bluuebunny/crossref_metadata_2025 huggingface dataset:
Establishment and Characterization of Mild Atopic Dermatitis in the DNCB-Induced Mouse Model
Authors: Riedl Rebecca , Kühn Annika , Rietz Denise , Hebecker Betty , Glowalla Karl-Gunther , Peltner Lukas K. , Jordan Paul M. , Werz Oliver , Lorkowski Stefan , Wiegand Cornelia , Wallert Maria
Published: August 2023

In dermatological research, 2,4-dinitrochlorbenzene (DNCB)-induced atopic dermatitis (AD) is a standard model as it displays many disease-associated characteristics of human AD. However, the reproducibility of the model is challenging due to the lack of information regarding the methodology and the description of the phenotype and endotype of the mimicked disease. In this study, a DNCB-induced mouse model was established with a detailed procedure description and classification of the AD human-like skin type. The disease was induced with 1% DNCB in the sensitization phase and repeated applications of 0.3% and 0.5% DNCB in the challenging phase which led to a mild phenotype of AD eczema. Pathophysiological changes of the dorsal skin were measured: thickening of the epidermis and dermis, altered skin barrier proteins, increased TH1 and TH2 cytokine expression, a shift in polyunsaturated fatty acids, increased pro-resolving and inflammatory mediator formation, and dysregulated inflammation-associated gene expression. A link to type I allergy reactions was evaluated by increased mast cell infiltration into the skin accompanied by elevated IgE and histamine levels in plasma. As expected for mild AD, no systemic inflammation was observed. In conclusion, this experimental setup demonstrates many features of a mild human-like extrinsic AD in murine skin.
Development and In Vitro–In Vivo Correlation Evaluation of IMM-H014 Extended-Release Tablets for the Treatment of Fatty Liver Disease
Authors: Zhang Chi , Shao Huihui , Han Zunsheng , Liu Bo , Feng Jing , Zhang Jie , Zhang Wenxuan , Zhang Kun , Yang Qingyun , Wu Song
Published: August 2023

This study aimed to develop extended-release tablets containing 25 mg IMM-H014, an original drug formulated by a direct powder pressing method based on pharmaceutical-grade hydrophilic matrix polymers such as hydroxypropyl methylcellulose, to establish an in vitro–in vivo correlation (IVIVC) to predict bioavailability. The tablets’ mechanical properties and in vitro and in vivo performance were studied. The formulation was optimized using a single-factor experiment and the reproducibility was confirmed. The in vitro dissolution profiles of the tablet were determined in five dissolution media, in which the drug released from the hydrophilic tablets followed the Ritger–Peppas model kinetics in 0.01 N HCl medium for the first 2 h, and in phosphate-buffered saline medium (pH 7.5) for a further 24 h. Accelerated stability studies (40 °C, 75% relative humidity) proved that the optimal formulation was stable for 6 months. The in vivo pharmacokinetics study in beagle dogs showed that compared to the IMM-H014 immediate release preparation, the maximum plasma concentration of the extended-release (ER) preparation was significantly decreased, while the maximum time to peak and mean residence time were significantly prolonged. The relative bioavailability was 97.9% based on the area under curve, indicating that the optimal formulation has an obvious ER profile, and a good IVIVC was established, which could be used to predict in vivo pharmacokinetics based on the formulation composition.
Pictilisib-Induced Resistance Is Mediated through FOXO1-Dependent Activation of Receptor Tyrosine Kinases in Mucinous Colorectal Adenocarcinoma Cells
Authors: Kuracha Murali R. , Govindarajan Venkatesh , Loggie Brian W. , Tobi Martin , McVicker Benita L.
Published: August 2023

The phosphatidylinositol (PI3K)/AKT/mTOR axis represents an important therapeutic target to treat human cancers. A well-described downstream target of the PI3K pathway is the forkhead box O (FOXO) transcription factor family. FOXOs have been implicated in many cellular responses, including drug-induced resistance in cancer cells. However, FOXO-dependent acute phase resistance mediated by pictilisib, a potent small molecule PI3K inhibitor (PI3Ki), has not been studied. Here, we report that pictilisib-induced adaptive resistance is regulated by the FOXO-dependent rebound activity of receptor tyrosine kinases (RTKs) in mucinous colorectal adenocarcinoma (MCA) cells. The resistance mediated by PI3K inhibition involves the nuclear localization of FOXO and the altered expression of RTKs, including ErbB2, ErbB3, EphA7, EphA10, IR, and IGF-R1 in MCA cells. Further, in the presence of FOXO siRNA, the pictilisib-induced feedback activation of RTK regulators (pERK and pAKT) was altered in MCA cells. Interestingly, the combinational treatment of pictilisib (Pi3Ki) and FOXO1i (AS1842856) synergistically reduced MCA cell viability and increased apoptosis. These results demonstrate that pictilisib used as a single agent induces acute resistance, partly through FOXO1 inhibition. Therefore, overcoming PI3Ki single-agent adaptive resistance by rational design of FOXO1 and PI3K inhibitor combinations could significantly enhance the therapeutic efficacy of PI3K-targeting drugs in MCA cells.
Development of a Cell-Based SARS-CoV-2 Pseudovirus Neutralization Assay Using Imaging and Flow Cytometry Analysis
Authors: Izac Jerilyn R. , Kwee Edward J. , Tian Linhua , Elsheikh Elzafir , Gaigalas Adolfas K. , Elliott John T. , Wang Lili
Published: August 2023

