bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of Efflux Pumps on Antimicrobial Resistance in Pseudomonas aeruginosa
Authors: Lorusso Andre Bittencourt , Carrara João Antônio , Barroso Carolina Deuttner Neumann , Tuon Felipe Francisco , Faoro Helisson
Published: December 2022

Antimicrobial resistance is an old and silent pandemic. Resistant organisms emerge in parallel with new antibiotics, leading to a major global public health crisis over time. Antibiotic resistance may be due to different mechanisms and against different classes of drugs. These mechanisms are usually found in the same organism, giving rise to multidrug-resistant (MDR) and extensively drug-resistant (XDR) bacteria. One resistance mechanism that is closely associated with the emergence of MDR and XDR bacteria is the efflux of drugs since the same pump can transport different classes of drugs. In Gram-negative bacteria, efflux pumps are present in two configurations: a transmembrane protein anchored in the inner membrane and a complex formed by three proteins. The tripartite complex has a transmembrane protein present in the inner membrane, a periplasmic protein, and a porin associated with the outer membrane. In Pseudomonas aeruginosa, one of the main pathogens associated with respiratory tract infections, four main sets of efflux pumps have been associated with antibiotic resistance: MexAB-OprM, MexXY, MexCD-OprJ, and MexEF-OprN. In this review, the function, structure, and regulation of these efflux pumps in P. aeruginosa and their actions as resistance mechanisms are discussed. Finally, a brief discussion on the potential of efflux pumps in P. aeruginosa as a target for new drugs is presented.
Developmental Changes of Immunity and Different Responses to Weaning Stress of Chinese Indigenous Piglets and Duroc Piglets during Suckling and Weaning Periods
Authors: Ding Sujuan , Cheng Yating , Azad Md. Abul Kalam , Zhu Qian , Huang Pan , Kong Xiangfeng
Published: December 2022

To investigate developmental changes in immunity and different responses to weaning stress of piglets from different breeds during suckling and weaning periods, a total of 30 litters of Taoyuan black (TB) piglets, Xiangcun black (XB) piglets, and Duroc (DR) piglets (ten litters per breed) were selected at 1, 10, 21, and 24 days of age, respectively. The results showed that the liver index of TB piglets was higher at 10 days of age than that of the other days of age and breeds. Regardless of the days of age, TB and XB piglets had a higher plasma IgA level and lower ileal IgM level than in the DR piglets, and XB piglets had a lower plasma IgG level than the other breeds. TB and XB piglets had a higher IL-6 level and lower IL-17 level in plasma at 24 days of age than DR piglets, regardless of the days of age. The ileal levels of IL-2, IL-10, IFN-γ, and TNF-α were lower in the TB and XB piglets at 24 days of age than in the DR piglets. The ileal expression levels of IRAK1, CD14, MyD88, and NF-κB were down-regulated in the TB and XB piglets at 24 days of age compared to those in the DR piglets. These findings suggest that there were differences in the development of immune function among different pig breeds. Moreover, TB and XB piglets presented stronger resistance to weaning stress than the DR piglets, which may be related to the immune regulation mediated by the MyD88/NF-κB signaling pathway.
Transcription Factors STAT3 and MYC Are Key Players of Human Platelet Lysate-Induced Cell Proliferation
Authors: Oeller Michaela , Jaksch-Bogensperger Heidi , Templin Markus , Gehwolf Renate , Rohde Eva , Schallmoser Katharina , Laner-Plamberger Sandra
Published: December 2022

Human platelet lysate (HPL) is an efficient alternative for animal serum supplements, significantly enhancing stromal cell proliferation. However, the molecular mechanism behind this growth-promoting effect remains elusive. The aim of this study was to investigate the effect of HPL on cell cycle gene expression in different human stromal cells and to identify the main key players that mediate HPL’s growth-enhancing effect. RT-qPCR and an antibody array revealed significant upregulation of cell cycle genes in stromal cells cultured in HPL. As HPL is rich in growth factors that are ligands of tyrosine kinase receptor (TKR) pathways, we used TKR inhibitors and could significantly reduce cell proliferation. Genome profiling, RT-qPCR and Western blotting revealed an enhanced expression of the transcription factors signal transducer and activator of transcription 3 (STAT3) and MYC, both known TKR downstream effectors and stimulators of cell proliferation, in response to HPL. In addition, specifically blocking STAT3 resulted in reduced cell proliferation and expression of cell cycle genes. Our data indicate that HPL-enhanced cell proliferation can, at least in part, be explained by the TKR-enhanced expression of STAT3 and MYC, which in turn induce the expression of genes being involved in the promotion and control of the cell cycle.
Neural Stem Cells Overexpressing Arginine Decarboxylase Improve Functional Recovery from Spinal Cord Injury in a Mouse Model
Authors: Park Yu Mi , Kim Jae Hwan , Lee Jong Eun
Published: December 2022

