bluuebunny/crossref_metadata_2025 huggingface dataset:
Dietary Advanced Glycation End Products and Risk of Overall and Cause-Specific Mortality: Results from the Golestan Cohort Study
Authors: Hosseini Elham , Mokhtari Zeinab , Poustchi Hossein , Khoshnia Masoud , Dawsey Sanford M. , Boffetta Paolo , Abnet Christian C. , Kamangar Farin , Etemadi Arash , Pourshams Akram , Sharafkhah Maryam , Brennan Paul , Malekzadeh Reza , Hekmatdoost Azita
Published: February 2023

Controversy exists regarding the association of dietary advanced glycation end products (dAGEs) with the risk of disease outcomes and mortality. We aimed to examine, prospectively, the association between dAGEs intake and the risk of overall and cause-specific mortality in the Golestan Cohort Study. The cohort was conducted between 2004 and 2008 in Golestan Province (Iran) recruiting 50,045 participants aged 40–75 years. Assessment of dietary intake over the last year was performed at baseline using a 116-item food frequency questionnaire. The dAGEs values for each individual were calculated based on published databases of AGE values of various food items. The main outcome was overall mortality at the time of follow-up (13.5 years). Hazard ratios (HRs) and 95% confidence intervals (CIs) for overall and cause-specific mortality were estimated according to the dAGEs quintiles. During 656, 532 person-years of follow-up, 5406 deaths in men and 4722 deaths in women were reported. Participants at the highest quintile of dAGE had a lower risk of overall mortality (HR: 0.89, 95% CI: 0.84, 0.95), CVD mortality (HR: 0.89, 95% CI: 0.84, 0.95), and death from other causes (HR: 0.89, 95% CI: 0.84, 0.95) compared to those in the first quintile after adjusting for confounders. We found no association of dAGEs with risk of mortality from cancer (all), respiratory and infectious diseases, and injuries. Our findings do not confirm a positive association between dAGEs and the risk of mortality in Iranian adults. There is still no agreement among studies investigating dAGEs and their health-related aspects. So, further high-quality studies are required to clarify this association.
Energy-Efficient 3D Path Planning for Complex Field Scenes Using the Digital Model with Landcover and Terrain
Authors: Ma Baodong , Liu Quan , Jiang Ziwei , Che Defu , Qiu Kehan , Shang Xiangxiang
Published: February 2023

Path planning is widely used in many domains, and it is crucial for the advancement of map navigation, autonomous driving, and robot path planning. However, existing path planning methods have certain limitations for complex field scenes with undulating terrain and diverse landcover types. This paper presents an energy-efficient 3D path planning algorithm based on an improved A* algorithm and the particle swarm algorithm in complex field scenes. The evaluation function of the A* algorithm was improved to be suitable for complex field scenes. The slope parameter and friction coefficient were respectively used in the evaluation function to represent different terrain features and landcover types. The selection of expanding nodes in the algorithm depends not only on the minimum distance but also on the minimum consumption cost. Furthermore, the turning radius factor and slope threshold factor of vehicles were added to the definition of impassable points in the improved A* algorithm, so that the accessibility of path planning could be guaranteed by excluding some bends and steep slopes. To meet the requirements for multi-target path planning, the improved A* algorithm was used as the fitness function of the particle swarm algorithm to solve the traveling salesman problem. The experimental results showed that the proposed algorithm is capable of multi-target path planning in complex field scenes. Furthermore, the path planned by this algorithm is more passable and more energy efficient. In this experimental environment model, the average energy-saving efficiency of the path planned by the improved algorithm is 14.7% compared to the traditional A* algorithm. This would be beneficial to the development of ecotourism and geological exploration.
Meta-Analysis of Cytotoxicity Studies Using Machine Learning Models on Physical Properties of Plant Extract-Derived Silver Nanoparticles
Authors: Desai Anjana , Ashok Aparna , Edis Zehra , Bloukh Samir , Gaikwad Mayur , Patil Rajendra , Pandey Brajesh , Bhagat Neeru
Published: February 2023

Silver nanoparticles (Ag-NPs) demonstrate unique properties and their use is exponentially increasing in various applications. The potential impact of Ag-NPs on human health is debatable in terms of toxicity. The present study deals with MTT(3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl-tetrazolium-bromide) assay on Ag-NPs. We measured the cell activity resulting from molecules’ mitochondrial cleavage through a spectrophotometer. The machine learning models Decision Tree (DT) and Random Forest (RF) were utilized to comprehend the relationship between the physical parameters of NPs and their cytotoxicity. The input features used for the machine learning were reducing agent, types of cell lines, exposure time, particle size, hydrodynamic diameter, zeta potential, wavelength, concentration, and cell viability. These parameters were extracted from the literature, segregated, and developed into a dataset in terms of cell viability and concentration of NPs. DT helped in classifying the parameters by applying threshold conditions. The same conditions were applied to RF to extort the predictions. K-means clustering was used on the dataset for comparison. The performance of the models was evaluated through regression metrics, viz. root mean square error (RMSE) and R2. The obtained high value of R2 and low value of RMSE denote an accurate prediction that could best fit the dataset. DT performed better than RF in predicting the toxicity parameter. We suggest using algorithms for optimizing and designing the synthesis of Ag-NPs in extended applications such as drug delivery and cancer treatments.
MitoSNARE Assembly and Disassembly Factors Regulate Basal Autophagy and Aging in C. elegans
Authors: Gkikas Ilias , Daskalaki Ioanna , Kounakis Konstantinos , Tavernarakis Nektarios , Lionaki Eirini
Published: February 2023

