (CD36). It suggests that FA/p-CA ameliorate NAFLD by inhibiting free fatty acid uptake via the HDAC1/PPARG axis, which may provide potential dietary supplements and drugs for prevention of NAFLD.
A Reduced Tryptophan Diet in Patients with Diarrhoea-Predominant Irritable Bowel Syndrome Improves Their Abdominal Symptoms and Their Quality of Life through Reduction of Serotonin Levels and Its Urinary Metabolites
Authors: Chojnacki Cezary , Medrek-Socha Marta , Blonska Aleksandra , Zajdel Radoslaw , Chojnacki Jan , Poplawski Tomasz
Published: December 2022

(1). An essential component of any treatment for patients with irritable bowel syndrome (IBS) is an adequate diet. Currently, a low FODMAP diet is recommended as a first-line therapy, but it does not relieve abdominal discomfort in all patients, and alternative nutritional treatment is required. The purpose of this study was to evaluate the effect of a tryptophan-lowering diet (TRP) on abdominal and mental symptoms in patients with irritable bowel syndrome with predominant diarrhea (IBS-D). (2). The study included 40 patients with IBS-D, and 40 healthy subjects served as a baseline for IBS-D patients, after excluding comorbidities. The TRP intake was calculated using the nutritional calculator. The severity of abdominal symptoms was assessed using the gastrointestinal symptom rating scale (GSRS-IBS). Mental state was assessed using the Hamilton anxiety rating scale (HAM-A), the Hamilton depression rating scale (HAM-D), and the insomnia severity index (ISI). The serum levels of serotonin and melatonin and the urinary excretion of their metabolites 5-hydroxyindoleacetic acid (5-HIAA) and 6-sulfatoxymelatonin (aMT6) were determined by the ELISA method. The severity of symptoms and laboratory data were analyzed before and after a 12 week diet with tryptophan restricted to a daily dose 10 mg per kilogram body weight. (3). Compared to the control group, patients with IBS-D had a higher serum level of serotonin (198.2 ± 38.1 vs. 142.3 ± 36.4 ng/mL; p < 0.001) but a similar level of melatonin (8.6 ± 1.1 vs. 9.4 ± 3.0 pg/mL; p > 0.05). The urinary excretion of 5-HIAA was also higher in patients with IBS-D patients (7.7 ± 1.5 vs. 6.0 ± 1.7 mg/24 h; p < 0.001). After nutritional treatment, both the serum serotonin level and the urinary 5-HIAA excretion significantly decreased (p < 0.001). The severity of the abdominal symptoms and anxiety also decreased, while the HAM-D score and the ISI score remained unchanged (4). Lowering the dietary intake of tryptophan may reduce abdominal complaints and does not alter the mental state of IBS-D patients.
Opposing Roles of DCs and iNKT Cells in the Induction of Foxp3 Expression by MLN CD25+CD4+ T Cells during IFNγ-Driven Colitis
Authors: Lee Sung Won , Park Hyun Jung , Van Kaer Luc , Hong Seokmann
Published: December 2022

We have previously shown that a deficiency of CD1d-restricted invariant natural killer T (iNKT) cells exacerbates dextran sulfate sodium (DSS)-induced colitis in Yeti mice that exhibit IFNγ-mediated hyper-inflammation. Although iNKT cell-deficiency resulted in reduced Foxp3 expression by mesenteric lymph node (MLN) CD4+ T cells in DSS-treated Yeti mice, the cellular mechanisms that regulate Foxp3 expression by CD25+CD4+ T cells during intestinal inflammation remain unclear. We found that Foxp3−CD25+CD4+ T cells expressing Th1 and Th17 phenotypic hallmarks preferentially expanded in the MLNs of DSS-treated Yeti/CD1d knockout (KO) mice. Moreover, adoptive transfer of Yeti iNKT cells into iNKT cell-deficient Jα18 KO mice effectively suppressed the expansion of MLN Foxp3−CD25+CD4+ T cells during DSS-induced colitis. Interestingly, MLN dendritic cells (DCs) purified from DSS-treated Yeti/CD1d KO mice promoted the differentiation of naive CD4+ T cells into Foxp3−CD25+CD4+ T cells rather than regulatory T (Treg) cells, indicating that MLN DCs might mediate Foxp3+CD25+CD4+ T cell expansion in iNKT cell-sufficient Yeti mice. Furthermore, we showed that Foxp3−CD25+CD4+ T cells were pathogenic in DSS-treated Yeti/CD1d KO mice. Our result suggests that pro-inflammatory DCs and CD1d-restricted iNKT cells play opposing roles in Foxp3 expression by MLN CD25+CD4+ T cells during IFNγ-mediated intestinal inflammation, with potential therapeutic implications.
The Soluble Guanylate Cyclase Stimulator BAY 41-2272 Attenuates Transforming Growth Factor β1-Induced Myofibroblast Differentiation of Human Corneal Keratocytes
Authors: Rosa Irene , Fioretto Bianca Saveria , Romano Eloisa , Buzzi Matilde , Mencucci Rita , Marini Mirca , Manetti Mirko
Published: December 2022

