bluuebunny/crossref_metadata_2025 huggingface dataset:
Distinct Changes in Calpain and Calpastatin during PNS Myelination and Demyelination in Rodent Models
Authors: Miller John A. , Drouet Domenica E. , Yermakov Leonid M. , Elbasiouny Mahmoud S. , Bensabeur Fatima Z. , Bottomley Michael , Susuki Keiichiro
Published: December 2022

Myelin forming around axons provides electrical insulation and ensures rapid and efficient transmission of electrical impulses. Disruptions to myelinated nerves often result in nerve conduction failure along with neurological symptoms and long-term disability. In the central nervous system, calpains, a family of calcium dependent cysteine proteases, have been shown to have a role in developmental myelination and in demyelinating diseases. The roles of calpains in myelination and demyelination in the peripheral nervous system remain unclear. Here, we show a transient increase of activated CAPN1, a major calpain isoform, in postnatal rat sciatic nerves when myelin is actively formed. Expression of the endogenous calpain inhibitor, calpastatin, showed a steady decrease throughout the period of peripheral nerve development. In the sciatic nerves of Trembler-J mice characterized by dysmyelination, expression levels of CAPN1 and calpastatin and calpain activity were significantly increased. In lysolecithin-induced acute demyelination in adult rat sciatic nerves, we show an increase of CAPN1 and decrease of calpastatin expression. These changes in the calpain-calpastatin system are distinct from those during central nervous system development or in acute axonal degeneration in peripheral nerves. Our results suggest that the calpain-calpastatin system has putative roles in myelination and demyelinating diseases of peripheral nerves.
Effects of β-amyloid (1-42) Administration on the Main Neurogenic Niches of the Adult Brain: Amyloid-Induced Neurodegeneration Influences Neurogenesis
Authors: Yenkoyan Konstantin , Margaryan Tigran , Matinyan Senik , Chavushyan Vergine , Danielyan Margarita , Davtyan Tigran , Aghajanov Michail
Published: December 2022

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder and warrants further study as well as timely treatment. Additionally, the mechanisms of the brain’s intrinsic defense against chronic injury are not yet fully understood. Herein, we examined the response of the main neurogenic niches to amyloid exposure and the associated changes in structure and synaptic activity. Flow cytometry of Nestin-, Vimentin-, Nestin/Vimentin-, NeuN-, GFAP-, NeuN/GFAP-, NSE-, BrdU-, Wnt-, BrdU/Wnt-, VEGF-, Sox14-, VEGF/Sox14-, Sox10-, Sox2-, Sox10/Sox2-, Bax-, and Bcl-xL-positive cells was performed in the subventricular zone (SVZ), hippocampus, and cerebral cortex of rat brains on 90th day after intracerebroventricular (i.c.v.) single injection of a fraction of β-amyloid (Aβ) (1-42). The relative structural changes in these areas and disruptions to synaptic activity in the entorhinal cortex–hippocampus circuit were also evaluated. Our flow analyses revealed a reduction in the numbers of Nestin-, Vimentin-, and Nestin/Vimentin-positive cells in neurogenic niches and the olfactory bulb. These changes were accompanied by an increased number of BrdU-positive cells in the hippocampus and SVZ. The latter changes were strongly correlated with changes in the numbers of VEGF- and VEGF/Sox14-positive cells. The morphological changes were characterized by significant neural loss, a characteristic shift in entorhinal cortex–hippocampus circuit activity, and decreased spontaneous alternation in a behavioral test. We conclude that although an injection of Aβ (1-42) induced stem cell proliferation and triggered neurogenesis at a certain stage, this process was incomplete and led to neural stem cell immaturity. We propose the idea of enhancing adult neurogenesis as a promising strategy for preventing dementia at healthy elderly people andpeople at high risk for developing AD, or treating patients diagnosed with AD.
Selenium in Bodily Homeostasis: Hypothalamus, Hormones, and Highways of Communication
Authors: Toh Pamela , Nicholson Jessica L. , Vetter Alyssa M. , Berry Marla J. , Torres Daniel J.
Published: December 2022

The ability of the body to maintain homeostasis requires constant communication between the brain and peripheral tissues. Different organs produce signals, often in the form of hormones, which are detected by the hypothalamus. In response, the hypothalamus alters its regulation of bodily processes, which is achieved through its own pathways of hormonal communication. The generation and transmission of the molecules involved in these bi-directional axes can be affected by redox balance. The essential trace element selenium is known to influence numerous physiological processes, including energy homeostasis, through its various redox functions. Selenium must be obtained through the diet and is used to synthesize selenoproteins, a family of proteins with mainly antioxidant functions. Alterations in selenium status have been correlated with homeostatic disturbances in humans and studies with animal models of selenoprotein dysfunction indicate a strong influence on energy balance. The relationship between selenium and energy metabolism is complicated, however, as selenium has been shown to participate in multiple levels of homeostatic communication. This review discusses the role of selenium in the various pathways of communication between the body and the brain that are essential for maintaining homeostasis.
The Metastatic Process through the Eyes of Epigenetic Regulation: A Promising Horizon for Cancer Therapy
Authors: Smolkova Bozena , Earl Julie , Kataki Agapi
Published: December 2022

