bluuebunny/crossref_metadata_2025 huggingface dataset:
Ribosomal Protein S6: A Potential Therapeutic Target against Cancer?
Authors: Yi Yong Weon , You Kyu Sic , Park Jeong-Soo , Lee Seok-Geun , Seong Yeon-Sun
Published: December 2021

Ribosomal protein S6 (RPS6) is a component of the 40S small ribosomal subunit and participates in the control of mRNA translation. Additionally, phospho (p)-RPS6 has been recognized as a surrogate marker for the activated PI3K/AKT/mTORC1 pathway, which occurs in many cancer types. However, downstream mechanisms regulated by RPS6 or p-RPS remains elusive, and the therapeutic implication of RPS6 is underappreciated despite an approximately half a century history of research on this protein. In addition, substantial evidence from RPS6 knockdown experiments suggests the potential role of RPS6 in maintaining cancer cell proliferation. This motivates us to investigate the current knowledge of RPS6 functions in cancer. In this review article, we reviewed the current information about the transcriptional regulation, upstream regulators, and extra-ribosomal roles of RPS6, with a focus on its involvement in cancer. We also discussed the therapeutic potential of RPS6 in cancer.
The Influence of Angiotensin Peptides on Survival and Motility of Human High-Grade Serous Ovarian Cancer Cells in Serum Starvation Conditions
Authors: Domińska Kamila , Urbanek Kinga Anna , Kowalska Karolina , Habrowska-Górczyńska Dominika Ewa , Kozieł Marta Justyna , Ochędalski Tomasz , Piastowska-Ciesielska Agnieszka Wanda
Published: December 2021

High-grade serous ovarian carcinoma (HGSOC) is the most frequent and malignant form of ovarian cancer. A local renin–angiotensin system (RAS) has been found in the ovary, and changes in selected components of this system were observed in pathological states and also in ovarian cancer. In the present study, we examined the effect of three peptides, Ang-(1-7), Ang-(1-9) and Ang-(3-7), on proliferation and motility of the OVPA8 cell line, a new well-defined and preclinical model of HGSOC. We confirmed the presence of mRNA for all angiotensin receptors in the tested cells. Furthermore, our findings indicate that all tested angiotensin peptides increased the metabolic serum in the medium by activation of cell defense mechanisms such as nuclear factor kappaB signaling pathway andapoptosis. Moreover, tested angiotensin peptides intensified serum starvation-induced cell cycle arrest at the G0/G1 phase. In the case of Ang-(3-7), a significant decrease in the number of Ki67 positive cells (Ki67+) and reduced percentage of activated ERK1/2 levels in ovarian cancer cells were additionally reported. The angiotensin-induced effect of the accumulation of cells in the G0/G1 phase was not observed in OVPA8 cells growing on the medium with 10% FBS. Moreover, in the case of Ang-(3-7), the tendency was quite the opposite. Ang-(1-7) but not Ang-(1-9) or Ang-(3-7) increased the mobility of reluctant-to-migrate OVAP8 cells cultured in the serum-free medium. In any cases, the changes in the expression of VIM and HIF1A gene, associated with epithelial–mesenchymal transition (EMT), were not observed. In conclusion, we speculate that the adaptation to starvation in nutrient-deprived tumors can be modulated by peptides from the renin–angiotensin system. The influence of angiotensin peptides on cancer cells is highly dependent on the availability of growth factors and nutrients.
A Quantitative Systems Approach to Define Novel Effects of Tumour p53 Mutations on Binding Oncoprotein MDM2
Authors: Fuentes Manuel , Srivastava Sanjeeva , Gronenborn Angela M. , LaBaer Joshua
Published: December 2021

Understanding transient protein interactions biochemically at the proteome scale remains a long-standing challenge. Current tools developed to study protein interactions in high-throughput measure stable protein complexes and provide binary readouts; they do not elucidate dynamic and weak protein interactions in a proteome. The majority of protein interactions are transient and cover a wide range of affinities. Nucleic acid programmable protein arrays (NAPPA) are self-assembling protein microarrays produced by freshly translating full-length proteins in situ on the array surface. Herein, we have coupled NAPPA to surface plasmon resonance imaging (SPRi) to produce a novel label-free platform that measures many protein interactions in real-time allowing the determination of the KDs and rate constants. The developed novel NAPPA-SPRi technique showed excellent ability to study protein-protein interactions of clinical mutants of p53 with its regulator MDM2. Furthermore, this method was employed to identify mutant p53 proteins insensitive to the drug nutlin-3, currently in clinical practice, which usually disrupts the p53-MDM2 interactions. Thus, significant differences in the interactions were observed for p53 mutants on the DNA binding domain (Arg-273-Cys, Arg-273-His, Arg-248-Glu, Arg-280-Lys), on the structural domain (His-179-Tyr, Cys-176-Phe), on hydrophobic moieties in the DNA binding domain (Arg-280-Thr, Pro-151-Ser, Cys-176-Phe) and hot spot mutants (Gly-245-Cys, Arg-273-Leu, Arg-248-Glu, Arg-248-Gly), which signifies the importance of point mutations on the MDM2 interaction and nutlin3 effect, even in molecular locations related to other protein activities.
The Non-Erythropoietic EPO Analogue Cibinetide Inhibits Osteoclastogenesis In Vitro and Increases Bone Mineral Density in Mice
Authors: Awida Zamzam , Bachar Almog , Saed Hussam , Gorodov Anton , Ben-Califa Nathalie , Ibrahim Maria , Kolomansky Albert , Iden Jennifer Ana , Graniewitz Visacovsky Liad , Liron Tamar , Hiram-Bab Sahar , Brines Michael , Gabet Yankel , Neumann Drorit
Published: December 2021