Current therapeutic strategies for spinal cord injury (SCI) cannot fully facilitate neural regeneration or improve function. Arginine decarboxylase (ADC) synthesizes agmatine, an endogenous primary amine with neuroprotective effects. Transfection of human ADC (hADC) gene exerts protective effects after injury in murine brain-derived neural precursor cells (mNPCs). Following from these findings, we investigated the effects of hADC-mNPC transplantation in SCI model mice. Mice with experimentally damaged spinal cords were divided into three groups, separately transplanted with fluorescently labeled (1) control mNPCs, (2) retroviral vector (pLXSN)-infected mNPCs (pLXSN-mNPCs), and (3) hADC-mNPCs. Behavioral comparisons between groups were conducted weekly up to 6 weeks after SCI, and urine volume was measured up to 2 weeks after SCI. A subset of animals was euthanized each week after cell transplantation for molecular and histological analyses. The transplantation groups experienced significantly improved behavioral function, with the best recovery occurring in hADC-mNPC mice. Transplanting hADC-mNPCs improved neurological outcomes, induced oligodendrocyte differentiation and remyelination, increased neural lineage differentiation, and decreased glial scar formation. Moreover, locomotor and bladder function were both rehabilitated. These beneficial effects are likely related to differential BMP-2/4/7 expression in neuronal cells, providing an empirical basis for gene therapy as a curative SCI treatment option.
Hyperpolarization Induced by Lipopolysaccharides but Not by Chloroform Is Inhibited by Doxapram, an Inhibitor of Two-P-Domain K+ Channel (K2P)
Authors: Cooper Robin L. , Krall Rebecca M.
Published: December 2022

Bacterial septicemia is commonly induced by Gram-negative bacteria. The immune response is triggered in part by the secretion of bacterial endotoxin lipopolysaccharide (LPS). LPS induces the subsequent release of inflammatory cytokines which can result in pathological conditions. There is no known blocker to the receptors of LPS. The Drosophila larval muscle is an amendable model to rapidly screen various compounds that affect membrane potential and synaptic transmission such as LPS. LPS induces a rapid hyperpolarization in the body wall muscles and depolarization of motor neurons. These actions are blocked by the compound doxapram (10 mM), which is known to inhibit a subtype of the two-P-domain K+ channel (K2P channels). However, the K2P channel blocker PK-THPP had no effect on the Drosophila larval muscle at 1 and 10 mM. These channels are activated by chloroform, which also induces a rapid hyperpolarization of these muscles, but the channels are not blocked by doxapram. Likewise, chloroform does not block the depolarization induced by doxapram. LPS blocks the postsynaptic glutamate receptors on Drosophila muscle. Pre-exposure to doxapram reduces the LPS block of these ionotropic glutamate receptors. Given that the larval Drosophila body wall muscles are depolarized by doxapram and hyperpolarized by chloroform, they offer a model to begin pharmacological profiling of the K2P subtype channels with the potential of identifying blockers for the receptors to mitigate the actions of the Gram-negative endotoxin LPS.
Microporous Biocarbons Derived from Inonotus obliquus Mushroom and Their Application in the Removal of Liquid and Gaseous Impurities
Authors: Bazan-Wozniak Aleksandra , Cielecka-Piontek Judyta , Nosal-Wiercińska Agnieszka , Pietrzak Robert
Published: December 2022

Biocarbons were obtained by physical and chemical activation of the residue of the extraction of chaga fungi (Inonotus obliquus). The residue was subjected to heat treatment carried out in a microwave oven and in a quartz tubular reactor. The materials were characterized by elemental analysis, low-temperature nitrogen adsorption, determination of pH, and the contents of acidic and basic oxygen functional groups on the surface of biocarbons by the Boehm method. The final biocarbon adsorbents have surface areas varying from 521–1004 m2/g. The physical activation of the precursor led to a strongly basic character of the surface. Chemical activation of Inonotus obliquus promoted the generation of acid functional groups. All biocarbons were used for methyl red sodium salt adsorption from the liquid phase. The sorption capacities of biocarbons towards the organic dye studied varied from 77 to 158 mg/g. The Langmuir model was found to better describe the experimental results. The results of the kinetic analysis showed that the adsorption of methyl red sodium salt on the biocarbons followed the pseudo-second-order model. The acidic environment was conducive to the adsorption of the dye on the obtained biocarbons. Moreover, thermodynamic studies confirmed that the organic dye adsorption on the biocarbons was a spontaneous endothermic process. The biocarbons obtained were also tested as adsorbents of hydrogen sulfide in dry and wet conditions. The sorption capacities towards hydrogen sulfide varied in the range of 21.9–77.9 mg. The results have shown that the adsorption of hydrogen sulfide depends on the process conditions and the activation procedure of biocarbons (method of activation and thermochemical treatment of samples). It has been shown that the initial material used can be a new precursor for obtaining cheap and—more importantly—universal bioadsorbents characterized by high effectiveness in the removal of air and water pollutants.
Clinical Impact of Next-Generation Sequencing Multi-Gene Panel Highlighting the Landscape of Germline Alterations in Ovarian Cancer Patients
Authors: Gurioli Giorgia , Tedaldi Gianluca , Farolfi Alberto , Petracci Elisabetta , Casanova Claudia , Comerci Giuseppe , Danesi Rita , Arcangeli Valentina , Ravegnani Mila , Calistri Daniele , Zampiga Valentina , Cangini Ilaria , Fonzi Eugenio , Virga Alessandra , Tassinari Davide , Rosati Marta , Ulivi Paola , De Giorgi Ugo
Published: December 2022