Genetic aberrations, including chromosomal rearrangements, loss or amplification of DNA, and point mutations, are major elements of cancer development [...]
Elevation of Anticancer Drug Toxicity by Caffeine in Spheroid Model of Human Lung Adenocarcinoma A549 Cells Mediated by Reduction in Claudin-2 and Nrf2 Expression
Authors: Eguchi Hiroaki , Kimura Riho , Onuma Saki , Ito Ayaka , Yu Yaqing , Yoshino Yuta , Matsunaga Toshiyuki , Endo Satoshi , Ikari Akira
Published: December 2022

Claudin-2 (CLDN2), a component of tight junctions, is abnormally expressed in human lung adenocarcinoma tissue. CLDN2 contributes to chemoresistance in human lung adenocarcinoma-derived A549 cells, and it may be a target for cancer therapy. Here, we found that coffee ingredients, namely caffeine and theobromine, decreased the protein level of CLDN2 in human lung adenocarcinoma-derived A549 cells. In contrast, other components, such as theophylline and chlorogenic acid, had no effect. These results indicate that the 7-methyl group in methylxanthines may play a key role in the reduction in CLDN2 expression. The caffeine-induced reduction in the CLDN2 protein was inhibited by chloroquine, a lysosome inhibitor. In a protein-stability assay using cycloheximide, CLDN2 protein levels decreased faster in caffeine-treated cells than in vehicle-treated cells. These results suggest that caffeine accelerates the lysosomal degradation of CLDN2. The accumulation and cytotoxicity of doxorubicin were dose-dependently increased, which was exaggerated by caffeine but not by theophylline in spheroids. Caffeine decreased nuclear factor-erythroid 2-related factor 2 (Nrf2) levels without affecting hypoxia-inducible factor-1α levels. Furthermore, caffeine decreased the expression of Nrf2-targeted genes. The effects of caffeine on CLDN2 expression and anticancer-drug-induced toxicity were also observed in lung adenocarcinoma RERF-LC-MS cells. We suggest that caffeine enhances doxorubicin-induced toxicity in A549 spheroids mediated by the reduction in CLDN2 and Nrf2 expression.
Molecular Features of the Mesenchymal and Osteoblastic Cells in Multiple Myeloma
Authors: Iannozzi Nicolas Thomas , Marchica Valentina , Toscani Denise , Burroughs Garcìa Jessica , Giuliani Nicola , Storti Paola
Published: December 2022

Multiple myeloma (MM) is a monoclonal gammopathy characterized by biological heterogeneity and unregulated proliferation of plasma cells (PCs) in bone marrow (BM). MM is a multistep process based on genomic instability, epigenetic dysregulation and a tight cross-talk with the BM microenvironment that plays a pivotal role supporting the proliferation, survival, drug-resistance and homing of PCs. The BM microenvironment consists of a hematopoietic and a non-hematopoietic compartment, which cooperate to create a tumor environment. Among the non-hematopoietic component, mesenchymal stromal cells (MSCs) and osteoblasts (OBs) appear transcriptionally and functionally different in MM patients compared to healthy donors (HDs) and to patients with pre-malignant monoclonal gammopathies. Alterations of both MSCs and OBs underly the osteolytic lesions that characterize myeloma-associated bone disease. In this review, we will discuss the different characteristics of MSCs and OBs in MM patients, analyzing the transcriptome, the deregulated molecular pathways and the role performed by miRNAs and exosome in the pathophysiology of MM.
Klotho Protein Decreases MMP-Mediated Degradation of Contractile Proteins during Ischaemia/Reperfusion Injury to the Cardiomyocytes
Authors: Olejnik Agnieszka , Krzywonos-Zawadzka Anna , Banaszkiewicz Marta , Bil-Lula Iwona
Published: December 2022

Ischaemia, followed by reperfusion, causes the generation of reactive oxygen species, overproduction of peroxynitrite, activation of matrix metalloproteinases (MMPs), and subsequently the degradation of heart contractile proteins in the cardiomyocytes. Klotho is a membrane-bound or soluble protein that regulates mineral metabolism and has antioxidative activity. This study aimed to examine the influence of Klotho protein on the MMP-mediated degradation of contractile proteins during ischaemia/reperfusion injury (IRI) to the cardiomyocytes. Human cardiac myocytes (HCM) underwent in vitro chemical IRI (with sodium cyanide and deoxyglucose), with or without the administration of recombinant Klotho protein. The expression of MMP genes, the expression and activity of MMP proteins, as well as the level of contractile proteins such as myosin light chain 1 (MLC1) and troponin I (TnI) in HCM were measured. Administration of Klotho protein resulted in a decreased activity of MMP-2 and reduced the release of MLC1 and TnI that followed in cells subjected to IRI. Thus, Klotho protein contributes to the inhibition of MMP-dependent degradation of contractile proteins and prevents injury to the cardiomyocytes during IRI.
Probing Interleukin-6 in Stroke Pathology and Neural Stem Cell Transplantation
Authors: Lockard Gavin Miles , Alayli Adam , Monsour Molly , Gordon Jonah , Schimmel Samantha , Elsayed Bassel , Borlongan Cesar V.
Published: December 2022