SNARE proteins reside between opposing membranes and facilitate vesicle fusion, a physiological process ubiquitously required for secretion, endocytosis and autophagy. With age, neurosecretory SNARE activity drops and is pertinent to age-associated neurological disorders. Despite the importance of SNARE complex assembly and disassembly in membrane fusion, their diverse localization hinders the complete understanding of their function. Here, we revealed a subset of SNARE proteins, the syntaxin SYX-17, the synaptobrevins VAMP-7, SNB-6 and the tethering factor USO-1, to be either localized or in close proximity to mitochondria, in vivo. We term them mitoSNAREs and show that animals deficient in mitoSNAREs exhibit increased mitochondria mass and accumulation of autophagosomes. The SNARE disassembly factor NSF-1 seems to be required for the effects of mitoSNARE depletion. Moreover, we find mitoSNAREs to be indispensable for normal aging in both neuronal and non-neuronal tissues. Overall, we uncover a previously unrecognized subset of SNAREs that localize to mitochondria and propose a role of mitoSNARE assembly and disassembly factors in basal autophagy regulation and aging.
Increased BAT Thermogenesis in Male Mouse Apolipoprotein A4 Transgenic Mice
Authors: LaRussa Zachary , Kuo Hsuan-Chih N. , West Kathryn , Shen Zhijun , Wisniewski Kevin , Tso Patrick , Coschigano Karen T. , Lo Chunmin C.
Published: February 2023

Dietary lipids induce apolipoprotein A4 (APOA4) production and brown adipose tissue (BAT) thermogenesis. Administration of exogenous APOA4 elevates BAT thermogenesis in chow-fed mice, but not high-fat diet (HFD)-fed mice. Chronic feeding of HFD attenuates plasma APOA4 production and BAT thermogenesis in wildtype (WT) mice. In light of these observations, we sought to determine whether steady production of APOA4 could keep BAT thermogenesis elevated, even in the presence of HFD consumption, with an aim toward eventual reduction of body weight, fat mass and plasma lipid levels. Transgenic mice with overexpression of mouse APOA4 in the small intestine (APOA4-Tg mice) produce greater plasma APOA4 than their WT controls, even when fed an atherogenic diet. Thus, we used these mice to investigate the correlation of levels of APOA4 and BAT thermogenesis during HFD consumption. The hypothesis of this study was that overexpression of mouse APOA4 in the small intestine and increased plasma APOA4 production would increase BAT thermogenesis and consequently reduce fat mass and plasma lipids of HFD-fed obese mice. To test this hypothesis, BAT thermogenic proteins, body weight, fat mass, caloric intake, and plasma lipids in male APOA4-Tg mice and WT mice fed either a chow diet or a HFD were measured. When fed a chow diet, APOA4 levels were elevated, plasma triglyceride (TG) levels were reduced, and BAT levels of UCP1 trended upward, while body weight, fat mass, caloric intake, and plasma lipids were comparable between APOA4-Tg and WT mice. After a four-week feeding of HFD, APOA4-Tg mice maintained elevated plasma APOA4 and reduced plasma TG, but UCP1 levels in BAT were significantly elevated in comparison to WT controls; body weight, fat mass and caloric intake were still comparable. After 10-week consumption of HFD, however, while APOA4-Tg mice still exhibited increased plasma APOA4, UCP1 levels and reduced TG levels, a reduction in body weight, fat mass and levels of plasma lipids and leptin were finally observed in comparison to their WT controls and independent of caloric intake. Additionally, APOA4-Tg mice exhibited increased energy expenditure at several time points when measured during the 10-week HFD feeding. Thus, overexpression of APOA4 in the small intestine and maintenance of elevated levels of plasma APOA4 appear to correlate with elevation of UCP1-dependent BAT thermogenesis and subsequent protection against HFD-induced obesity in mice.
All-Atom Molecular Dynamics Simulations Indicated the Involvement of a Conserved Polar Signaling Channel in the Activation Mechanism of the Type I Cannabinoid Receptor
Authors: Sarkar Arijit , Mitra Argha , Borics Attila
Published: February 2023

The type I cannabinoid G protein-coupled receptor (CB1, GPCR) is an intensely investigated pharmacological target, owing to its involvement in numerous physiological functions as well as pathological processes such as cancers, neurodegenerative diseases, metabolic disorders and neuropathic pain. In order to develop modern medications that exert their effects through binding to the CB1 receptor, it is essential to understand the structural mechanism of activation of this protein. The pool of atomic resolution experimental structures of GPCRs has been expanding rapidly in the past decade, providing invaluable information about the function of these receptors. According to the current state of the art, the activity of GPCRs involves structurally distinct, dynamically interconverting functional states and the activation is controlled by a cascade of interconnecting conformational switches in the transmembrane domain. A current challenge is to uncover how different functional states are activated and what specific ligand properties are responsible for the selectivity towards those different functional states. Our recent studies of the μ-opioid and β2-adrenergic receptors (MOP and β2AR, respectively) revealed that the orthosteric binding pockets and the intracellular surfaces of these receptors are connected through a channel of highly conserved polar amino acids whose dynamic motions are in high correlation in the agonist- and G protein-bound active states. This and independent literature data led us to hypothesize that, in addition to consecutive conformational transitions, a shift of macroscopic polarization takes place in the transmembrane domain, which is furnished by the rearrangement of polar species through their concerted movements. Here, we examined the CB1 receptor signaling complexes utilizing microsecond scale, all-atom molecular dynamics (MD) simulations in order to see if our previous assumptions could be applied to the CB1 receptor too. Apart from the identification of the previously proposed general features of the activation mechanism, several specific properties of the CB1 have been indicated that could possibly be associated with the signaling profile of this receptor.
Circular RNAs: Biogenesis, Biological Functions, and Roles in Myocardial Infarction
Authors: Li Jialei , Han Yu , Wang Shuang , Wu Xiaolei , Cao Jimin , Sun Teng
Published: February 2023