BRCA1 and BRCA2 are the most frequently mutated genes in ovarian cancer (OC) crucial both for the identification of cancer predisposition and therapeutic choices. However, germline variants in other genes could be involved in OC susceptibility. We characterized OC patients to detect mutations in genes other than BRCA1/2 that could be associated with a high risk of developing OC and permit patients to enter the most appropriate treatment and surveillance program. Next-generation sequencing analysis with a 94-gene panel was performed on germline DNA of 219 OC patients. We identified 34 pathogenic/likely pathogenic variants in BRCA1/2 and 38 in other 21 genes. The patients with pathogenic/likely pathogenic variants in the non-BRCA1/2 genes mainly developed OC alone compared to the other groups that also developed breast cancer or other tumors (p = 0.001). Clinical correlation analysis showed that the low-risk patients were significantly associated with platinum sensitivity (p < 0.001). Regarding PARP inhibitors (PARPi) response, the patients with pathogenic mutations in the non-BRCA1/2 genes had worse PFS and OS. Moreover, a statistically significantly worse PFS was found for every increase of one thousand platelets before PARPi treatment. To conclude, knowledge about molecular alterations in genes beyond BRCA1/2 in OC could allow for more personalized diagnostic, predictive, prognostic, and therapeutic strategies for OC patients.
Genetic and Diet-Induced Animal Models for Non-Alcoholic Fatty Liver Disease (NAFLD) Research
Authors: Flessa Christina-Maria , Nasiri-Ansari Narjes , Kyrou Ioannis , Leca Bianca M. , Lianou Maria , Chatzigeorgiou Antonios , Kaltsas Gregory , Kassi Eva , Randeva Harpal S.
Published: December 2022

A rapidly increasing incidence of non-alcoholic fatty liver disease (NAFLD) is noted worldwide due to the adoption of western-type lifestyles and eating habits. This makes the understanding of the molecular mechanisms that drive the pathogenesis of this chronic disease and the development of newly approved treatments of utmost necessity. Animal models are indispensable tools for achieving these ends. Although the ideal mouse model for human NAFLD does not exist yet, several models have arisen with the combination of dietary interventions, genetic manipulations and/or administration of chemical substances. Herein, we present the most common mouse models used in the research of NAFLD, either for the whole disease spectrum or for a particular disease stage (e.g., non-alcoholic steatohepatitis). We also discuss the advantages and disadvantages of each model, along with the challenges facing the researchers who aim to develop and use animal models for translational research in NAFLD. Based on these characteristics and the specific study aims/needs, researchers should select the most appropriate model with caution when translating results from animal to human.
Apoptosis Evaluation in Circulating CD34+-Enriched Hematopoietic Stem and Progenitor Cells in Patients with Abnormally Increased Production of Endogenous Glucocorticoids in Course of Cushing’s Syndrome
Authors: Kawa Miłosz P. , Sobuś Anna , Pius-Sadowska Ewa , Łuczkowska Karolina , Rogińska Dorota , Wnęk Szymon , Paczkowska Edyta , Walczak Mieczysław , Syrenicz Anhelli , Machaliński Bogusław
Published: December 2022

Abnormalities in hematological parameters of peripheral blood have been noted in patients with endogenous Cushing’s Syndrome (CS) in the corticotropin (ACTH)-dependent and ACTH-independent forms. Nevertheless, the exact mechanism of glucocorticoids (GCs) action on human hematopoiesis is still not entirely clear. The aim of the study was to determine whether endogenous excessive production of GCs could affect apoptosis of CD34+ cells enriched in hematopoietic stem and progenitor cells (HSPCs) collected from the peripheral blood of newly diagnosed CS patients. Flow cytometry, Annexin-V enzyme-linked immunosorbent assay, TUNEL assay, real-time quantitative PCR, and microarray RNA/miRNA techniques were used to characterize CS patients’ HSPCs. We found that the glucocorticoid receptor (GR) protein expression levels in CS were higher than in healthy controls. A complex analysis of apoptotic status of CS patients’ HSPC cells showed that GCs significantly augmented apoptosis in peripheral blood-derived CD34+ cells and results obtained using different methods to detect early and late apoptosis in analyzed cell population were consistent. CS was also associated with significant upregulation in several members of the BCL-2 superfamily and other genes associated with apoptosis control. Furthermore, global gene expression analysis revealed significantly higher expression of genes associated with programmed cell death control in HSPCs from CS patients. These findings suggest that human endogenous GCs have a direct pro-apoptotic activity in hematopoietic CD34+ cells derived from CS subjects before treatment.
Investigations with Drugs and Pesticides Revealed New Species- and Substrate-Dependent Inhibition by Elacridar and Imazalil in Human and Mouse Organic Cation Transporter OCT2
Authors: Kuehne Annett , Floerl Saskia , Hagos Yohannes
Published: December 2022