The two erythropoietin (EPO) receptor forms mediate different cellular responses to erythropoietin. While hematopoiesis is mediated via the homodimeric EPO receptor (EPOR), tissue protection is conferred via a heteromer composed of EPOR and CD131. In the skeletal system, EPO stimulates osteoclast precursors and induces bone loss. However, the underlying molecular mechanisms are still elusive. Here, we evaluated the role of the heteromeric complex in bone metabolism in vivo and in vitro by using Cibinetide (CIB), a non-erythropoietic EPO analogue that exclusively binds the heteromeric receptor. CIB is administered either alone or in combination with EPO. One month of CIB treatment significantly increased the cortical (~5.8%) and trabecular (~5.2%) bone mineral density in C57BL/6J WT female mice. Similarly, administration of CIB for five consecutive days to female mice that concurrently received EPO on days one and four, reduced the number of osteoclast progenitors, defined by flow cytometry as Lin−CD11b−Ly6Chi CD115+, by 42.8% compared to treatment with EPO alone. In addition, CIB alone or in combination with EPO inhibited osteoclastogenesis in vitro. Our findings introduce CIB either as a stand-alone treatment, or in combination with EPO, as an appealing candidate for the treatment of the bone loss that accompanies EPO treatment.
Fluorescent CQD-Doped Styrene Acrylic Emulsion Coating Film with Enhanced Optical Properties
Authors: Wang Xiaohui , Xu Li , Yang Rui , Huang Runzhou , Mao Haiyan
Published: December 2021

Styrene acrylic emulsions (SAEs) have emerged as a promising material for water-based coatings. However, they are still limited by their own defects in practical applications, poor weatherability, and degradation of performance at lower or higher temperatures. Here, we introduce a facile approach to producing fluorescent carbon quantum dots (CQDs) from wood processing residues and fabricating fluorescent CQD/SAE coating films via emulsion-casting. The addition of the fluorescent CQDs enhanced the optical performance of the CQD/SAE coating films. The fluorescent CQDs were prepared via a hydrothermal approach and were obtained after heating at 180 °C for 6 h at a reaction concentration of 50 mg/mL. The synthesized CQDs resulted in a high fluorescence, and the CQDs had an average size of 1.63 nm. Various concentrations of the fluorescent CQDs were doped into the SAE coating film, which improved its optical properties. We also characterized and discussed the products and then explored their optical properties. This study presents the potential of fluorescent CQD/SAE coating films for applications in anti-counterfeiting coatings, fluorescent adhesives, and papermaking.
Systematic Analysis of Clemastine, a Candidate Apicomplexan Parasite-Selective Tubulin-Targeting Agent
Authors: Abbaali Izra , Truong Danny A. , Day Shania D. , Haro-Ramirez Nancy , Morrissette Naomi S.
Published: December 2021

Apicomplexan parasites, such as Toxoplasma gondii, Plasmodium spp., Babesia spp., and Cryptosporidium spp., cause significant morbidity and mortality. Existing treatments are problematic due to toxicity and the emergence of drug-resistant parasites. Because protozoan tubulin can be selectively disrupted by small molecules to inhibit parasite growth, we assembled an in vitro testing cascade to fully delineate effects of candidate tubulin-targeting drugs on Toxoplasma gondii and vertebrate host cells. Using this analysis, we evaluated clemastine, an antihistamine that has been previously shown to inhibit Plasmodium growth by competitively binding to the CCT/TRiC tubulin chaperone as a proof-of-concept. We concurrently analyzed astemizole, a distinct antihistamine that blocks heme detoxification in Plasmodium. Both drugs have EC50 values of ~2 µM and do not demonstrate cytotoxicity or vertebrate microtubule disruption at this concentration. Parasite subpellicular microtubules are shortened by treatment with either clemastine or astemizole but not after treatment with pyrimethamine, indicating that this effect is not a general response to antiparasitic drugs. Immunoblot quantification indicates that the total α-tubulin concentration of 0.02 pg/tachyzoite does not change with clemastine treatment. In conclusion, the testing cascade allows profiling of small-molecule effects on both parasite and vertebrate cell viability and microtubule integrity.
Loss of αA or αB-Crystallin Accelerates Photoreceptor Cell Death in a Mouse Model of P23H Autosomal Dominant Retinitis Pigmentosa
Authors: Wang Tiantian , Yao Jingyu , Jia Lin , Fort Patrice E. , Zacks David N.
Published: December 2021

Inherited retinal degenerations (IRD) are a leading cause of visual impairment and can result from mutations in any one of a multitude of genes. Mutations in the light-sensing protein rhodopsin (RHO) is a leading cause of IRD with the most common of those being a missense mutation that results in substitution of proline-23 with histidine. This variant, also known as P23H-RHO, results in rhodopsin misfolding, initiation of endoplasmic reticulum stress, the unfolded protein response, and activation of cell death pathways. In this study, we investigate the effect of α-crystallins on photoreceptor survival in a mouse model of IRD secondary to P23H-RHO. We find that knockout of either αA- or αB-crystallin results in increased intraretinal inflammation, activation of apoptosis and necroptosis, and photoreceptor death. Our data suggest an important role for the ⍺-crystallins in regulating photoreceptor survival in the P23H-RHO mouse model of IRD.
Elevation of Hyaluronan Synthase by Magnesium Supplementation Mediated through the Activation of GSK3 and CREB in Human Keratinocyte-Derived HaCaT Cells
Authors: Marunaka Kana , Shu Shokoku , Kobayashi Mao , Goto Makiko , Katsuta Yuji , Yoshino Yuta , Ikari Akira
Published: December 2021