Corneal transparency, necessary for vision and depending on the high organization of stromal extracellular matrix, is maintained by keratocytes. Severe or continuous corneal injuries determine exaggerated healing responses resulting in the formation of irreversible fibrotic scars and vision impairment. Soluble guanylate cyclase (sGC) stimulation demonstrated antifibrotic effects in both experimental fibrosis and human lung and skin fibroblasts. Here, we assessed whether sGC stimulation with BAY 41-2272 could attenuate transforming growth factor β1 (TGFβ1)-induced myofibroblast differentiation of human corneal keratocytes. Cells were challenged with TGFβ1, with/without BAY 41-2272 preincubation, and subsequently assessed for viability, proliferation, migration, chemoinvasion, as well for the expression of myofibroblast/fibroblast activation markers and contractile abilities. Treatment with BAY 41-2272 did not affect keratocyte viability, while preincubation of cells with the sGC stimulator was able to inhibit TGFβ1-induced proliferation, wound healing capacity, and invasiveness. BAY 41-2272 was also able to attenuate TGFβ1-induced myofibroblast-like profibrotic phenotype of keratocytes, as demonstrated by the significant decrease in ACTA2, COL1A1, COL1A2, FN1 and PDPN gene expression, as well as in α-smooth muscle actin, α-1 chain of type I collagen, podoplanin, vimentin and N-cadherin protein expression. Finally, BAY 41-2272 significantly counteracted the TGFβ1-induced myofibroblast-like ability of keratocytes to contract collagen gels, reduced phosphorylated Smad3 protein levels, and attenuated gene expression of proinflammatory cytokines. Collectively, our data show for the first time that BAY 41-2272 is effective in counteracting keratocyte-to-myofibroblast transition, thus providing the rationale for the development of sGC stimulators as novel promising modulators of corneal scarring and fibrosis.
Mangiferin Ameliorates Obesity-Associated Inflammation and Autophagy in High-Fat-Diet-Fed Mice: In Silico and In Vivo Approaches
Authors: Noh Ji-Won , Lee Han-Young , Lee Byung-Cheol
Published: December 2022

Obesity-induced insulin resistance is the fundamental cause of metabolic syndrome. Accordingly, we evaluated the effect of mangiferin (MGF) on obesity and glucose metabolism focusing on inflammatory response and autophagy. First, an in silico study was conducted to analyze the mechanism of MGF in insulin resistance. Second, an in vivo experiment was conducted by administering MGF to C57BL/6 mice with high-fat-diet (HFD)-induced metabolic disorders. The in silico analysis revealed that MGF showed a high binding affinity with macrophage-related inflammatory cytokines and autophagy proteins. In the in vivo study, mice were divided into three groups: normal chow, HFD, and HFD + MGF 150 mg/kg. MGF administration to obese mice significantly improved the body weight, insulin-sensitive organs weights, glucose and lipid metabolism, fat accumulation in the liver, and adipocyte size compared to HFD alone. MGF significantly reduced the macrophages in adipose tissue and Kupffer cells, inhibited the gene expression ratio of tumor necrosis factor-α and F4/80 in adipose tissue, reduced the necrosis factor kappa B gene, and elevated autophagy-related gene 7 and fibroblast growth factor 21 gene expressions in the liver. Thus, MGF exerted a therapeutic effect on metabolic diseases by improving glucose and lipid metabolism through inhibition of the macrophage-mediated inflammatory responses and activation of autophagy.
Deciphering the Binding of the Nuclear Localization Sequence of Myc Protein to the Nuclear Carrier Importin α3
Authors: Rizzuti Bruno , Iovanna Juan L. , Neira José L.
Published: December 2022