Multiple drugs are used to treat various indications as well as pesticides that are ingested unintentionally and enter the bloodstream. The residence time or bioavailability of these substances in circulation depends on several mechanisms, such as drug–drug interaction (DDI), drug–pesticide interaction, metabolizing enzymes and the hepatic and renal transport systems, involved in the elimination of the compounds from the body. One of these transporters is the Organic Cation Transporter 2 (OCT2) member of the solute carrier (SLC22) transporter family. OCT2 is highly expressed in the proximal tubule epithelial cells in human and mouse kidney, where it mediates the uptake of endogenous organic cations as well as numerous drugs and xenobiotics, and contributes to the first step of renal clearance. In this study, we examined OCT2 on two subjects: First, the transferability of data from mouse to human, since mice are initially examined in the development of new drugs to assess the renal excretion of organic cations. Second, to what extent the choice of substrate affects the properties of an inhibitor. For this purpose, the functional properties of hOCT2 and mOct2 were validated under the same experimental conditions with the known substrates metformin and 1-Methyl-4-phenylpyridinium iodide (MPP). While hOCT2 and mOct2 showed very low affinities for metformin with Km values of 3.9 mM and 3.5 mM, the affinity of hOCT2 and mOct2 for MPP (62 and 40 µM) was 64- and 89-fold higher, respectively. For our positive control inhibitor decynium22, we determined the following IC50 values for hOCT2 and mOct2: 2.2 and 2.6 µM for metformin uptake, and 16 and 6.9 µM for MPP uptake. A correlation analysis of the inhibitory effects of 13 drugs and 9 pesticides on hOCT2- and mOct2-mediated transport of metformin showed a correlation coefficient R2 of 0.88, indicating good interspecies correlation. Nevertheless, the bioenhancer elacridar and the fungicide imazalil showed species-dependent inhibitory potentials. Concentration-dependent inhibition of hOCT2- and mOct2-mediated metformin uptake by elacridar showed IC50 values of 20 µM and 1.9 µM and by imazalil 4.7 µM and 0.58 µM, respectively. In conclusion, although our data show comparable species-independent interactions for most compounds, there can be large species–specific differences in the interactions of individual compounds, which should be considered when extrapolating data from mice to humans. Furthermore, a comparison of the inhibitory potential of elacridar and imazalil on metformin uptake with that on MPP uptake reveals substrate-dependent differences in hOCT2 and mOct2 for both inhibitors. Therefore, it might be useful to test two different substrates in inhibition studies.
The Role of ABA in the Interaction between Citrus Fruit and Penicillium digitatum
Authors: Lafuente María T. , González-Candelas Luis
Published: December 2022

Abscisic acid (ABA) protects citrus fruit against Penicillium digitatum infection. The global mechanisms involved in the role of ABA in the P. digitatum–citrus fruit interaction are unknown. Here, we determine the transcriptome differences between the Navelate (Citrus sinensis (L.) Osbeck) orange and its ABA-deficient mutant Pinalate, which is less resistant to infection. Low ABA levels may affect both the constitutive mechanisms that protect citrus fruit against P. digitatum and early responses to infection. The repression of terpenoid, phenylpropanoid and glutation metabolism; of oxidation–reduction processes; and of processes related to the defense response to fungus and plant hormone signal transduction may be one part of the constitutive defense reduced in the mutant against P. digitatum. Our results also provide potential targets for developing P. digitatum-citrus fruit-resistant varieties. Of those up-regulated by ABA, a thaumatin protein and a bifunctional inhibitor/LTP, which are relevant in plant immunity, were particularly remarkable. It is also worth highlighting chlorophyllase 1 (CLH1), induced by infection in Pinalate, and the OXS3 gene, which was down-regulated by ABA, because the absence of OXS3 activates ABA-responsive genes in plants.
The New General Biological Property of Stem-like Tumor Cells (Part II: Surface Molecules, Which Belongs to Distinctive Groups with Particular Functions, Form a Unique Pattern Characteristic of a Certain Type of Tumor Stem-like Cells)
Authors: Petrova Daria D. , Dolgova Evgeniya V. , Proskurina Anastasia S. , Ritter Genrikh S. , Ruzanova Vera S. , Efremov Yaroslav R. , Potter Ekaterina A. , Kirikovich Svetlana S. , Levites Evgeniy V. , Taranov Oleg S. , Ostanin Alexandr A. , Chernykh Elena R. , Kolchanov Nikolay A. , Bogachev Sergey S.
Published: December 2022

An ability of poorly differentiated cells of different genesis, including tumor stem-like cells (TSCs), to internalize extracellular double-stranded DNA (dsDNA) fragments was revealed in our studies. Using the models of Krebs-2 murine ascites carcinoma and EBV-induced human B-cell lymphoma culture, we demonstrated that dsDNA internalization into the cell consists of several mechanistically distinct phases. The primary contact with cell membrane factors is determined by electrostatic interactions. Firm contacts with cell envelope proteins are then formed, followed by internalization into the cell of the complex formed between the factor and the dsDNA probe bound to it. The key binding sites were found to be the heparin-binding domains, which are constituents of various cell surface proteins of TSCs—either the C1q domain, the collagen-binding domain, or domains of positively charged amino acids. These results imply that the interaction between extracellular dsDNA fragments and the cell, as well as their internalization, took place with the involvement of glycocalyx components (proteoglycans/glycoproteins (PGs/GPs) and glycosylphosphatidylinositol-anchored proteins (GPI-APs)) and the system of scavenger receptors (SRs), which are characteristic of TSCs and form functional clusters of cell surface proteins in TSCs. The key provisions of the concept characterizing the principle of organization of the “group-specific” cell surface factors of TSCs of various geneses were formulated. These factors belong to three protein clusters: GPs/PGs, GIP-APs, and SRs. For TSCs of different tumors, these clusters were found to be represented by different members with homotypic functions corresponding to the general function of the cluster to which they belong.
Assessment of Small Cellular Particles from Four Different Natural Sources and Liposomes by Interferometric Light Microscopy
Authors: Romolo Anna , Jan Zala , Bedina Zavec Apolonija , Kisovec Matic , Arrigler Vesna , Spasovski Vesna , Podobnik Marjetka , Iglič Aleš , Pocsfalvi Gabriella , Kogej Ksenija , Kralj-Iglič Veronika
Published: December 2022