Non-coding RNAs have been excavated as important cardiac function modulators and linked to heart diseases. Significant advances have been obtained in illuminating the effects of microRNAs and long non-coding RNAs. Nevertheless, the characteristics of circular RNAs are rarely mined. Circular RNAs (circRNAs) are widely believed to participate in cardiac pathologic processes, especially in myocardial infarction. In this review, we round up the biogenesis of circRNAs, briefly describe their biological functions, and summarize the latest literature on multifarious circRNAs related to new therapies and biomarkers for myocardial infarction.
Identification of and Mechanistic Insights into SARS-CoV-2 Main Protease Non-Covalent Inhibitors: An In-Silico Study
Authors: Shen Jian-Xin , Du Wen-Wen , Xia Yuan-Ling , Zhang Zhi-Bi , Yu Ze-Fen , Fu Yun-Xin , Liu Shu-Qun
Published: February 2023

The indispensable role of the SARS-CoV-2 main protease (Mpro) in the viral replication cycle and its dissimilarity to human proteases make Mpro a promising drug target. In order to identify the non-covalent Mpro inhibitors, we performed a comprehensive study using a combined computational strategy. We first screened the ZINC purchasable compound database using the pharmacophore model generated from the reference crystal structure of Mpro complexed with the inhibitor ML188. The hit compounds were then filtered by molecular docking and predicted parameters of drug-likeness and pharmacokinetics. The final molecular dynamics (MD) simulations identified three effective candidate inhibitors (ECIs) capable of maintaining binding within the substrate-binding cavity of Mpro. We further performed comparative analyses of the reference and effective complexes in terms of dynamics, thermodynamics, binding free energy (BFE), and interaction energies and modes. The results reveal that, when compared to the inter-molecular electrostatic forces/interactions, the inter-molecular van der Waals (vdW) forces/interactions are far more important in maintaining the association and determining the high affinity. Given the un-favorable effects of the inter-molecular electrostatic interactions—association destabilization by the competitive hydrogen bond (HB) interactions and the reduced binding affinity arising from the un-compensable increase in the electrostatic desolvation penalty—we suggest that enhancing the inter-molecular vdW interactions while avoiding introducing the deeply buried HBs may be a promising strategy in future inhibitor optimization.
YTHDF1 Attenuates TBI-Induced Brain-Gut Axis Dysfunction in Mice
Authors: Huang Peizan , Liu Min , Zhang Jing , Zhong Xiang , Zhong Chunlong
Published: February 2023

The brain-gut axis (BGA) is a significant bidirectional communication pathway between the brain and gut. Traumatic brain injury (TBI) induced neurotoxicity and neuroinflammation can affect gut functions through BGA. N6-methyladenosine (m6A), as the most popular posttranscriptional modification of eukaryotic mRNA, has recently been identified as playing important roles in both the brain and gut. However, whether m6A RNA methylation modification is involved in TBI-induced BGA dysfunction is not clear. Here, we showed that YTHDF1 knockout reduced histopathological lesions and decreased the levels of apoptosis, inflammation, and oedema proteins in brain and gut tissues in mice after TBI. We also found that YTHDF1 knockout improved fungal mycobiome abundance and probiotic (particularly Akkermansia) colonization in mice at 3 days post-CCI. Then, we identified the differentially expressed genes (DEGs) in the cortex between YTHDF1-knockout and WT mice. These genes were primarily enriched in the regulation of neurotransmitter-related neuronal signalling pathways, inflammatory signalling pathways, and apoptotic signalling pathways. This study reveals that the ITGA6-mediated cell adhesion molecule signalling pathway may be the key feature of m6A regulation in TBI-induced BGA dysfunction. Our results suggest that YTHDF1 knockout could attenuate TBI-induced BGA dysfunction.
Adjuvant Therapy for Renal Cell Carcinoma: Hype or Hope?
Authors: Cosso Federica , Roviello Giandomenico , Nesi Gabriella , Shabani Sonia , Spatafora Pietro , Villari Donata , Catalano Martina
Published: February 2023

Renal cell carcinoma (RCC) is the third most common genitourinary cancer accounting for approximately 180,000 deaths worldwide in 2020. Although over two-thirds of patients initially present localized disease, up to 50% of them may progress to metastatic disease. Adjuvant therapy aims to reduce the recurrence risk and improve outcomes in several types of cancers but is currently an unmet need in RCC. The results achieved with tyrosine kinase inhibitors in metastatic RCC led to the evaluation of these target therapies in an early setting with conflicting results for disease-free survival and no overall survival (OS) benefit. Likewise, the results of immune checkpoint inhibitors (ICIs) in an adjuvant setting are conflicting. Available data did not show an improvement in OS with ICIs in the early phase, although a positive trend for pembrolizumab has been recorded, receiving the Food and Drug Administration’s approval in this setting. However, the disappointing results of several ICIs and the heterogeneous pattern of RCC warrant biomarker identification and subgroup analyses to evaluate which patients could benefit from adjuvant therapy. In this review, we will discuss the rationale for adjuvant treatment in RCC, summarizing the results of the most important adjuvant therapy trials and current applications, to outline possible future directions.
Nuclear High Mobility Group A2 (HMGA2) Interactome Revealed by Biotin Proximity Labeling
Authors: Gaudreau-Lapierre Antoine , Klonisch Thomas , Nicolas Hannah , Thanasupawat Thatchawan , Trinkle-Mulcahy Laura , Hombach-Klonisch Sabine
Published: February 2023

