bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical Characteristics and Laboratory Findings in Children with Multisystem Inflammatory Syndrome (MIS-C)—A Retrospective Study of a Tertiary Care Center from Constanta, Romania
Authors: Mihai Cristina Maria , Chisnoiu Tatiana , Balasa Adriana Luminita , Frecus Corina Elena , Mihai Larisia , Pantazi Alexandru Cosmin , Stuparu Alina Zorina , Axelerad Any
Published: February 2023

A new hyper-inflammatory syndrome in children was identified after SARS-CoV-2 infection as a post-infectious complication that is temporally associated with coronavirus disease (COVID-19). Fever, rash, conjunctival hyperemia, and gastrointestinal problems are all clinical manifestations of multisystem inflammatory syndrome in children. This condition, in some cases, causes multisystem involvement, affecting multiple organ systems and necessitating admission to a pediatric intensive care unit. Due to limited clinical studies, it is necessary to analyze the characteristics of the pathology in order to improve the management and long-term follow-up of high-risk patients. The objective of the study was to analyze the clinical and paraclinical characteristics of children diagnosed with MIS-C. The clinical study is a retrospective, observational, descriptive research work that includes patients diagnosed with MIS-C, temporally associated with coronavirus disease, and it contains clinical characteristics, laboratory data, and demographic information. The majority of patients had normal or slightly increased leukocyte counts, which were associated with neutrophilia, lymphocytopenia, and significantly elevated inflammatory markers, including high levels of C-reactive protein, fibrinogen, the erythrocyte sedimentation rate, serum ferritin, and IL 6 and elevated levels of the cardiac enzymes NT-proBNP and D-dimers, owing to the cardiovascular system involvement in the pro-inflammatory process. At the same time, renal system involvement led to raised creatinine and high proteinuria in association with hypoalbuminemia. This characteristic of the pro-inflammatory status as well as multisystem impairment are highly suggestive of the post-infection immunological reaction of the multisystem syndrome temporally associated with SARS-CoV-2 infection.
Pediatric Nephrolithiasis
Authors: Cao Brent , Daniel Roby , McGregor Ryan , Tasian Gregory E.
Published: February 2023

The prevalence of pediatric nephrolithiasis has increased dramatically in the past two decades for reasons that have yet to be fully elucidated. Workup of pediatric kidney stones should include metabolic assessment to identify and address any risk factors predisposing patients to recurrent stone formation, and treatment should aim to facilitate stone clearance while minimizing complications, radiation and anesthetic exposure, and other risks. Treatment methods include observation and supportive therapy, medical expulsive therapy, and surgical intervention, with choice of treatment method determined by clinicians’ assessments of stone size, location, anatomic factors, comorbidities, other risk factors, and preferences and goals of patients and their families. Much of the current research into nephrolithiasis is restricted to adult populations, and more data are needed to better understand many aspects of the epidemiology and treatment of pediatric kidney stones.
Disentangling the Cost of Orphan Drugs Marketed in the United States
Authors: Althobaiti Hana , Seoane-Vazquez Enrique , Brown Lawrence M. , Fleming Marc L. , Rodriguez-Monguio Rosa
Published: February 2023

The increasing number and high prices of orphan drugs have triggered concern among patients, payers, and policymakers about the affordability of new drugs approved using the incentives set by the Orphan Drug Act (ODA) of 1983. This study evaluated the factors associated to the differences in the treatment cost of new orphan and non-orphan drugs approved by the FDA from 2017 to 2021. A generalized linear model (GLM) with the Gamma log-link analysis was used to ascertain the association of drug characteristics with the treatment costs of orphan and non-orphan drugs. The results of the study showed that the median and interquartile range (IQR) drug cost was USD 218,872 (IQR = USD 23,105) for orphan drugs and USD 12,798 (IQR = USD 57,940) for non-orphan drugs (p < 0.001). Higher market entry prices were associated with biologics (108%; p < 0.001), orphan status (177%; p < 0.001), US sponsor companies (48%; p = 0.035), chronic use (1083%; p < 0.001), treatment intent (163%; p = 0.004), and indications for oncology (624%; p < 0.001) or genetic disorders (624%; p < 0.001). Higher market entry treatment cost for newly approved drugs were associated with biologics, orphan status, US sponsor companies, chronic use, therapeutic intent, and indications for oncology or genetic disorders.
Effects of Auxin-Type Plant Growth Regulators and Cold Stress on the Endogenous Polyamines in Pea Plants
Authors: Jankovska-Bortkevič Elžbieta , Katerova Zornitsa , Todorova Dessislava , Jankauskienė Jurga , Mockevičiūtė Rima , Sergiev Iskren , Jurkonienė Sigita
Published: February 2023

The effect of pre-application of structural auxin analogues TA-12 (1-[2-chloroethoxycarbonyl-methyl]-4-naphthalenesulfonic acid calcium salt) and TA-14 (1-[2-dimethylaminoethoxicarbonylmethyl] naphthalenechlormethylate) on biochemical parameters of pea (Pisum sativum L. cv. Jablo) plants subjected to low temperature (LT, −1 °C, for 24h) was studied. For the first time the effects of these auxin analogues, applied with or without LT were investigated on the endogenous polyamine (PA) content. The LT treatment increased free and bound putrescine (Put) and spermine (Spm), conjugated and bound spermidine (Spd), accompanied by a decrease in conjugated Put and Spm, and free Spd. Stress biomarkers hydrogen peroxide (H2O2) and malondialdehyde (MDA) as well as proline were augmented by LT treatment. The TAs application decreased conjugated polyamines (Put, Spm and Spd), free Spd, H2O2 and MDA but increased bound Spm and proline in pea plants. The application of TAs before LT lessened the alterations in PAs (mainly in free and bound fractions) and stress biomarkers content caused by LT, and enhanced conjugated Spd and phenolics, which contributed to increased plant cold tolerance.
Effects of Using Plasma-Activated Water as a Nitrate Source on the Growth and Nutritional Quality of Hydroponically Grown Green Oak Lettuces
Authors: Ruamrungsri Soraya , Sawangrat Choncharoen , Panjama Kanokwan , Sojithamporn Phanumas , Jaipinta Suchanuch , Srisuwan Wimada , Intanoo Malinee , Inkham Chaiartid , Thanapornpoonpong Sa-nguansak
Published: February 2023