COVID-19 is an ongoing, global pandemic caused by the novel, highly infectious SARS-CoV-2 virus. Efforts to mitigate the effects of SARS-CoV-2, such as mass vaccination and development of monoclonal therapeutics, require precise measurements of correlative, functional neutralizing antibodies that block virus infection. The development of rapid, safe, and easy-to-use neutralization assays is essential for faster diagnosis and treatment. Here, we developed a vesicular stomatitis virus (VSV)-based neutralization assay with two readout methods, imaging and flow cytometry, that were capable of quantifying varying degrees of neutralization in patient serum samples. We tested two different spike-pseudoviruses and conducted a time-course assay at multiple multiplicities of infection (MOIs) to optimize the assay workflow. The results of this assay correlate with the results of previously developed serology and surrogate neutralization assays. The two pseudovirus readout methods produced similar values of 50% neutralization titer values. Harvest-free in situ readouts for live-cell imaging and high-throughput analysis results for flow cytometry can provide unique capabilities for fast evaluation of neutralization, which is critical for the mitigation of future pandemics.
Protaetia Brevitarsis-Derived Protein Hydrolysate Reduces Obesity-Related Colitis Induced by High-Fat Diet in Mice through Anti-Inflammatory Pathways
Authors: Kwon Hyung Jun , Chun So Young , Lee Eun Hye , Yoon BoHyun , Han Man-Hoon , Chung Jae-Wook , Ha Yun-Sok , Lee Jun Nyung , Kim Hyun Tae , Kim Dae Hwan , Kwon Tae Gyun , Kim Bum Soo , Lee Syng-Ook , Jang Byung Ik
Published: August 2023

Ulcerative colitis is an inflammatory bowel disease characterized by inflammation in the mucosal and submucosal layers of the colon. Obesity is closely related to the occurrence and progression of colitis. The most plausible mechanism linking obesity and colitis is an excessive adipogenesis-related inflammatory response, which causes mucosal dysfunction. Obesity and colitis are linked by several etiologic mechanisms, including excessive adipogenesis, lipotoxicity, pro-inflammatory adipokines/cytokines, macrophage polarization, oxidative stress, endoplasmic reticulum (ER) stress, and gut microbiota. These low-grade enteric inflammations cause mucosal layer damage, especially goblet cell dysfunction through mucin 2 (MUC2) misfolding, ultimately leading to colitis. Inhibiting the inflammatory response can be the most effective approach for treating obesity-related colitis. We focused on the anti-inflammatory effects of polyphenols in Protaectia brevitas larvae. The P. brevitas was prepared as a low molecular protein hydrolysate (PHPB) to increase the concentration of anti-inflammatory molecules. In the current study, we investigated the anti-inflammatory effect of PHPB in an obesity-induced colitis mouse model. Compared with the high-fat diet (HFD) group, the group treated with PHPB exhibited reduced body/organ/fat weight, appetite/food intake inhibition, hypolipidemic effect on ectopic fat, and anti-adipogenic mechanism through the AMPK signaling pathway. Furthermore, we observed attenuated expression of PPARγ and C/EBPα, inhibition of pro-inflammatory molecules, stimulation of anti-inflammatory molecules, probiotic-like effect against obesogenic gut microbiota, inhibition of macrophage polarization into M1, suppression of oxidative/ER stress, and reduction of Muc2 protein misfolding in colon. These diverse anti-inflammatory responses caused histological and functional recovery of goblet cells, eventually improving colitis. Therefore, our findings suggest that the protein hydrolysate of Protaetia brevitarsis can improve obesity-related colitis through its anti-inflammatory activities.
Cholesterol-Depletion-Induced Membrane Repair Carries a Raft Conformer of P-Glycoprotein to the Cell Surface, Indicating Enhanced Cholesterol Trafficking in MDR Cells, Which Makes Them Resistant to Cholesterol Modifications
Authors: Gutay-Tóth Zsuzsanna , Gellen Gabriella , Doan Minh , Eliason James F. , Vincze János , Szente Lajos , Fenyvesi Ferenc , Goda Katalin , Vecsernyés Miklós , Szabó Gábor , Bacso Zsolt
Published: August 2023

The human P-glycoprotein (P-gp), a transporter responsible for multidrug resistance, is present in the plasma membrane’s raft and non-raft domains. One specific conformation of P-gp that binds to the monoclonal antibody UIC2 is primarily associated with raft domains and displays heightened internalization in cells overexpressing P-gp, such as in NIH-3T3 MDR1 cells. Our primary objective was to investigate whether the trafficking of this particular P-gp conformer is dependent on cholesterol levels. Surprisingly, depleting cholesterol using cyclodextrin resulted in an unexpected increase in the proportion of raft-associated P-gp within the cell membrane, as determined by UIC2-reactive P-gp. This increase appears to be a compensatory response to cholesterol loss from the plasma membrane, whereby cholesterol-rich raft micro-domains are delivered to the cell surface through an augmented exocytosis process. Furthermore, this exocytotic event is found to be part of a complex trafficking mechanism involving lysosomal exocytosis, which contributes to membrane repair after cholesterol reduction induced by cyclodextrin treatment. Notably, cells overexpressing P-gp demonstrated higher total cellular cholesterol levels, an increased abundance of stable lysosomes, and more effective membrane repair following cholesterol modifications. These modifications encompassed exocytotic events that involved the transport of P-gp-carrying rafts. Importantly, the enhanced membrane repair capability resulted in a durable phenotype for MDR1 expressing cells, as evidenced by significantly improved viabilities of multidrug-resistant Pgp-overexpressing immortal NIH-3T3 MDR1 and MDCK-MDR1 cells compared to their parents when subjected to cholesterol alterations.
Cytokine Inhibitors Upregulate Extracellular Matrix Anabolism of Human Intervertebral Discs under Alginate Beads and Alginate-Embedded Explant Cultures
Authors: Kakutani Kenichiro , Yurube Takashi , An Howard S. , Doita Minoru , Masuda Koichi
Published: August 2023

