bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeting of Intracellular TMEM16 Proteins to the Plasma Membrane and Activation by Purinergic Signaling
Authors: Schreiber Rainer , Ousingsawat Jiraporn , Kunzelmann Karl
Published: June 2020

Anoctamins such as TMEM16A and TMEM16B are Ca2+-dependent Cl− channels activated through purinergic receptor signaling. TMEM16A (ANO1), TMEM16B (ANO2) and TMEM16F (ANO6) are predominantly expressed at the plasma membrane and are therefore well accessible for functional studies. While TMEM16A and TMEM16B form halide-selective ion channels, TMEM16F and probably TMEM16E operate as phospholipid scramblases and nonselective ion channels. Other TMEM16 paralogs are expressed mainly in intracellular compartments and are therefore difficult to study at the functional level. Here, we report that TMEM16E (ANO5), -H (ANO8), -J (ANO9) and K (ANO10) are targeted to the plasma membrane when fused to a C-terminal CAAX (cysteine, two aliphatic amino acids plus methionin, serine, alanin, cystein or glutamin) motif. These paralogs produce Ca2+-dependent ion channels. Surprisingly, expression of the TMEM16 paralogs in the plasma membrane did not produce additional scramblase activity. In contrast, endogenous scrambling induced by stimulation of purinergic P2X7 receptors was attenuated, in parallel with reduced plasma membrane blebbing. This could suggest that intracellular TMEM16 paralogs operate differently when compared to plasma membrane-localized TMEM16F, and may even stabilize intracellular membranes. Alternatively, CAAX tagging, which leads to expression in non-raft compartments of the plasma membrane, may antagonize phosphatidylserine exposure by endogenous raft-located TMEM16F. CAAX-containing constructs may be useful to further investigate the molecular properties of intracellular TMEM16 proteins.
Apelin-13 Inhibits Methylglyoxal-Induced Unfolded Protein Responses and Endothelial Dysfunction via Regulating AMPK Pathway
Authors: Kim Sujin , Kim Suji , Hwang Ae-Rang , Choi Hyoung Chul , Lee Ji-Yun , Woo Chang-Hoon
Published: June 2020

It has been suggested that methylglyoxal (MGO), a glycolytic metabolite, has more detrimental effects on endothelial dysfunction than glucose itself. Recent reports showed that high glucose and MGO induced endoplasmic reticulum (ER) stress and myocyte apoptosis in ischemic heart disease was inhibited by apelin. The goal of the study is to investigate the molecular mechanism by which MGO induces endothelial dysfunction via the regulation of ER stress in endothelial cells, and to examine whether apelin-13, a cytoprotective polypeptide ligand, protects MGO-induced aortic endothelial dysfunction. MGO-induced ER stress and apoptosis were determined by immunoblotting and MTT assay in HUVECs. Aortic endothelial dysfunction was addressed by en face immunostaining and acetylcholine-induced vasodilation analysis with aortic rings from mice treated with MGO in the presence or absence of apelin ex vivo. TUDCA, an inhibitor of ER stress, inhibited MGO-induced apoptosis and reduction of cell viability, suggesting that MGO signaling to endothelial apoptosis is mediated via ER stress, which leads to activation of unfolded protein responses (UPR). In addition, MGO-induced UPR and aortic endothelial dysfunction were significantly diminished by apelin-13. Finally, this study showed that apelin-13 protects MGO-induced UPR and endothelial apoptosis through the AMPK pathway. Apelin-13 reduces MGO-induced UPR and endothelial dysfunction via regulating the AMPK activating pathway, suggesting the therapeutic potential of apelin-13 in diabetic cardiovascular complications.
Transcriptome-Based Analysis of Tomato Genotypes Resistant to Bacterial Spot (Xanthomonas perforans) Race T4
Authors: Shi Rui , Panthee Dilip R.
Published: June 2020