Nitrate is a major source of the inorganic nitrogen taken up by the roots of plants. Nitrate sources are generally derived from inorganic minerals by an energy-consuming chemical process; as a result, the price of chemical fertilizers is gradually increasing year by year. NO3-N, generated from N2 using the plasma technique, is an alternative method of producing nitrate from the air. Therefore, in this research, we aimed to determine the efficiency of generating NO3-N using plasma-activated water (PAW) to replace nitrates from chemical fertilizer in a nutrient solution. Green oak lettuce (Lactuca sativa L.) was grown in a hydroponics system using the double-pot technique. The plants were supplied with three different nutrient solutions (based on Hoagland’s solution), i.e., T1, no nitrate in the nutrient solution (NO3− = 0); T2, using nitrate sourced from a commercial chemical fertilizer (normal nitrate); and T3, using a nitrate source generated using the pinhole plasma jet technique (plasma nitrate). The other macronutrients and micronutrients in each treatment were equally supplied. The results show that, at the harvested stage (21 days after the plants received treatment), the no-nitrate (T1) treatment provided lower growth and yields. Moreover, compared with the normal nitrate (T2) and plasma nitrate (T3), the results indicate that most growth and yields showed no statistical differences. In terms of nitrate accumulation within plants, it was found that the normal nitrate treatment (T2) had the highest levels of nitrate accumulation, in both the underground and aboveground parts of green oak lettuce. These results confirmed that plasma nitrate could be an alternative source of nitrate N which provided a safer way for the environment and human health in terms of nitrate accumulation. In addition, data related to the chemical analysis of free amino acid concentrations in each treatment are discussed in this research.
Matching Standard and Secant Parallels in Cylindrical Projections
Authors: Lapaine Miljenko
Published: February 2023

Map projections are usually interpreted by mapping a sphere onto an auxiliary surface, and then the surface is developed into a plane. It is taken as a fact without proof that the parallels in which the auxiliary surface intersects the sphere are mapped without distortions. In a previous paper, based on a theoretical consideration and illustrated with several examples, the author concluded that explaining cylindrical projections as mapping onto a cylindrical surface is not a good approach, because it leads to misunderstanding important properties of projection. In this paper I prove that there are no equal-area, equidistant, or conformal cylindrical projections for which the standard parallel will coincide with secant parallel after folding the map into a cylinder.
A Comprehensive Virulence and Resistance Characteristics of Listeria monocytogenes Isolated from Fish and the Fish Industry Environment
Authors: Zakrzewski Arkadiusz Józef , Kurpas Monika , Zadernowska Anna , Chajęcka-Wierzchowska Wioleta , Fraqueza Maria João
Published: February 2023

Listeria monocytogenes is an important pathogen, often associated with fish, that can adapt and survive in products and food processing plants, where it can persist for many years. It is a species characterized by diverse genotypic and phenotypic characteristics. Therefore, in this study, a total of 17 L. monocytogenes strains from fish and fish-processing environments in Poland were characterized for their relatedness, virulence profiles, and resistance genes. The Core Genome Multilocus Sequence Typing (cgMLST) analysis revealed that the most frequent serogroups were IIa and IIb; sequence types (ST) were ST6 and ST121; and clonal complexes (CC) were CC6 and CC121. Core genome multilocus sequence typing (cgMLST) analysis was applied to compare the present isolates with the publicly available genomes of L. monocytogenes strains recovered in Europe from humans with listeriosis. Despite differential genotypic subtypes, most strains had similar antimicrobial resistance profiles; however, some of genes were located on mobile genetic elements that could be transferred to commensal or pathogenic bacteria. The results of this study showed that molecular clones of tested strains were characteristic for L. monocytogenes isolated from similar sources. Nevertheless, it is worth emphasizing that they could present a major public health risk due to their close relation with strains isolated from human listeriosis.
Complexification of In Vitro Models of Intestinal Barriers, A True Challenge for a More Accurate Alternative Approach
Authors: Haddad Michelle J. , Sztupecki Wendy , Delayre-Orthez Carine , Rhazi Larbi , Barbezier Nicolas , Depeint Flore , Anton Pauline M.
Published: February 2023

The use of cell models is common to mimic cellular and molecular events in interaction with their environment. In the case of the gut, the existing models are of particular interest to evaluate food, toxicants, or drug effects on the mucosa. To have the most accurate model, cell diversity and the complexity of the interactions must be considered. Existing models range from single-cell cultures of absorptive cells to more complex combinations of two or more cell types. This work describes the existing solutions and the challenges that remain to be solved.
Thermal Titration Molecular Dynamics (TTMD): Not Your Usual Post-Docking Refinement
Authors: Menin Silvia , Pavan Matteo , Salmaso Veronica , Sturlese Mattia , Moro Stefano
Published: February 2023