We investigated the effects of the cytokine inhibitors IL-1 receptor antagonist (IL-1Ra) and soluble tumor necrosis factor receptor-1 (sTNFR1) on the extracellular matrix metabolism of human intervertebral discs (IVDs) and the roles of IL-1β and TNF in the homeostasis of IVD cells. The 1.2% alginate beads and the explants obtained from 35 human lumbar discs were treated with cytokine inhibitors. Extracellular matrix metabolism was evaluated by proteoglycan (PG) and collagen syntheses and IL-1β, TNF, and IL-6 expressions after three days of culture in the presence or absence of IL-1Ra, sTNFR1, and cycloheximide. Simultaneous treatment with IL-1Ra and sTNFR1 stimulated PG and collagen syntheses in the NP and AF cells and explants. The IL-1β concentration was significantly correlated to the relative increase in PG synthesis in AF explants after simultaneous cytokine inhibitor treatment. The relative increase in PG synthesis induced by simultaneous cytokine treatment was significantly higher in an advanced grade of MRI. Expressions of IL-1β and TNF were upregulated by each cytokine inhibitor, and simultaneous treatment suppressed IL-1β and TNF productions. In conclusion, IL-1Ra and sTNFR1 have the potential to increase PG and collagen synthesis in IVDs. IL-1β and TNF have a feedback pathway to maintain optimal expression, resulting in the control of homeostasis in IVD explants.
Deciphering the Biology of Circulating Tumor Cells through Single-Cell RNA Sequencing: Implications for Precision Medicine in Cancer
Authors: Orrapin Santhasiri , Thongkumkoon Patcharawadee , Udomruk Sasimol , Moonmuang Sutpirat , Sutthitthasakul Songphon , Yongpitakwattana Petlada , Pruksakorn Dumnoensun , Chaiyawat Parunya
Published: August 2023

Circulating tumor cells (CTCs) hold unique biological characteristics that directly involve them in hematogenous dissemination. Studying CTCs systematically is technically challenging due to their extreme rarity and heterogeneity and the lack of specific markers to specify metastasis-initiating CTCs. With cutting-edge technology, single-cell RNA sequencing (scRNA-seq) provides insights into the biology of metastatic processes driven by CTCs. Transcriptomics analysis of single CTCs can decipher tumor heterogeneity and phenotypic plasticity for exploring promising novel therapeutic targets. The integrated approach provides a perspective on the mechanisms underlying tumor development and interrogates CTCs interactions with other blood cell types, particularly those of the immune system. This review aims to comprehensively describe the current study on CTC transcriptomic analysis through scRNA-seq technology. We emphasize the workflow for scRNA-seq analysis of CTCs, including enrichment, single cell isolation, and bioinformatic tools applied for this purpose. Furthermore, we elucidated the translational knowledge from the transcriptomic profile of individual CTCs and the biology of cancer metastasis for developing effective therapeutics through targeting key pathways in CTCs.
Literature-Based Discovery Predicts Antihistamines Are a Promising Repurposed Adjuvant Therapy for Parkinson’s Disease
Authors: Tandra Gabriella , Yoone Amy , Mathew Rhea , Wang Minzhi , Hales Chadwick M. , Mitchell Cassie S.
Published: August 2023

Parkinson’s disease (PD) is a movement disorder caused by a dopamine deficit in the brain. Current therapies primarily focus on dopamine modulators or replacements, such as levodopa. Although dopamine replacement can help alleviate PD symptoms, therapies targeting the underlying neurodegenerative process are limited. The study objective was to use artificial intelligence to rank the most promising repurposed drug candidates for PD. Natural language processing (NLP) techniques were used to extract text relationships from 33+ million biomedical journal articles from PubMed and map relationships between genes, proteins, drugs, diseases, etc., into a knowledge graph. Cross-domain text mining, hub network analysis, and unsupervised learning rank aggregation were performed in SemNet 2.0 to predict the most relevant drug candidates to levodopa and PD using relevance-based HeteSim scores. The top predicted adjuvant PD therapies included ebastine, an antihistamine for perennial allergic rhinitis; levocetirizine, another antihistamine; vancomycin, a powerful antibiotic; captopril, an angiotensin-converting enzyme (ACE) inhibitor; and neramexane, an N-methyl-D-aspartate (NMDA) receptor agonist. Cross-domain text mining predicted that antihistamines exhibit the capacity to synergistically alleviate Parkinsonian symptoms when used with dopamine modulators like levodopa or levodopa–carbidopa. The relationship patterns among the identified adjuvant candidates suggest that the likely therapeutic mechanism(s) of action of antihistamines for combatting the multi-factorial PD pathology include counteracting oxidative stress, amending the balance of neurotransmitters, and decreasing the proliferation of inflammatory mediators. Finally, cross-domain text mining interestingly predicted a strong relationship between PD and liver disease.
Antarctic Soil Metabolomics: A Pilot Study
Authors: Ciaramelli Carlotta , Palmioli Alessandro , Brioschi Maura , Viglio Simona , D’Amato Maura , Iadarola Paolo , Tosi Solveig , Zucconi Laura , Airoldi Cristina
Published: August 2023