The oncoprotein Myc is a transcription factor regulating global gene expression and modulating cell proliferation, apoptosis, and metabolism. Myc has a nuclear localization sequence (NLS) comprising residues Pro320 to Asp328, to allow for nuclear translocation. We designed a peptide comprising such region and the flanking residues (Ala310-Asn339), NLS-Myc, to study, in vitro and in silico, the ability to bind importin α3 (Impα3) and its truncated species (ΔImpα3) depleted of the importin binding domain (IBB), by using fluorescence, circular dichroism (CD), biolayer interferometry (BLI), nuclear magnetic resonance (NMR), and molecular simulations. NLS-Myc interacted with both importin species, with affinity constants of ~0.5 µM (for Impα3) and ~60 nM (for ΔImpα3), as measured by BLI. The molecular simulations predicted that the anchoring of NLS-Myc took place in the major binding site of Impα3 for the NLS of cargo proteins. Besides clarifying the conformational behavior of the isolated NLS of Myc in solution, our results identified some unique properties in the binding of this localization sequence to the nuclear carrier Impα3, such as a difference in the kinetics of its release mechanism depending on the presence or absence of the IBB domain.
Mechanism of Synergy between Piceatannol and Ciprofloxacin against Staphylococcus aureus
Authors: Shi Mengyan , Bai Yubin , Qiu Yanhua , Zhang Xinxin , Zeng Zikang , Chen Lingling , Cheng Fusheng , Zhang Jiyu
Published: December 2022

Piceatannol (PIC) is a natural stilbene extracted from grape skins that exhibits biological activities such as antibacterial, antitumor, and antioxidant activities. The present study was carried out to further investigate the effect of PIC on the antibacterial activity of different antibiotics and to reveal the antibacterial mechanism of PIC. We found that PIC had an inhibitory effect against Staphylococcus aureus (S. aureus); its minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were 128 μg/mL and 256 μg/ mL, respectively. Additionally, we measured the fractional inhibitory concentration (FIC) of PIC combined with antibiotics via the checkerboard method. The results showed that when PIC and ciprofloxacin (CIP) were combined, they displayed a synergistic effect against S. aureus. Moreover, this synergistic effect was verified by time–kill assays. Further, the results of the membrane permeability assay and proton motive force assay revealed that PIC could enhance the sensitivity of S. aureus to CIP by dissipating the bacterial proton motive force (PMF), particularly the ∆ψ component, rather than increasing membrane permeability. PIC also inhibited bacterial adenosine triphosphate (ATP) synthesis and was less likely to induce bacterial resistance but exhibited slight hemolytic activity on mammalian erythrocytes. In summary, the combination of PIC and CIP is expected to become a new drug combination to combat S. aureus.
Freehand Gestural Selection with Haptic Feedback in Wearable Optical See-Through Augmented Reality
Authors: Wang Gang , Ren Gang , Hong Xinye , Peng Xun , Li Wenbin , O’Neill Eamonn
Published: December 2022

Augmented reality (AR) technologies can blend digital and physical space and serve a variety of applications intuitively and effectively. Specifically, wearable AR enabled by optical see-through (OST) AR head-mounted displays (HMDs) might provide users with a direct view of the physical environment containing digital objects. Besides, users could directly interact with three-dimensional (3D) digital artefacts using freehand gestures captured by OST HMD sensors. However, as an emerging user interaction paradigm, freehand interaction with OST AR still requires further investigation to improve user performance and satisfaction. Thus, we conducted two studies to investigate various freehand selection design aspects in OST AR, including target placement, size, distance, position, and haptic feedback on the hand and body. The user evaluation results indicated that 40 cm might be an appropriate target distance for freehand gestural selection. A large target size might lower the selection time and error rate, and a small target size could minimise selection effort. The targets positioned in the centre are the easiest to select, while those in the corners require extra time and effort. Furthermore, we discovered that haptic feedback on the body could lead to high user preference and satisfaction. Based on the research findings, we conclude with design recommendations for effective and comfortable freehand gestural interaction in OST AR.
Patient-Perceived Satisfaction and Knowledge Uptake in a Combined Cardio-Obstetrics Clinic
Authors: Florio Karen L. , White Darcy , Gosch Kensey , Patel Neil , Daming Tara , Williams Emily M. , Hostetter Sarah , Gray Rebecca , Nelson Lynne , Swearingen Kathleen , Henricks Christine , Grodzinsky Anna , Rader Valerie , Lee John , Magalski Anthony , Schmidt Laura
Published: December 2022