Stem cell transplantation is historically understood as a powerful preclinical therapeutic following stroke models. Current clinical strategies including clot busting/retrieval are limited by their time windows (tissue plasminogen activator: 3–4 h) and inevitable reperfusion injuries. However, 24+ h post-stroke, stem cells reduce infarction size, improve neurobehavioral performance, and reduce inflammatory agents including interleukins. Typically, interleukin-6 (IL-6) is regarded as proinflammatory, and thus, preclinical studies often discuss it as beneficial for neurological recuperation when stem cells reduce IL-6′s expression. However, some studies have also demonstrated neurological benefit with upregulation of IL-6 or preconditioning of stem cells with IL-6. This review specifically focuses on stem cells and IL-6, and their occasionally disparate, occasionally synergistic roles in the setting of ischemic cerebrovascular insults.
Chronic Intermittent Hypoxia during Sleep Causes Browning of Interscapular Adipose Tissue Accompanied by Local Insulin Resistance in Mice
Authors: Dahan Tehila , Nassar Shahd , Yajuk Olga , Steinberg Eliana , Benny Ofra , Abudi Nathalie , Plaschkes Inbar , Benyamini Hadar , Gozal David , Abramovitch Rinat , Gileles-Hillel Alex
Published: December 2022

Obstructive sleep apnea (OSA) is a highly prevalent condition, characterized by intermittent hypoxia (IH), sleep disruption, and altered autonomic nervous system function. OSA has been independently associated with dyslipidemia, insulin resistance, and metabolic syndrome. Brown adipose tissue (BAT) has been suggested as a modulator of systemic glucose tolerance through adaptive thermogenesis. Reductions in BAT mass have been associated with obesity and metabolic syndrome. No studies have systematically characterized the effects of chronic IH on BAT. Thus, we aimed to delineate IH effects on BAT and concomitant metabolic changes. C57BL/6J 8-week-old male mice were randomly assigned to IH during sleep (alternating 90 s cycles of 6.5% FIO2 followed by 21% FIO2) or normoxia (room air, RA) for 10 weeks. Mice were subjected to glucose tolerance testing and 18F-FDG PET–MRI towards the end of the exposures followed by BAT tissues analyses for morphological and global transcriptomic changes. Animals exposed to IH were glucose intolerant despite lower total body weight and adiposity. BAT tissues in IH-exposed mice demonstrated characteristic changes associated with “browning”—smaller lipids, increased vascularity, and a trend towards higher protein levels of UCP1. Conversely, mitochondrial DNA content and protein levels of respiratory chain complex III were reduced. Pro-inflammatory macrophages were more abundant in IH-exposed BAT. Transcriptomic analysis revealed increases in fatty acid oxidation and oxidative stress pathways in IH-exposed BAT, along with a reduction in pathways related to myogenesis, hypoxia, and IL-4 anti-inflammatory response. Functionally, IH-exposed BAT demonstrated reduced absorption of glucose on PET scans and reduced phosphorylation of AKT in response to insulin. Current studies provide initial evidence for the presence of a maladaptive response of interscapular BAT in response to chronic IH mimicking OSA, resulting in a paradoxical divergence, namely, BAT browning but tissue-specific and systemic insulin resistance. We postulate that oxidative stress, mitochondrial dysfunction, and inflammation may underlie these dichotomous outcomes in BAT.
Sterol O-Acyltransferase Inhibition Ameliorates High-Fat Diet-Induced Renal Fibrosis and Tertiary Lymphoid Tissue Maturation after Ischemic Reperfusion Injury
Authors: Ariyasu Yuki , Sato Yuki , Isobe Yosuke , Taniguchi Keisuke , Yanagita Motoko , Arita Makoto
Published: December 2022

Metabolic syndrome is associated with the development of chronic kidney disease (CKD). We previously demonstrated that aged kidneys are prone to developing tertiary lymphoid tissues (TLTs) and sustain inflammation after injury, leading to CKD progression; however, the relationship between renal TLT and metabolic syndrome is unknown. In this study, we demonstrated that a high-fat diet (HFD) promoted renal TLT formation and inflammation via sterol O-acyltransferase (SOAT) 1-dependent mechanism. Mice fed a HFD prior to ischemic reperfusion injury (IRI) exhibited pronounced renal TLT formation and sustained inflammation compared to the controls. Untargeted lipidomics revealed the increased levels of cholesteryl esters (CEs) in aged kidneys with TLT formation after IRI, and, consistently, the Soat1 gene expression increased. Treatment with avasimibe, a SOAT inhibitor, attenuated TLT maturation and renal inflammation in HFD-fed mice subjected to IRI. Our findings suggest the importance of SOAT1-dependent CE accumulation in the pathophysiology of CKDs associated with TLT.
Distribution of KIR Genes and Their HLA Ligands in Different Viral Infectious Diseases: Frequency Study in Sicilian Population
Authors: Ligotti Mattia Emanuela , Aiello Anna , Accardi Giulia , Calabrò Anna , Ciaccio Marcello , Colomba Claudia , Di Bona Danilo , Lo Sasso Bruna , Pojero Fanny , Tuttolomondo Antonino , Caruso Calogero , Candore Giuseppina , Duro Giovanni
Published: December 2022

Natural killer (NK) cells play a role in defence against viral infections by killing infected cells or by producing cytokines and interacting with adaptive immune cells. Killer immunoglobulin-like receptors (KIRs) regulate the activation of NK cells through their interaction with human leucocyte antigens (HLA). Ninety-six Sicilian patients positive to Human Immunodeficiency Virus-1 (HIV) and ninety-two Sicilian patients positive to SARS-CoV-2 were genotyped for KIRs and their HLA ligands. We also included fifty-six Sicilian patients with chronic hepatitis B (CHB) already recruited in our previous study. The aim of this study was to compare the distribution of KIR–HLA genes/groups of these three different infected populations with healthy Sicilian donors from the literature. We showed that the inhibitory KIR3DL1 gene and the KIR3DL1/HLA-B Bw4 pairing were more prevalent in individual CHB. At the same time, the frequency of HLA-C2 was increased in CHB compared to other groups. In contrast, the HLA-C1 ligand seems to have no contribution to CHB progression whereas it was significantly higher in COVID-19 and HIV-positive than healthy controls. These results suggest that specific KIR–HLA combinations can predict the outcome/susceptibility of these viral infections and allows to plan successful customized therapeutic strategies.
Redox-Activation of Neutrophils Induced by Pericardium Scaffolds
Authors: Vlasova Irina I. , Suleimanov Shakir K. , Mikhalchik Elena V. , Urmantaeva Nailya T. , Salimov Emin L. , Ragimov Aligeydar A. , Khlebnikova Tatyana M. , Timashev Peter S.
Published: December 2022