In Antarctica, ice-free areas can be found along the coast, on mountain peaks, and in the McMurdo Dry Valleys, where microorganisms well-adapted to harsh conditions can survive and reproduce. Metabolic analyses can shed light on the survival mechanisms of Antarctic soil communities from both coastal sites, under different plant coverage stages, and inner sites where slow-growing or dormant microorganisms, low water availability, salt accumulation, and a limited number of primary producers make metabolomic profiling difficult. Here, we report, for the first time, an efficient protocol for the extraction and the metabolic profiling of Antarctic soils based on the combination of NMR spectroscopy and mass spectrometry (MS). This approach was set up on samples harvested along different localities of Victoria Land, in continental Antarctica, devoid of or covered by differently developed biological crusts. NMR allowed for the identification of thirty metabolites (mainly sugars, amino acids, and organic acids) and the quantification of just over twenty of them. UPLC-MS analysis identified more than twenty other metabolites, in particular flavonoids, medium- and long-chain fatty acids, benzoic acid derivatives, anthracenes, and quinones. Our results highlighted the complementarity of the two analytical techniques. Moreover, we demonstrated that their combined use represents the “gold standard” for the qualitative and quantitative analysis of little-explored samples, such as those collected from Antarctic soils.
Cyclooxygenase and Cancer: Fundamental Molecular Investigations
Authors: Coluccia Mauro
Published: August 2023

The involvement of prostaglandins in cancer was first observed in human esophageal carcinoma cells, whose invasive and metastatic potential in nude mice was found to be related to PGE2 and PGF2a production [...]
Sortilin Is Upregulated in Osteoarthritis-Dependent Cartilage Calcification and Associated with Cellular Senescence
Authors: Richter Elisabeth , Lohmann Christoph H. , Dell’Accio Francesco , Goettsch Claudia , Bertrand Jessica
Published: August 2023

Osteoarthritis (OA) is a chronic joint disease characterized by articular cartilage calcification, loss of articular cartilage, bone changes, pain, and disability. Cartilage calcification is one hallmark of OA and is predominantly caused by basic calcium crystals formed due to an imbalance of the pyrophosphate pathway. Sortilin is a transmembrane protein that contributes to vascular calcification in atherosclerosis by externalizing alkaline phosphatase (ALP)-containing vesicles. Calcification in atherosclerosis and osteoarthritis has been associated with cellular senescence. The aim of this study was to investigate the potential role of sortilin and senescence in osteoarthritis-dependent cartilage calcification. Osteoarthritic cartilage from human knee joints was collected after joint replacement, and samples were analyzed by immunohistochemistry and quantitative RT-PCR analysis. Human chondrocytes were treated with osteogenic medium for up to 21 days to induce calcification. Western blots for sortilin and ALP, as well as an ALP activity assay, were performed. Human chondrocytes were treated with mitomycin C to induce senescence, and sortilin expression was quantified at the protein and gene levels. Sections of knee joints from a murine model of osteoarthritis were stained for sortilin and p16 and analyzed by immunohistochemistry. Treatment of wild-type chondrocytes using an osteogenic medium similar to human chondrocytes was performed. Osteoarthritic cartilage from mouse and human knee joints showed an increased number of sortilin and p16-positive chondrocytes compared to healthy cartilage. This observation was corroborated by increased gene expression of sortilin and p16 in mild and moderate osteoarthritic cartilage samples. To investigate the mechanism of sortilin regulation, human chondrocytes were treated with osteogenic medium to induce calcification. Sortilin protein levels and expression were increased after 7 days of stimulation, whereas ALP levels and activity were upregulated after 21 days of stimulation. Similar observations were made in a murine osteoarthritis model. Mechanistically, senescent chondrocytes induced by mitomycin C showed an upregulation of sortilin and ALP gene expression compared to non-senescent chondrocytes. Our data indicate that sortilin and ALP are upregulated during cartilage calcification, which is associated with chondrocyte senescence and thus might contribute to the pathogenesis of osteoarthritis. Cellular senescence seems to induce sortilin expression.
Correction: Lombardi et al. AcidoCEST-UTE MRI Reveals an Acidic Microenvironment in Knee Osteoarthritis. Int. J. Mol. Sci. 2022, 23, 4466
Authors: Lombardi Alecio F. , Ma Yajun , Jang Hyungseok , Jerban Saeed , Tang Qingbo , Searleman Adam C. , Meyer Robert Scott , Du Jiang , Chang Eric Y.
Published: August 2023

In the original publication, there was a mistake in Figure 1 as published [...]
Vitamin D Receptor Deficiency Upregulates Pulmonary Artery Kv7 Channel Activity
Authors: Olivencia Miguel A. , Villegas-Esguevillas Marta , Sancho Maria , Barreira Bianca , Paternoster Elena , Adão Rui , Larriba María Jesús , Cogolludo Angel , Perez-Vizcaino Francisco
Published: August 2023

Recent evidence suggests that vitamin D is involved in the development of pulmonary arterial hypertension (PAH). The aim of this study was to analyze the electrophysiological and contractile properties of pulmonary arteries (PAs) in vitamin D receptor knockout mice (Vdr−/−). PAs were dissected and mounted in a wire myograph. Potassium membrane currents were recorded in freshly isolated PA smooth muscle cells (PASMCs) using the conventional whole-cell configuration of the patch-clamp technique. Potential vitamin D response elements (VDREs) in Kv7 channels coding genes were studied, and their protein expression was analyzed. Vdr−/− mice did not show a pulmonary hypertensive phenotype, as neither right ventricular hypertrophy nor endothelial dysfunction was apparent. However, resistance PA from these mice exhibited increased response to retigabine, a Kv7 activator, compared to controls and heterozygous mice. Furthermore, the current sensitive to XE991, a Kv7 inhibitor, was also higher in PASMCs from knockout mice. A possible VDRE was found in the gene coding for KCNE4, the regulatory subunit of Kv7.4. Accordingly, Vdr−/− mice showed an increased expression of KCNE4 in the lungs, with no changes in Kv7.1 and Kv7.4. These results indicate that the absence of Vdr in mice, as occurred with vitamin D deficient rats, is not sufficient to induce PAH. However, the contribution of Kv7 channel currents to the regulation of PA tone is increased in Vdr−/− mice, resembling animals and humans suffering from PAH.
Topical Probiotic Formulation Promotes Rapid Healing in Dog Keratinocyte Cells: A Promising Approach for Wound Management
Authors: Barthe Manon , Gillot Lionel , Perdigon Laurie , Jacobs Aline , Schoonbroodt Gregory , Mauhin Paul , Bouhajja Emna , Osman-Ponchet Hanan
Published: August 2023