Skin barrier damage is present in the patients with hereditary disorders of the magnesium channel, but the molecular mechanism has not been fully understood. We found that the expressions of hyaluronan synthase (HAS), HAS2 and HAS3 are influenced by MgCl2 concentration in human keratinocyte-derived HaCaT cells. The exposure of cells to a high concentration (5.8 mM) of MgCl2 induced the elevation of HAS2/3 expression, which was inhibited by mRNA knockdown of nonimprinted in Prader-Willi/Angelman syndrome-like domain containing 4 (NIPAL4). Similarly, the content of hyaluronic acid (HA) was changed according to MgCl2 concentration and the expression of NIPAL4. The MgCl2 supplementation increased the reporter activities of HAS2/3, which were inhibited by NIPAL4 knockdown, indicating that the expressions of HAS2/3 are up-regulated at the transcriptional level. The reporter activities and mRNA levels of HAS2/3, and the production of HA were inhibited by CHIR-99021, a glycogen synthase kinase-3 (GSK3) inhibitor, and naphthol AS-E, a cyclic AMP-response element binding protein (CREB) inhibitor. Furthermore, the mutation in putative CREB-binding sites of promoter region in HAS2/3 genes inhibited the MgCl2 supplementation-induced elevation of promoter activity. Our results indicate that the expressions of HAS2/3 are up-regulated by MgCl2 supplementation in HaCaT cells mediated through the activation of GSK3 and CREB. Magnesium may play a pivotal role in maintaining the skin barrier function and magnesium supplementation may be useful to enhance moisturization and wound repair in the skin.
Spontaneous Platelet Aggregation in Blood Is Mediated by FcγRIIA Stimulation of Bruton’s Tyrosine Kinase
Authors: Duan Rundan , Goldmann Luise , Li Ya , Weber Christian , Siess Wolfgang , von Hundelshausen Philipp
Published: December 2021

High platelet reactivity leading to spontaneous platelet aggregation (SPA) is a hallmark of cardiovascular diseases; however, the mechanism underlying SPA remains obscure. Platelet aggregation in stirred hirudin-anticoagulated blood was measured by multiple electrode aggregometry (MEA) for 10 min. SPA started after a delay of 2–3 min. In our cohort of healthy blood donors (n = 118), nine donors (8%) with high SPA (>250 AU*min) were detected. Pre-incubation of blood with two different antibodies against the platelet Fc-receptor (anti-FcγRIIA, CD32a) significantly reduced high SPA by 86%. High but not normal SPA was dose-dependently and significantly reduced by blocking Fc of human IgG with a specific antibody. SPA was completely abrogated by blood pre-incubation with the reversible Btk-inhibitor (BTKi) fenebrutinib (50 nM), and 3 h after intake of the irreversible BTKi ibrutinib (280 mg) by healthy volunteers. Increased SPA was associated with higher platelet GPVI reactivity. Anti-platelet factor 4 (PF4)/polyanion IgG complexes were excluded as activators of the platelet Fc-receptor. Our results indicate that high SPA in blood is due to platelet FcγRIIA stimulation by unidentified IgG complexes and mediated by Btk activation. The relevance of our findings for SPA as possible risk factor of cardiovascular diseases and pathogenic factor contributing to certain autoimmune diseases is discussed.
The Effect of Age and Intrinsic Aerobic Exercise Capacity on the Expression of Inflammation and Remodeling Markers in Rat Achilles Tendons
Authors: Kinitz Runa , Heyne Estelle , Koch Lauren G. , Britton Steven L. , Thierbach Manuela , Wildemann Britt
Published: December 2021

Old age, adiposity, and metabolic disorders are known as risk factors for chronic tendinopathy, which is a common problem in both athletes and the general population. However, the importance of these influencing factors has not yet been well understood. This study investigated alterations in gene expression and histology of Achilles tendons of young (10 weeks) and old (100 weeks) rats bred for low (low capacity runners, LCR) and high (high capacity runners, HCR) intrinsic aerobic exercise capacity. In this rat model, LCR displayed a phenotype of reduced exercise capacity, higher body weight, and metabolic dysfunctions compared to HCR. We hypothesized that the risk factors for tendinopathy in old LCR could lead to more pronounced impairments in Achilles tendon tissue. In quantitative real-time PCR (qPCR), age-related downregulation of tenocyte markers e.g., tenomodulin, genes related to matrix modeling and remodeling (e.g., collagens, elastin, biglycan, fibronectin, tenascin C) as well as transforming growth factor beta 3 (Tgfb3) have been detected. Inflammation marker cyclooxygenase 2 (Cox2) was downregulated in old rats, while microsomal prostaglandin E synthase 2 (Ptges2) was upregulated in old HCR and old LCR. In all groups, interleukin 6 (Il6), interleukin 1 beta (Il1b), and tumor necrosis factor alpha (Tnfa) showed no significant alteration. In histological evaluation, tendons of old rats had fewer and more elongated tenocyte nuclei than young rats. Even though a higher content of glycosaminoglycans, a sign of degeneration, was found in old HCR and LCR, no further signs of tendinopathy were detectable in tendons of old rats by histological evaluation. Low intrinsic aerobic exercise capacity and the associated phenotype did not show significant effects on gene expression and tendon histology. These findings indicate that aging seems to play a prominent role in molecular and structural alterations of Achilles tendon tissue and suggests that other risk factors associated with intrinsic aerobic exercise capacity are less influential in this rat model.
Targeting the ERβ/HER Oncogenic Network in KRAS Mutant Lung Cancer Modulates the Tumor Microenvironment and Is Synergistic with Sequential Immunotherapy
Authors: Almotlak Abdulaziz A. , Farooqui Mariya , Soloff Adam C. , Siegfried Jill M. , Stabile Laura P.
Published: December 2021