Implantation of scaffolds causes a local inflammatory response whereby the early recruitment of neutrophils is of great importance not only for fighting the infection, but also for facilitating effective regeneration. We used luminol-dependent chemiluminescence, flow cytometry, ELISA, and confocal microscopy to assess the responses of neutrophils after the exposure to the scaffold-decellularized bovine pericardium (collagen type I) crosslinked with genipin (DBPG). We demonstrated that DBPG activated neutrophils in whole blood causing respiratory burst, myeloperoxidase (MPO) secretion, and formation of neutrophil extracellular trap-like structures (NETs). In addition, we studied platelets, another important player of the immediate immune host response. We found that platelets triggered redox-activation of isolated neutrophils by the pericardium scaffold, and likely participate in the NETs formation. Free radicals generated by neutrophils and hypochlorous acid produced by MPO are potent oxidizing agents which can oxidatively degrade biological structures. Understanding the mechanisms and consequences of redox activation of neutrophils by pericardium scaffolds is important for the development of new approaches to increase the efficiency of tissue regeneration.
Bioanalysis of Oligonucleotide by LC–MS: Effects of Ion Pairing Regents and Recent Advances in Ion-Pairing-Free Analytical Strategies
Authors: Liu Aowen , Cheng Ming , Zhou Yixuan , Deng Pan
Published: December 2022

Oligonucleotides (OGNs) are relatively new modalities that offer unique opportunities to expand the therapeutic targets. Reliable and high-throughput bioanalytical methods are pivotal for preclinical and clinical investigations of therapeutic OGNs. Liquid chromatography–mass spectrometry (LC–MS) is now evolving into being the method of choice for the bioanalysis of OGNs. Ion paring reversed-phase liquid chromatography (IP-RPLC) has been widely used in sample preparation and LC–MS analysis of OGNs; however, there are technical issues associated with these methods. IP-free methods, such as hydrophilic interaction liquid chromatography (HILIC) and anion-exchange techniques, have emerged as promising approaches for the bioanalysis of OGNs. In this review, the state-of-the-art IP-RPLC–MS bioanalytical methods of OGNs and their metabolites published in the past 10 years (2012–2022) are critically reviewed. Recent advances in IP-reagent-free LC–MS bioanalysis methods are discussed. Finally, we describe future opportunities for developing new methods that can be used for the comprehensive bioanalysis of OGNs.
Phenotypic and Genotypic Virulence Characterisation of Staphylococcus pettenkoferi Strains Isolated from Human Bloodstream and Diabetic Foot Infections
Authors: Magnan Chloé , Ahmad-Mansour Nour , Pouget Cassandra , Morsli Madjid , Huc-Brandt Sylvaine , Pantel Alix , Dunyach-Remy Catherine , Sotto Albert , Molle Virginie , Lavigne Jean-Philippe
Published: December 2022

Staphylococcus pettenkoferi is a recently described coagulase-negative Staphylococcus identified in human diseases, especially in infections of foot ulcers in patients living with diabetes mellitus. To date, its pathogenicity remains underexplored. In this study, whole-genome analysis was performed on a collection of 29 S. pettenkoferi clinical strains isolated from bloodstream and diabetic foot infections with regard to their phylogenetic relationships and comprehensive analysis of their resistome and virulome. Their virulence was explored by their ability to form biofilm, their growth kinetics and in an in vivo zebrafish embryo infection model. Our results identified two distinct clades (I and II) and two subclades (I-a and I-b) with notable genomic differences. All strains had a slow bacterial growth. Three profiles of biofilm formation were noted, with 89.7% of isolates able to produce biofilm and harbouring a high content of biofilm-encoding genes. Two virulence profiles were also observed in the zebrafish model irrespective of the strains’ origin or biofilm profile. Therefore, this study brings new insights in S. pettenkoferi pathogenicity.
The Role of microRNAs in Inflammation
Authors: Das Kaushik , Rao L. Vijaya Mohan
Published: December 2022

Inflammation is a biological response of the immune system to various insults, such as pathogens, toxic compounds, damaged cells, and radiation. The complex network of pro- and anti-inflammatory factors and their direction towards inflammation often leads to the development and progression of various inflammation-associated diseases. The role of small non-coding RNAs (small ncRNAs) in inflammation has gained much attention in the past two decades for their regulation of inflammatory gene expression at multiple levels and their potential to serve as biomarkers and therapeutic targets in various diseases. One group of small ncRNAs, microRNAs (miRNAs), has become a key regulator in various inflammatory disease conditions. Their fine-tuning of target gene regulation often turns out to be an important factor in controlling aberrant inflammatory reactions in the system. This review summarizes the biogenesis of miRNA and the mechanisms of miRNA-mediated gene regulation. The review also briefly discusses various pro- and anti-inflammatory miRNAs, their targets and functions, and provides a detailed discussion on the role of miR-10a in inflammation.
Regulation of P-glycoprotein and Breast Cancer Resistance Protein Expression Induced by Focused Ultrasound-Mediated Blood-Brain Barrier Disruption: A Pilot Study
Authors: Conti Allegra , Geffroy Francoise , Kamimura Hermes A. S. , Novell Anthony , Tournier Nicolas , Mériaux Sébastien , Larrat Benoit
Published: December 2022

