bluuebunny/crossref_metadata_2025 huggingface dataset:
Treatment of Chronic Kidney Disease with Extracellular Vesicles from Mesenchymal Stem Cells and CD133+ Expanded Cells: A Comparative Preclinical Analysis
Authors: Miyasaki Dayane Mayumi , Senegaglia Alexandra Cristina , de Moura Sérgio Adriane Bezerra , Leitolis Amanda , Capriglione Luiz Guilherme Achcar , Fracaro Letícia , Boldrini Leite Lidiane Maria , Utumi Paulo Henrique , Fragoso Felipe Yukio Ishikawa , Meyer Fernando , Correa Alejandro , Brofman Paulo Roberto Slud
Published: February 2022

Chronic kidney disease (CKD) is characterized by structural abnormalities and the progressive loss of kidney function. Extracellular vesicles (EVs) from human umbilical cord tissue (hUCT)-derived mesenchymal stem cells (MSCs) and expanded human umbilical cord blood (hUCB)-derived CD133+ cells (eCD133+) maintain the characteristics of the parent cells, providing a new form of cell-free treatment. We evaluated the effects of EVs from hUCT-derived MSCs and hUCB-derived CD133+ cells on rats with CDK induced by an adenine-enriched diet. EVs were isolated by ultracentrifugation and characterized by nanoparticle tracking analysis (NTA) and electron microscopy. The animals were randomized and divided into the MSC-EV group, eEPC-EV group and control group. Infusions occurred on the seventh and 14th days after CKD induction. Evaluations of kidney function were carried out by biochemical and histological analyses. Intense labeling of the α-SMA protein was observed when comparing the control with MSC-EVs. In both groups treated with EVs, a significant increase in serum albumin was observed, and the increase in cystatin C was inhibited. The results indicated improvements in renal function in CKD, demonstrating the therapeutic potential of EVs derived from MSCs and eCD133+ cells and suggesting the possibility that in the future, more than one type of EV will be used concurrently.
Pioglitazone-Loaded PLGA Nanoparticles: Towards the Most Reliable Synthesis Method
Authors: Todaro Biagio , Moscardini Aldo , Luin Stefano
Published: February 2022

Recent findings have proved the benefits of Pioglitazone (PGZ) against atherosclerosis and type 2 diabetes. Since the systematic and controllable release of this drug is of significant importance, encapsulation of this drug in nanoparticles (NPs) can minimize uncontrolled issues. In this context, drug delivery approaches based on several poly(lactic-co-glycolic acid) (PLGA) nanoparticles have been rising in popularity due to their promising capabilities. However, a fully reliable and reproducible synthetic methodology is still lacking. In this work, we present a rational optimization of the most critical formulation parameters for the production of PGZ-loaded PLGA NPs by the single emulsification-solvent evaporation or nanoprecipitation methods. We examined the influence of several variables (e.g., component concentrations, phases ratio, injection flux rate) on the synthesis of the PGZ-NPs. In addition, a comparison of these synthetic methodologies in terms of nanoparticle size, polydispersity index (PDI), zeta potential (ζp), drug loading (DL%), entrapment efficiency (EE%), and stability is offered. According to the higher entrapment efficiency content, enhanced storage time and suitable particle size, the nanoprecipitation approach appears to be the simplest, most rapid and most reliable synthetic pathway for these drug nanocarriers, and we demonstrated a very slow drug release in PBS for the best formulation obtained by this synthesis.
Theophylline Extracted from Fu Brick Tea Affects the Metabolism of Preadipocytes and Body Fat in Mice as a Pancreatic Lipase Inhibitor
Authors: Liu Tian-Tian , Liu Xiao-Tian , Huang Gui-Li , Liu Long , Chen Qing-Xi , Wang Qin
Published: February 2022

The dramatic increase in obesity is putting people under increasing pressure. Lipase inhibitors, as a kind of effective anti-obesity drug, have attracted more and more researchers’ attention in recent years because of their advantages of acting on the intestinal tract and having no side effects on the central nervous system. In this study, lipase inhibitor Fu Brick Theophylline (FBT) was screened based on enzyme molecular dynamics, and the inhibition mechanism of lipase inhibitors on obesity was analyzed and discussed at the cellular level and animal model level. We found that FBT had high inhibition effects of lipase with an IC50 of 1.02~0.03 μg/mL. Firstly, the laboratory used 3T3-L1 proadipocytes as models, flow cytometry was used to detect the effects of FBT on the cycle, apoptosis and intracellular ROS activity of proadipocytes. To study the contents of triglyceride, total cholesterol, related metabolites and related gene and protein expression in adipocytes. The results showed that FBT could reduce ROS production and inflammatory factor mRNA expression during cell differentiation. Secondly, by establishing the animal model of high-fat feed ob nutritional obese mice, the morphological observation and gene expression analysis of body weight, fat rate, adipocyte and hepatocyte metabolism of FBT obese mice were further discussed. It was proven that FBT can effectively reduce the degree of fatty liver, prevent liver fibrosis and fat accumulation, and improve the damage of mitochondrial membrane structure. This study provides a theoretical basis for the screening and clinical treatment of lipase inhibitors.
Possible Action of Olaparib for Preventing Invasion of Oral Squamous Cell Carcinoma In Vitro and In Vivo
Authors: Nakamura Nanami , Fujihara Hisako , Kawaguchi Koji , Yamada Hiroyuki , Nakayama Ryoko , Yasukawa Masaaki , Kishi Yuta , Hamada Yoshiki , Masutani Mitsuko
Published: February 2022