Molecular docking is one of the most widely used computational approaches in the field of rational drug design, thanks to its favorable balance between the rapidity of execution and the accuracy of provided results. Although very efficient in exploring the conformational degrees of freedom available to the ligand, docking programs can sometimes suffer from inaccurate scoring and ranking of generated poses. To address this issue, several post-docking filters and refinement protocols have been proposed throughout the years, including pharmacophore models and molecular dynamics simulations. In this work, we present the first application of Thermal Titration Molecular Dynamics (TTMD), a recently developed method for the qualitative estimation of protein-ligand unbinding kinetics, to the refinement of docking results. TTMD evaluates the conservation of the native binding mode throughout a series of molecular dynamics simulations performed at progressively increasing temperatures with a scoring function based on protein-ligand interaction fingerprints. The protocol was successfully applied to retrieve the native-like binding pose among a set of decoy poses of drug-like ligands generated on four different pharmaceutically relevant biological targets, including casein kinase 1δ, casein kinase 2, pyruvate dehydrogenase kinase 2, and SARS-CoV-2 main protease.
An Experimental Anodized and Low-Pressure Oxygen Plasma-Treated Titanium Dental Implant Surface—Preliminary Report
Authors: Hadzik Jakub , Jurczyszyn Kamil , Gębarowski Tomasz , Trytek Andrzej , Gedrange Tomasz , Kozakiewicz Marcin , Dominiak Marzena , Kubasiewicz-Ross Paweł , Trzcionka-Szajna Anna , Szajna Ernest , Simka Wojciech
Published: February 2023

Chemical composition and physical parameters of the implant surface, such as roughness, regulate the cellular response leading to implant bone osseointegration. Possible implant surface modifications include anodization or the plasma electrolytic oxidation (PEO) treatment process that produces a thick and dense oxide coating superior to normal anodic oxidation. Experimental modifications with Plasma Electrolytic Oxidation (PEO) titanium and titanium alloy Ti6Al4V plates and PEO additionally treated with low-pressure oxygen plasma (PEO-S) were used in this study to evaluate their physical and chemical properties. Cytotoxicity of experimental titanium samples as well as cell adhesion to their surface were assessed using normal human dermal fibroblasts (NHDF) or L929 cell line. Moreover, the surface roughness, fractal dimension analysis, and texture analysis were calculated. Samples after surface treatment have substantially improved properties compared to the reference SLA (sandblasted and acid-etched) surface. The surface roughness (Sa) was 0.59–2.38 µm, and none of the tested surfaces had cytotoxic effect on NHDF and L929 cell lines. A greater cell growth of NHDF was observed on the tested PEO and PEO-S samples compared to reference SLA sample titanium.
Altered Faecal Microbiota Composition and Structure of Ghanaian Children with Acute Gastroenteritis
Authors: Quaye Emmanuel Kofi , Adjei Raymond Lovelace , Isawumi Abiola , Allen David J. , Caporaso J. Gregory , Quaye Osbourne
Published: February 2023

Acute gastroenteritis (AGE) is a disease of global public health importance. Recent studies show that children with AGE have an altered gut microbiota relative to non-AGE controls. Yet, how the gut microbiota differs in Ghanaian children with and without AGE remains unclear. Here, we explore the 16S rRNA gene-based faecal microbiota profiles of Ghanaian children five years of age and younger, comprising 57 AGE cases and 50 healthy controls. We found that AGE cases were associated with lower microbial diversity and altered microbial sequence profiles relative to the controls. The faecal microbiota of AGE cases was enriched for disease-associated bacterial genera, including Enterococcus, Streptococcus, and Staphylococcus. In contrast, the faecal microbiota of controls was enriched for potentially beneficial genera, including Faecalibacterium, Prevotella, Ruminococcus, and Bacteroides. Lastly, distinct microbial correlation network characteristics were observed between AGE cases and controls, thereby supporting broad differences in faecal microbiota structure. Altogether, we show that the faecal microbiota of Ghanaian children with AGE differ from controls and are enriched for bacterial genera increasingly associated with diseases.
Towards Arginase Inhibition: Hybrid SAR Protocol for Property Mapping of Chlorinated N-arylcinnamamides
Authors: Bak Andrzej , Kos Jiri , Degotte Gilles , Swietlicka Aleksandra , Strharsky Tomas , Pindjakova Dominika , Gonec Tomas , Smolinski Adam , Francotte Pierre , Frederich Michel , Kozik Violetta , Jampilek Josef
Published: February 2023

A series of seventeen 4-chlorocinnamanilides and seventeen 3,4-dichlorocinnamanilides were characterized for their antiplasmodial activity. In vitro screening on a chloroquine-sensitive strain of Plasmodium falciparum 3D7/MRA-102 highlighted that 23 compounds possessed IC50 < 30 µM. Typically, 3,4-dichlorocinnamanilides showed a broader range of activity compared to 4-chlorocinnamanilides. (2E)-N-[3,5-bis(trifluoromethyl)phenyl]-3-(3,4-dichlorophenyl)prop-2-en-amide with IC50 = 1.6 µM was the most effective agent, while the other eight most active derivatives showed IC50 in the range from 1.8 to 4.6 µM. A good correlation between the experimental logk and the estimated clogP was recorded for the whole ensemble of the lipophilicity generators. Moreover, the SAR-mediated similarity assessment of the novel (di)chlorinated N-arylcinnamamides was conducted using the collaborative (hybrid) ligand-based and structure-related protocols. In consequence, an ‘averaged’ selection-driven interaction pattern was produced based in namely ‘pseudo–consensus’ 3D pharmacophore mapping. The molecular docking approach was engaged for the most potent antiplasmodial agents in order to gain an insight into the arginase-inhibitor binding mode. The docking study revealed that (di)chlorinated aromatic (C-phenyl) rings are oriented towards the binuclear manganese cluster in the energetically favorable poses of the chloroquine and the most potent arginase inhibitors. Additionally, the water-mediated hydrogen bonds were formed via carbonyl function present in the new N-arylcinnamamides and the fluorine substituent (alone or in trifluoromethyl group) of N-phenyl ring seems to play a key role in forming the halogen bonds.
AQP1 in the Gastrointestinal Tract of Mice: Expression Pattern and Impact of AQP1 Knockout on Colonic Function
Authors: Volkart Stefanie , Kym Urs , Braissant Olivier , Delgado-Eckert Edgar , Al-Samir Samer , Angresius Rebecca , Huo Zihe , Holland-Cunz Stefan , Gros Stephanie J.
Published: February 2023