The blood-brain barrier (BBB) controls brain homeostasis; it is formed by vascular endothelial cells that are physically connected by tight junctions (TJs). The BBB expresses efflux transporters such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), which limit the passage of substrate molecules from blood circulation to the brain. Focused ultrasound (FUS) with microbubbles can create a local and reversible detachment of the TJs. However, very little is known about the effect of FUS on the expression of efflux transporters. We investigated the in vivo effects of moderate acoustic pressures on both P-gp and BCRP expression for up to two weeks after sonication. Magnetic resonance-guided FUS was applied in the striatum of 12 rats. P-gp and BCRP expression were determined by immunohistochemistry at 1, 3, 7, and 14 days postFUS. Our results indicate that FUS-induced BBB opening is capable of (i) decreasing P-gp expression up to 3 days after sonication in both the treated and in the contralateral brain regions and is capable of (ii) overexpressing BCRP up to 7 days after FUS in the sonicated regions only. Our findings may help improve FUS-aided drug delivery strategies by considering both the mechanical effect on the TJs and the regulation of P-gp and BCRP.
Mebendazole Increases Anticancer Activity of Radiotherapy in Radiotherapy-Resistant Triple-Negative Breast Cancer Cells by Enhancing Natural Killer Cell-Mediated Cytotoxicity
Authors: Choi Hoon Sik , Ko Young Shin , Jin Hana , Kang Ki Mun , Ha In Bong , Jeong Hojin , Lee Jeong-hee , Jeong Bae Kwon , Kim Hye Jung
Published: December 2022

Breast cancer is the most commonly diagnosed cancer worldwide and ranks first in terms of both prevalence and cancer-related mortality in women. In this study, we aimed to evaluate the anticancer effect of mebendazole (MBZ) and radiotherapy (RT) concomitant use in triple-negative breast cancer (TNBC) cells and elucidate the underlying mechanisms of action. Breast cancer mouse models and several types of breast cancer cells, including TNBC-derived RT-resistant (RT-R) MDA-MB-231 cells, were treated with MBZ and/or RT. In mice, changes in body weight, renal and liver toxicity, tumor volume, and number of lung metastases were determined. In cells, cell viability, colony formation, scratch wound healing, Matrigel invasion, and protein expression using western blotting were determined. Our findings showed that MBZ and RT combined treatment increased the anticancer effect of RT without additional toxicity. In addition, we noted that cyclin B1, PH2AX, and natural killer (NK) cell-mediated cytotoxicity increased following MBZ + RT treatment compared to unaided RT. Our results suggest that MBZ + RT have an enhanced anticancer effect in TNBC which acquires radiation resistance through blocking cell cycle progression, initiating DNA double-strand breaks, and promoting NK cell-mediated cytotoxicity.
The Essential Role of Prolines and Their Conformation in Allosteric Regulation of Kaiso Zinc Finger DNA-Binding Activity by the Adjacent C-Terminal Loop
Authors: Belova Elena , Maksimenko Oksana , Georgiev Pavel , Bonchuk Artem
Published: December 2022

Kaiso is a methyl-DNA-binding protein containing three C2H2 zinc fingers with a C-terminal extension that participates in DNA binding. The linker between the last zinc finger and the DNA-binding portion of the extension contains two prolines that are highly conserved in vertebrates and in cognate ZBTB4 and ZBTB38 proteins. Prolines provide chain rigidity and can exist in cis and trans conformations that can be switched by proline isomerases, affecting protein function. We found that substitution of the conserved proline P588, but not of P577, to alanine, negatively affected KaisoDNA-binding according to molecular dynamics simulation and in vitro DNA-binding assays. Molecular dynamics simulations of the Kaiso DNA-binding domain with P588 either substituted to alanine or switched to the cis-conformation revealed similar alterations in the H-bonding network and uncovered allosteric effects leading to structural rearrangements in the entire domain that resulted in the weakening of DNA-binding affinity. The substitution of proline with a large hydrophobic residue led to the same negative effects despite its ability to partially rescue the intrinsic DNA-binding activity of the C-terminal loop. Thus, the presence of the C-terminal extension and cis-conformation of proline residues are essential for efficient Kaiso–DNA binding, which likely involves intramolecular tension squeezing the DNA chain.
Nitrogen Promotes the Salt-Gathering Capacity of Suaeda salsa and Alleviates Nutrient Competition in the Intercropping of Suaeda salsa/Zea mays L.
Authors: Wang Shoule , Ge Shaoqing , Mai Wenxuan , Tian Changyan
Published: December 2022