The non-histone chromatin binding protein High Mobility Group AT-hook protein 2 (HMGA2) has important functions in chromatin remodeling, and genome maintenance and protection. Expression of HMGA2 is highest in embryonic stem cells, declines during cell differentiation and cell aging, but it is re-expressed in some cancers, where high HMGA2 expression frequently coincides with a poor prognosis. The nuclear functions of HMGA2 cannot be explained by binding to chromatin alone but involve complex interactions with other proteins that are incompletely understood. The present study used biotin proximity labeling, followed by proteomic analysis, to identify the nuclear interaction partners of HMGA2. We tested two different biotin ligase HMGA2 constructs (BioID2 and miniTurbo) with similar results, and identified known and new HMGA2 interaction partners, with functionalities mainly in chromatin biology. These HMGA2 biotin ligase fusion constructs offer exciting new possibilities for interactome discovery research, enabling the monitoring of nuclear HMGA2 interactomes during drug treatments.
Potential Novel Role of Membrane-Associated Carbonic Anhydrases in the Kidney
Authors: Lee Seong-Ki , Boron Walter F. , Occhipinti Rossana
Published: February 2023

Carbonic anhydrases (CAs), because they catalyze the interconversion of carbon dioxide (CO2) and water into bicarbonate (HCO3−) and protons (H+), thereby influencing pH, are near the core of virtually all physiological processes in the body. In the kidneys, soluble and membrane-associated CAs and their synergy with acid–base transporters play important roles in urinary acid secretion, the largest component of which is the reabsorption of HCO3− in specific nephron segments. Among these transporters are the Na+-coupled HCO3− transporters (NCBTs) and the Cl−-HCO3− exchangers (AEs)—members of the “solute-linked carrier” 4 (SLC4) family. All of these transporters have traditionally been regarded as “HCO3−“ transporters. However, recently our group has demonstrated that two of the NCBTs carry CO32− rather than HCO3− and has hypothesized that all NCBTs follow suit. In this review, we examine current knowledge on the role of CAs and “HCO3−” transporters of the SLC4 family in renal acid–base physiology and discuss how our recent findings impact renal acid secretion, including HCO3− reabsorption. Traditionally, investigators have associated CAs with producing or consuming solutes (CO2, HCO3−, and H+) and thus ensuring their efficient transport across cell membranes. In the case of CO32− transport by NCBTs, however, we hypothesize that the role of membrane-associated CAs is not the appreciable production or consumption of substrates but the minimization of pH changes in nanodomains near the membrane.
A Dual Coverage Monitoring of the Bile Acids Profile in the Liver–Gut Axis throughout the Whole Inflammation-Cancer Transformation Progressive: Reveal Hepatocellular Carcinoma Pathogenesis
Authors: Xing Luwen , Zhang Yiwen , Li Saiyu , Tong Minghui , Bi Kaishun , Zhang Qian , Li Qing
Published: February 2023

Hepatocellular carcinoma (HCC) is the terminal phase of multiple chronic liver diseases, and evidence supports chronic uncontrollable inflammation being one of the potential mechanisms leading to HCC formation. The dysregulation of bile acid homeostasis in the enterohepatic circulation has become a hot research issue concerning revealing the pathogenesis of the inflammatory-cancerous transformation process. We reproduced the development of HCC through an N-nitrosodiethylamine (DEN)-induced rat model in 20 weeks. We achieved the monitoring of the bile acid profile in the plasma, liver, and intestine during the evolution of “hepatitis-cirrhosis-HCC” by using an ultra-performance liquid chromatography-tandem mass spectrometer for absolute quantification of bile acids. We observed differences in the level of primary and secondary bile acids both in plasma, liver, and intestine when compared to controls, particularly a sustained reduction of intestine taurine-conjugated bile acid level. Moreover, we identified chenodeoxycholic acid, lithocholic acid, ursodeoxycholic acid, and glycolithocholic acid in plasma as biomarkers for early diagnosis of HCC. We also identified bile acid-CoA:amino acid N-acyltransferase (BAAT) by gene set enrichment analysis, which dominates the final step in the synthesis of conjugated bile acids associated with the inflammatory-cancer transformation process. In conclusion, our study provided comprehensive bile acid metabolic fingerprinting in the liver–gut axis during the inflammation-cancer transformation process, laying the foundation for providing a new perspective for the diagnosis, prevention, and treatment of HCC.
Interplay between Learning and Voluntary Wheel Running in Male C57BL/6NCrl Mice
Authors: Niiranen Laura , Stenbäck Ville , Tulppo Mikko , Herzig Karl-Heinz , Mäkelä Kari A.
Published: February 2023