Small particles in natural sources are a subject of interest for their potential role in intercellular, inter-organism, and inter-species interactions, but their harvesting and assessment present a challenge due to their small size and transient identity. We applied a recently developed interferometric light microscopy (ILM) to assess the number density and hydrodynamic radius (Rh) of isolated small cellular particles (SCPs) from blood preparations (plasma and washed erythrocytes) (B), spruce needle homogenate (S), suspension of flagellae of microalgae Tetraselmis chuii (T), conditioned culture media of microalgae Phaeodactylum tricornutum (P), and liposomes (L). The aliquots were also assessed by flow cytometry (FCM), dynamic light scattering (DLS), ultraviolet-visible spectrometry (UV-vis), and imaging by cryogenic transmission electron microscopy (cryo-TEM). In Rh, ILM showed agreement with DLS within the measurement error in 10 out of 13 samples and was the only method used here that yielded particle density. Cryo-TEM revealed that representative SCPs from Tetraselmis chuii flagella (T) did not have a globular shape, so the interpretation by Rh of the batch methods was biased. Cryo-TEM showed the presence of thin filaments in isolates from Phaeodactylum tricornutum conditioned culture media (P), which provides an explanation for the considerably larger Rh obtained by batch methods than the sizes of particles observed by cryo-TEM images. ILM proved convenient for assessment of number density and Rh of SCPs in blood preparations (e.g., plasma); therefore, its use in population and clinical studies is indicated.
Untargeted NMR Metabolomics Reveals Alternative Biomarkers and Pathways in Alkaptonuria
Authors: Grasso Daniela , Geminiani Michela , Galderisi Silvia , Iacomelli Gabriella , Peruzzi Luana , Marzocchi Barbara , Santucci Annalisa , Bernini Andrea
Published: December 2022

Alkaptonuria (AKU) is an ultra-rare metabolic disease caused by the accumulation of homogentisic acid (HGA), an intermediate product of phenylalanine and tyrosine degradation. AKU patients carry variants within the gene coding for homogentisate-1,2-dioxygenase (HGD), which are responsible for reducing the enzyme catalytic activity and the consequent accumulation of HGA and formation of a dark pigment called the ochronotic pigment. In individuals with alkaptonuria, ochronotic pigmentation of connective tissues occurs, leading to inflammation, degeneration, and eventually osteoarthritis. The molecular mechanisms underlying the multisystemic development of the disease severity are still not fully understood and are mostly limited to the metabolic pathway segment involving HGA. In this view, untargeted metabolomics of biofluids in metabolic diseases allows the direct investigation of molecular species involved in pathways alterations and their interplay. Here, we present the untargeted metabolomics study of AKU through the nuclear magnetic resonance of urine from a cohort of Italian patients; the study aims to unravel molecular species and mechanisms underlying the AKU metabolic disorder. Dysregulation of metabolic pathways other than the HGD route and new potential biomarkers beyond homogentisate are suggested, contributing to a more comprehensive molecular signature definition for AKU and the development of future adjuvant treatment.
Redox State of Human Serum Albumin in Multiple Sclerosis: A Pilot Study
Authors: Paar Margret , Seifried Katharina , Cvirn Gerhard , Buchmann Arabella , Khalil Michael , Oettl Karl
Published: December 2022

Like in many other pathologies, oxidative stress is involved in the development of neurodegenerative disorders. Human serum albumin (HSA) is the main protein in different body fluids including cerebrospinal fluid (CSF). By its redox state in terms of cysteine-34, albumin serves as marker for oxidative burden. We aimed to evaluate the redox state of HSA in patients with multiple sclerosis in serum and CSF in comparison to controls to identify possible correlations with disease activity and severity. Samples were stored at −70 °C until analysis by HPLC for the determination of albumin redox state in terms of the fractions of human mercaptalbumin (HMA), human nonmercaptalbumin1 (HNA1), and human nonmercaptalbumin2 (HNA2). Albumin in CSF showed significantly higher fractions of the reduced form HMA and decreased HNA1 and HNA2. There was no difference between albumin redox states in serum of patients and controls. In CSF of patients HNA2 showed a trend to higher fractions compared to controls. Albumin redox state in serum was associated with physical disability in remission while albumin redox state in CSF was related to disease activity. Thus, albumin redox state in serum and CSF of patients in relation to disease condition merits further investigation.
Dysbiosis: An Indicator of COVID-19 Severity in Critically Ill Patients
Authors: Cuenca Silvia , Soler Zaida , Serrano-Gómez Gerard , Xie Zixuan , Barquinero Jordi , Roca Joaquim , Sirvent Jose-Maria , Manichanh Chaysavanh
Published: December 2022

Here, we examined the dynamics of the gut and respiratory microbiomes in severe COVID-19 patients in need of mechanical ventilation in the intensive care unit (ICU). We recruited 85 critically ill patients (53 with COVID-19 and 32 without COVID-19) and 17 healthy controls (HCs) and monitored them for up to 4 weeks. We analyzed the bacterial and fungal taxonomic profiles and loads of 232 gut and respiratory samples and we measured the blood levels of Interleukin 6, IgG, and IgM in COVID-19 patients. Upon ICU admission, the bacterial composition and load in the gut and respiratory samples were altered in critically ill patients compared with HCs. During their ICU stay, the patients experienced increased bacterial and fungal loads, drastic decreased bacterial richness, and progressive changes in bacterial and fungal taxonomic profiles. In the gut samples, six bacterial taxa could discriminate ICU-COV(+) from ICU-COV(−) cases upon ICU admission and the bacterial taxa were associated according to age, PaO2/FiO2, and CRP levels. In the respiratory samples of the ICU-COV(+) patients, bacterial signatures including Pseudomonas and Streptococcus were found to be correlated with the length of ICU stay. Our findings demonstrated that the gut and respiratory microbiome dysbiosis and bacterial signatures associated with critical illness emerged as biomarkers of COVID-19 severity and could be a potential predictor of ICU length of stay. We propose using a high-throughput sequencing approach as an alternative to traditional isolation techniques to monitor ICU patient infection.
Mechanism Underlying Naringenin Hypocholesterolemic Effects: Involvement of Estrogen Receptor α Subtype
Authors: Pallottini Valentina , Segatto Marco , Acconcia Filippo , Fiocchetti Marco , Marino Maria
Published: December 2022