Aquaporin 1 (AQP1) is one of thirteen known mammalian aquaporins. Its main function is the transport of water across cell membranes. Lately, a role of AQP has been attributed to other physiological and pathological functions including cell migration and peripheral pain perception. AQP1 has been found in several parts of the enteric nervous system, e.g., in the rat ileum and in the ovine duodenum. Its function in the intestine appears to be multifaceted and is still not completely understood. The aim of the study was to analyze the distribution and localization of AQP1 in the entire intestinal tract of mice. AQP1 expression was correlated with the hypoxic expression profile of the various intestinal segments, intestinal wall thickness and edema, as well as other aspects of colon function including the ability of mice to concentrate stools and their microbiome composition. AQP1 was found in a specific pattern in the serosa, the mucosa, and the enteric nervous system throughout the gastrointestinal tract. The highest amount of AQP1 in the gastrointestinal tract was found in the small intestine. AQP1 expression correlated with the expression profiles of hypoxia-dependent proteins such as HIF-1α and PGK1. Loss of AQP1 through knockout of AQP1 in these mice led to a reduced amount of bacteroidetes and firmicutes but an increased amount of the rest of the phyla, especially deferribacteres, proteobacteria, and verrucomicrobia. Although AQP-KO mice retained gastrointestinal function, distinct changes regarding the anatomy of the intestinal wall including intestinal wall thickness and edema were observed. Loss of AQP1 might interfere with the ability of the mice to concentrate their stool and it is associated with a significantly different composition of the of the bacterial stool microbiome.
Multifaceted Nature of DNA Polymerase θ
Authors: Kruchinin Alexander A. , Makarova Alena V.
Published: February 2023

DNA polymerase θ belongs to the A family of DNA polymerases and plays a key role in DNA repair and damage tolerance, including double-strand break repair and DNA translesion synthesis. Pol θ is often overexpressed in cancer cells and promotes their resistance to chemotherapeutic agents. In this review, we discuss unique biochemical properties and structural features of Pol θ, its multiple roles in protection of genome stability and the potential of Pol θ as a target for cancer treatment.
TFIIIC as a Potential Epigenetic Modulator of Histone Acetylation in Human Stem Cells
Authors: Vezzoli Marco , de Llobet Cucalon Lara Isabel , Di Vona Chiara , Morselli Marco , Montanini Barbara , de la Luna Susana , Teichmann Martin , Dieci Giorgio , Ferrari Roberto
Published: February 2023

Regulation of histone acetylation dictates patterns of gene expression and hence cell identity. Due to their clinical relevance in cancer biology, understanding how human embryonic stem cells (hESCs) regulate their genomic patterns of histone acetylation is critical, but it remains largely to be investigated. Here, we provide evidence that acetylation of histone H3 lysine-18 (H3K18ac) and lysine-27 (H3K27ac) is only partially established by p300 in stem cells, while it represents the main histone acetyltransferase (HAT) for these marks in somatic cells. Our analysis reveals that whereas p300 marginally associated with H3K18ac and H3K27ac in hESCs, it largely overlapped with these histone marks upon differentiation. Interestingly, we show that H3K18ac is found at “stemness” genes enriched in RNA polymerase III transcription factor C (TFIIIC) in hESCs, whilst lacking p300. Moreover, TFIIIC was also found in the vicinity of genes involved in neuronal biology, although devoid of H3K18ac. Our data suggest a more complex pattern of HATs responsible for histone acetylations in hESCs than previously considered, suggesting a putative role for H3K18ac and TFIIIC in regulating “stemness” genes as well as genes associated with neuronal differentiation of hESCs. The results break ground for possible new paradigms for genome acetylation in hESCs that could lead to new avenues for therapeutic intervention in cancer and developmental diseases.
Bioinorganic Modulators of Ferroptosis: A Review of Recent Findings
Authors: Bartos Adrian , Sikora Joanna
Published: February 2023

Ferroptosis was first reported as a separate modality of regulated cell death in 2008 and distinguished under its current name in 2012 after it was first induced with erastin. In the following decade, multiple other chemical agents were researched for their pro- or anti-ferroptotic properties. Complex organic structures with numerous aromatic moieties make up the majority of this list. This review fills a more overlooked niche by gathering, outlining and setting out conclusions regarding less prominent cases of ferroptosis induced by bioinorganic compounds and reported on within the last few years. The article contains a short summary of the application of bioinorganic chemicals based on gallium, several chalcogens, transition metals and elements known as human toxicants used for the purpose of evoking ferroptotic cell death in vitro or in vivo. These are used in the form of free ions, salts, chelates, gaseous and solid oxides or nanoparticles. Knowledge of how exactly these modulators promote or inhibit ferroptosis could be beneficial in the context of future therapies aimed against cancer or neurodegenerative diseases, respectively.
Transcriptome and Metabolome Analysis Reveals Salt-Tolerance Pathways in the Leaves and Roots of ZM-4 (Malus zumi) in the Early Stages of Salt Stress
Authors: Wang Dajiang , Wang Kun , Sun Simiao , Yan Peng , Lu Xiang , Liu Zhao , Li Qingshan , Li Lianwen , Gao Yuan , Liu Jihong
Published: February 2023