Nitrogen accelerates salt accumulation in the root zone of an euhalophyte, which might be beneficial for inhibiting the salt damage and interspecific competition for nutrients of non-halophytes in intercropping. However, the variations in the effect of euhalophyte/non-halophyte intercropping with nitrogen supply are poorly understood. Here, we selected the euhalophyte Suaeda salsa (suaeda) and non-halophyte Zea mays L. (maize) as the research objects, setting up three cropping patterns in order to explore the influence of nitrogen application on the intercropping effect in the suaeda/maize intercropping. The results showed that the biomass of maize in the intercropping was significantly lower than that in the monoculture, while for suaeda, it was higher in the intercropping than that in the monoculture. The biomass of maize under NO3−-N treatment performed significantly higher than that under no nitrogen treatment. Moreover, under suitable NO3−-N treatment, more salt ions (Na+, K+) gathered around the roots of suaeda, which weakened the salt damage on maize growth. In the intercropping, the effect of NO3−-N on the maize growth was enhanced when compared with the non-significant effect of NH4+-N, but a positive effect of NH4+-N on suaeda growth was found. Therefore, the disadvantage of maize growth in the intercropping suaeda/maize might be caused by interspecific competition to a certain extent, providing an effective means for the improvement of saline–alkali land by phytoremediation.
Sex Lethal Gene Manipulates Gonadal Development of Medaka, Oryzias latipes, through Estrogenic Interventions
Authors: Chakraborty Tapas , Mohapatra Sipra , Matsuyama Michiya , Nagahama Yoshitaka , Ohta Kohei
Published: December 2022

Germ cells are pivotal for gonadal sexuality maintenance and reproduction. Sex lethal (sxl), the somatic sex determining gene of Drosophila, is the known regulator and initiator of germ cell femininity in invertebrates. However, the role of the Sxl homologue has rarely been investigated in vertebrates. So, we used medaka to clarify the role of sxl in vertebrate gonadogenesis and sexuality and identified two Sxl homologues, i.e., Sxl1a and Sxl1b. We found that sxl1a specifically expresses in the primordial germ cells (PGC), ovary, (early gonia and oocytes), while sxl1b distributions are ubiquitous. An mRNA overexpression of sxl1a accelerated germ cell numbers in 10 DAH XY fish, and sxl1a knockdown (KD), on the other hand, induced PGC mis-migration, aberrant PGC structuring and ultimately caused significant germ cell reduction in XX fish. Using an in vitro promoter analysis and in vivo steroid treatment, we found a strong link between sxl1a and estrogenic germ cell-population maintenance. Further, using sxl1a-KD and erβ2-knockout fish, we determined that sxl1 acts through erβ2 and controls PGC sexuality. Cumulatively, our study highlights the novel role of sxl1a in germ cell maintenance and sexual identity assignment and thus might become a steppingstone to understanding the commonalities of animal sexual development.
Investigations concerning the Flow Stabilization of Backward Curved Centrifugal Impellers at Low Flow Rate
Authors: Lörcher Frieder , Hub Sandra , Sanjosé Marlène , Moreau Stéphane
Published: December 2022

For a backward curved centrifugal fan, reducing volume flow rate from design operating point towards part load yields an increase in noise emission together with a reduction of efficiency. The spectral content of the emerging noise emission can be characterized by a subharmonic hump with several harmonics. Based on narrow-band acoustic measurements and numerical Lattice-Boltzmann simulations, a deeper insight is sought after. Downstream unsteady flow patterns are identified to play a central role in this performance deterioration; and geometrical flow stabilization means are investigated.
OA-Pain-Sense: Machine Learning Prediction of Hip and Knee Osteoarthritis Pain from IMU Data
Authors: Almuhammadi Wafaa Salem , Agu Emmanuel , King Jean , Franklin Patricia
Published: December 2022

Joint pain is a prominent symptom of Hip and Knee Osteoarthritis (OA), impairing patients’ movements and affecting the joint mechanics of walking. Self-report questionnaires are currently the gold standard for Hip OA and Knee OA pain assessment, presenting several problems, including the fact that older individuals often fail to provide accurate self-pain reports. Passive methods to assess pain are desirable. This study aims to explore the feasibility of OA-Pain-Sense, a passive, automatic Machine Learning-based approach that predicts patients’ self-reported pain levels using SpatioTemporal Gait features extracted from the accelerometer signal gathered from an anterior-posterior wearable sensor. To mitigate inter-subject variability, we investigated two types of data rescaling: subject-level and dataset-level. We explored six different binary machine learning classification models for discriminating pain in patients with Hip OA or Knee OA from healthy controls. In rigorous evaluation, OA-Pain-Sense achieved an average accuracy of 86.79% using the Decision Tree and 83.57% using Support Vector Machine classifiers for distinguishing Hip OA and Knee OA patients from healthy subjects, respectively. Our results demonstrate that OA-Pain-Sense is feasible, paving the way for the development of a pain assessment algorithm that can support clinical decision-making and be used on any wearable device, such as smartphones.
Palladium(II) and Platinum(II) Deprotonated Diaminocarbene Complexes Based on N-(2-Pyridyl)ureas with Oxadiazole Periphery
Authors: Geyl Kirill K. , Baykova Svetlana O. , Andoskin Pavel A. , Sharoyko Vladimir V. , Eliseeva Anastasiya A. , Baykov Sergey V. , Semenov Konstantin N. , Boyarskiy Vadim P.
Published: December 2022