Heart disease is the leading cause of pregnancy-related mortality in the United States and has led to the development of combined cardio-obstetrics (COB) clinics as a model for prenatal care. In other areas of medicine, these types of collaborative care models have shown improvement in morbidity, mortality, and patient satisfaction. There is some data to suggest that a combined COB clinic improves maternal outcomes but there is no data to suggest patients prefer this type of care model. This study aims to evaluate patient satisfaction in a combined COB clinic and whether this type of model enhances perceived communication and knowledge uptake. A quality questionnaire was developed to assess patient perceptions regarding communication, satisfaction, and perceived knowledge. Patients who attended the clinic (n = 960) from 2014–2020 were contacted by email, with a response received from 119 (12.5%). Participants completed a questionnaire assessing satisfaction and perceived knowledge uptake with answers based on a Likert scale (7 representing very satisfied and 1 representing very unsatisfied). Safe and effective contraceptive use was evaluated by multiple choice options. Knowledge was also assessed by comparing contraceptive use before and after the clinic. Participants reported high levels of satisfaction with the clinic (6.2 ± 1.5), provider-to-patient communication (6.1 ± 1.6), and with the multidisciplinary appointment approach (6.3 ± 1.5). As well, participants reported an increase in knowledge about heart disease a result of collaborative counseling. In summary, a multidisciplinary approach to cardio-obstetrics not only improves outcomes but is a patient satisfier.
4-Year Follow-Up after Transatrial Transcatheter Tricuspid Valve Replacement with the LuX-Valve
Authors: Ning Xiaoping , Cao Jingyi , Wang Wei , Zhou Guangwei , Yang Fan , Xu Zhiyun , Han Lin , Qiao Fan , Lu Fanglin
Published: December 2022

Tricuspid regurgitation (TR) has become one of the most common valve diseases. Patients with severe TR are often at high surgical mortality risk. Transcatheter tricuspid valve interventions have emerged as a promising alternative to open-heart surgery. The LuX-Valve is a novel radial force-independent transcatheter tricuspid valve replacement system. We presented here the first patient treated for symptomatic TR using the LuX-Valve replacement system in September 2018. Four-year follow-up outcomes suggested that the bioprosthesis was in normal function, with stable hemodynamics (mean transtricuspid gradient 2.55 mmHg) and the patient’s clinical symptoms were significantly improved; thus indicating that it is a safe, effective, and satisfactory case of the LuX-Valve application in treating a patient with severe TR.
Lung Cancer Clinical Trials with a Seamless Phase II/III Design: Systematic Review
Authors: Palermos Dionysios , Sergentanis Theodoros N. , Gavriatopoulou Maria , Malandrakis Panagiotis , Psaltopoulou Theodora , Terpos Evangelos , Ntanasis-Stathopoulos Ioannis
Published: December 2022

Current lung cancer clinical research focuses on biomarkers and personalized treatment strategies. Adaptive clinical trial designs have gained significant ground due to their increased flexibility, compared to the conventional model of drug development from phase I to phase IV trials. One such adaptive approach is the seamless phase II/III design, which has been used to reduce the total sample size and drug development time. In this context, an algorithmic systematic search was conducted in MEDLINE (PUBMED), SCOPUS, EMBASE and Cochrane Central Register of Controlled Trials until 31 June 2022 in order to identify lung cancer trials of systematic treatments that have employed the seamless phase II/III methodology and to describe their characteristics. The search strategy yielded a total of 1420 records that were screened through their title and abstract; 28 eligible trials were included in the systematic review. Based on the study endpoints, the most common subtype included phase II/III trials with inefficacy/futility analyses (61%; 17/28), followed by dose escalation phase II/III trials (18%; 5/28), one multi-arm multi stage trial and 5 trials with other design (18%). Most eligible trials were open-label (71%; 20/27), included patients with non-small cell lung cancer (82%; 23/28), evaluated targeted therapies and/or immunotherapies (82%; 23/28) and recruited patients with advanced disease (89.3%; 25/28). In conclusion, the seamless phase II/III design is a feasible and suitable approach in lung cancer research, with distinct design subcategories according to study endpoints.
A 25 mm Circular Stapler Anastomosis Is Associated with Higher Anastomotic Leakage Rates Following Minimally Invasive Ivor Lewis Operation
Authors: Hofmann Tobias , Biebl Matthias , Knitter Sebastian , Fehrenbach Uli , Chopra Sascha , Cetinkaya-Hosgor Candan , Raakow Jonas , Seika Philippa , Langer Rupert , Pratschke Johann , Denecke Christian , Kröll Dino
Published: December 2022