Bacterial spot (BS) is one of the most devastating foliar bacterial diseases of tomato and is caused by multiple species of Xanthomonas. We performed the RNA sequencing (RNA-Seq) analysis of three tomato lines with different levels of resistance to Xanthomonas perforans race T4 to study the differentially expressed genes (DEGs) and transcript-based sequence variations. Analysis between inoculated and control samples revealed that resistant genotype Solanum pimpinellifolium accession PI 270443 had more DEGs (834), followed by susceptible genotype tomato (S. lycopersicum L) breeding line NC 714 (373), and intermediate genotype tomato breeding line NC 1CELBR (154). Gene ontology (GO) terms revealed that more GO terms (51) were enriched for upregulated DEGs in the resistant genotype PI 270443, and more downregulated DEGs (67) were enriched in the susceptible genotype NC 714. DEGs in the biotic stress pathway showed more upregulated biotic stress pathway DEGs (67) for PI 270443 compared to more downregulated DEGs (125) for the susceptible NC 714 genotype. Resistant genotype PI 270443 has three upregulated DEGs for pathogenesis-related (PR) proteins, and susceptible genotype NC 714 has one downregulated R gene. Sequence variations called from RNA-Seq reads against the reference genome of susceptible Heinz 1706 showed that chr11, which has multiple reported resistance quantitative trait loci (QTLs) to BS race T4, is identical between two resistant lines, PI 270443 and NC 1CELBR, suggesting that these two lines share the same resistance QTLs on this chromosome. Several loci for PR resistance proteins with sequence variation between the resistant and susceptible tomato lines were near the known Rx4 resistance gene on chr11, and additional biotic stress associated DEGs near to the known Rx4 resistance gene were also identified from the susceptible NC 714 line.
Ras Suppressor-1 (RSU1) in Cancer Cell Metastasis: A Tale of a Tumor Suppressor
Authors: Louca Maria , Stylianopoulos Triantafyllos , Gkretsi Vasiliki
Published: June 2020

Cancer is a multifactorial disease responsible for millions of deaths worldwide. It has a strong genetic background, as mutations in oncogenes or tumor suppressor genes contribute to the initiation of cancer development. Integrin signaling as well as the signaling pathway of Ras oncogene, have been long implicated both in carcinogenesis and disease progression. Moreover, they have been involved in the promotion of metastasis, which accounts for the majority of cancer-related deaths. Ras Suppressor-1 (RSU1) was identified as a suppressor of Ras-induced transformation and was shown to localize to cell-extracellular matrix adhesions. Recent findings indicate that its expression is elevated in various cancer types, while its role in regulating metastasis-related cellular processes remains largely unknown. Interestingly, there is no in vivo work in the field to date, and thus, all relevant knowledge stems from in vitro studies. In this review, we summarize recent studies using breast, liver and brain cancer cell lines and highlight the role of RSU1 in regulating cancer cell invasion.
Editorial for the Special Issue “New Strategies in Cancer Pharmacotherapy: Development of Hormonal Antineoplastic Drugs, Cytotoxic Drugs and Targeted Therapies”
Authors: Martínez-Campa Carlos , Alonso-González Carolina
Published: June 2020

The Special Issue entitled “New Strategies in Cancer Pharmacotherapy: Development of Hormonal Antineoplastic Drugs, Cytotoxic Drugs and Targeted Therapies” was conceived with the idea of compiling information on the latest advances in the treatment of both hormone-dependent and hormone-independent cancers [...]
Beyond Macrophages and T Cells: B Cells and Immunoglobulins Determine the Fate of the Atherosclerotic Plaque
Authors: Mangge Harald , Prüller Florian , Schnedl Wolfgang , Renner Wilfried , Almer Gunter
Published: June 2020

Atherosclerosis (AS) leading to myocardial infarction and stroke remains worldwide the main cause for mortality. Vulnerable atherosclerotic plaques are responsible for these life-threatening clinical endpoints. Atherosclerosis is a chronic, complex, inflammatory disease with interactions between metabolic dysfunction, dyslipidemia, disturbed microbiome, infectious triggers, vascular, and immune cells. Undoubtedly, the immune response is a most important piece of the pathological puzzle in AS. Although macrophages and T cells have been the focus of research in recent years, B cells producing antibodies and regulating T and natural killer (NKT) cell activation are more important than formerly thought. New results show that the B cells exert a prominent role with atherogenic and protective facets mediated by distinct B cell subsets and different immunoglobulin effects. These new insights come, amongst others, from observations of the effects of innovative B cell targeted therapies in autoimmune diseases like systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). These diseases associate with AS, and the beneficial side effects of B cell subset depleting (modifying) therapies on atherosclerotic concomitant disease, have been observed. Moreover, the CANTOS study (NCT01327846) showed impressive results of immune-mediated inflammation as a new promising target of action for the fight against atherosclerotic endpoints. This review will reflect the putative role of B cells in AS in an attempt to connect observations from animal models with the small spectrum of the thus far available human data. We will also discuss the clinical therapeutic potency of B cell modulations on the process of AS.
Redox-Modulating Agents in the Treatment of Viral Infections
Authors: Checconi Paola , De Angelis Marta , Marcocci Maria Elena , Fraternale Alessandra , Magnani Mauro , Palamara Anna Teresa , Nencioni Lucia
Published: June 2020