Despite recent advances in treatment, the prognosis of oral cancer remains poor, and prevention of recurrence and metastasis is critical. Olaparib is a PARP1 inhibitor that blocks polyADP-ribosylation, which is involved in the epithelial–mesenchymal transition (EMT) characteristic of tumor recurrence. We explored the potential of olaparib in inhibiting cancer invasion in oral carcinoma using three oral cancer cell lines, HSC-2, Ca9-22, and SAS. Olaparib treatment markedly reduced their proliferation, migration, invasion, and adhesion. Furthermore, qRT-PCR revealed that olaparib inhibited the mRNA expression of markers associated with tumorigenesis and EMT, notably Ki67, Vimentin, β-catenin, MMP2, MMP9, p53, and integrin α2 and β1, while E-Cadherin was upregulated. In vivo analysis of tumor xenografts generated by injection of HSC-2 cells into the masseter muscles of mice demonstrated significant inhibition of tumorigenesis and bone invasion by olaparib compared with the control. This was associated with reduced expression of proteins involved in osteoclastogenesis, RANK and RANKL. Moreover, SNAIL and PARP1 were downregulated, while E-cadherin was increased, indicating the effect of olaparib on proteins associated with EMT in this model. Taken together, these findings confirm the effects of olaparib on EMT and bone invasion in oral carcinoma and suggest a new therapeutic strategy for this disease.
Fertility-Sparing Approaches in Atypical Endometrial Hyperplasia and Endometrial Cancer Patients: Current Evidence and Future Directions
Authors: Contreras Nayanar-Adela , Sabadell Jordi , Verdaguer Paula , Julià Carla , Fernández-Montolí Maria-Eulalia
Published: February 2022

Endometrial cancer (EC) is the fourth most common cancer in women in developed countries. Although it is usually diagnosed in postmenopausal women, its incidence has increased in young women, as well in recent decades, with an estimated rate of 4% in those under 40 years of age. Factors involved in this increase, particularly in resource-rich countries, include delayed childbearing and the rise in obesity. The new molecular classification of EC should help to personalize treatment, through appropriate candidate selection. With the currently available evidence, the use of oral progestin either alone or in combination with other drugs such as metformin, levonorgestrel-releasing intrauterine devices and hysteroscopic resection, seems to be feasible and safe in women with early-stage EC limited to the endometrium. However, there is a lack of high-quality evidence of the efficacy and safety of conservative management in EC. Randomized clinical trials in younger women and obese patients are currently underway.
Oxytocin-Selective Nanogel Antibody Mimics
Authors: Mahajan Rashmi , Suriyanarayanan Subramanian , Olsson Gustaf D. , Wiklander Jesper G. , Aastrup Teodor , Sellergren Börje , Nicholls Ian A.
Published: February 2022

Oxytocin imprinted polymer nanoparticles were synthesized by glass bead supported solid phase synthesis, with NMR and molecular dynamics studies used to investigate monomer–template interactions. The nanoparticles were characterized by dynamic light scattering, scanning- and transmission electron microscopy and X-ray photoelectron spectroscopy. Investigation of nanoparticle-template recognition using quartz crystal microbalance-based studies revealed sub-nanomolar affinity, kd ≈ 0.3 ± 0.02 nM (standard error of the mean), comparable to that of commercial polyclonal antibodies, kd ≈ 0.02–0.2 nM.
Effects of Ruxolitinib and Calcitriol Combination Treatment on Various Molecular Subtypes of Breast Cancer
Authors: Schneider Jean , Jeon Ye Won , Suh Young Jin , Lim Seung Taek
Published: February 2022

The anticancer effects of ruxolitinib and calcitriol against breast cancer were reported previously. However, the effect of ruxolitinib and calcitriol combination treatment on various molecular subtypes of breast cancer remains unexplored. In this study, we used MCF-7, SKBR3, and MDA-MB-468 cells to investigate the effect of ruxolitinib and calcitriol combination treatment on cell proliferation, apoptosis, cell cycle, and cell signaling markers, in vitro and in vivo. Our results revealed the synergistic anticancer effect of ruxolitinib and calcitriol combination treatment in SKBR3 and MDA-MB-468 cells, but not in MCF-7 cells in vitro, via cell proliferation inhibition, apoptosis induction, cell cycle arrest, and the alteration of cell signaling protein expression, including cell cycle-related (cyclin D1, CDK1, CDK4, p21, and p27), apoptosis-related (c-caspase and c-PARP), and cell proliferation-related (c-Myc, p-p53, and p-JAK2) proteins. Furthermore, in the MDA-MB-468 xenograft mouse model, we demonstrated the synergistic antitumor effect of ruxolitinib and calcitriol combination treatment, including the alteration of c-PARP, cyclin D1, and c-Myc expression, without significant drug toxicity. The combination exhibited a synergistic effect in HER2-enriched and triple-negative breast cancer subtypes. In conclusion, our results suggest different effects of the combination treatment of ruxolitinib and calcitriol depending on the molecular subtype of breast cancer.
CabHLH79 Acts Upstream of CaNAC035 to Regulate Cold Stress in Pepper
Authors: Wang Ziyu , Zhang Yumeng , Hu Huifang , Chen Lang , Zhang Huafeng , Chen Rugang
Published: February 2022