(1) Background: Minimally invasive oesophagectomy (MIE) with intrathoracic anastomosis is increasingly used in treating patients with oesophageal cancer. Anastomotic leakage (AL) remains a critical perioperative complication, despite recent advances in surgical techniques. It remains unclear to what extent the size of the circular stapler (CS), a 25 mm CS or a bigger CS, may affect the incidence of AL. This study aimed to evaluate whether the CS size in oesophagogastrostomy affects the postoperative AL rates and related morbidity in MIE. (2) Methods: We conducted a retrospective review of consecutive patients who had undergone thoracic MIE between August 2014 and July 2019 using a CS oesophagogastric anastomosis at the level of the Vena azygos. The patients were grouped according to CS size (mm): small-sized (SS25) and large-sized (LS29). The patient demographics, data regarding morbidity, and clinical outcomes were compared. The primary outcome measure was the AL rate related to the stapler size. (3) Results: A total of 119 patients were included (SS25: n = 65; LS29: n = 54). Except for the distribution of squamous cell carcinoma, the demographics were similar in each group. The AL rate was 3.7% in the LS29 group and 18.5% in the SS25 group (p = 0.01). The major morbidity (CD ≥ 3a) was significantly more frequent in the SS25 group compared with the LS29 group (p = 0.02). CS size, pulmonary complications, and cardiovascular disease were independent risk factors for AL in the multivariate analysis. (4) Conclusions: A 29 mm CS is associated with significantly improved surgical outcomes following standard MIE at the level of the azygos vein and should be conducted whenever technically feasible.
Mid-Term Outcome of Ventricular Arrhythmias Catheter Ablation in Patients with Chronic Coronary Total Occlusion Compared to Ischemic and Non-Ischemic Patients
Authors: Narducci Maria Lucia , Niccoli Giampaolo , Flore Francesco , Perna Francesco , Bencardino Gianluigi , Montone Rocco Antonio , Pelargonio Gemma , Crea Filippo
Published: December 2022

Chronic coronary total occlusions (CTO) are considered an emerging predictor of ventricular arrhythmias (VAs), but currently there are few data on arrhythmic outcomes in patients affected by CTO undergoing radiofrequency catheter ablation of VAs. This study sought to evaluate the impact of unrevascularized CTO on the recurrence of VAs after catheter ablation. This was a single-center retrospective study enrolling 120 patients between 2015 and 2020. All patients were admitted for ventricular tachycardia (VT) or high premature ventricular contractions burden (>25% detected by Holter ECG), without evidence of acute coronary syndrome; they underwent coronary angiography, electrophysiology (EP) study, and three-dimensional electroanatomic mapping (3D-EAM) followed by VAs ablation. Twenty-eight patients (23%) of 120 patients showed CTO at coronary angiography. At baseline, the CTO group presented with higher prevalence of hypertension, chronic renal disease, systolic ventricular dysfunction, secondary prevention ICD implantation, and higher rate of LAVA by 3D-EAM compared with the non-CTO group. At a median follow-up of 15 months (range 1–96 months) after catheter ablation, the only independent predictor of VAs recurrence was the presence of moderate to severe left ventricular (LV) dysfunction. Therefore, the presence of CTO does not predict VAs recurrence after catheter ablation, which is instead predicted by LV dysfunction.
Validation of the Ischaemia Severity Scale (ISS) Based on Non-Invasive Vascular Assessments (SEWSS) for Predicting Outcomes of Diabetic Foot Attack
Authors: Martinez-De Jesús Fermín Rafael , Hernandez-Luevano Emmanuel , Rodriguez-Ramírez Neftalí , Cendejas-Alatorre Rafael , Muñoa Prado José Antonio , Carrera Maigua Favio , Zambrano-Loaiza Elízabeth
Published: December 2022