Metal mediated coupling of isocyanides with substituted N-(pyridine-2-yl) ureas was first used to incorporate privileged biological motifs into platinum metal complexes. We synthesized two palladium(II) and two platinum(II) cyclometallated species with oxadiazole cores. The compounds were isolated in good yields (61–73%) and characterized by high-resolution mass spectrometry and 1H, 13C, and 195Pt NMR spectroscopies. The structures of three complexes were additionally elucidated by X-ray diffraction analysis. These complexes indeed showed cytotoxic activity. The species bearing the 1,3,4-oxadiazole moiety exhibit more potency than the ones with the 1,2,4-oxadiazole ring. Particularly, the cytotoxic effect of both 1,3,4-oxadiazole-based complexes towards T98G cells significantly exceeds the common antitumor metal-drug cisplatin.
Left Ventricular Responses during Exercise in Highly Trained Youth Athletes: Echocardiographic Insights on Function and Adaptation
Authors: Unnithan Viswanath B. , Beaumont Alexander , Rowland Thomas , George Keith , Sculthorpe Nicholas , Lord Rachel N. , Bakhshi Andisheh , Oxborough David
Published: December 2022

There is an increase in the prevalence of elite youth sports academies, whose sole aim is to develop future elite athletes. This involves the exposure of the child and adolescent athlete to high-volume training during a period of volatile growth. The large amount of data in this area has been garnered from the resting echocardiographic left ventricular (LV) evaluation of the youth athlete; while this can provide some insight on the functional adaptations to training, it is unable to elucidate a comprehensive overview of the function of the youth athletes’ LV during exercise. Consequently, there is a need to interrogate the LV responses in-exercise. This review outlines the feasibility and functional insight of capturing global indices of LV function (Stroke Index-SVIndex and Cardiac Index-QIndex), systolic and diastolic markers, and cardiac strain during submaximal and maximal exercise. Larger SVI and QI were noted in these highly trained young athletes compared to recreationally active peers during submaximal and maximal exercise. The mechanistic insights suggest that there are minimal functional systolic adaptions during exercise compared to their recreationally active peers. Diastolic function was superior during exercise in these young athletes, and this appears to be underpinned by enhanced determinants of pre-load.
Long-Term Effects of Breast Cancer Therapy and Care: Calm after the Storm?
Authors: Tommasi Chiara , Balsano Rita , Corianò Matilde , Pellegrino Benedetta , Saba Giorgio , Bardanzellu Fabio , Denaro Nerina , Ramundo Matteo , Toma Ilaria , Fusaro Alessandro , Martella Serafina , Aiello Marco Maria , Scartozzi Mario , Musolino Antonino , Solinas Cinzia
Published: December 2022

Breast cancer is still a lethal disease and the leading cause of death in women, undermining patients’ survival and quality of life. Modern techniques of surgery and radiotherapy allow for the obtaining of good results in terms of survival, however they cause long-term side effects that persist over time, such as lymphedema and neuropathy. Similarly, the advent of new therapies such as endocrine therapy revolutionized breast cancer outcomes, but side effects are still present even in years of follow-up after cure. Besides the side effects of medical and surgical therapy, breast cancer is a real disruption in patients’ lives considering quality of life-related aspects such as the distortion of body image, the psychological consequences of the diagnosis, and the impact on family dynamics. Therefore, the doctor-patient relationship is central to providing the best support both during treatment and afterwards. The aim of this review is to summarize the consequences of medical and surgical treatment on breast cancer patients and to emphasize the importance of early prevention of side effects to improve patients’ quality of life.
Current Medical and Surgical Treatment of Hidradenitis Suppurativa—A Comprehensive Review
Authors: Ocker Lennart , Abu Rached Nessr , Seifert Caroline , Scheel Christina , Bechara Falk G.
Published: December 2022

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease presenting with recurrent inflammatory lesions in intertriginous body regions. HS has a pronounced impact on patients’ quality of life and is associated with a variety of comorbidities. Treatment of HS is often complex, requiring an individual approach with medical and surgical treatments available. However, especially in moderate-to-severe HS, there is an urgent need for new treatment approaches. In recent years, increased research has led to the identification of new potential therapeutic targets. This review aims to give a comprehensive and practical overview of current treatment options for HS. Furthermore, the clinically most advanced novel treatment approaches will be discussed.
Physical Activity, Psychological and Functional Outcomes in Non-Ambulatory Stroke Patients during Rehabilitation—A Pilot Study
Authors: Błaszcz Marcin , Prucnal Nina , Wrześniewski Krzysztof , Pasiut Szymon , Mika Piotr , Kucia Małgorzata , Stach Beata , Woźniak Marcin , Mirek Elżbieta
Published: December 2022

Despite the extensive literature on stroke rehabilitation, there are few studies that comprehensively show non-ambulatory stroke patients. The aim of the study was to explore the dynamics of the change in physical activity (PA), psychological and functional outcomes, and the correlation between them in non-ambulatory patients during early in-patient post-stroke rehabilitation. Measurements were taken on 21 participants at the beginning of and 6 weeks post-conventional rehabilitation with the Barthel Index (BI), Berg Balance Scale (BBS), Trunk Control Test (TCT), Stroke Impact Scale (SIS), General Self-Efficacy Scale, Stroke Self-Efficacy Questionnaire (SSEQ), the original scale of belief in own impact on recovery (BiOIoR), Hospital Anxiety and Depression Scale, Acceptance of Illness Scale and when the patient could walk—Time Up & Go and 6 Minute Walk Test. Daily PA was assessed over 6 weeks using a Caltrac accelerometer. Only outcomes for BI, BBS, TCT, SIS, and SSEQ significantly improved 6 weeks post-rehabilitation. PA energy expenditure per day significantly increased over time (p < 0.001; effect size = 0.494), but PA only increased significantly up to the third week. PA change was correlated with BiOIoR post-treatment. Self-efficacy in self-management mediated improvement in SIS. The BiOIoR and confidence in self-management could be important factors in the rehabilitation process.
Physico-Chemical, Rheological, and Viscoelastic Properties of Starch Bio-Based Materials
Authors: Ragoubi Mohamed , Terrié Caroline , Leblanc Nathalie
Published: December 2022