The breeding of salt-tolerant rootstock relies heavily on the availability of salt-tolerant Malus germplasm resources. The first step in developing salt-tolerant resources is to learn their molecular and metabolic underpinnings. Hydroponic seedlings of both ZM-4 (salt-tolerant resource) and M9T337 (salt-sensitive rootstock) were treated with a solution of 75 mM salinity. ZM-4’s fresh weight increased, then decreased, and then increased again after being treated with NaCl, whereas M9T337′s fresh weight continued to decrease. The results of transcriptome and metabolome after 0 h (CK) and 24 h of NaCl treatment showed that the leaves of ZM-4 had a higher content of flavonoids (phloretinm, naringenin-7-O-glucoside, kaempferol-3-O-galactoside, epiafzelechin, etc.) and the genes (CHI, CYP, FLS, LAR, and ANR) related to the flavonoid synthesis pathway showed up-regulation, suggesting a high antioxidant capacity. In addition to the high polyphenol content (L-phenylalanine, 5-O-p-coumaroyl quinic acid) and the high related gene expression (4CLL9 and SAT), the roots of ZM-4 exhibited a high osmotic adjustment ability. Under normal growing conditions, the roots of ZM-4 contained a higher content of some amino acids (L-proline, tran-4-hydroxy-L-prolin, L-glutamine, etc.) and sugars (D−fructose 6−phosphate, D−glucose 6−phosphate, etc.), and the genes (GLT1, BAM7, INV1, etc.) related to these two pathways were highly expressed. Furthermore, some amino acids (S-(methyl) glutathione, N-methyl-trans-4-hydroxy-L-proline, etc.) and sugars (D-sucrose, maltotriose, etc.) increased and genes (ALD1, BCAT1, AMY1.1, etc.) related to the pathways showed up-regulation under salt stress. This research provided theoretical support for the application of breeding salt-tolerant rootstocks by elucidating the molecular and metabolic mechanisms of salt tolerance during the early stages of salt treatment for ZM-4.
Indoxyl Sulphate Retention Is Associated with Microvascular Endothelial Dysfunction after Kidney Transplantation
Authors: Hobson Sam , Arefin Samsul , Rahman Awahan , Hernandez Leah , Ebert Thomas , de Loor Henriette , Evenepoel Pieter , Stenvinkel Peter , Kublickiene Karolina
Published: February 2023

Kidney transplantation (KTx) is the preferred form of renal replacement therapy in chronic kidney disease (CKD) patients, owing to increased quality of life and reduced mortality when compared to chronic dialysis. Risk of cardiovascular disease is reduced after KTx; however, it is still a leading cause of death in this patient population. Thus, we aimed to investigate whether functional properties of the vasculature differed two years post-KTx (postKTx) compared to baseline (time of KTx). Using the EndoPAT device in 27 CKD patients undergoing living-donor KTx, we found that vessel stiffness significantly improved while endothelial function worsened postKTx vs. baseline. Furthermore, baseline serum indoxyl sulphate (IS), but not p-cresyl sulphate, was independently negatively associated with reactive hyperemia index, a marker of endothelial function, and independently positively associated with P-selectin postKTx. Finally, to better understand the functional effects of IS in vessels, we incubated human resistance arteries with IS overnight and performed wire myography experiments ex vivo. IS-incubated arteries showed reduced bradykinin-mediated endothelium-dependent relaxation compared to controls via reduced nitric oxide (NO) contribution. Endothelium-independent relaxation in response to NO donor sodium nitroprusside was similar between IS and control groups. Together, our data suggest that IS promotes worsened endothelial dysfunction postKTx, which may contribute to the sustained CVD risk.
Localization and Characterization of Major Neurogenic Niches in the Brain of the Lesser-Spotted Dogfish Scyliorhinus canicula
Authors: Bagnoli Sara , Chiavacci Elena , Cellerino Alessandro , Terzibasi Tozzini Eva
Published: February 2023

Adult neurogenesis is defined as the ability of specialized cells in the postnatal brain to produce new functional neurons and to integrate them into the already-established neuronal network. This phenomenon is common in all vertebrates and has been found to be extremely relevant for numerous processes, such as long-term memory, learning, and anxiety responses, and it has been also found to be involved in neurodegenerative and psychiatric disorders. Adult neurogenesis has been studied extensively in many vertebrate models, from fish to human, and observed also in the more basal cartilaginous fish, such as the lesser-spotted dogfish, Scyliorhinus canicula, but a detailed description of neurogenic niches in this animal is, to date, limited to the telencephalic areas. With this article, we aim to extend the characterization of the neurogenic niches of S. canicula in other main areas of the brain: we analyzed via double immunofluorescence sections of telencephalon, optic tectum, and cerebellum with markers of proliferation (PCNA) and mitosis (pH3) in conjunction with glial cell (S100β) and stem cell (Msi1) markers, to identify the actively proliferating cells inside the neurogenic niches. We also labeled adult postmitotic neurons (NeuN) to exclude double labeling with actively proliferating cells (PCNA). Lastly, we observed the presence of the autofluorescent aging marker, lipofuscin, contained inside lysosomes in neurogenic areas.
Isosinensetin Stimulates Glucagon-like Peptide-1 Secretion via Activation of hTAS2R50 and the Gβγ-Mediated Signaling Pathway
Authors: Lee Seung-Hyeon , Ko Hyun Min , Jee Wona , Kim Hyungsuk , Chung Won-Seok , Jang Hyeung-Jin
Published: February 2023