Cold stress is one of the main restricting factors affecting plant growth and agricultural production. Complex cold signaling pathways induce the expression of hundreds of cold-sensitive genes. The NAC transcription factor CaNAC035 has previously been reported to significantly influence the response of pepper to cold stress. Here, using Yeast one-hybrid (Y1H) library screened to search for other relevant molecular factors, we identified that CabHLH79 directly binds to the CaNAC035 promoter. Different basic helix–loop–helix (bHLH) transcription factors (TFs) in plants significantly respond to multiple plant stresses, but the mechanism of bHLHs in the cold tolerance of pepper is still unclear. This study investigated the functional characterization of CabHLH79 in the regulation of cold resistance in pepper. Down-regulation of CabHLH79 in pepper by virus-induced gene silencing (VIGS) increased its sensitivity to low temperature, whereas overexpression of CabHLH79 in pepper or Arabidopsis enhanced cold resistance. Compared with control plants, VIGS mediated of CabHLH79 had lower enzyme activity and related gene expression levels, accompanied by higher reactive oxygen species (ROS) accumulation, relative electrolyte leakage (REL), and malondialdehyde accumulation (MDA) contents. Transient overexpression of CabHLH79 pepper positively regulated cold stress response genes and ROS genes, which reduced REL and MDA contents. Similarly, ectopic expression of CabHLH79 in Arabidopsis showed less ROS accumulation, and higher enzymes activities and expression levels. These results indicated that CabHLH79 enhanced cold tolerance by enhancing the expression of ROS-related and other cold stress tolerance-related genes. Taken together, our results showed a multifaceted module of bHLH79-NAC035 in the cold stress of pepper.
Transcriptomic and Network Analyses Reveal Immune Modulation by Endocannabinoids in Approach/Avoidance Traits
Authors: Termine Andrea , Fabrizio Carlo , Gimenez Juliette , Panuccio Anna , Balsamo Francesca , Passarello Noemi , Caioli Silvia , Saba Luana , De Bardi Marco , Della Valle Francesco , Orlando Valerio , Petrosini Laura , Laricchiuta Daniela
Published: February 2022

Approach and avoidance (A/A) tendencies are stable behavioral traits in responding to rewarding and fearful stimuli. They represent the superordinate division of emotion, and individual differences in such traits are associated with disease susceptibility. The neural circuitry underlying A/A traits is retained to be the cortico-limbic pathway including the amygdala, the central hub for the emotional processing. Furthermore, A/A-specific individual differences are associated with the activity of the endocannabinoid system (ECS) and especially of CB1 receptors whose density and functionality in amygdala differ according to A/A traits. ECS markedly interacts with the immune system (IS). However, how the interplay between ECS and IS is associated with A/A individual differences is still ill-defined. To fill this gap, here we analyzed the interaction between the gene expression of ECS and immune system (IS) in relation to individual differences. To unveil the deep architecture of ECS-IS interaction, we performed cell-specific transcriptomics analysis. Differential gene expression profiling, functional enrichment, and protein–protein interaction network analyses were performed in amygdala pyramidal neurons of mice showing different A/A behavioral tendencies. Several altered pro-inflammatory pathways were identified as associated with individual differences in A/A traits, indicating the chronic activation of the adaptive immune response sustained by the interplay between endocannabinoids and the IS. Furthermore, results showed that the interaction between the two systems modulates synaptic plasticity and neuronal metabolism in individual difference-specific manner. Deepening our knowledge about ECS/IS interaction may provide useful targets for treatment and prevention of psychopathology associated with A/A traits.
Comparison of Injectable Biphasic Calcium Phosphate and a Bovine Xenograft in Socket Preservation: Qualitative and Quantitative Histologic Study in Humans
Authors: Čandrlić Marija , Tomas Matej , Karl Matej , Malešić Lucija , Včev Aleksandar , Perić Kačarević Željka , Matijević Marko
Published: February 2022

This study is the first histologic evaluation of an injectable biphasic calcium phosphate (IBCP) in humans six months after socket preservation according to the principles of guided bone regeneration. After tooth extraction, the alveolar ridge of 21 patients was augmented with IBCP (maxresorb® inject) in the test group, while 20 patients in the control group received a bovine xenograft (BX) (cerabone®). Six months after augmentation, a reentry procedure was performed to collect biopsies of regenerated bone for qualitative and quantitative histologic analysis. A total of 20 biopsies were taken for analysis. Qualitative histologic analysis showed complete integration of the biomaterial and no inflammatory tissue reaction, indicating the biocompatibility of the bone grafts and the surrounding tissue in both groups. Histomorphometric analysis showed comparable results in terms of newly formed bone (IBCP: 26.47 ± 14.71%, BX: 30.47 ± 16.39%) and residual biomaterial (IBCP: 13.1 ± 14.07%, BX: 17.89 ± 11.81%), with no significant difference found across groups (p > 0.05, Mann—Whitney U test). Statistical significance between groups was found in the result of soft tissue percentage (IBCP: 60.43 ± 12.73%, BX: 51.64 ± 14.63%, p = 0.046, Mann—Whitney U test). To conclude, IBCP and BX showed good osteoconductivity and biocompatibility with comparable new bone formation six months after alveolar ridge preservation.
Identification of Novel and Potent Indole-Based Benzenesulfonamides as Selective Human Carbonic Anhydrase II Inhibitors: Design, Synthesis, In Vitro, and In Silico Studies
Authors: Elkamhawy Ahmed , Woo Jiyu , Nada Hossam , Angeli Andrea , Bedair Tarek M. , Supuran Claudiu T. , Lee Kyeong
Published: February 2022