Naringenin (Nar) is one of major citrus flavonoids predominantly found in grapefruit and orange. In vivo studies have demonstrated Nar potential as a normolipidemic agent capable to reduce circulating cholesterol in hypercholesterolemic rabbits, rats, and patients, suggesting a new role for this molecule in cardiovascular disease prevention. Although Nar cholesterol-lowering effects are known, the underlying mechanisms have not yet been elucidated. Interestingly, Nar binds to the estrogen receptors (ERs), modulating both transcriptional and membrane-initiating signals. Although estrogen and ERs are deeply involved in lipid metabolism, no data are available regarding a putative role of these nuclear receptors as mediators of the hypocholesterolemic effect exerted by Nar. Thus, the aim of this work was to study the involvement of ERs in Nar-induced modulation of cholesterol metabolism. Results obtained in HepG2 cell line demonstrate that Nar can modulate the molecular network of cholesterol homeostasis. However, these effects were only partially dependent on the activity of estrogen receptor α. As a whole, our data highlight new molecular mechanisms by which Nar influences cholesterol metabolism, opening a new scenery about dietary impact on human health.
Current Insights on the Use of Insulin and the Potential Use of Insulin Mimetics in Targeting Insulin Signalling in Alzheimer’s Disease
Authors: Woodfield Amy , Gonzales Tatiana , Helmerhorst Erik , Laws Simon , Newsholme Philip , Porter Tenielle , Verdile Giuseppe
Published: December 2022

Alzheimer’s disease (AD) and type 2 diabetes (T2D) are chronic diseases that share several pathological mechanisms, including insulin resistance and impaired insulin signalling. Their shared features have prompted the evaluation of the drugs used to manage diabetes for the treatment of AD. Insulin delivery itself has been utilized, with promising effects, in improving cognition and reducing AD related neuropathology. The most recent clinical trial involving intranasal insulin reported no slowing of cognitive decline; however, several factors may have impacted the trial outcomes. Long-acting and rapid-acting insulin analogues have also been evaluated within the context of AD with a lack of consistent outcomes. This narrative review provided insight into how targeting insulin signalling in the brain has potential as a therapeutic target for AD and provided a detailed update on the efficacy of insulin, its analogues and the outcomes of human clinical trials. We also discussed the current evidence that warrants the further investigation of the use of the mimetics of insulin for AD. These small molecules may provide a modifiable alternative to insulin, aiding in developing drugs that selectively target insulin signalling in the brain with the aim to attenuate cognitive dysfunction and AD pathologies.
A Coupled Transport-Adhesion Mechanism Responsible for the Attachment of Adventitious Root Hairs of Climbing Plants to the Surrounding Surface
Authors: Liu Yan , Gao Morgan
Published: December 2022

Biological adhesive systems in both geckoes and climbing plants share similar hierarchical structures, such as the toe-seta-spatula structure in geckoes and the root-rootlet-hair structure in English ivy (Hedera helix). The former operates at a spectrum of length scales that are much smaller than the latter. Consequently, the spatula adhesion in geckoes exhibits a flaw-insensitive behavior, or in other words, the large-scale-bridging characteristics shield the stress singularities at the adhesive contact front. In contrast, adventitious root hairs from commonly seen household climbing plants are of several tens to hundreds of micrometers long, so that the adhesive contact appears to resemble a linear elastic crack and thus would have a very low pulling force for de-adhesion. This apparent contradiction between modeling and observations is resolved in this work by a coupled transport–adhesion mechanism, in which an adhesive layer that carries gluing nanoparticles flows towards the adhesive contact front. This provides an effective way to shield the stress singularity, resulting in a scenario that completely differs from gecko adhesion. Finite element simulations have been conducted to illustrate this proposed mechanism and then compared to available experimental observations in the literature.
Design of an Energy Pile Based on CPT Data Using Soft Computing Techniques
Authors: Kumar Pramod , Samui Pijush
Published: December 2022

The present study focused on the design of geothermal energy piles based on cone penetration test (CPT) data, which was obtained from the Perniö test site in Finland. The geothermal piles are heat-capacity systems that provide both a supply of energy and structural support to civil engineering structures. In geotechnical engineering, it is necessary to provide an efficient, reliable, and precise method for calculating the group capacity of the energy piles. In this research, the first aim is to determine the most significant variables required to calculate the energy pile capacity, i.e., the pile length (L), pile diameter (D), average cone resistance (qc0), minimum cone resistance (qc1), average of minimum cone resistance (qc2), cone resistance (qc), Young’s modulus (E), coefficient of thermal expansion (αc), and temperature change (ΔT). The values of qc0, qc1, qc2, qc, and E are then employed as model inputs in soft computing algorithms, which includes random forest (RF), the support vector machine (SVM), the gradient boosting machine (GBM), and extreme gradient boosting (XGB) in order to predict the pile group capacity. The developed soft computing models were then evaluated by using several statistical criteria, and the lowest system error with the best performance was attained by the GBM technique. The performance parameters, such as the coefficient of determination (R2), root mean square error (RMSE), mean absolute error (MAE), mean biased error (MBE), median absolute deviation (MAD), weighted mean absolute percentage error (WMAPE), expanded uncertainty (U95), global performance indicator (GPI), Theil’s inequality index (TIC), and the index of agreement (IA) values of the testing data for the GBM models are 0.80, 0.10, 0.08, −0.01, 0.06, 0.21, 0.28, −0.00, 0.11, and 0.94, respectively, demonstrating the strength and capacity of this soft computing algorithm in evaluating the pile’s group capacity for the energy pile. Rank analysis, error matrix, Taylor’s diagram, and the reliability index have all been developed to compare the proposed model’s accuracy. The results of this research also show that the GBM model developed is better at estimating the group capacity of energy piles than the other soft computing models.
Two Antenna-Enriched Odorant Binding Proteins in Dioryctria abietella Tuned to General Odorants and Insecticides
Authors: Wu Chun , Yin Ningna , Guo Yuruo , Wang Zhengquan , Liu Naiyong
Published: December 2022