Exercise is shown to improve cognitive function in various human and animal studies. Laboratory mice are often used as a model to study the effects of physical activity and running wheels provide a voluntary and non-stressful form of exercise. The aim of the study was to analyze whether the cognitive state of a mouse is related to its wheel-running behavior. Twenty-two male C57BL/6NCrl mice (9.5 weeks old) were used in the study. The cognitive function of group-housed mice (n = 5–6/group) was first analyzed in the IntelliCage system followed by individual phenotyping with the PhenoMaster with access to a voluntary running wheel. The mice were divided into three groups according to their running wheel activity: low, average, and high runners. The learning trials in the IntelliCage showed that the high-runner mice exhibited a higher error rate at the beginning of learning trials but improved their outcome and learning performance more compared to the other groups. The high-runner mice ate more compared to the other groups in the PhenoMaster analyses. There were no differences in the corticosterone levels between the groups, indicating similar stress responses. Our results demonstrate that high-runner mice exhibit enhanced learning capabilities prior to access to voluntary running wheels. In addition, our results also show that individual mice react differently when introduced to running wheels, which should be taken into consideration when choosing animals for voluntary endurance exercise studies.
Glycyl-tRNA Synthetase (GARS) Expression Is Associated with Prostate Cancer Progression and Its Inhibition Decreases Migration, and Invasion In Vitro
Authors: Khosh Kish Ealia , Gamallat Yaser , Choudhry Muhammad , Ghosh Sunita , Seyedi Sima , Bismar Tarek A.
Published: February 2023

Glycyl-tRNA synthetase (GARS) is a potential oncogene associated with poor overall survival in various cancers. However, its role in prostate cancer (PCa) has not been investigated. Protein expression of GARS was investigated in benign, incidental, advanced, and castrate-resistant PCa (CRPC) patient samples. We also investigated the role of GARS in vitro and validated GARS clinical outcomes and its underlying mechanism, utilizing The Cancer Genome Atlas Prostate Adenocarcinoma (TCGA PRAD) database. Our data revealed a significant association between GARS protein expression and Gleason groups. Knockdown of GARS in PC3 cell lines attenuated cell migration and invasion and resulted in early apoptosis signs and cellular arrest in S phase. Bioinformatically, higher GARS expression was observed in TCGA PRAD cohort, and there was significant association with higher Gleason groups, pathological stage, and lymph nodes metastasis. High GARS expression was also significantly correlated with high-risk genomic aberrations such as PTEN, TP53, FXA1, IDH1, SPOP mutations, and ERG, ETV1, and ETV4 gene fusions. Gene Set Enrichment Analysis (GSEA) of GARS through the TCGA PRAD database provided evidence for upregulation of biological processes such as cellular proliferation. Our findings support the oncogenic role of GARS involved in cellular proliferation and poor clinical outcome and provide further evidence for its use as a potential biomarker in PCa.
Human Colonoid–Myofibroblast Coculture for Study of Apical Na+/H+ Exchangers of the Lower Cryptal Neck Region
Authors: Salari Azam , Zhou Kunyan , Nikolovska Katerina , Seidler Ursula , Amiri Mahdi
Published: February 2023

Cation and anion transport in the colonocyte apical membrane is highly spatially organized along the cryptal axis. Because of lack of experimental accessibility, information about the functionality of ion transporters in the colonocyte apical membrane in the lower part of the crypt is scarce. The aim of this study was to establish an in vitro model of the colonic lower crypt compartment, which expresses the transit amplifying/progenitor (TA/PE) cells, with accessibility of the apical membrane for functional study of lower crypt-expressed Na+/H+ exchangers (NHEs). Colonic crypts and myofibroblasts were isolated from human transverse colonic biopsies, expanded as three-dimensional (3D) colonoids and myofibroblast monolayers, and characterized. Filter-grown colonic myofibroblast–colonic epithelial cell (CM-CE) cocultures (myofibroblasts on the bottom of the transwell and colonocytes on the filter) were established. The expression pattern for ion transport/junctional/stem cell markers of the CM-CE monolayers was compared with that of nondifferentiated (EM) and differentiated (DM) colonoid monolayers. Fluorometric pHi measurements were performed to characterize apical NHEs. CM-CE cocultures displayed a rapid increase in transepithelial electrical resistance (TEER), paralleled by downregulation of claudin-2. They maintained proliferative activity and an expression pattern resembling TA/PE cells. The CM-CE monolayers displayed high apical Na+/H+ exchange activity, mediated to >80% by NHE2. Human colonoid–myofibroblast cocultures allow the study of ion transporters that are expressed in the apical membrane of the nondifferentiated colonocytes of the cryptal neck region. The NHE2 isoform is the predominant apical Na+/H+ exchanger in this epithelial compartment.
Neonatal Screening for Congenital Adrenal Hyperplasia in Indian Newborns with Reflex Genetic Analysis of 21-Hydroxylase Deficiency
Authors: Tippabathani Jayakrishna , Seenappa Venu , Murugan Alagupandian , Phani Nagaraja Mahishi , Hampe Mahesh H. , Appaswamy Giridharan , Sadashiv Gambhir Prakash
Published: February 2023

Congenital adrenal hyperplasia (CAH), screened for in neonates, is the second most common endocrinopathy after congenital hypothyroidism.Newborn screening for CAH due to CYP21A2 deficiency is performed by immunologic assay for 17-hydroxyprogesterone (17-OHP). The second-tier test for confirmation of diagnosis is carried out on recall venous blood sample from screen positives measuring 17-OHP, or other metabolites of steroid metabolism by liquid chromatography–tandem mass spectroscopy. However, as steroid metabolism is dynamic, it can affect these parameters even in the recall sample of a stressed neonate. Moreover, there is some time delay in recalling the neonate for repeat testing. Reflex genetic analysis of blood spot from the initial Guthrie cards of screen positive neonates, if used for confirmatory testing, can avoid this time delay as well as the effect of stress on steroid metabolism. In this study, we used Sanger sequencing and MLPA in a reflex manner for molecular genetic analysis to confirm CYP21A2-mediated CAH. Out of 220,000 newborns screened, 97 were positive on the initial biochemical screen, of which 54 were confirmed true positives with genetic reflex testing, giving incidence of CAH as 1:4074. Point mutations were more common than deletions, indicating that Sanger sequencing should be used ahead of MLPA for molecular diagnosis in India. Amongst the variants detected, the most common was I2G-Splice variant (44.5%), followed by c.955C>T (p.Gln319Ter) (21.2%); Del 8 bp and c.-113G>A were detected with frequencies of 20.3% and 20%, respectively. In conclusion, reflex genetic testing is an effective strategy for identifying true positives in CAH screening in neonates. This will obviate need for recall samples and also aid effective counselling and timely prenatal diagnosis in the future. In Indian newborns, as point mutations are more common than large deletions, Sanger sequencing should be the initial method of choice for genotyping, ahead of MLPA.
Comparison of Tree-Based Machine Learning Algorithms to Predict Reporting Behavior of Electronic Billing Machines
Authors: Murorunkwere Belle Fille , Ihirwe Jean Felicien , Kayijuka Idrissa , Nzabanita Joseph , Haughton Dominique
Published: February 2023