The use of probiotics has gained increasing attention as a strategy for wound healing to decrease microbial resistance to disinfectants and antibiotics. This study aimed to investigate the potential of a non-medicinal topical cocktail of probiotic bacteria (CPB) in promoting wound healing in dogs using in vitro scratch assay. Canine Progenitors Epidermal Keratinocytes (CPEK) were exposed to a prototype product formulated with CPB (PPP), non-formulated CPB, and the vehicle. The viability of CPB and CPEK cells was first evaluated in the co-culture model. Then, wound closure was analyzed over time. The CPB required a minimum concentration of 75 CFU/mL for better viability with CPEK. While the CPEK preserved 100% of their viability when PPP was diluted to up to 75,000 CFU/mL. At higher concentrations, the viability of CPEK was reduced by the concomitant effect of the non-formulated CPB and the vehicle. The formulated and non-formulated CPB and the vehicle seem to lead to a dose-dependent increase in cell migration compared to the control. Importantly, at the concentration of 750,000 CFU/mL, the PPP showed a 20% increase in wound closure. Taken together, our findings suggest the potential beneficial effects of the probiotic-based topical cocktail (PPP) on wound healing. However, to confirm and validate these effects, further experiments are necessary to provide more robust evidence and allow us to confidently establish the potential beneficial effects of the probiotic bacteria (CPB) in promoting wound healing.
Overcoming the Limitation of Spin Statistics in Organic Light Emitting Diodes (OLEDs): Hot Exciton Mechanism and Its Characterization
Authors: Park Soo Wan , Kim Dongwook , Rhee Young Min
Published: August 2023

Triplet harvesting processes are essential for enhancing efficiencies of fluorescent organic light-emitting diodes. Besides more conventional thermally activated delayed fluorescence and triplet-triplet annihilation, the hot exciton mechanism has been recently noticed because it helps reduce the efficiency roll-off and improve device stability. Hot exciton materials enable the conversion of triplet excitons to singlet ones via reverse inter-system crossing from high-lying triplet states and thereby the depopulation of long-lived triplet excitons that are prone to chemical and/or efficiency degradation. Although their anti-Kasha characteristics have not been clearly explained, numerous molecules with behaviors assigned to the hot exciton mechanism have been reported. Indeed, the related developments appear to have just passed the stage of infancy now, and there will likely be more roles that computational elucidations can play. With this perspective in mind, we review some selected experimental studies on the mechanism and the related designs and then on computational studies. On the computational side, we examine what has been found and what is still missing with regard to properly understanding this interesting mechanism. We further discuss potential future points of computational interests toward aiming for eventually presenting in silico design guides.
Fighting Celiac Disease: Improvement of pH Stability of Cathepsin L In Vitro by Computational Design
Authors: Chugunov Anton O. , Dvoryakova Elena A. , Dyuzheva Maria A. , Simonyan Tatyana R. , Tereshchenkova Valeria F. , Filippova Irina Yu. , Efremov Roman G. , Elpidina Elena N.
Published: August 2023

Roughly 1% of the global population is susceptible to celiac disease (CD)—inheritable autoimmune inflammation of the small intestine caused by intolerance to gliadin proteins present in wheat, rye, and barley grains, and called gluten in wheat. Classical treatment is a life-long gluten-free diet, which is constraining and costly. An alternative approach is based upon the development and oral reception of effective peptidases that degrade in the stomach immunogenic proline- and glutamine-rich gliadin peptides, which are the cause of the severe reaction in the intestine. In previous research, we have established that the major digestive peptidase of an insect Tribolium castaneum—cathepsin L—hydrolyzes immunogenic prolamins after Gln residues but is unstable in the extremely acidic environment (pH 2–4) of the human stomach and cannot be used as a digestive aid. In this work, using molecular dynamics simulations, we discover the probable cause of the pH instability of cathepsin L—loss of the catalytically competent rotameric state of one of the active site residues, His 275. To “fix” the correct orientation of this residue, we designed a V277A mutant variant, which extends the range of stability of the peptidase in the acidic environment while retaining most of its activity. We suggest this protein as a lead glutenase for the development of oral medical preparation that fights CD and gluten intolerance in susceptible people.
Strategic Design and Synthesis of Ferrocene Linked Porous Organic Frameworks toward Tunable CO2 Capture and Energy Storage
Authors: Mousa Aya Osama , Chuang Cheng-Hsin , Kuo Shiao-Wei , Mohamed Mohamed Gamal
Published: August 2023