The management of forest pests has become a significant challenge, particularly for wood borers, because they spend most of the time in the trunks or cones. The coneworm, Dioryctria abietella, is a representative of cone borers as its larvae feed on the cones of Pinaceae plants. The molecular mechanisms underlying the interactions between this species and host plants or habitats can assist in developing strategies for pest control. In this study, we extended the expression profiles of 32 odorant binding proteins (OBPs) in the reproductive tissues of D. abietella, revealing the detectable transcription of 29 genes. Using two DabiOBPs highly expressed in antennae (DabiOBP5 and DabiOBP14) as targets, six compounds with high affinities (dissociation constants < 13 μM) were identified through a reverse chemical ecology strategy, including insecticides widely used for the control of lepidopteran pests. Of these compounds, a floral volatile β-ionone and a pear-produced ester ethyl-(2E,4Z)-decadienoate may serve as behaviorally active compounds in D. abietella. The strong binding of DabiOBPs to insecticides suggested their involvement in insecticide resistance, reflecting sophisticated detoxification mechanisms of this moth. In the molecular simulations, DabiOBP14 possessed stronger interactions with the six ligands compared to DabiOBP5, in which a few key residues within the binding pockets were involved in the formation of hydrogen bonds. This study provides some valuable reference active compounds for the development of lures or repellents in D. abietella and unravels the putative roles of two antenna-dominant DabiOBPs in the perception of plant-derived odorants and insecticides.
Clinical Relevance of Serum Klotho Concentration and Sagittal Abdominal Diameter
Authors: Huang Jun-Wei , Fang Wen-Hui , Chen Wei-Liang
Published: December 2022

Klotho is an anti-aging gene. Studies have revealed its association with insulin resistance. Visceral fat is related to insulin resistance, and the sagittal abdominal diameter (SAD) can serve as a biomarker for visceral fat (VF). This study investigated the association between SAD and serum Klotho concentration (SKC). We enrolled 2301 participants from the 2011–2012 National Health and Nutrition Examination Survey (NHANES) dataset, and 49.2% of the enrolled individuals were male. Qualified participants were separated into four quartiles according to the SAD value. SKC values were obtained by ELISA. Demographic characteristics, body mass index (BMI), systolic blood pressure, and biochemistry parameters with significance were analyzed using multivariate linear regression models. The mean age of the study participants was 57.22 ± 10.53 years. The fully adjusted regression model showed a negative association between SAD and SKC (p < 0.05), with a β-coefficient of −12.02. We also analyzed subgroups of participants according to age and BMI. Participants with an age ≥65 and <65 years old were each negatively associated with SKC, and this association was significant for participants with a BMI ≥ 30 kg/m2 (p = 0.001, β-coefficient: −18.83). We also found a concentration-dependent relationship between SAD and SKC. In conclusion, VF and SKC are associated, and SAD can serve as a surrogate of VF and an indicator of SKC.
Prognostic Value of Serum Transferrin Analysis in Patients with Ovarian Cancer and Cancer-Related Functional Iron Deficiency: A Retrospective Case–Control Study
Authors: Ivanova Tatiana I. , Klabukov Ilya D. , Krikunova Ludmila I. , Poluektova Marina V. , Sychenkova Natalia I. , Khorokhorina Vera A. , Vorobyev Nikolay V. , Gaas Margarita Ya. , Baranovskii Denis S. , Goryainova Oksana S. , Sachko Anastasiya M. , Shegay Peter V. , Kaprin Andrey D. , Tillib Sergei V.
Published: December 2022

(1) Background: There are no reliable and widely available markers of functional iron deficiency (FID) in cancer. The aim of the study was to evaluate the role of transferrin (Tf) as a marker of cancer of the ovary (CrO) and related FID. (2) Methods: The study groups consisted of 118 patients with CrO and 69 control females. Blood serum iron status was determined on a Beckman Coulter AU (USA) analyzer. Tf quantification was performed by immunoturbidimetry. The relative contents of apo- and holo-Tf (iron-free and iron-saturated Tf, respectively) were determined in eight patients and a control female by immunochromatographic analysis based on the use of monoclonal single-domain antibodies (nanobodies). (3) Results: Four groups of patients with different iron statuses were selected according to ferritin and transferrin saturation values: absolute iron deficiency (AID) (n = 42), FID (n = 70), iron overload (n = 4), normal iron status (n = 2). The groups differed significantly in Tf values (p < 0.0001). Lower values of Tf were associated with FID. Furthermore, FID is already found in the initial stages of CrO (26%). Immunosorbents based on nanobodies revealed the accumulation of apo-Tf and the decrease in holo-Tf in patients with CrO. (4) Conclusions: Tf may be a promising tool for diagnosing both CrO and associated FID.
Lifestyle and Symptom Risk Factors for Dry Eye Disease in Asian Gout Population: A Population-Based Case–Control Study
Authors: Lee Chia-Yi , Lian Ie-Bin , Jhan Yan-Ni , Yang Shun-Fa , Chang Chao-Kai
Published: December 2022