Tax fraud is a common problem for many tax administrations, costing billions of dollars. Different tax administrations have considered several options to optimize revenue; among them, there is the so-called electronic billing machine (EBM), which aims to monitor all business transactions and, as a result, boost value added tax (VAT) revenue and compliance. Most of the current research has focused on the impact of EBMs on VAT revenue collection and compliance rather than understanding how EBM reporting behavior influences future compliance. The essential contribution of this study is that it leverages both EBM’s historical reporting behavior and actual business characteristics to understand and predict the future reporting behavior of EBMs. Herein, tree-based machine learning algorithms such as decision trees, random forest, gradient boost, and XGBoost are utilized, tested, and compared for better performance. The results exhibit the robustness of the random forest model, among others, with an accuracy of 92.3%. This paper clearly presents our approach contribution with respect to existing approaches through well-defined research questions, analysis mechanisms, and constructive discussions. Once applied, we believe that our approach could ultimately help the tax-collecting agency conduct timely interventions on EBM compliance, which will help achieve the EBM objective of improving VAT compliance.
Cardioplegia in Open Heart Surgery: Age Matters
Authors: Bradić Jovana , Andjić Marijana , Novaković Jovana , Jeremić Nevena , Jakovljević Vladimir
Published: February 2023

Introduction: Cardioplegia is a pharmacological approach essential for the protection of the heart from ischemia–reperfusion (I–R) injury. Over the years, numerous cardioplegic solutions have been developed, with each cardioplegic approach having its advantages and disadvantages. Cardioplegic solutions can be divided into crystalloid and blood cardioplegic solutions, and an experienced surgeon chooses the type of solution based on the individual needs of patients in order to provide optimal heart protection. Importantly, the pediatric immature myocardium is structurally, physiologically, and metabolically different from the adult heart, and consequently its needs to achieve cardioplegic arrest strongly differ. Therefore, the present review aimed to provide a summary of the cardioplegic solutions available to pediatric patients with a special focus on emphasizing differences in heart injury after various cardioplegic solutions, the dosing strategies, and regimens. Material and methods: The PubMed database was searched using the terms cardioplegia, I–R, and pediatric population, and studies that investigated the influence of cardioplegic strategies on markers of cardiac muscle damage were further analyzed in this review. Conclusions: A large body of evidence suggested more prominent benefits achieved with blood compared to those with crystalloid cardioplegia in pediatric myocardium preservation. However, standardized and uniform protocols have not been established so far, and an experienced surgeon chooses the type of cardioplegia solution based on the individual needs of patients, while the severity of myocardial damage strongly depends on the type and duration of the surgical procedure, overall patient condition, and presence of comorbidities, etc.
Endoscopic Grading as a Predictor to Develop Strictures in Corrosive Esophagitis in Children
Authors: Badiu Tisa Ioana , Pepelea Lia , Pirvan Alexandru , Lupan Iulia , Samasca Gabriel , Bordea Madalina Adriana
Published: February 2023

Introduction. The incidence of corrosive esophagitis, also known as caustic esophagitis in children, is still increasing in developing countries, according to different clinical reports. Acids and alkalis are, in the same manner, involved in the pathogenesis of corrosive esophagitis in children. The aim of our study was to determine the incidence and endoscopic grading of corrosive esophagitis in a cohort of children from a developing country. Materials and methods. We performed a retrospective analysis of all pediatric patients who were admitted for corrosive ingestion at Pediatric Clinic II, Emergency Hospital for Children, Cluj-Napoca, over 10 years. Results. A total of 22 patients consisting of 13 (59.09%) girls and 9 boys (40.91%) were found in the present research. The majority of children lived in rural areas (69.2%). The results of laboratory tests were not well correlated with the degree of the injury. White blood cell counts over 20,000 cells/mm3, an increase in the C-reactive protein level and hypoalbuminemia were noticed only in three patients with strictures. The lesions were associated with increased levels of the pro-inflammatory cytokines, including interleukin (IL)-2, IL-5 and Interferon-gamma. Severe late complications such as strictures have been noticed in children with grade 3A injuries. The endoscopic dilation was done after the six months endoscopy. None of the patients treated with endoscopic dilation required surgical intervention for esophageal or pyloric perforation or dilation failure. The majority of complications (such as malnutrition) were noticed in children with grade 3A injuries. In consequence, prolonged hospitalization has been required. The second endoscopy (done six months after ingestion) revealed stricture as the most common late complication (n = 13, 60.60%: eight patients with grade 2B and five with grade 3A). Conclusion. There is a low incidence of corrosive esophagitis in children in our geographic area. Endoscopic grading is a predictor of late complications such as strictures. Grade 2B and 3A corrosive esophagitis are likely to develop strictures. It is crucial to avoid strictures and to prevent malnutrition.
Oral Cell Lysates Reduce the Inflammatory Response of Activated Macrophages
Authors: Panahipour Layla , Oladzad Abbasabadi Azarakhsh , Gruber Reinhard
Published: February 2023