Bitter taste receptors (TAS2Rs) are G protein-coupled receptors localized in the taste buds of the tongue. They may also be present in non-lingual organs, including the brain, lung, kidney, and gastrointestinal (GI) tract. Recent studies on bitter taste receptor functions have suggested TAS2Rs as potential therapeutic targets. The human bitter taste receptor subtype hTAS2R50 responds to its agonist isosinensetin (ISS). Here, we demonstrated that, unlike other TAS2R agonists, isosinensetin activated hTAS2R50 as well as increased Glucagon-like peptide 1 (GLP-1) secretion through the Gβγ-mediated pathway in NCI-H716 cells. To confirm this mechanism, we showed that ISS increased intracellular Ca2+ and was suppressed by the IP3R inhibitor 2-APB as well as the PLC inhibitor U73122, suggesting that TAS2Rs alters the physiological state of enteroendocrine L cells in a PLC-dependent manner. Furthermore, we demonstrated that ISS upregulated proglucagon mRNA and stimulated GLP-1 secretion. ISS-mediated GLP-1 secretion was suppressed in response to small interfering RNA-mediated silencing of Gα-gust and hTAS2R50 as well as 2-APB and U73122. Our findings improved the understanding of how ISS modulates GLP-1 secretion and indicates the possibility of using ISS as a therapeutic agent in the treatment of diabetes mellitus.
Genome-Wide Identification of the ERF Transcription Factor Family for Structure Analysis, Expression Pattern, and Response to Drought Stress in Populus alba × Populus glandulosa
Authors: Zeng Dong , Dai Li-Juan , Li Xiang , Li Wei , Qu Guan-Zheng , Li Shuang
Published: February 2023

The Ethylene Responsive Factor (ERF) transcription factor family is important for regulating plant growth and stress responses. Although the expression patterns of ERF family members have been reported in many plant species, their role in Populus alba × Populus glandulosa, an important model plant for forest research, remains unclear. In this study, we identified 209 PagERF transcription factors by analyzing the P. alba × P. glandulosa genome. We analyzed their amino acid sequences, molecular weight, theoretical pI (Isoelectric point), instability index, aliphatic index, grand average of hydropathicity, and subcellular localization. Most PagERFs were predicted to localize in the nucleus, with only a few PagERFs localized in the cytoplasm and nucleus. Phylogenetic analysis divided the PagERF proteins into ten groups, Class I to X, with those belonging to the same group containing similar motifs. Cis-acting elements associated with plant hormones, abiotic stress responses, and MYB binding sites were analyzed in the promoters of PagERF genes. We used transcriptome data to analyze the expression patterns of PagERF genes in different tissues of P. alba × P. glandulosa, including axillary buds, young leaves, functional leaves, cambium, xylem, and roots, and the results indicated that PagERF genes are expressed in all tissues of P. alba × P. glandulosa, especially in roots. Quantitative verification results were consistent with transcriptome data. When P. alba × P. glandulosa seedlings were treated with 6% polyethylene glycol 6000 (PEG6000), the results of RT-qRCR showed that nine PagERF genes responded to drought stress in various tissues. This study provides a new perspective on the roles of PagERF family members in regulating plant growth and development, and responses to stress in P. alba × P. glandulosa. Our study provides a theoretical basis for ERF family research in the future.
Progress in Discovering Transcriptional Noise in Aging
Authors: Bartz Josh , Jung Hannim , Wasiluk Karen , Zhang Lei , Dong Xiao
Published: February 2023

Increasing stochasticity is a key feature in the aging process. At the molecular level, in addition to genome instability, a well-recognized hallmark of aging, cell-to-cell variation in gene expression was first identified in mouse hearts. With the technological breakthrough in single-cell RNA sequencing, most studies performed in recent years have demonstrated a positive correlation between cell-to-cell variation and age in human pancreatic cells, as well as mouse lymphocytes, lung cells, and muscle stem cells during senescence in vitro. This phenomenon is known as the “transcriptional noise” of aging. In addition to the increasing evidence in experimental observations, progress also has been made to better define transcriptional noise. Traditionally, transcriptional noise is measured using simple statistical measurements, such as the coefficient of variation, Fano factor, and correlation coefficient. Recently, multiple novel methods have been proposed, e.g., global coordination level analysis, to define transcriptional noise based on network analysis of gene-to-gene coordination. However, remaining challenges include a limited number of wet-lab observations, technical noise in single-cell RNA sequencing, and the lack of a standard and/or optimal data analytical measurement of transcriptional noise. Here, we review the recent technological progress, current knowledge, and challenges to better understand transcriptional noise in aging.
Impairment of Endogenous Synthesis of Omega-3 DHA Exacerbates T-Cell Inflammatory Responses
Authors: Talamonti Emanuela , Jacobsson Anders , Chiurchiù Valerio
Published: February 2023