In recent decades, human carbonic anhydrase inhibitors (hCAIs) have emerged as an important therapeutic class with various applications including antiglaucoma, anticonvulsants, and anticancer agents. Herein, a novel series of indole-based benzenesulfonamides were designed, synthesized, and biologically evaluated as potential hCAIs. A regioisomerism of the sulfonamide moiety was carried out to afford a total of fifteen indole-based benzenesulfonamides possessing different amide linkers that enable the ligands to be flexible and develop potential H-bond interaction(s) with the target protein. The activity of the synthesized compounds was evaluated against four hCA isoforms (I, II, IX and, XII). Compounds 2b, 2c, 2d, 2f, 2h and 2o exhibited potent and selective profiles over the hCA II isoform with Ki values of 7.3, 9.0, 7.1, 16.0, 8.6 and 7.5 nM, respectively. Among all, compound 2a demonstrated the most potent inhibition against the hCA II isoform with an inhibitory constant (Ki) of 5.9 nM, with 13-, 34-, and 9-fold selectivity for hCA II over I, IX and XII isoforms, respectively. Structure–activity relationship data attained for various substitutions were rationalized. Furthermore, a molecular docking study gave insights into both inhibitory activity and selectivity of the target compounds. Accordingly, this report presents a successful scaffold hoping approach that reveals compound 2a as a highly potent and selective indole-based hCA II inhibitor worthy of further investigation.
Hierarchically Structured Surfaces Prepared by Phase Separation: Tissue Mimicking Culture Substrate
Authors: Kadlečková Markéta , Skopalová Kateřina , Ptošková Barbora , Wrzecionko Erik , Daďová Eliška , Kocourková Karolína , Mráček Aleš , Musilová Lenka , Smolka Petr , Humpolíček Petr , Minařík Antonín
Published: February 2022

The pseudo 3D hierarchical structure mimicking in vivo microenvironment was prepared by phase separation on tissue culture plastic. For surface treatment, time-sequenced dosing of the solvent mixture with various concentrations of polymer component was used. The experiments showed that hierarchically structured surfaces with macro, meso and micro pores can be prepared with multi-step phase separation processes. Changes in polystyrene surface topography were characterized by atomic force microscopy, scanning electron microscopy and contact profilometry. The cell proliferation and changes in cell morphology were tested on the prepared structured surfaces. Four types of cell lines were used for the determination of impact of the 3D architecture on the cell behavior, namely the mouse embryonic fibroblast, human lung carcinoma, primary human keratinocyte and mouse embryonic stem cells. The increase of proliferation of embryonic stem cells and mouse fibroblasts was the most remarkable. Moreover, the embryonic stem cells express different morphology when cultured on the structured surface. The acquired findings expand the current state of knowledge in the field of cell behavior on structured surfaces and bring new technological procedures leading to their preparation without the use of problematic temporary templates or additives.
Senescent CD4+CD28− T Lymphocytes as a Potential Driver of Th17/Treg Imbalance and Alveolar Bone Resorption during Periodontitis
Authors: González-Osuna Luis , Sierra-Cristancho Alfredo , Cafferata Emilio A. , Melgar-Rodríguez Samanta , Rojas Carolina , Carvajal Paola , Cortez Cristian , Vernal Rolando
Published: February 2022

Senescent cells express a senescence-associated secretory phenotype (SASP) with a pro-inflammatory bias, which contributes to the chronicity of inflammation. During chronic inflammatory diseases, infiltrating CD4+ T lymphocytes can undergo cellular senescence and arrest the surface expression of CD28, have a response biased towards T-helper type-17 (Th17) of immunity, and show a remarkable ability to induce osteoclastogenesis. As a cellular counterpart, T regulatory lymphocytes (Tregs) can also undergo cellular senescence, and CD28− Tregs are able to express an SASP secretome, thus severely altering their immunosuppressive capacities. During periodontitis, the persistent microbial challenge and chronic inflammation favor the induction of cellular senescence. Therefore, senescence of Th17 and Treg lymphocytes could contribute to Th17/Treg imbalance and favor the tooth-supporting alveolar bone loss characteristic of the disease. In the present review, we describe the concept of cellular senescence; particularly, the one produced during chronic inflammation and persistent microbial antigen challenge. In addition, we detail the different markers used to identify senescent cells, proposing those specific to senescent T lymphocytes that can be used for periodontal research purposes. Finally, we discuss the existing literature that allows us to suggest the potential pathogenic role of senescent CD4+CD28− T lymphocytes in periodontitis.
Integrated Proteomics and Metabolomics Analysis of Nitrogen System Regulation on Soybean Plant Nodulation and Nitrogen Fixation
Authors: Lyu Xiaochen , Sun Chunyan , Zhang Jin , Wang Chang , Zhao Shuhong , Ma Chunmei , Li Sha , Li Hongyu , Gong Zhenping , Yan Chao
Published: February 2022

The specific mechanisms by which nitrogen affects nodulation and nitrogen fixation in leguminous crops are still unclear. To study the relationship between nitrogen, nodulation and nitrogen fixation in soybeans, dual-root soybean plants with unilateral nodulation were prepared by grafting. At the third trifoliate leaf (V3) to fourth trifoliate leaf (V4) growth stages (for 5 days), nitrogen nutrient solution was added to the non-nodulated side, while nitrogen-free nutrient solution was added to the nodulated side. The experiment was designed to study the effects of exogenous nitrogen on proteins and metabolites in root nodules and provide a theoretical reference for analyzing the physiological mechanisms of the interaction between nitrogen application and nitrogen fixation in soybean root nodules. Compared with no nitrogen treatment, exogenous nitrogen regulated the metabolic pathways of starch and sucrose metabolism, organic acid metabolism, nitrogen metabolism, and amino acid metabolism, among others. Additionally, exogenous nitrogen promoted the synthesis of signaling molecules, including putrescine, nitric oxide, and asparagine in root nodules, and inhibited the transformation of sucrose to malic acid; consequently, the rhizobia lacked energy for nitrogen fixation. In addition, exogenous nitrogen reduced cell wall synthesis in the root nodules, thus inhibiting root nodule growth and nitrogen fixation.
Mast Cells in the Mammalian Testis and Epididymis—Animal Models and Detection Methods
Authors: Himelreich-Perić Marta , Katušić-Bojanac Ana , Hohšteter Marko , Sinčić Nino , Mužić-Radović Vedrana , Ježek Davor
Published: February 2022