This study describes the elaboration and characterization of plasticized starch composites based on lignocellulosic fibers. The transformation of native to plasticized starch (TPS) and the preparation of TPS blends were performed with a new lab-scale mixer based on an original concept. Firstly, the morphology and chemical composition of flax shives were analyzed to better understand the intrinsic properties of these natural fillers. Then, the impact of the processing parameters (temperature, speed screw) on the quality and the structural properties of plasticized starch were examined by SEM and DRX. After that, we focused on the elaboration of various formulations based on plasticized starch matrix by varying TPS formulation and filler content (from 10 to 30%). The viscoelastic and rheological properties of TPS/flax blends have been analyzed by TGA, SEM, and DMTA.
Investigating External and Internal Loads in Male Older Adult Basketball Players during Official Games
Authors: Conte Daniele , Palumbo Federico , Guidotti Flavia , Matulaitis Kestutis , Capranica Laura , Tessitore Antonio
Published: December 2022

This study aimed at assessing the external [Player Load (PL), acceleration (ACC), changes of direction (COD), JUMP, and their relative values (PL/min; ACC/min; COD/min and JUMP/min)] and internal [percentage of the peak heart rate (%HRpeak) and the training load calculated with the session rating of perceived exertion (sRPE) method (sRPE-load)] loads of masters (senior citizen) basketball players during official games. Thirteen male basketball masters players (age: 66.6 ± 2.1 years; body mass: 89.9 ± 8.7 kg; stature: 183.7 ± 4.6 cm) were monitored during an official Lietuvos Krepsinio Veteranu Lyga (LKVL) 65-year game. Beside descriptive analysis, a chi-square goodness of fit test was adopted to assess the differences in the distribution within JUMP, ACC and COD classes of intensities (i.e., low, medium and high). The results revealed PL = 269.9 ± 83.3 AU and PL/min = 6.54 ± 1.29 AU/min. Moreover, significant differences (p < 0.001) in the distribution of the intensity classes were found for JUMP, ACC, and COD, with the lowest intensities as the most frequent. Finally, HRpeak = 81.7 ± 8.1% and sRPE-load = 148.9 ± 69.7 AU were found, with sRPE = ~3 AU. In conclusion, a low external load during an official basketball game was found compared to other basketball populations. Moreover, a high objective internal load did not correspond to a low perceived demand, which might increase the training adherence and motivation during long-term studies.
Spectral Acoustic Fingerprints of Sand and Sandstone Sea Bottoms
Authors: Kushnir Uri , Frid Vladimir
Published: December 2022

Modern studies which dealt with the frequency domain analysis showed that a frequency-domain approach has an essential advantage and mentioned an inner qualitative relationship between the subsurface structure and its frequency spectra. This paper deals with the acoustic spectral response of sand and sandstone sediments at the sea bottom. An acoustic data collection campaign was conducted over two sand sites and two sandstone sites. The analysis of the results shows that reflections of acoustic signals from sand and sandstone sea bottom are characterized by various spectral features in the 2.75–6.75 kHz range. The differences in acoustic response of sand and sandstone can be quantified by examining the maximal normalized reflected power, the mean frequency, and the number of crossings at different power levels. The statistical value distribution of these potential classifiers was calculated and analyzed. These classifiers, and especially the roughness of the spectrum quantified by the number of crossings parameter can give information to assess the probability for sand or sandstone based on the reflected spectra and be used for actual distinction between sand and sandstone in sub bottom profiler data collection campaigns.
Calcineurin Inhibitor CN585 Exhibits Off-Target Effects in the Human Fungal Pathogen Aspergillus fumigatus
Authors: Juvvadi Praveen R. , Bobay Benjamin G. , Cole D. Christopher , Awwa Monaf , Steinbach William J.
Published: December 2022

Calcineurin (CN) is an attractive antifungal target as it is critical for growth, stress response, drug resistance, and virulence in fungal pathogens. The immunosuppressive drugs, tacrolimus (FK506) and cyclosporin A (CsA), are fungistatic and specifically inhibit CN through binding to their respective immunophilins, FK506-binding protein (FKBP12), and cyclophilin (CypA). We are focused on CN structure-based approaches for the development of non-immunosuppressive FK506 analogs as antifungal therapeutics. Here, we examined the effect of the novel CN inhibitor, CN585, on the growth of the human pathogen Aspergillus fumigatus, the most common cause of invasive aspergillosis. Unexpectedly, in contrast to FK506, CN585 exhibited off-target effect on A. fumigatus wild-type and the azole- and echinocandin-resistant strains. Unlike with FK506 and CsA, the A. fumigatus CN, FKBP12, CypA mutants (ΔcnaA, Δfkbp12, ΔcypA) and various FK506-resistant mutants were all sensitive to CN585. Furthermore, in contrast to FK506 the cytosolic to nuclear translocation of the CN-dependent transcription factor (CrzA-GFP) was not inhibited by CN585. Molecular docking of CN585 onto human and A. fumigatus CN complexes revealed differential potential binding sites between human CN versus A. fumigatus CN. Our results indicate CN585 may be a non-specific inhibitor of CN with a yet undefined antifungal mechanism of activity.