High ERβ/HER oncogenic signaling defines lung tumors with an aggressive biology. We previously showed that combining the anti-estrogen fulvestrant with the pan-HER inhibitor dacomitinib reduced ER/HER crosstalk and produced synergistic anti-tumor effects in immunocompromised lung cancer models, including KRAS mutant adenocarcinoma. How this combination affects the tumor microenvironment (TME) is not known. We evaluated the effects of fulvestrant and dacomitinib on murine bone marrow-derived macrophages (BMDMs) and CD8+ T cells, and tested the efficacy of the combination in vivo, using the KRAS mutant syngeneic lung adenocarcinoma model, FVBW-17. While this combination synergistically inhibited proliferation of FVBW-17 cells, it had unwanted effects on immune cells, by reducing CD8+ T cell activity and phagocytosis in BMDMs and inducing PD-1. The effects were largely attributed to dacomitinib, which caused downregulation of Src family kinases and Syk in immune cells. In a subcutaneous flank model, the combination induced an inflamed TME with increased myeloid cells and CD8+ T cells and enhanced PD-1 expression in the splenic compartment. Concomitant administration of anti-PD-1 antibody with fulvestrant and dacomitinib was more efficacious than fulvestrant plus dacomitinib alone. Administering anti-PD-1 sequentially after fulvestrant plus dacomitinib was synergistic, with a two-fold greater tumor inhibitory effect compared to concomitant therapy, in both the flank model and in a lung metastasis model. Sequential triple therapy has potential for treating lung cancer that shows limited response to current therapies, such as KRAS mutant lung adenocarcinoma.
A Comprehensive Assessment of Genetic and Epigenetic Alterations Identifies Frequent Variations Impacting Six Prototypic SCF Complex Members
Authors: Campos Gudiño Rubi , Farrell Ally C. , Neudorf Nicole M. , McManus Kirk J.
Published: December 2021

The SKP1, CUL1, F-box protein (SCF) complex represents a family of 69 E3 ubiquitin ligases that poly-ubiquitinate protein substrates marking them for proteolytic degradation via the 26S proteasome. Established SCF complex targets include transcription factors, oncoproteins and tumor suppressors that modulate cell cycle activity and mitotic fidelity. Accordingly, genetic and epigenetic alterations involving SCF complex member genes are expected to adversely impact target regulation and contribute to disease etiology. To gain novel insight into cancer pathogenesis, we determined the prevalence of genetic and epigenetic alterations in six prototypic SCF complex member genes (SKP1, CUL1, RBX1, SKP2, FBXW7 and FBXO5) from patient datasets extracted from The Cancer Genome Atlas (TCGA). Collectively, ~45% of observed SCF complex member mutations are predicted to impact complex structure and/or function in 10 solid tumor types. In addition, the distribution of encoded alterations suggest SCF complex members may exhibit either tumor suppressor or oncogenic mutational profiles in a cancer type dependent manner. Further bioinformatic analyses reveal the potential functional implications of encoded alterations arising from missense mutations by examining predicted deleterious mutations with available crystal structures. The SCF complex also exhibits frequent copy number alterations in a variety of cancer types that generally correspond with mRNA expression levels. Finally, we note that SCF complex member genes are differentially methylated across cancer types, which may effectively phenocopy gene copy number alterations. Collectively, these data show that SCF complex member genes are frequently altered at the genetic and epigenetic levels in many cancer types, which will adversely impact the normal targeting and timely destruction of protein substrates, which may contribute to the development and progression of an extensive array of cancer types.
Functional and Molecular Characterisation of Heart Failure Progression in Mice and the Role of Myosin Regulatory Light Chains in the Recovery of Cardiac Muscle Function
Authors: Markandran Kasturi , Yu Haiyang , Song Weihua , Lam Do Thuy Uyen Ha , Madathummal Mufeeda Changaramvally , Ferenczi Michael A.
Published: December 2021

Heart failure (HF) as a result of myocardial infarction (MI) is a major cause of fatality worldwide. However, the cause of cardiac dysfunction succeeding MI has not been elucidated at a sarcomeric level. Thus, studying the alterations within the sarcomere is necessary to gain insights on the fundamental mechansims leading to HF and potentially uncover appropriate therapeutic targets. Since existing research portrays regulatory light chains (RLC) to be mediators of cardiac muscle contraction in both human and animal models, its role was further explored In this study, a detailed characterisation of the physiological changes (i.e., isometric force, calcium sensitivity and sarcomeric protein phosphorylation) was assessed in an MI mouse model, between 2D (2 days) and 28D post-MI, and the changes were related to the phosphorylation status of RLCs. MI mouse models were created via complete ligation of left anterior descending (LAD) coronary artery. Left ventricular (LV) papillary muscles were isolated and permeabilised for isometric force and Ca2+ sensitivity measurement, while the LV myocardium was used to assay sarcomeric proteins’ (RLC, troponin I (TnI) and myosin binding protein-C (MyBP-C)) phosphorylation levels and enzyme (myosin light chain kinase (MLCK), zipper interacting protein kinase (ZIPK) and myosin phosphatase target subunit 2 (MYPT2)) expression levels. Finally, the potential for improving the contractility of diseased cardiac papillary fibres via the enhancement of RLC phosphorylation levels was investigated by employing RLC exchange methods, in vitro. RLC phosphorylation and isometric force potentiation were enhanced in the compensatory phase and decreased in the decompensatory phase of HF failure progression, respectively. There was no significant time-lag between the changes in RLC phosphorylation and isometric force during HF progression, suggesting that changes in RLC phosphorylation immediately affect force generation. Additionally, the in vitro increase in RLC phosphorylation levels in 14D post-MI muscle segments (decompensatory stage) enhanced its force of isometric contraction, substantiating its potential in HF treatment. Longitudinal observation unveils potential mechanisms involving MyBP-C and key enzymes regulating RLC phosphorylation, such as MLCK and MYPT2 (subunit of MLCP), during HF progression. This study primarily demonstrates that RLC phosphorylation is a key sarcomeric protein modification modulating cardiac function. This substantiates the possibility of using RLCs and their associated enzymes to treat HF.
MiR-155: An Important Regulator of Neuroinflammation
Authors: Zingale Valeria Domenica , Gugliandolo Agnese , Mazzon Emanuela
Published: December 2021

MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression at the post-transcriptional level and that play an important role in many cellular processes, including modulation of inflammation. MiRNAs are present in high concentrations in the central nervous system (CNS) and are spatially and temporally expressed in a specific way. Therefore, an imbalance in the expression pattern of these small molecules can be involved in the development of neurological diseases. Generally, CNS responds to damage or disease through the activation of an inflammatory response, but many neurological disorders are characterized by uncontrolled neuroinflammation. Many studies support the involvement of miRNAs in the activation or inhibition of inflammatory signaling and in the promotion of uncontrolled neuroinflammation with pathological consequences. MiR-155 is a pro-inflammatory mediator of the CNS and plays an important regulatory role. The purpose of this review is to summarize how miR-155 is regulated and the pathological consequences of its deregulation during neuroinflammatory disorders, including multiple sclerosis, Alzheimer’s disease and other neuroinflammatory disorders. Modulation of miRNAs’ expression could be used as a therapeutic strategy in the treatment of pathological neuroinflammation.
AU-Rich Element RNA Binding Proteins: At the Crossroads of Post-Transcriptional Regulation and Genome Integrity
Authors: Sidali Ahmed , Teotia Varsha , Solaiman Nadeen Shaikh , Bashir Nahida , Kanagaraj Radhakrishnan , Murphy John J. , Surendranath Kalpana
Published: December 2021

Genome integrity must be tightly preserved to ensure cellular survival and to deter the genesis of disease. Endogenous and exogenous stressors that impose threats to genomic stability through DNA damage are counteracted by a tightly regulated DNA damage response (DDR). RNA binding proteins (RBPs) are emerging as regulators and mediators of diverse biological processes. Specifically, RBPs that bind to adenine uridine (AU)-rich elements (AREs) in the 3′ untranslated region (UTR) of mRNAs (AU-RBPs) have emerged as key players in regulating the DDR and preserving genome integrity. Here we review eight established AU-RBPs (AUF1, HuR, KHSRP, TIA-1, TIAR, ZFP36, ZFP36L1, ZFP36L2) and their ability to maintain genome integrity through various interactions. We have reviewed canonical roles of AU-RBPs in regulating the fate of mRNA transcripts encoding DDR genes at multiple post-transcriptional levels. We have also attempted to shed light on non-canonical roles of AU-RBPs exploring their post-translational modifications (PTMs) and sub-cellular localization in response to genotoxic stresses by various factors involved in DDR and genome maintenance. Dysfunctional AU-RBPs have been increasingly found to be associated with many human cancers. Further understanding of the roles of AU-RBPS in maintaining genomic integrity may uncover novel therapeutic strategies for cancer.
The Class I HDAC Inhibitor, MS-275, Prevents Oxaliplatin-Induced Chronic Neuropathy and Potentiates Its Antiproliferative Activity in Mice
Authors: Lamoine Sylvain , Cumenal Mélissa , Barriere David A. , Pereira Vanessa , Fereyrolles Mathilde , Prival Laëtitia , Barbier Julie , Boudieu Ludivine , Brasset Emilie , Bertin Benjamin , Renaud Yoan , Miot-Noirault Elisabeth , Civiale Marie-Ange , Balayssac David , Aissouni Youssef , Eschalier Alain , Busserolles Jérôme
Published: December 2021

Oxaliplatin, the first-line chemotherapeutic agent against colorectal cancer (CRC), induces peripheral neuropathies, which can lead to dose limitation and treatment discontinuation. Downregulation of potassium channels, which involves histone deacetylase (HDAC) activity, has been identified as an important tuner of acute oxaliplatin-induced hypersensitivity. MS-275, a class I histone deacetylase inhibitor (HDACi), prevents acute oxaliplatin-induced peripheral neuropathy (OIPN). Moreover, MS-275 exerts anti-tumor activity in several types of cancers, including CRC. We thus hypothesized that MS-275 could exert both a preventive effect against OIPN and potentially a synergistic effect combined with oxaliplatin against CRC development. We first used RNAseq to assess transcriptional changes occurring in DRG neurons from mice treated by repeated injection of oxaliplatin. Moreover, we assessed the effects of MS-275 on chronic oxaliplatin-induced peripheral neuropathy development in vivo on APCMin/+ mice and on cancer progression when combined with oxaliplatin, both in vivo on APCMin/+ mice and in a mouse model of an orthotopic allograft of the CT26 cell line as well as in vitro in T84 and HT29 human CRC cell lines. We found 741 differentially expressed genes (DEGs) between oxaliplatin- and vehicle-treated animals. While acute OIPN is known as a channelopathy involving HDAC activity, chronic OIPN exerts weak ion channel transcriptional changes and no HDAC expression changes in peripheral neurons from OIPN mice. However, MS-275 prevents the development of sensory neuropathic symptoms induced by repeated oxaliplatin administration in APCMin/+ mice. Moreover, combined with oxaliplatin, MS-275 also exerts synergistic antiproliferative and increased survival effects in CT26-bearing mice. Consistently, combined drug associations exert synergic apoptotic and cell death effects in both T84 and HT29 human CRC cell lines. Our results strongly suggest combining oxaliplatin and MS-275 administration in CRC patients in order to potentiate the antiproliferative action of chemotherapy, while preventing its neurotoxic effect.
Anti-Inflammatory, Antioxidant, and Antifibrotic Effects of Gingival-Derived MSCs on Bleomycin-Induced Pulmonary Fibrosis in Mice
Authors: Wang Xishuai , Zhao Shiyu , Lai Junhui , Guan Weijun , Gao Yang
Published: December 2021