Necrotic cell damage occurs as a consequence of invasive dental procedures. Loss of membrane integrity being the hallmark of necrotic cells leads to the release of cytoplasmic and membranous components. Macrophages are predestined to respond to lysates originating from necrotic cells. Here, we implement necrotic lysates from human gingival fibroblasts, HSC2, and TR146 oral epithelial cell lines, and RAW264.7 macrophage cell lines to be tested for their potential to modulate the inflammatory response of macrophages. To this aim, necrotic cell lysates were prepared by sonication or freezing/thawing of the respective cell suspension. Necrotic cell lysates were tested for their potential to modulate the lipopolysaccharide (LPS)-induced expression of inflammatory cytokines using RAW264.7 macrophages as a bioassay. We show here that all necrotic cell lysates, independent of the origin and the preparation way, reduced the expression of IL1 and IL6 in LPS-induced RAW264.7 macrophages, most obviously shown for TR146 cells. This finding was supported in a bioassay when macrophages were exposed to poly (I:C) HMW, an agonist of TLR-3. Consistently, all necrotic lysates from gingival fibroblasts, HSC2, TR146, and RAW264.7 cells reduced the nuclear translocation of p65 in LPS-exposed macrophages. This screening approach supports the overall concept that necrotic cell lysates can modulate the inflammatory capacity of macrophages.
Exploring Pharmacological Treatments for Chronic Idiopathic Constipation in Adults: A Look Back to the Future
Authors: Bassotti Gabrio , Villanacci Vincenzo , Corsetti Maura
Published: February 2023

Despite great progress in pharmaceutical research, the medical treatment of chronic idiopathic constipation is far from ideal. The aim of the present article was to review literature data, focusing on poorly studied or commercially unavailable/unapproved drugs potentially useful for the treatment of chronic idiopathic constipation in adults. An extensive online literature search was conducted using the keywords “chronic constipation”, “colon”, “constipation”, “drugs”, “laxatives”, and “treatment”, in various combinations between January 1960 and December 2022. The literature search showed the presence of some drugs whose efficacy has only recently been demonstrated by modern investigations, and which are likely to be incorporated into future guidelines, of others that are proven effective and potentially effective on constipated patients but limited by small or relatively old studies, or by side effects which could be used in experienced hands, and of others that might be useful but lack a solid scientific background. Looking into the future for patients with chronic constipation might add some more tools to the therapeutic portfolio, especially for certain subgroups of these patients.
Dental Implant Surface Decontamination and Surface Change of an Electrolytic Method versus Mechanical Approaches: A Pilot In Vitro Study
Authors: Assunção Mariana Anselmo , Botelho João , Machado Vanessa , Proença Luís , Matos António P. A. , Mendes José João , Bessa Lucinda J. , Taveira Nuno , Santos Alexandre
Published: February 2023

Dental implants are the preferred fixed oral rehabilitation for replacing lost teeth. When peri-implant tissues become inflamed, the removal of plaque accumulating around the implant becomes imperative. Recently, several new strategies have been developed for this purpose, with electrolytic decontamination showing increased potential compared to traditional mechanical strategies. In this in vitro pilot study, we compare the efficacy of an electrolytic decontaminant (Galvosurge®) with an erythritol jet system (PerioFlow®) and two titanium brushes (R-Brush™ and i-Brush™) in removing Pseudomonas aeruginosa PAO1 biofilms from implants. Changes in the implant surface after each approach were also evaluated. Twenty titanium SLA implants were inoculated with P. aeruginosa and then randomly assigned to each treatment group. After treatment, decontamination efficacy was assessed by quantifying colony-forming units (log10 CFU/cm2) from each implant surface. Scanning electron microscopy was used to analyse changes in the implant surface. With the exception of R-Brush, all treatment strategies were similarly effective in removing P. aeruginosa from implants. Major surface changes were observed only in implants treated with titanium brushes. In conclusion, this pilot study suggests that electrolytic decontamination, erythritol-chlorhexidine particle jet system and i-Brush™ brushing have similar performance in removing P. aeruginosa biofilm from dental implants. Further studies are needed to evaluate the removal of more complex biofilms. Titanium brushes caused significant changes to the implant surface, the effects of which need to be evaluated.
Non-Diabetic Kidney Disease in Type 2 Diabetes Mellitus: A Changing Spectrum with Therapeutic Ascendancy
Authors: Prasad Narayan , Veeranki Vamsidhar , Bhadauria Dharmendra , Kushwaha Ravi , Meyyappan Jeyakumar , Kaul Anupama , Patel Manas , Behera Manas , Yachha Monika , Agrawal Vinita , Jain Manoj
Published: February 2023