This work focuses on porous organic polymers (POPs), which have gained significant global attention for their potential in energy storage and carbon dioxide (CO2) capture. The study introduces the development of two novel porous organic polymers, namely FEC-Mel and FEC-PBDT POPs, constructed using a simple method based on the ferrocene unit (FEC) combined with melamine (Mel) and 6,6′-(1,4-phenylene)bis(1,3,5-triazine-2,4-diamine) (PBDT). The synthesis involved the condensation reaction between ferrocenecarboxaldehyde monomer (FEC-CHO) and the respective aryl amines. Several analytical methods were employed to investigate the physical characteristics, chemical structure, morphology, and potential applications of these porous materials. Through thermogravimetric analysis (TGA), it was observed that both FEC-Mel and FEC-PBDT POPs exhibited exceptional thermal stability. FEC-Mel POP displayed a higher surface area and porosity, measuring 556 m2 g−1 and 1.26 cm3 g−1, respectively. These FEC-POPs possess large surface areas, making them promising materials for applications such as supercapacitor (SC) electrodes and gas adsorption. With 82 F g−1 of specific capacitance at 0.5 A g−1, the FEC-PBDT POP electrode has exceptional electrochemical characteristics. In addition, the FEC-Mel POP showed remarkable CO2 absorption capabilities, with 1.34 and 1.75 mmol g−1 (determined at 298 and 273 K; respectively). The potential of the FEC-POPs created in this work for CO2 capacity and electrical testing are highlighted by these results.
Scale-Resolving Hybrid RANS-LES Simulation of a Model Kaplan Turbine on a 400-Million-Element Mesh
Authors: Joßberger Simon , Riedelbauch Stefan
Published: August 2023

Double-regulated Kaplan turbines with adjustable guide vanes and runner blades offer a high degree of flexibility and good efficiency for a wide range of operating points. However, this also leads to a complex geometry and flow guidance with, for example, vortices of different sizes and strengths. The flow in a draft tube is especially challenging to simulate mainly due to flow phenomena, like swirl, separation and strong adverse pressure gradients, and a strong dependency on the upstream flow conditions. Standard simulation approaches with RANS turbulence models, a coarse mesh and large time step size often fail to correctly predict performance and can even lead to wrong tendencies in the overall behavior. To reveal occurring flow phenomena and physical effects, a scale-resolving hybrid RANS-LES simulation on a block structured mesh of about 400 million hexahedral elements of a double-regulated five-blade model Kaplan turbine is carried out. In this paper, first, the results of the ongoing simulation are presented. The major part of the simulation domain is running in LES mode and seems to be properly resolved. The validation of the simulation results with the experimental data shows mean deviations of less than 0.8% in the global results, i.e., total head and power, and a good visual agreement with the three-dimensional PIV measurements of the velocity in the cone and both diffuser channels of the draft tube. In particular, the trend of total head and the results for the draft tube differ significantly between the scale-resolving simulation and a standard RANS simulation. The standard RANS simulation exhibits a highly unsteady behavior of flow, which is not observed in the experiments or scale-resolving simulation.
Reinforcement Learning for Reducing the Interruptions and Increasing Fault Tolerance in the Cloud Environment
Authors: Lahande Prathamesh , Kaveri Parag , Saini Jatinderkumar
Published: August 2023

Cloud computing delivers robust computational services by processing tasks on its virtual machines (VMs) using resource-scheduling algorithms. The cloud’s existing algorithms provide limited results due to inappropriate resource scheduling. Additionally, these algorithms cannot process tasks generating faults while being computed. The primary reason for this is that these existing algorithms need an intelligence mechanism to enhance their abilities. To provide an intelligence mechanism to improve the resource-scheduling process and provision the fault-tolerance mechanism, an algorithm named reinforcement learning-shortest job first (RL-SJF) has been implemented by integrating the RL technique with the existing SJF algorithm. An experiment was conducted in a simulation platform to compare the working of RL-SJF with SJF, and challenging tasks were computed in multiple scenarios. The experimental results convey that the RL-SJF algorithm enhances the resource-scheduling process by improving the aggregate cost by 14.88% compared to the SJF algorithm. Additionally, the RL-SJF algorithm provided a fault-tolerance mechanism by computing 55.52% of the total tasks compared to 11.11% of the SJF algorithm. Thus, the RL-SJF algorithm improves the overall cloud performance and provides the ideal quality of service (QoS).
Quarantine Disinfestation of Papaya Mealybug, Paracoccus marginatus (Hemiptera: Pseudococcidae) Using Gamma and X-rays Irradiation
Authors: Song Zi-Jiao , Zhao Qing-Ying , Ma Chen , Chen Ran-Ran , Ma Tian-Bi , Li Zhi-Hong , Zhan Guo-Ping
Published: August 2023

Paracoccus marginatus is a highly polyphagous invasive pest that poses a significant quarantine threat to tropical and subtropical countries. Infested commodities in international trade should undergo phytosanitary treatment, and irradiation is recommended as a viable alternative to replace methyl bromide fumigation. Dose-response tests were conducted on the 2-, 4-, and 6-day-old eggs and gravid females of P. marginatus using the X-ray radiation doses of 15–105 Gy with an interval of 15 Gy. Radiotolerance was compared using ANOVA, fiducial overlapping and lethal dose ratio (LDR) test, resulting in no significant difference among treatments, except for the overall mortality and LDR at LD90 (a dose causing 90% mortality at 95% confidence level). The estimated dose for LD99.9968 was 176.5–185.2 Gy, which was validated in the confirmatory tests. No nymphs emerged from a total of 60,386 gravid females exposed to a gamma radiation dose range of 146.8–185.0 Gy in the confirmatory tests. The largest dose in confirmatory tests should be the minimum threshold for phytosanitary treatment, consequently, a minimum dose of 185 Gy is recommended for the phytosanitary irradiation treatment of papaya mealybug-infested commodities, ensuring a treatment efficacy of ≥99.9950% at 95% confidence level.
Lipid-Lowering Treatment and the Lipid Goals Attainment in Patients with a Very High Cardiovascular Risk
Authors: Lis Anna , Lis Paulina , Łowicka Weronika , Grabarczyk Małgorzata , Wita Michał , Żarczyński Piotr , Żarczyńska Małgorzata , Haberka Maciej
Published: August 2023