Mast cells (MCs) are an evolutionary well-conserved type of cells, mediating and modulating allergic responses in innate immunity and tissue remodeling after chronic inflammation. Among other tissues, they inhabit both the testis and epididymis. In the testis, MCs usually appear in the interstitial compartment in humans, but not in other standard experimental models, like rats and mice. MCs seem to be responsible for testicular tissue fibrosis in different causes of infertility. Although experimental animal models follow the effect on MC activation or penetration to the interstitial tissue like in humans to some extent, there is an inconsistency in the available literature regarding experimental design, animal strain, and detection methods used. This comprehensive review offers an insight into the literature on MCs in mammalian testes and epididymides. We aimed to find the most suitable model for research on MC and offer recommendations for future experimental designs. When using in vivo animal models, tunica albuginea incorporation and standard histological assessment need to be included. Domesticated boar strains kept in modified controlled conditions exhibit the highest similarity to the MC distribution in the human testis. 3D testicular models are promising but need further fine-tuning to become a valid model for MC investigation.
Alternative Brain Slice-on-a-Chip for Organotypic Culture and Effective Fluorescence Injection Testing
Authors: Herreros Pedro , Tapia-González Silvia , Sánchez-Olivares Laura , Laguna Heras María Fe , Holgado Miguel
Published: February 2022

Mouse brain slices are one of the most common models to study brain development and functioning, increasing the number of study models that integrate microfluidic systems for hippocampal slice cultures. This report presents an alternative brain slice-on-a-chip, integrating an injection system inside the chip to dispense a fluorescent dye for long-term monitoring. Hippocampal slices have been cultured inside these chips, observing fluorescence signals from living cells, maintaining the cytoarchitecture of the slices. Having fluorescence images of biological samples inside the chip demonstrates the effectiveness of the staining process using the injection method avoiding leaks or biological contamination. The technology developed in this study presents a significant improvement in the local administration of reagents within a brain slice-on-a-chip system, which could be a suitable option for organotypic cultures in a microfluidic chip acting as a highly effective bioreactor.
Mesenchymal Stem Cells: Therapeutic Mechanisms for Stroke
Authors: Zhang Yuchen , Dong Naijun , Hong Huanle , Qi Jingxuan , Zhang Shibo , Wang Jiao
Published: February 2022

Due to aging of the world’s population, stroke has become increasingly prevalent, leading to a rise in socioeconomic burden. In the recent past, stroke research and treatment have become key scientific issues that need urgent solutions, with a sharp focus on stem cell transplantation, which is known to treat neurodegenerative diseases related to traumatic brain injuries, such as stroke. Indeed, stem cell therapy has brought hope to many stroke patients, both in animal and clinical trials. Mesenchymal stem cells (MSCs) are most commonly utilized in biological medical research, due to their pluripotency and universality. MSCs are often obtained from adipose tissue and bone marrow, and transplanted via intravenous injection. Therefore, this review will discuss the therapeutic mechanisms of MSCs and extracellular vehicles (EVs) secreted by MSCs for stroke, such as in attenuating inflammation through immunomodulation, releasing trophic factors to promote therapeutic effects, inducing angiogenesis, promoting neurogenesis, reducing the infarct volume, and replacing damaged cells.
Modulation of Inflammatory Cytokine Production in Human Monocytes by cGMP and IRAK3
Authors: Nguyen Trang H. , Axell Anna , Turek Ilona , Wright Bree , Meehan-Andrews Terri , Irving Helen R.
Published: February 2022

Interleukin-1 receptor-associated kinase-3 (IRAK3) is a critical checkpoint molecule of inflammatory responses in the innate immune system. The pseudokinase domain of IRAK3 contains a guanylate cyclase (GC) centre that generates small amounts of cyclic guanosine monophosphate (cGMP) associated with IRAK3 functions in inflammation. However, the mechanisms of IRAK3 actions are poorly understood. The effects of low cGMP levels on inflammation are unknown, therefore a dose–response effect of cGMP on inflammatory markers was assessed in THP-1 monocytes challenged with lipopolysaccharide (LPS). Sub-nanomolar concentrations of membrane permeable 8-Br-cGMP reduced LPS-induced NFκB activity, IL-6 and TNF-α cytokine levels. Pharmacologically upregulating cellular cGMP levels using a nitric oxide donor reduced cytokine secretion. Downregulating cellular cGMP using a soluble GC inhibitor increased cytokine levels. Knocking down IRAK3 in THP-1 cells revealed that unlike the wild type cells, 8-Br-cGMP did not suppress inflammatory responses. Complementation of IRAK3 knockdown cells with wild type IRAK3 suppressed cytokine production while complementation with an IRAK3 mutant at GC centre only partially restored this function. Together these findings indicate low levels of cGMP form a critical component in suppressing cytokine production and in mediating IRAK3 action, and this may be via a cGMP enriched nanodomain formed by IRAK3 itself.
Physicochemical and Theoretical Characterization of a New Small Non-Metal Schiff Base with a Differential Antimicrobial Effect against Gram-Positive Bacteria
Authors: Gacitúa Manuel , Carreño Alexander , Morales-Guevara Rosaly , Páez-Hernández Dayán , Martínez-Araya Jorge I. , Araya Eyleen , Preite Marcelo , Otero Carolina , Rivera-Zaldívar María Macarena , Silva Andrés , Fuentes Juan A.
Published: February 2022