Background: Mesenchymal stem cell (MSC) intervention has been associated with lung protection. We attempted to determine whether mouse gingival-derived mesenchymal stem cells (GMSCs) could protect against bleomycin-induced pulmonary fibrosis. Methods: Mice were divided into three groups: control (Con), bleomycin (Bl), and bleomycin + MSCs (Bl + MSCs). Mice were treated with 5 mg/kg bleomycin via transtracheal instillation to induce pulmonary fibrosis. We assessed the following parameters: histopathological severity of injury in the lung, liver, kidney, and aortic tissues; the degree of pulmonary fibrosis; pulmonary inflammation; pulmonary oedema; profibrotic factor levels in bronchoalveolar lavage fluid (BALF) and lung tissue; oxidative stress-related indicators and apoptotic index in lung tissue; and gene expression levels of IL-1β, IL-8, TNF-α, lysophosphatidic acid (LPA), lysophosphatidic acid receptor 1 (LPA1), TGF-β, matrix metalloproteinase 9 (MMP-9), neutrophil elastase (NE), MPO, and IL-10 in lung tissue. Results: GMSC intervention attenuated bleomycin-induced pulmonary fibrosis, pulmonary inflammation, pulmonary oedema, and apoptosis. Bleomycin instillation notably increased expression levels of the IL-1β, IL-8, TNF-α, LPA, LPA1, TGF-β, MMP-9, NE, and MPO genes and attenuated expression levels of the IL-10 gene in lung tissue, and these effects were reversed by GMSC intervention. Bleomycin instillation notably upregulated MDA and MPO levels and downregulated GSH and SOD levels in lung tissue, and these effects were reversed by GMSC intervention. GMSC intervention prevented upregulation of neutrophil content in the lung, liver, and kidney tissues and the apoptotic index in lung tissue. Conclusions: GMSC intervention exhibits anti-inflammatory and antioxidant capacities. Deleterious accumulation of neutrophils, which is reduced by GMSC intervention, is a key component of bleomycin-induced pulmonary fibrosis. GMSC intervention impairs bleomycin-induced NE, MMP-9, LPA, APL1, and TGF-β release.
Effects of Melatonin on Diabetic Neuropathy and Retinopathy
Authors: Oliveira-Abreu Klausen , Cipolla-Neto José , Leal-Cardoso Jose Henrique
Published: December 2021

Diabetes mellitus (DM) leads to complications, the majority of which are nephropathy, retinopathy, and neuropathy. Redox imbalance and inflammation are important components of the pathophysiology of these complications. Many studies have been conducted to find a specific treatment for these neural complications, and some of them have investigated the therapeutic potential of melatonin (MEL), an anti-inflammatory agent and powerful antioxidant. In the present article, we review studies published over the past 21 years on the therapeutic efficacy of MEL in the treatment of DM-induced neural complications. Reports suggest that there is a real prospect of using MEL as an adjuvant treatment for hypoglycemic agents. However, analysis shows that there is a wide range of approaches regarding the doses used, duration of treatment, and treatment times in relation to the temporal course of DM. This wide range hinders an objective analysis of advances and prospective vision of the paths to be followed for the unequivocal establishment of parameters to be used in an eventual therapeutic validation of MEL in neural complications of DM.
Low-Altitude Aerial Video Surveillance via One-Class SVM Anomaly Detection from Textural Features in UAV Images
Authors: Avola Danilo , Cinque Luigi , Di Mambro Angelo , Diko Anxhelo , Fagioli Alessio , Foresti Gian Luca , Marini Marco Raoul , Mecca Alessio , Pannone Daniele
Published: December 2021