Background and objectives: Owing to changing epidemiology and therapeutic practices, a change in the spectrum of renal involvement in Type-2 diabetes mellitus (T2DM) has also been noted. The treatment of non-diabetic kidney disease (NDKD) differs from diabetic kidney disease (DKD) and the reversibility of NDKD in many cases to normal, prompts biopsy for rapid and accurate diagnosis. Data are scarce on kidney biopsy findings in T2DM. Study design & setting: In this observational study, we prospectively collected the data of kidney biopsies of patients aged ≥ 18 years with T2DM admitted between 1 August 2005 and 31 July 2022. The clinical, demographic and histopathological data were evaluated. The spectrum of kidney involvement in the form of DKD and/or NDKD was studied. The impact of these findings with the use of drugs retarding disease progression was also analyzed. Results: A total of 5485 biopsies were performed during the study period and of these 538 patients had T2DM. The mean age of the study population was 56.9 ± 11.5 years and 81% were males. The mean duration of DM was 6.4 ± 6.1 years. Diabetic retinopathy (DR) was noted in 29.7%. The most common indication for biopsy was an acute rise in creatinine (147, 27.3%). Amongst the 538 diabetic patients who underwent biopsy, histological features only of DKD were noted in 166 patients (33%), NDKD alone in 262 (49%) and NDKD with DKD lesions in 110 (20%). On multivariate analysis, duration of DM less than 5 years, absence of CAD, absence of DR, oliguria at presentation, an acute rise in creatinine and low C3 were associated with NDKD. Conclusions: The prevalence of NDKD among diabetics and ATIN in particular might be on an increasing trend in the current era of changing T2DM epidemiological patterns. The use of anti-pro-teinuric agents was associated with lesser degrees of histopathological chronicity in T2DM.
Transcutaneous Carbon Dioxide Monitoring More Accurately Detects Hypercapnia than End-Tidal Carbon Dioxide Monitoring during Non-Intubated Video-Assisted Thoracic Surgery: A Retrospective Cohort Study
Authors: Lee Hyun Jung , Woo Jae Hee , Cho Sooyoung , Moon Sunyoung , Sung Sook Whan
Published: February 2023

Transcutaneous carbon dioxide (PtcCO2) monitoring is known to be effective at estimating the arterial partial pressure of carbon dioxide (PaCO2) in patients with sedation-induced respiratory depression. We aimed to investigate the accuracy of PtcCO2 monitoring to measure PaCO2 and its sensitivity to detect hypercapnia (PaCO2 > 60 mmHg) compared to nasal end-tidal carbon dioxide (PetCO2) monitoring during non-intubated video-assisted thoracoscopic surgery (VATS). This retrospective study included patients undergoing non-intubated VATS from December 2019 to May 2021. Datasets of PetCO2, PtcCO2, and PaCO2 measured simultaneously were extracted from patient records. Overall, 111 datasets of CO2 monitoring during one-lung ventilation (OLV) were collected from 43 patients. PtcCO2 had higher sensitivity and predictive power for hypercapnia during OLV than PetCO2 (84.6% vs. 15.4%, p < 0.001; area under the receiver operating characteristic curve; 0.912 vs. 0.776, p = 0.002). Moreover, PtcCO2 was more in agreement with PaCO2 than PetCO2, indicated by a lower bias (bias ± standard deviation; −1.6 ± 6.5 mmHg vs. 14.3 ± 8.4 mmHg, p < 0.001) and narrower limit of agreement (−14.3–11.2 mmHg vs. −2.2–30.7 mmHg). These results suggest that concurrent PtcCO2 monitoring allows anesthesiologists to provide safer respiratory management for patients undergoing non-intubated VATS.
Shock Index for Early Detection of Low Plasma Fibrinogen in Trauma: A Prospective Observational Cohort Pilot Study
Authors: Škola Josef , Bílská Marcela , Horáková Michala , Tégl Václav , Beneš Jan , Škulec Roman , Černý Vladimír
Published: February 2023

Shock index (a ratio between heart rate and systolic blood pressure) predicts transfusion requirements and the need for haemostatic resuscitation in severe trauma patients. In the present study, we aimed to determine whether prehospital and on-admission shock index values can be used to predict low plasma fibrinogen in trauma patients. Between January 2016 and February 2017, trauma patients admitted from the helicopter emergency medical service into two large trauma centres in the Czech Republic were prospectively assessed for demographic, laboratory and trauma-associated variables and shock index at scene, during transport and at admission to the emergency department. Hypofibrinogenemia defined as fibrinogen plasma level of 1.5 g.L−l was deemed as a cut-off for further analysis. Three hundred and twenty-two patients were screened for eligibility. Of these, 264 (83%) were included for further analysis. The hypofibrinogenemia was predicted by the worst prehospital shock index with the area under the receiver operating characteristics curve (AUROC) of 0.79 (95% CI 0.64–0.91) and by the admission shock index with AUROC of 0.79 (95% CI 0.66–0.91). For predicting hypofibrinogenemia, the prehospital shock index ≥ 1 has 0.5 sensitivity (95% CI 0.19–0.81), 0.88 specificity (95% CI 0.83–0.92) and a negative predictive value of 0.98 (0.96–0.99). The shock index may help to identify trauma patients at risk of hypofibrinogenemia early in the prehospital course.
SERPINA1 and More? A Putative Genetic Contributor to Pulmonary Dysfunction in Alpha-1 Antitrypsin Deficiency
Authors: Jezela-Stanek Aleksandra , Chorostowska-Wynimko Joanna
Published: February 2023

Alpha-1 antitrypsin deficiency (AATD) is a common inherited disorder associated with an increased risk of pulmonary disease. Its clinical presentation, including the nature and severity of organ involvement, is highly variable and unpredictable and is not as strongly linked to genotype and environmental exposure (e.g., smoking history) as might be expected. Significant differences were observed within matched populations of severe AATD patients regarding risk of complications, age at onset, and disease course, including the dynamics of lung function decline. Genetic factors are among the putative modifiers contributing to the clinical variability in AATD, yet their role remains elusive. Here, we review and summarise our current understanding of epigenetic and genetic modifiers of pulmonary dysfunction in subjects with AATD.