Hypercholesterolemia is the main cardiovascular (CV) risk factor with a large body of evidence. Our aim was to assess the achievement of the main therapeutic goal of Low-Density Lipoprotein Cholesterol (LDL-C) in patients with a very high CV risk and a high-dose statin therapy. The study group consisted of 1413 consecutive patients hospitalised at the Upper-Silesian Medical Centre in Katowice due to acute myocardial infarction (AMI) treated with atorvastatin ≥ 40 mg or rosuvastatin ≥ 20 mg. The lipid profile was performed on admission and within 12 months after AMI. The main therapeutic goal was defined as LDL-C < 55 mg%. The study group (n = 1413) included 979 males (69.3%) with arterial hypertension (83.3%), diabetes (33.5%), peripheral artery disease (13.6%) and nicotinism (46.2%). In the study group, only 61 patients (4.3%) were additionally taking ezetimibe. During hospitalisation, the primary LDL-C goal was found in only 186 patients (13.2%). Subsequently, a follow-up lipidogram within 12 months was performed in 652 patients (46%), and the therapeutic goal was achieved in 255 patients (39%). There were 258 (18.26%) patients who died within 12 months after myocardial infarction. The lowest mortality rate was found in the subgroup of patients with LDL-C < 55 mg% during follow-up (11.02%). The primary lipid goal attainment among patients with a high-dose statin and a very high CV risk is low and far from the expected rate. Patients hospitalised for AMI should be given a combination of statin and ezetimibe more frequently. Low LDL-C levels measured at follow-up predict a lower risk of death at 12-month follow-up in a large group of patients.
Injectable Pectin–Alginate Hydrogels for Improving Vascularization and Adipogenesis of Human Fat Graft
Authors: Janarthanan Ramu , Jayakumar Rangasamy , Iyer Subramania
Published: August 2023

Autologous fat grafting (AFG) is the most prevailing tool for soft tissue regeneration in clinics, although efficiency is limited to unpredictable volume resorption due to poor vascularization and eventual necrosis. This study sought to improve the AFG efficiency using a hydrogel as a carrier for human fat graft (F) with and without platelet-rich plasma (PRP). PRP is clinically well known for the local release of several endogenous growth factors and has been in clinical use already. A human-fat-graft-encapsulated pectin–alginate hydrogel (FG) was developed and characterized. PRP was added to F to develop a human fat graft with PRP (FP). FP was admixed with a pectin–alginate hydrogel to develop FGP. FG and FGP showed the smooth injectable, elastic, and shear-thinning properties. FG and FGP groups showed enhanced cell viability and proliferation compared to the control F in vitro. We also investigated the in vivo angiogenesis and neo-adipogenesis ability of F, FG, FGP, and FP in nude mice after subcutaneous injection. After 2 and 4 weeks, an MRI of the mice was conducted, followed by graft explantation. The explanted grafts were also assessed histologically and with immunohistochemistry (IHC) studies. MRI and histology results revealed better vascularity of the FG and FGP system compared to fat graft alone. Further, the IHC studies, CD 31, and perilipin staining also revealed better vasculature and adipogenesis of FG and FGP systems. These results indicate the enhanced angiogenesis and adipogenesis of FG and FGP. Thus, developed pectin–alginate hydrogel-based fat graft systems FG and FGP replenish the native microenvironment by mediating angiogenesis and adipogenesis, thereby maximizing the clinical outcomes of autologous fat grafting.
Classification of a 3D Film Pattern Image Using the Optimal Height of the Histogram for Quality Inspection
Authors: Lee Jaeeun , Choi Hongseok , Yum Kyeongmin , Park Jungwon , Kim Jongnam
Published: August 2023

A 3D film pattern image was recently developed for marketing purposes, and an inspection method is needed to evaluate the quality of the pattern for mass production. However, due to its recent development, there are limited methods to inspect the 3D film pattern. The good pattern in the 3D film has a clear outline and high contrast, while the bad pattern has a blurry outline and low contrast. Due to these characteristics, it is challenging to examine the quality of the 3D film pattern. In this paper, we propose a simple algorithm that classifies the 3D film pattern as either good or bad by using the height of the histograms. Despite its simplicity, the proposed method can accurately and quickly inspect the 3D film pattern. In the experimental results, the proposed method achieved 99.09% classification accuracy with a computation time of 6.64 s, demonstrating better performance than existing algorithms.
Risk and Bankruptcy Research: Mapping the State of the Art
Authors: Almeida Luís
Published: August 2023

This article presents a bibliometric study on different types of risk and bankruptcy, aiming to contribute to academic knowledge in this area. We used the bibliometrix tools in R and VOSviewer, following the main laws of bibliometrics (Bradford’s law, Lotka’s law, and Zipf’s law). We analyzed 7163 relevant academic publications retrieved from the WOS database between 1995 and 2023. The characterization of the literature identified trends, importance, and scientific relevance of works, journals, and authors. This allows for promoting collaborations among researchers and provides insights for strategic decision making, advancing knowledge in the field. The most relevant journal was the “Journal of Banking and Finance”, with Edward Altman as the prominent author. The United States and China were the most active countries in research. The current research highlights terms such as “board size”, “CRS”, “responsibility”, and “governance”, which are commonly found in recent works. The themes of greatest centrality include risk, model, and debt. The bibliometric review revealed gaps in knowledge and research, indicating a growing trend of studies in this area. This article provides valuable information for researchers and managers, supporting decision making in risk management and bankruptcy.
The Application of a Human Rights Approach toward Crimes of Corruption: Analyzing Anti-Corruption Regulations and Judicial Decisions
Authors: Ali Mahrus , Muliyono Andi , Nurhidayat Syarif
Published: August 2023