In recent years, small-scale Unmanned Aerial Vehicles (UAVs) have been used in many video surveillance applications, such as vehicle tracking, border control, dangerous object detection, and many others. Anomaly detection can represent a prerequisite of many of these applications thanks to its ability to identify areas and/or objects of interest without knowing them a priori. In this paper, a One-Class Support Vector Machine (OC-SVM) anomaly detector based on customized Haralick textural features for aerial video surveillance at low-altitude is presented. The use of a One-Class SVM, which is notoriously a lightweight and fast classifier, enables the implementation of real-time systems even when these are embedded in low-computational small-scale UAVs. At the same time, the use of textural features allows a vision-based system to detect micro and macro structures of an analyzed surface, thus allowing the identification of small and large anomalies, respectively. The latter aspect plays a key role in aerial video surveillance at low-altitude, i.e., 6 to 15 m, where the detection of common items, e.g., cars, is as important as the detection of little and undefined objects, e.g., Improvised Explosive Devices (IEDs). Experiments obtained on the UAV Mosaicking and Change Detection (UMCD) dataset show the effectiveness of the proposed system in terms of accuracy, precision, recall, and F1-score, where the model achieves a 100% precision, i.e., never misses an anomaly, but at the expense of a reasonable trade-off in its recall, which still manages to reach up to a 71.23% score. Moreover, when compared to classical Haralick textural features, the model obtains significantly higher performances, i.e., ≈20% on all metrics, further demonstrating the approach effectiveness.
Temporal Viability of Aedes aegypti and Aedes albopictus Eggs Using Two Hygroscopic Substances as Preservatives under a Sterile Insect Technique (SIT) Program in Southern Mexico
Authors: Martínez-García Eunice Nayeli , Díaz-González Esteban E. , Marina Carlos F. , Bond J. Guillermo , Rodríguez-Rojas Jorge J. , Ponce-García Gustavo , Sánchez-Casas Rosa M. , Fernández-Salas Ildefonso
Published: December 2021

Dengue and other Aedes-borne diseases have dramatically increased over the last decades. The Sterile Insect Technique (SIT) has been successfully used as part of integrated pest strategies to control populations of insect-plant and livestock pests and is currently being tested as a potential method to reduce mosquito populations in an environmentally friendly approach. However, during the mass rearing steps needed to produce millions of mosquitoes, egg storage and preservation are essential for a certain amount of time. Eggs of Aedes aegypti have a chorionic pad that functions as a sticky substance to glue them onto the inner walls of larval breeding sites. The chorionic pad is chemically made of hyaluronic acid, a hygroscopic compound, responsible to protect them from desiccation over time. Two commercial products with hygroscopic properties, hydrolyzed collagen, and Hyalurosmooth®, both were tested to assess their ability to prolong egg life storage for A. aegypti and A. albopictus. Results showed that 85–95% of Ae. aegypti eggs were able to hatch up to week 8 after being treated with both hydrophilic compounds, compared with the control 66.3%. These two substances showed promising effects for keeping Ae. aegypti eggs viable during prolonged storage in mass rearing insect production focused on vector control SIT programs.
Health-Related Quality of Life Outcomes in Patients with Myelodysplastic Syndromes with Ring Sideroblasts Treated with Luspatercept in the MEDALIST Phase 3 Trial
Authors: Oliva Esther Natalie , Platzbecker Uwe , Garcia-Manero Guillermo , Mufti Ghulam J. , Santini Valeria , Sekeres Mikkael A. , Komrokji Rami S. , Shetty Jeevan K. , Tang Derek , Guo Shien , Liao Weiqin , Zhang George , Ha Xianwei , Ito Rodrigo , Lord-Bessen Jennifer , Backstrom Jay T. , Fenaux Pierre
Published: December 2021

Patients with myelodysplastic syndromes (MDS) often experience chronic anemia and long-term red blood cell transfusion dependence associated with significant burden on clinical and health-related quality of life (HRQoL) outcomes. In the MEDALIST trial (NCT02631070), luspatercept significantly reduced transfusion burden in patients with lower-risk MDS who had ring sideroblasts and were refractory to, intolerant to, or ineligible for prior treatment with erythropoiesis-stimulating agents. We evaluated the effect of luspatercept on HRQoL in patients enrolled in MEDALIST using the EORTC QLQ-C30 and the QOL-E questionnaire. Change in HRQoL was assessed every 6 weeks in patients receiving luspatercept with best supportive care (+ BSC) and placebo + BSC from baseline through week 25. No clinically meaningful within-group changes and between-group differences across all domains of the EORTC QLQ-C30 and QOL-E were observed. On one item of the QOL-E MDS-specific disturbances domain, patients treated with luspatercept reported marked improvements in their daily life owing to the reduced transfusion burden, relative to placebo. Taken together with previous reports of luspatercept + BSC reducing transfusion burden in patients from baseline through week 25 in MEDALIST, these results suggest luspatercept may offer a treatment option for patients that reduces transfusion burden while providing stability in HRQoL.
Early Diagnosis of Liver Metastases from Colorectal Cancer through CT Radiomics and Formal Methods: A Pilot Study
Authors: Rocca Aldo , Brunese Maria Chiara , Santone Antonella , Avella Pasquale , Bianco Paolo , Scacchi Andrea , Scaglione Mariano , Bellifemine Fabio , Danzi Roberta , Varriano Giulia , Vallone Gianfranco , Calise Fulvio , Brunese Luca
Published: December 2021

Background: Liver metastases are a leading cause of cancer-associated deaths in patients affected by colorectal cancer (CRC). The multidisciplinary strategy to treat CRC is more effective when the radiological diagnosis is accurate and early. Despite the evolving technologies in radiological accuracy, the radiological diagnosis of Colorectal Cancer Liver Metastases (CRCLM) is still a key point. The aim of our study was to define a new patient representation different by Artificial Intelligence models, using Formal Methods (FMs), to help clinicians to predict the presence of liver metastasis when still undetectable using the standard protocols. Methods: We retrospectively reviewed from 2013 to 2020 the CT scan of nine patients affected by CRC who would develop liver lesions within 4 months and 8 years. Seven patients developed liver metastases after primary staging before any liver surgery, and two patients were enrolled after R0 liver resection. Twenty-one patients were enrolled as the case control group (CCG). Regions of Interest (ROIs) were identified through manual segmentation on the medical images including only liver parenchyma and eventual benign lesions, avoiding major vessels and biliary ducts. Our predictive model was built based on formally verified radiomic features. Results: The precision of our methods is 100%, scheduling patients as positive only if they will be affected by CRCLM, showing a 93.3% overall accuracy. Recall was 77.8%. Conclusion: FMs can provide an effective early detection of CRCLM before clinical diagnosis only through non-invasive radiomic features even in very heterogeneous and small clinical samples.
Laser Scanning Based Object Detection to Realize Digital Blank Shadows for Autonomous Process Planning in Machining
Authors: Denkena Berend , Wichmann Marcel , Heide Klaas Maximilian , Räker René
Published: December 2021