Omega-3 (ω-3) polyunsaturated fatty acids, including docosahexaenoic acid (DHA), are involved in numerous biological processes and have a range of health benefits. DHA is obtained through the action of elongases (ELOVLs) and desaturases, among which Elovl2 is the key enzyme involved in its synthesis, and can be further metabolized into several mediators that regulate the resolution of inflammation. Our group has recently reported that ELOVL2 deficient mice (Elovl2−/−) not only display reduced DHA levels in several tissues, but they also have higher pro-inflammatory responses in the brain, including the activation of innate immune cells such as macrophages. However, whether impaired synthesis of DHA affects cells of adaptive immunity, i.e., T lymphocytes, is unexplored. Here we show that Elovl2−/− mice have significantly higher lymphocytes in peripheral blood and that both CD8+ and CD4+ T cell subsets produce greater amounts of pro-inflammatory cytokines in both blood and spleen compared to wild type mice, with a higher percentage of cytotoxic CD8+ T cells (CTLs) as well as IFN-γ-producing Th1 and IL-17-producing Th17 CD4+ cells. Furthermore, we also found that DHA deficiency impacts the cross-talk between dendritic cells (DC) and T cells, inasmuch as mature DCs of Elovl2−/− mice bear higher expression of activation markers (CD80, CD86 and MHC-II) and enhance the polarization of Th1 and Th17 cells. Reintroducing DHA back into the diets of Elovl2−/− mice reversed the exacerbated immune responses observed in T cells. Hence, impairment of endogenous synthesis of DHA exacerbates T cell inflammatory responses, accounting for an important role of DHA in regulating adaptive immunity and in potentially counteracting T-cell-mediated chronic inflammation or autoimmunity.
HER2 Expression in Bladder Cancer: A Focused View on Its Diagnostic, Prognostic, and Predictive Role
Authors: Sanguedolce Francesca , Zanelli Magda , Palicelli Andrea , Bisagni Alessandra , Zizzo Maurizio , Ascani Stefano , Pedicillo Maria Carmela , Cormio Angelo , Falagario Ugo Giovanni , Carrieri Giuseppe , Cormio Luigi
Published: February 2023

Bladder cancer (BC) is a heterogeneous disease from a molecular, morphological, and clinical standpoint. HER2 is a known oncogene involved in bladder carcinogenesis. Assessing HER2 overexpression as a result of its molecular changes in a routine pathology practice using immunohistochemistry might be a useful adjunct in several scenarios, namely (1) to correctly identify flat urothelial lesions and inverted urothelial lesions in the diagnostic setting; (2) to provide prognostic hints in both non-muscle invasive (NMI) and muscle invasive (MI) tumors, thus supplementing risk stratification tools, especially when evaluating higher-risk tumors such as those with variant morphology; (3) to improve antibody panels as a surrogate marker of BC molecular subtyping. Furthermore, the potential of HER2 as a therapeutic target has been only partly explored so far, in light of the ongoing development of novel target therapies.
An Insight into the Combined Toxicity of 3,4-Dichloroaniline with Two-Dimensional Nanomaterials: From Classical Mixture Theory to Structure-Activity Relationship
Authors: Wang Zhuang , Yu Le
Published: February 2023

The assessment and prediction of the toxicity of engineered nanomaterials (NMs) present in mixtures is a challenging research issue. Herein, the toxicity of three advanced two-dimensional nanomaterials (TDNMs), in combination with an organic chemical (3,4-dichloroaniline, DCA) to two freshwater microalgae (Scenedesmus obliquus and Chlorella pyrenoidosa), was assessed and predicted not only from classical mixture theory but also from structure-activity relationships. The TDNMs included two layered double hydroxides (Mg-Al-LDH and Zn-Al-LDH) and a graphene nanoplatelet (GNP). The toxicity of DCA varied with the type and concentration of TDNMs, as well as the species. The combination of DCA and TDNMs exhibited additive, antagonistic, and synergistic effects. There is a linear relationship between the different levels (10, 50, and 90%) of effect concentrations and a Freundlich adsorption coefficient (KF) calculated by isotherm models and adsorption energy (Ea) obtained in molecular simulations, respectively. The prediction model incorporating both parameters KF and Ea had a higher predictive power for the combined toxicity than the classical mixture model. Our findings provide new insights for the development of strategies aimed at evaluating the ecotoxicological risk of NMs towards combined pollution situations.
Three Starch Synthase IIa (SSIIa) Alleles Reveal the Effect of SSIIa on the Thermal and Rheological Properties, Viscoelasticity, and Eating Quality of Glutinous Rice
Authors: Nakano Tsukine , Crofts Naoko , Miura Satoko , Oitome Naoko F. , Hosaka Yuko , Ishikawa Kyoko , Fujita Naoko
Published: February 2023

Glutinous rice accumulates amylose-free starch and is utilized for rice cakes and crackers, owing to the loss of the Waxy gene which encodes granule-bound starch synthase I (GBSSI). Starch synthase IIa (SSIIa) elongates amylopectin chains with a degree of polymerization (DP) of 6–12 to 13–24 and greatly influences starch properties. To elucidate the relationship between the branch length of amylopectin and the thermal and rheological properties, viscoelasticity, and eating quality of glutinous rice, three allelic near isogenic lines with high, low, or no SSIIa activity were generated (designated as SS2a wx, ss2aL wx, and ss2a wx, respectively). Chain length distribution analyses revealed that ss2a wx exhibited the highest short chain (DP < 12) number and lowest gelatinization temperature, whereas SS2a wx showed the opposite results. Gel filtration chromatography showed that the three lines contained essentially no amylose. Viscoelasticity analyses of rice cakes stored at low temperature for different durations revealed that ss2a wx maintained softness and elasticity for up to 6 days, while SS2a wx hardened within 6 h. Sensory evaluation was consistent with mechanical evaluation. The relationship of amylopectin structure with the thermal and rheological properties, viscoelasticity, and eating quality of glutinous rice is discussed.
Structural Insight into Catalysis by the Flavin-Dependent NADH Oxidase (Pden_5119) of Paracoccus denitrificans
Authors: Kryl Martin , Sedláček Vojtěch , Kučera Igor
Published: February 2023