This study aimed to examine the connection between the crime of corruption and human rights violations. Indonesia’s corruption-eradication regulations have increased the possibility of handling human rights-based corruption cases. This study employed doctrinal legal research that mainly relied on anti-corruption legislation and corruption cases in judicial decisions. The results showed that the law states that corruption infringes on people’s economic, social, and cultural rights. We employed a plausible scenario to provide practical explanations of the relationship between the two variables. The types of crimes of corruption have a direct nexus to the violation of human rights. In addition, there was inadequate proof of the connection between corruption and human rights violations in court rulings. Specifically, a few court decisions relate corruption to human rights violations. Judges consider the relationship more thoroughly when making legal considerations and when it is not applied as an aggravated circumstance, resulting in significantly milder prison sentences. The findings imply the necessity of mainstreaming corruption as a human rights violation through comprehensive and massive studies. Furthermore, legal enforcement institutions need to issue guidelines and provide continuous training on handling human rights-based corruption cases to the police, public prosecutors, and judges.
Soccer, Sleep, Repeat: Effects of Training Characteristics on Sleep Quantity and Sleep Architecture
Authors: Frytz Patricia , Heib Dominik P. J. , Hoedlmoser Kerstin
Published: August 2023

Due to the high demands of competitive sports, the sleep architecture of adolescent athletes may be influenced by their regular training. To date, there is no clear evidence on how training characteristics (intensity, time of day, number of sessions) influence sleep quality and quantity. 53 male soccer players (M = 14.36 years, SD = 0.55) of Austrian U15 (n = 45) and U16 elite teams (n = 8) were tested on at least three consecutive days following their habitual training schedules. Participants completed daily sleep protocols (7 a.m., 8 p.m.) and questionnaires assessing sleep quality (PSQI), chronotype (D-MEQ), competition anxiety (WAI-T), and stress/recovery (RESTQ). Electrocardiography (ECG) and actigraphy devices measured sleep. Using sleep protocols and an ECG-based multi-resolution convolutional neural network (MCNN), we found that higher training intensity leads to more wake time, that later training causes longer sleep duration, and that one training session per day was most advantageous for sleep quality. In addition, somatic complaints assessed by the WAI-T negatively affected adolescent athletes’ sleep. Individual training loads and longer recovery times after late training sessions during the day should be considered in training schedules, especially for adolescent athletes. MCNN modeling based on ECG data seems promising for efficient sleep analysis in athletes.
Reichardt’s Dye-Based Solvent Polarity and Abraham Solvent Parameters: Examining Correlations and Predictive Modeling
Authors: Acree William E. , Lang Andrew S. I. D.
Published: August 2023

The concept of “solvent polarity” is widely used to explain the effects of using different solvents in various scientific applications. However, a consensus regarding its definition and quantitative measure is still lacking, hindering progress in solvent-based research. This study hopes to add to the conversation by presenting the development of two linear regression models for solvent polarity, based on Reichardt’s ET(30) solvent polarity scale, using Abraham solvent parameters and a transformer-based model for predicting solvent polarity directly from molecular structure. The first linear model incorporates the standard Abraham solvent descriptors s, a, b, and the extended model ionic descriptors j+ and j−, achieving impressive test-set statistics of R2 = 0.940 (coefficient of determination), MAE = 0.037 (mean absolute error), and RMSE = 0.050 (Root-Mean-Square Error). The second model, covering a more extensive chemical space but only using the descriptors s, a, and b, achieves test-set statistics of R2 = 0.842, MAE = 0.085, and RMSE = 0.104. The transformer-based model, applicable to any solvent with an associated SMILES string, achieves test-set statistics of R2 = 0.824, MAE = 0.066, and RMSE = 0.095. Our findings highlight the significance of Abraham solvent parameters, especially the dipolarity/polarizability, hydrogen-bond acidity/basicity, and ionic descriptors, in predicting solvent polarity. These models offer valuable insights for researchers interested in Reichardt’s ET(30) solvent polarity parameter and solvent polarity in general.
Parametric Study of Planetary Milling to Produce Cu-CuO Powders for Pore Formation by Oxide Reduction
Authors: Tse Lop Kun Julian E. , Rutherford Adam P. , Learn Ryan S. , Atwater Mark A.
Published: August 2023

Powder-based methods that are used to make porous metals are relatively simple and scalable, and porosity can be controlled by interparticle spacing as well as the addition of a sacrificial template. A relatively new process based on reducing oxides in a metal matrix has been demonstrated to produce microscale porosity within individual powder particles and thereby may be used to enhance other powder metal techniques. Templating methods require relatively large quantities of powder, but oxide-reduction feedstock powders have only been produced by small-batch ball milling processes (e.g., 10 s of grams). Planetary ball milling is capable of processing larger quantities of powder (e.g., 100 s of grams) but has significantly different milling characteristics. To successfully apply this technique, it was systematically studied in terms of composition, milling conditions, and the addition of stearic acid to control powder size and morphology along with final porosity. It was found that by controlling basic parameters, such as oxide levels and milling time, a relatively high porosity (25%) and powder percentage (99%) can be achieved in Cu-2 mol% CuO with only 0.035 wt% stearic acid and only 90 min of milling.