The automated process chain of an unmanned production system is a distinct challenge in the technical state of the art. In particular, accurate and fast raw-part recognition is a current problem in small-batch production. This publication proposes a method for automatic optical raw-part detection to generate a digital blank shadow, which is applied for adapted CAD/CAM (computer-aided design/computer-aided manufacturing) planning. Thereby, a laser-triangulation sensor is integrated into the machine tool. For an automatic raw-part detection and a workpiece origin definition, a dedicated algorithm for creating a digital blank shadow is introduced. The algorithm generates adaptive scan paths, merges laser lines and machine axis data, filters interference signals, and identifies part edges and surfaces according to a point cloud. Furthermore, a dedicated software system is introduced to investigate the created approach. This method is integrated into a CAD/CAM system, with customized software libraries for communication with the CNC (computer numerical control) machine. The results of this study show that the applied method can identify the positions, dimensions, and shapes of different raw parts autonomously, with deviations less than 1 mm, in 2.5 min. Moreover, the measurement and process data can be transferred without errors to different hardware and software systems. It was found that the proposed approach can be applied for rough raw-part detection, and in combination with a touch probe for accurate detection.
Volatile Organic Compound Profile Fingerprints Using DART–MS Shows Species-Specific Patterns in Fusarium Mycotoxin Producing Fungi
Authors: Busman Mark , Roberts Ethan , Proctor Robert H. , Maragos Chris M.
Published: December 2021

Fungal volatile organic compounds (VOCs) are low-molecular weight fungal metabolites that have high vapor pressure at ambient temperatures and can function as airborne signals. Here, we report a VOC study of several different species of Fusarium. Direct analysis in real time mass spectrometry (DART–MS) was applied for non-invasive VOC fingerprinting of Fusarium isolates growing under standardized conditions. A large number of ions were detected from the headspaces of the Fusarium species sampled here. Ions were detected with distinctively high concentrations in some species. While there were few VOCs produced by only one species, the relative concentrations of VOCs differed between species. The methodology has potential for convenient detection and identification of Fusarium contamination in agricultural commodities.
Conservation Education Impacts of Animal Ambassadors in Zoos
Authors: Clifford-Clarke Megan Marie , Whitehouse-Tedd Katherine , Ellis Clare Frances
Published: December 2021

To mitigate the effects of anthropogenic environmental impacts, conservation education (CE) aims to increase public awareness of biodiversity and encourage the uptake of pro-environmental behaviours (PEB). One way of achieving this goal is the use of controlled animal interactions with animal ambassadors to promote CE goals. This study aimed to determine how differing experiences with ambassador Humboldt penguins (Spheniscus humboldti) affected visitors’ knowledge of conservation actions (CA) and their likelihood to perform PEBs in a UK zoo. A quasi-experimental repeated measures questionnaire was used to investigate this aim. Visit types were categorised as (a) ‘penguin parade’, (b) ‘animal encounter’, (c) ‘exhibit viewing’ and (d) a ‘control’ groups. A Kruskal–Wallis test was used to determine if responses to rating scale items related to PEBs differed according to experience. No significant (p > 0.05) differences were detectable between groups. Qualitative data provided in open ended questions relating to CAs were coded into themes and the percentage of responses were calculated for each theme. Whilst the ‘exhibit viewing’ group mentioned sustainable fish significantly more (p = 0.017) than the ‘control’ group, no significant difference was found for any other pair-wise comparison (p > 0.05 in all cases). Overall, this study highlights that zoo visitors gained specific conservation-based knowledge and had higher behavioural intentions towards PEBs than they previously had. However, no evidence was found to suggest that animal encounters improved CE outcomes. To ensure best practice is followed and CE outcomes are considered equally alongside ambassador animal welfare concerns, further research is recommended.
The Effect of Circulating Fluidised Bed Bottom Ash Content on the Mechanical Properties and Drying Shrinkage of Cement-Stabilised Soil
Authors: Wang Yuanlong , Zhao Yongqi , Han Yunshan , Zhou Min
Published: December 2021

This study aimed to determine the effect of circulating fluidised bed bottom ash (CFB-BA) content on the mechanical properties and drying shrinkage of cement-stabilised soil. Experiments were performed to study the changes in unconfined compressive strength and expansibility of cement-stabilised soil with different CFB-BA contents and the underlying mechanisms based on microscopic properties. The results show that CFB-BA can effectively increase the unconfined compressive strength of the specimen and reduce the amount of cement in the soil. When the combined content of CFB-BA and cement in the soil was 30%, the unconfined compressive strength of the specimen with C/CFB = 2 after 60 days of curing was 10.138 MPa, which is 1.4 times that of the pure cement specimen. However, the CFB-BA does not significantly improve the strength of the soil and cannot be added alone as a cementing material to the soil. Additionally, swelling tests showed that the addition of CFB-BA to cement-stabilised soil can significantly reduce the drying shrinkage. This research project provides reference values for the application of CFB-BA in cement–soil mixing piles, including compressive strength and the reduction in the shrinkage deformation of specimens.