Searching for adequate and effective compounds displaying antimicrobial activities, especially against Gram-positive bacteria, is an important research area due to the high hospitalization and mortality rates of these bacterial infections in both the human and veterinary fields. In this work, we explored (E)-4-amino-3-((3,5-di-tert-butyl-2-hydroxybenzylidene)amino) benzoic acid (SB-1, harboring an intramolecular hydrogen bond) and (E)-2-((4-nitrobenzilidene)amino)aniline (SB-2), two Schiff bases derivatives. Results demonstrated that SB-1 showed an antibacterial activity determined by the minimal inhibitory concentration (MIC) against Staphylococcus aureus, Enterococcus faecalis, and Bacillus cereus (Gram-positive bacteria involved in human and animal diseases such as skin infections, pneumonia, diarrheal syndrome, and urinary tract infections, among others), which was similar to that shown by the classical antibiotic chloramphenicol. By contrast, this compound showed no effect against Gram-negative bacteria (Klebsiella pneumoniae, Escherichia coli, and Salmonella enterica). Furthermore, we provide a comprehensive physicochemical and theoretical characterization of SB-1 (as well as several analyses for SB-2), including elemental analysis, ESMS, 1H and 13C NMR (assigned by 1D and 2D techniques), DEPT, UV-Vis, FTIR, and cyclic voltammetry. We also performed a computational study through the DFT theory level, including geometry optimization, TD-DFT, NBO, and global and local reactivity analyses.
Evaluation of Myeloperoxidase as Target for Host-Directed Therapy in Tuberculosis In Vivo
Authors: Linnemann Lara C. , Schaible Ulrich E. , Dallenga Tobias K.
Published: February 2022

Due to the rise of tuberculosis cases infected with multi and extensively drug-resistant Mycobacterium tuberculosis strains and the emergence of isolates resistant to antibiotics newly in clinical use, host-directed therapies targeting pathogenesis-associated immune pathways adjunct to antibiotics may ameliorate disease and bacterial clearance. Active tuberculosis is characterized by neutrophil-mediated lung pathology and tissue destruction. Previously, we showed that preventing M. tuberculosis induced necrosis in human neutrophils by inhibition of myeloperoxidase (MPO) promoted default apoptosis and subsequent control of mycobacteria by macrophages taking up the mycobacteria-infected neutrophils. To translate our findings in an in vivo model, we tested the MPO inhibitor 4-aminobenzoic acid hydrazide (ABAH) in C3HeB/FeJ mice, which are highly susceptible to M. tuberculosis infection manifesting in neutrophil-associated necrotic granulomas. MPO inhibition alone or as co-treatment with isoniazid, a first-line antibiotic in tuberculosis treatment, did not result in reduced bacterial burden, improved pathology, or altered infiltrating immune cell compositions. MPO inhibition failed to prevent M. tuberculosis induced neutrophil necrosis in C3Heb/FeJ mice in vivo as well as in murine neutrophils in vitro. In contrast to human neutrophils, murine neutrophils do not respond to M. tuberculosis infection in an MPO-dependent manner. Thus, the murine C3HeB/FeJ model does not fully resemble the pathomechanisms in active human tuberculosis. Consequently, murine infection models of tuberculosis are not necessarily adequate to evaluate host-directed therapies targeting neutrophils in vivo.
Activation of Mast-Cell-Derived Chymase in the Lacrimal Glands of Patients with IgG4-Related Ophthalmic Disease
Authors: Fujita Yasushi , Jin Denan , Mimura Masashi , Sato Yohei , Takai Shinji , Kida Teruyo
Published: February 2022

The purpose of this present study was to investigate the distribution and expression of chymase in the lacrimal glands (LGs) of patients afflicted with IgG4-related ophthalmic disease (IgG4-ROD). LGs from patients with severe canalicular obstruction were considered the control group. Toluidine blue staining confirmed a significant increase in the number of mast cells in the LGs obtained from the IgG4-ROD patients. In addition, immunostaining of serial sections from the LGs showed a significant increase in the number of chymase-positive cells and tryptase-positive cells in the IgG4-ROD LGs compared to the normal control LGs. The mRNA expression of chymase, tryptase, TGF-β1, and collagen-I tended to increase in the IgG4-ROD LGs. Immunostaining of vimentin and α-smooth muscle actin (α-SMA) showed that myofibroblasts were the main cellular components in severely fibrotic regions of LGs in patients with IgG4-ROD. Linear regression analyses on the number of mast cells, chymase-positive cells, and tryptase-positive cells revealed significant positive correlations between those respective cells. Our findings suggest that chymase may play a role in the fibrotic disorder of IgG4-ROD LGs through the regulation of TGF-β1 activation and collagen-I deposition, and that it may be a therapeutic target for patients afflicted with IgG4-ROD.
A Hybrid Machine Learning and Network Analysis Approach Reveals Two Parkinson’s Disease Subtypes from 115 RNA-Seq Post-Mortem Brain Samples
Authors: Termine Andrea , Fabrizio Carlo , Strafella Claudia , Caputo Valerio , Petrosini Laura , Caltagirone Carlo , Cascella Raffaella , Giardina Emiliano
Published: February 2022