The Pden_5119 protein oxidizes NADH with oxygen under mediation by the bound flavin mononucleotide (FMN) and may be involved in the maintenance of the cellular redox pool. In biochemical characterization, the curve of the pH-rate dependence was bell-shaped with pKa1 = 6.6 and pKa2 = 9.2 at 2 μM FMN while it contained only a descending limb pKa of 9.7 at 50 μM FMN. The enzyme was found to undergo inactivation by reagents reactive with histidine, lysine, tyrosine, and arginine. In the first three cases, FMN exerted a protective effect against the inactivation. X-ray structural analysis coupled with site-directed mutagenesis identified three amino acid residues important to the catalysis. Structural and kinetic data suggest that His-117 plays a role in the binding and positioning of the isoalloxazine ring of FMN, Lys-82 fixes the nicotinamide ring of NADH to support the proS-hydride transfer, and Arg-116 with its positive charge promotes the reaction between dioxygen and reduced flavin.
Transcriptome Mechanisms of Tomato Seedlings Induced by Low-Red to Far-Red Light Ratio under Calcium Nitrate Stress
Authors: Zhou Xiaoting , Huang Jia , Gan Yirong , Li Zelin , Su Lihong , He Zhongqun , Yang Junwei , Wang Zhihui , Jiang Chengyao , Huang Zhi , Lu Wei , Zheng Wangang
Published: February 2023

In recent times, the excessive accumulation of nitrate has been one of the main reasons for the secondary salinization of greenhouse soils. Light plays a key role in a plant’s growth, development, and response to stress. A low-red to far-red (R:FR) light ratio could enhance plant salinity tolerance, but the mechanism at a molecular level is unclear. Thus, we analyzed the transcriptome responses of tomato seedlings to calcium nitrate stress under either a low R:FR ratio (0.7) or normal light conditions. Under calcium nitrate stress, a low R:FR ratio enhanced both the antioxidant defense system and the rapid physiological accumulation of proline in tomato leaves, which promoted plant adaptability. Using weighted gene co-expression network analysis (WGCNA), three modules including 368 differentially expressed genes (DEGs) were determined to be significantly associated with these plant traits. Functional annotations showed that the responses of these DEGs to a low R:FR ratio under excessive nitrate stress were enriched in the areas of hormone signal transduction, amino acid biosynthesis, sulfide metabolism, and oxidoreductase activity. Furthermore, we identified important novel hub genes encoding certain proteins, including FBNs, SULTRs, and GATA-like transcription factor, which may play a vital role in low R:FR light-induced salt responses. These findings offer a new perspective on the mechanisms and environmental implications behind low R:FR ratio light-modulated tomato saline tolerance.
A Three-Dimensional Xeno-Free Culture Condition for Wharton’s Jelly-Mesenchymal Stem Cells: The Pros and Cons
Authors: Koh Benson , Sulaiman Nadiah , Fauzi Mh Busra , Law Jia Xian , Ng Min Hwei , Yuan Too Lih , Azurah Abdul Ghani Nur , Mohd Yunus Mohd Heikal , Idrus Ruszymah Bt Hj , Yazid Muhammad Dain
Published: February 2023

Xeno-free three-dimensional cultures are gaining attention for mesenchymal stem cell (MSCs) expansion in clinical applications. We investigated the potential of xeno-free serum alternatives, human serum and human platelet lysate, to replace the current conventional use of foetal bovine serum for subsequent MSCs microcarrier cultures. In this study, Wharton’s Jelly MSCs were cultured in nine different media combinations to identify the best xeno-free culture media for MSCs culture. Cell proliferation and viability were identified, and the cultured MSCs were characterised in accordance with the minimal criteria for defining multipotent mesenchymal stromal cells by the International Society for Cellular Therapy (ISCT). The selected culture media was then used in the microcarrier culture of MSCs to determine the potential of a three-dimensional culture system in the expansion of MSCs for future clinical applications, and to identify the immunomodulatory potential of cultured MSCs. Low Glucose DMEM (LG) + Human Platelet (HPL) lysate media appeared to be good candidates for replacing conventional MSCs culture media in our monolayer culture system. MSCs cultured in LG-HPL achieved high cell yield, with characteristics that remained as described by ISCT, although the overall mitochondrial activity of the cells was lower than the control and the subsequent effects remained unknown. MSC microcarrier culture, on the other hand, showed comparable cell characteristics with monolayer culture, yet had stagnated cell proliferation, which is potentially due to the inactivation of FAK. Nonetheless, both the MSCs monolayer culture and the microcarrier culture showed high suppressive activity on TNF-α, and only the MSC microcarrier culture has a better suppression of IL-1 secretion. In conclusion, LG-HPL was identified as a good xeno-free media for WJMSCs culture, and although further mechanistic research is needed, the results show that the xeno-free three-dimensional culture maintained MSC characteristics and improved immunomodulatory activities, suggesting the potential of translating the monolayer culture into this culture system in MSC expansion for future clinical application.
Market Analysis with Business Intelligence System for Marketing Planning
Authors: Kongthanasuwan Treerak , Sriwiboon Nakarin , Horbanluekit Banpot , Laesanklang Wasakorn , Krityakierne Tipaluck
Published: February 2023

The automotive and auto parts industries are important economic sectors in Thailand. With rapidly changing technology, every organization should understand what needs to be improved clearly, and shift their strategies to meet evolving consumer demands. The purpose of this research is to develop a Business Intelligence system for a brake pad manufacturing company in Thailand. By analyzing the relationship between market demand and supply components of the company through regression analysis and the principles of the marketing mix, we develop a product lifecycle curve for forecasting product sales. The developed system increases the workflow efficiency of the case study company, being able to simplify the traditional data preparation process that requires employees to collect and summarize data every time a request is made. An intelligence dashboard is subsequently created to help support decision-making, facilitate communication within the company, and eventually improve team efficiency and productivity.