We aim to investigate the lifestyle and symptom factors related to dry eye disease (DED) presence in patients with persistent gout using the Taiwan Biobank (TWB) database. A retrospective case–control study was conducted, and patients with a history of gout longer than 10 years were enrolled in the persistent-gout group. Each persistent-gout patient was age- and sex-matched to two non-gout individuals who served as the control group, and we included a total of 973 and 1946 patients in the persistent-gout group and non-gout groups. The main outcome of our study is the presence of DED and the distribution of several lifestyle and symptom risk factors of DED in persistent-gout and non-gout individuals. Logistic regression considering the age and sex and interaction test was applied to estimate the correlation of each lifestyle and symptom risk factor to DED in the two groups. A total of 95 and 140 DED events were found in the persistent-gout and non-gout groups, with a significantly higher percentage in the persistent-gout population (aOR: 1.167, 95% CI: 1.073–3.855, p = 0.0415). The visual display terminal (VDT) user (p = 0.0026) and persistent alcohol drinking (p = 0.0384) were associated with DED more often in the persistent-gout population than the non-gout population. Moreover, the percentages of DED in the patients with gout intervals of 10–20 years and more than 20 years were statistically insignificant (aOR: 1.042, 95% CI: 0.886–1.910, p = 0.5279). In conclusion, VDT usage and persistent alcohol drinking are prominent lifestyle and symptom risk factors for DED occurrence in patients who have experienced gout for more than 10 years.
An Integrative Model for Understanding Obsessive-Compulsive Disorder: Merging Cognitive Behavioral Theory with Insights from Clinical Neuroscience
Authors: Kalanthroff Eyal , Wheaton Michael G.
Published: December 2022

Several models have been proposed for the emergence and maintenance of obsessive-compulsive disorder (OCD). Although these models have provided important insights and inspired treatment development, no single model has yet sufficiently accounted for the complexed phenotype of the disorder. In the current paper, we propose a novel model that integrates elements from cognitive behavioral models of OCD with neurocognitive approaches to the disorder. This Reciprocal Interaction Model (RIM) for OCD is based on two assumptions: (a) similar observed symptoms can stem from different etiological processes; and (b) neuropsychological deficits (such as reduced response inhibition and overreliance on the habit formation system) and cognitive behavioral processes (such as temporary reduction in anxiety after engaging in compulsive behaviors) mutually affect each other such that abnormalities in one system influence the second system and vice-versa—creating a vicious cycle of pathological processes. Indeed, the bidirectional inhibitory connection between anxiety/obsessions and executive control is at the heart of the model. We begin by briefly reviewing the current models for OCD. We then move on to describe the RIM, the supporting evidence for the model, the model’s predictions, and potential clinical implications.
Prognostic Value of Neoadjuvant Chemotherapy in Patients with Borderline Resectable Pancreatic Carcinoma Followed by Pancreatectomy with Portal Vein Resection and Reconstruction with Venous Allograft
Authors: Huang Jin-Can , Pan Bing , Wang Han-Xuan , Chen Qing , He Qiang , Lyu Shao-Cheng
Published: December 2022

Background: Neo-adjuvant chemotherapy (NAC) represents one of the current research hotspots in the field of pancreatic ductal adenocarcinoma (PDAC). The aim of this study is to evaluate the prognostic value of NAC in patients with borderline resectable pancreatic cancer (BRPC) followed by pancreatectomy with portal vein (PV) resection and reconstruction with venous allograft (VAG). Methods: Medical records of patients with BPRC who underwent pancreatectomy with concomitant PV resection and reconstruction with VAG between April 2013 and March 2021 were analyzed retrospectively. Outcomes of patients with and without NAC (NAC, Group 1 vs. non-NAC, Group 2) were compared with focus on R0 resection rates, morbidity, and survival. Results: Of the 77 patients with pancreatectomy, PV resection and reconstruction with VAG were identified. Overall survival (OS) rates of 0.5-, 1-, and 2-year were 80.5%, 59.7%, and 31.2%, respectively (median survival time, MST, 14 months). Of these, 24 patients (Group 1) underwent operation following received NAC, and the remaining 53 patients did not (Group 2). The R0 resection rate of vascular margin was 100% vs. 84.9% (p = 0.04), respectively. Morbidity of post-operative pancreatic fistula (POPF) was 0% vs. 17.8% (p = 0.07), respectively. The OS of 0.5-, 1- and 2-year and MST of 2 groups were 83.3%, 66.7%, 41.7%, 16 months, and 79.2%, 55.6%, 26.4%, 13 months, respectively. Multivariate analysis revealed that carbohydrate antigen 19-9 (CA19-9) serum level and postoperative chemotherapy were independent prognostic factors in patients with BRPC after surgery. Conclusion: NAC might improve the R0 resection rate and POPF in patients with BRPC who underwent pancreatectomy with concomitant PV resection and reconstruction with VAG. Survival benefit exists in patients with BRPC who received NAC before pancreatectomy. Postoperative chemotherapy also had a favorable effect on OS of BRPC patients. Elevated CA 19-9 serum level is associated with poor prognosis, even after NAC-combining operation.