Precision medicine emphasizes fine-grained diagnostics, taking individual variability into account to enhance treatment effectiveness. Parkinson’s disease (PD) heterogeneity among individuals proves the existence of disease subtypes, so subgrouping patients is vital for better understanding disease mechanisms and designing precise treatment. The purpose of this study was to identify PD subtypes using RNA-Seq data in a combined pipeline including unsupervised machine learning, bioinformatics, and network analysis. Two hundred and ten post mortem brain RNA-Seq samples from PD (n = 115) and normal controls (NCs, n = 95) were obtained with systematic data retrieval following PRISMA statements and a fully data-driven clustering pipeline was performed to identify PD subtypes. Bioinformatics and network analyses were performed to characterize the disease mechanisms of the identified PD subtypes and to identify target genes for drug repurposing. Two PD clusters were identified and 42 DEGs were found (p adjusted ≤ 0.01). PD clusters had significantly different gene network structures (p < 0.0001) and phenotype-specific disease mechanisms, highlighting the differential involvement of the Wnt/β-catenin pathway regulating adult neurogenesis. NEUROD1 was identified as a key regulator of gene networks and ISX9 and PD98059 were identified as NEUROD1-interacting compounds with disease-modifying potential, reducing the effects of dopaminergic neurodegeneration. This hybrid data analysis approach could enable precision medicine applications by providing insights for the identification and characterization of pathological subtypes. This workflow has proven useful on PD brain RNA-Seq, but its application to other neurodegenerative diseases is encouraged.
Staphylococcal Enterotoxin Genes in Coagulase-Negative Staphylococci—Stability, Expression, and Genomic Context
Authors: Banaszkiewicz Sylwia , Wałecka-Zacharska Ewa , Schubert Justyna , Tabiś Aleksandra , Król Jarosław , Stefaniak Tadeusz , Węsierska Ewelina , Bania Jacek
Published: February 2022

In the current study, we screened a collection of coagulase-negative staphylococci (CoNS) isolates for orthologues of staphylococcal enterotoxins (SEs) involved in S. aureus-related staphylococcal food poisoning (SFP). The amplicons corresponding to SEs were detected in S. chromogenes, S. epidermidis, S. haemolyticus, S. borealis, S. pasteuri, S. saprophyticus, S. vitulinus, S. warneri, and S. xylosus. All amplicons were sequenced and identified as parts of known S. aureus or S. epidermidis SE genes. Quantitative real-time PCR allowed determining the relative copy number of each SE amplicon. A significant portion of the amplicons of the sea, seb, sec, and seh genes occurred at low copy numbers. Only the amplicons of the sec gene identified in three isolates of S. epidermidis displayed relative copy numbers comparable to sec in the reference enterotoxigenic S. aureus and S. epidermidis strains. Consecutive passages in microbiological media of selected CoNS isolates carrying low copy numbers of sea, seb, sec, and seh genes resulted in a decrease of gene copy number. S. epidermidis isolates harbored a high copy number of sec, which remained stable over the passages. We demonstrated that enterotoxin genes may occur at highly variable copy numbers in CoNS. However, we could identify enterotoxin genes only in whole-genome sequences of CoNS carrying them in a stable form at high copy numbers. Only those enterotoxins were expressed at the protein level. Our results indicate that PCR-based detection of enterotoxin genes in CoNS should always require an additional control, like analysis of their presence in the bacterial genome. We also demonstrate S. epidermidis as a CoNS species harboring SE genes in a stable form at a specific chromosome site and expressing them as a protein.
Synergistic Control of Transmitter Turnover at Glycinergic Synapses by GlyT1, GlyT2, and ASC-1
Authors: Eulenburg Volker , Hülsmann Swen
Published: February 2022

In addition to being involved in protein biosynthesis and metabolism, the amino acid glycine is the most important inhibitory neurotransmitter in caudal regions of the brain. These functions require a tight regulation of glycine concentration not only in the synaptic cleft, but also in various intracellular and extracellular compartments. This is achieved not only by confining the synthesis and degradation of glycine predominantly to the mitochondria, but also by the action of high-affinity large-capacity glycine transporters that mediate the transport of glycine across the membranes of presynaptic terminals or glial cells surrounding the synapses. Although most cells at glycine-dependent synapses express more than one transporter with high affinity for glycine, their synergistic functional interaction is only poorly understood. In this review, we summarize our current knowledge of the two high-affinity transporters for glycine, the sodium-dependent glycine transporters 1 (GlyT1; SLC6A9) and 2 (GlyT2; SLC6A5) and the alanine–serine–cysteine-1 transporter (Asc-1; SLC7A10).
Imbalances in TCA, Short Fatty Acids and One-Carbon Metabolisms as Important Features of Homeostatic Disruption Evidenced by a Multi-Omics Integrative Approach of LPS-Induced Chronic Inflammation in Male Wistar Rats
Authors: Hernandez-Baixauli Julia , Abasolo Nerea , Palacios-Jordan Hector , Foguet-Romero Elisabet , Suñol David , Galofré Mar , Caimari Antoni , Baselga-Escudero Laura , Del Bas Josep M , Mulero Miquel
Published: February 2022