Assessment of ischaemia severity includes a variety of measures, such as pedal pulse palpation, the ankle/brachial index (ABI), and the toe/brachial index (TBI), but there is a lack of consensus regarding which ischaemia scale is the most effective for determining outcome prognosis. The purpose of this study is to validate the application of the ischaemia severity scale (ISS) in the effective prediction of wound healing, amputations, and mortality for diabetic foot wounds (DFW). This prospective study included 235 consecutive patients graded according to the Saint Elian Wound Score System (SEWSS). The ISS is part of this system, with patients being scored as non-ischaemic (0) or having mild (1), moderate (2), or severe (3) ischaemia. Age, diabetes duration in years, and ulcer size were found to be associated with a longer mean ischaemia of increasing severity. A trend of reduction in the pulse palpation rates (70.4%, 50%, 8.5% to 0%; p < 0.01), ABI (1.1 ± 0.1, 0.86 ± 0.3, 0.68 ± 0.2, 0.47 ± 0.2, p < 0.01), TBI average values (0.90 ± 0.35, 0.62 ± 0.52, 0.50 ± 0.33, 0.10 ± 0.42, p < 0.01), wound healing success (88.7%, 57.7%, 40.7%, 12.9%; p < 0.01), and delay in weeks (Kaplan–Meier: log-rank 44.2, p < 0.01) was observed with increasing values of the ISS (0, 1, 2, and 3). The odds ratio for adverse outcomes increased for each additional level of ischaemia severity. Thus, we demonstrate that the ISS is useful in effectively predicting adverse outcomes for DFW.
Externalized Reusable Permanent Pacemaker for Prolonged Temporary Cardiac Pacing in Critical Cardiac Care Units: An Observational Monocentric Retrospective Study
Authors: Beneyto Maxime , Seguret Matthieu , Taranzano Marine , Mondoly Pierre , Biendel Caroline , Rollin Anne , Bounes Fanny , Elbaz Meyer , Maury Philippe , Delmas Clément
Published: December 2022

Introduction: The use of temporary cardiac pacing is frequent in critical care units for severe bradycardia or electrical storm, but may be associated with frequent and potentially severe complications, especially when indwelling for several days. In some cases, transient indication or ongoing contraindication for a permanent pacemaker justifies prolonged temporary pacing. In that case, the implantation of an active-fixation lead connected to an externalized pacemaker represents a valuable option to increase safety and patient comfort. Yet, evidence remains scarce. We aimed to describe the population receiving prolonged temporary cardiac pacing (PTCP) and their outcomes. Methods: We retrospectively included all consecutive patients, admitted to our hospital from 2016 to 2021, who underwent PTCP. We collected in-hospital and six-month outcomes. Results: Forty-six patients (median age of 73, 63% male) were included, and twenty-nine (63%) had prior heart disease. Indications for PTCP were found: seventeen (37%) potentially reversible high-grade conduction disorders, fourteen (30%) indications for permanent pacemaker but ongoing infection, seven (15%) cardiac implantable electronic device infections requiring extraction in pacing-dependent patients, seven (15%) severe vagal hyperreactivity in prolonged critical care hospitalizations, and one (2%) recurrent sustained ventricular tachycardia requiring overdrive pacing. The median PTCP duration was nine (5–13) days. Ten (22%) patients exhibited at least one complication during hospitalization. Twenty-six (56.5%) patients required definite device implantation (twenty-five pacemakers and one cardioverter-defibrillator) and twenty (43.5%) did not (fifteen PTCP device removal for recovery and five deaths under PTCP). At six months, two (5%) deaths and two (5%) new infections of a definite implanted device occurred, all in patients with initial active infection. Conclusion: The use of prolonged temporary cardiac pacing, with an active -fixation lead connected to an externalized pacemaker, is possible and reasonable; this would allow for the possible recovery or resolution of contraindication for definite device implantation.
Antibiotics Use in COVID-19 Patients: A Systematic Literature Review
Authors: Granata Guido , Schiavone Francesco , Pipitone Giuseppe , Taglietti Fabrizio , Petrosillo Nicola
Published: December 2022

The issue of bacterial infections in COVID-19 patients has received increasing attention among scientists. Antibiotics were widely prescribed during the early phase of the pandemic. We performed a literature review to assess the reasons, evidence and practices on the use of antibiotics in COVID-19 in- and outpatients. Published articles providing data on antibiotics use in COVID-19 patients were identified through computerized literature searches on the MEDLINE and SCOPUS databases. Searching the MEDLINE database, the following search terms were adopted: ((antibiotic) AND (COVID-19)). Searching the SCOPUS database, the following search terms were used: ((antibiotic treatment) AND (COVID-19)). The risk of bias in the included studies was not assessed. Both quantitative and qualitative information were summarized by means of textual descriptions. Five-hundred-ninety-three studies were identified, published from January 2020 to 30 October 2022. Thirty-six studies were included in this systematic review. Of the 36 included studies, 32 studies were on the use of antibiotics in COVID-19 inpatients and 4 on antibiotic use in COVID-19 outpatients. Apart from the studies identified and included in the review, the main recommendations on antibiotic treatment from 5 guidelines for the clinical management of COVID-19 were also summarized in a separate paragraph. Antibiotics should not be prescribed during COVID-19 unless there is a strong clinical suspicion of bacterial coinfection or superinfection.