Chronic inflammation is an important risk factor in a broad variety of physical and mental disorders leading to highly prevalent non-communicable diseases (NCDs). However, there is a need for a deeper understanding of this condition and its progression to the disease state. For this reason, it is important to define metabolic pathways and complementary biomarkers associated with homeostatic disruption in chronic inflammation. To achieve that, male Wistar rats were subjected to intraperitoneal and intermittent injections with saline solution or increasing lipopolysaccharide (LPS) concentrations (0.5, 5 and 7.5 mg/kg) thrice a week for 31 days. Biochemical and inflammatory parameters were measured at the end of the study. To assess the omics profile, GC-qTOF and UHPLC-qTOF were performed to evaluate plasma metabolome; 1H-NMR was used to evaluate urine metabolome; additionally, shotgun metagenomics sequencing was carried out to characterize the cecum microbiome. The chronicity of inflammation in the study was evaluated by the monitoring of monocyte chemoattractant protein-1 (MCP-1) during the different weeks of the experimental process. At the end of the study, together with the increased levels of MCP-1, levels of interleukin-6 (IL-6), tumour necrosis factor alpha (TNF-α) and prostaglandin E2 (PGE2) along with 8-isoprostanes (an indicative of oxidative stress) were significantly increased (p-value < 0.05). The leading features implicated in the current model were tricarboxylic acid (TCA) cycle intermediates (i.e., alpha-ketoglutarate, aconitic acid, malic acid, fumaric acid and succinic acid); lipids such as specific cholesterol esters (ChoEs), lysophospholipids (LPCs) and phosphatidylcholines (PCs); and glycine, as well as N, N-dimethylglycine, which are related to one-carbon (1C) metabolism. These metabolites point towards mitochondrial metabolism through TCA cycle, β-oxidation of fatty acids and 1C metabolism as interconnected pathways that could reveal the metabolic effects of chronic inflammation induced by LPS administration. These results provide deeper knowledge concerning the impact of chronic inflammation on the disruption of metabolic homeostasis.
Anisotropic Elasticity of the Myosin Motor in Muscle
Authors: Caremani Marco , Reconditi Massimo
Published: February 2022

To define the mechanics and energetics of the myosin motor action in muscles, it is mandatory to know fundamental parameters such as the stiffness and the force of the single myosin motor, and the fraction of motors attached during contraction. These parameters can be defined in situ using sarcomere−level mechanics in single muscle fibers under the assumption that the stiffness of a myosin dimer with both motors attached (as occurs in rigor, when all motors are attached) is twice that of a single motor (as occurs in the isometric contraction). We use a mechanical/structural model to identify the constraints that underpin the stiffness of the myosin dimer with both motors attached to actin. By comparing the results of the model with the data in the literature, we conclude that the two-fold axial stiffness of the dimers with both motors attached is justified by a stiffness of the myosin motor that is anisotropic and higher along the axis of the myofilaments. A lower azimuthal stiffness of the motor plays an important role in the complex architecture of the sarcomere by allowing the motors to attach to actin filaments at different azimuthal angles relative to the thick filament.
Measurement in the Age of Information
Authors: Webler Forrest , Andersen Marilyne
Published: February 2022

Information is the resolution of uncertainty and manifests itself as patterns. Although complex, most observable phenomena are not random and instead are associated with deterministic, chaotic systems. The underlying patterns and symmetries expressed from these phenomena determine their information content and compressibility. While some patterns, such as the existence of Fourier modes, are easy to extract, advances in machine learning have enabled more comprehensive methods in feature extraction, most notably in their ability to elicit non-linear relationships. Herein we review methods concerned with the encoding and reconstruction of natural signals and how they might inform the discovery of useful transform bases. Additionally, we illustrate the efficacy of data-driven bases over generic ones in encoding information whilst discussing these developments in the context of “fourth paradigm” metrology. Toward this end, we propose that existing metrological standards and norms may need to be redefined within the context of a data-rich world.
Observer-Based Active Fault-Tolerant Control of an Asymmetric Twin Wind Turbine
Authors: Makni Mariem , Haidar Ihab , Barbot Jean-Pierre , Plestan Franck , Feki Nabih , Abbes Mohamed Slim
Published: February 2022

This paper deals with the design of an active fault-tolerant control based on observers for a twin wind turbine, consisting of two wind turbines mounted on the same tower. We consider an asymmetric conditions case, when only one turbine is affected by an inter-turn short circuit fault of a permanent magnet synchronous machine. A diagnosis design is developed which combines the fault estimation method together with an active fault-tolerant control. The main advantage of the proposed method is to detect and correct the considered fault in a short time in order that the twin wind turbine behaves as it does in the healthy case.
Visual Analytics for Predicting Disease Outcomes Using Laboratory Test Results
Authors: Rostamzadeh Neda , Abdullah Sheikh S. , Sedig Kamran , Garg Amit X. , McArthur Eric
Published: February 2022

Laboratory tests play an essential role in the early and accurate diagnosis of diseases. In this paper, we propose SUNRISE, a visual analytics system that allows the user to interactively explore the relationships between laboratory test results and a disease outcome. SUNRISE integrates frequent itemset mining (i.e., Eclat algorithm) with extreme gradient boosting (XGBoost) to develop more specialized and accurate prediction models. It also includes interactive visualizations to allow the user to interact with the model and track the decision process. SUNRISE helps the user probe the prediction model by generating input examples and observing how the model responds. Furthermore, it improves the user’s confidence in the generated predictions and provides them the means to validate the model’s response by illustrating the underlying working mechanism of the prediction models through visualization representations. SUNRISE offers a balanced distribution of processing load through the seamless integration of analytical methods with interactive visual representations to support the user’s cognitive tasks. We demonstrate the usefulness of SUNRISE through a usage scenario of exploring the association between laboratory test results and acute kidney injury, using large provincial healthcare databases from Ontario, Canada.