Viruses use cell machinery to replicate their genome and produce viral proteins. For this reason, several intracellular factors, including the redox state, might directly or indirectly affect the progression and outcome of viral infection. In physiological conditions, the redox balance between oxidant and antioxidant species is maintained by enzymatic and non-enzymatic systems, and it finely regulates several cell functions. Different viruses break this equilibrium and induce an oxidative stress that in turn facilitates specific steps of the virus lifecycle and activates an inflammatory response. In this context, many studies highlighted the importance of redox-sensitive pathways as novel cell-based targets for therapies aimed at blocking both viral replication and virus-induced inflammation. In the review, we discuss the most recent findings in this field. In particular, we describe the effects of natural or synthetic redox-modulating molecules in inhibiting DNA or RNA virus replication as well as inflammatory pathways. The importance of the antioxidant transcription factor Nrf2 is also discussed. Most of the data reported here are on influenza virus infection. We believe that this approach could be usefully applied to fight other acute respiratory viral infections characterized by a strong inflammatory response, like COVID-19.
HSP70-Mediated NLRP3 Inflammasome Suppression Underlies Reversal of Acute Kidney Injury Following Extracellular Vesicle and Focused Ultrasound Combination Therapy
Authors: Ullah Mujib , Liu Daniel D. , Rai Sravanthi , Concepcion Waldo , Thakor Avnesh S.
Published: June 2020

Acute kidney injury (AKI) is the abrupt loss of renal function, for which only supportive therapies exist. Mesenchymal stromal cell (MSC)-derived extracellular vesicles (EVs) have been shown to be therapeutically effective in treating AKI by spurring endogenous cell proliferation and survival while suppressing inflammation. Pre-treating kidneys with pulsed focused ultrasound (pFUS) has also been shown to enhance MSC therapy for AKI, but its role in MSC-derived EV therapy remains unexplored. Using a mouse model of cisplatin-induced AKI, we show that combination therapy with pFUS and EVs restores physiological and molecular markers of kidney function, more so than either alone. Both pFUS and EVs downregulate heat shock protein 70 (HSP70), the NLRP3 inflammasome, and its downstream pro-inflammatory cytokines IL-1β and IL-18, all of which are highly upregulated in AKI. In vitro knockdown studies suggest that HSP70 is a positive regulator of the NLRP3 inflammasome. Our study therefore demonstrates the ability of pFUS to enhance EV therapy for AKI and provides further mechanistic understanding of their anti-inflammatory and regenerative effects.
Role of Serotonin Transporter in Eye Development of Drosophila melanogaster
Authors: Pham Tuan L. A. , Binh Tran Duy , Liu Guanchen , Nguyen Thanh Q. C. , Nguyen Yen D. H. , Sahashi Ritsuko , Men Tran Thanh , Kamei Kaeko
Published: June 2020

Serotonin transporter (SerT) in the brain is an important neurotransmitter transporter involved in mental health. However, its role in peripheral organs is poorly understood. In this study, we investigated the function of SerT in the development of the compound eye in Drosophila melanogaster. We found that SerT knockdown led to excessive cell death and an increased number of cells in S-phase in the posterior eye imaginal disc. Furthermore, the knockdown of SerT in the eye disc suppressed the activation of Akt, and the introduction of PI3K effectively rescued this phenotype. These results suggested that SerT plays a role in the healthy eye development of D. melanogaster by controlling cell death through the regulation of the PI3K/Akt pathway.
Optimization of microRNA Acquirement from Seminal Plasma and Identification of Diminished Seminal microRNA-34b as Indicator of Low Semen Concentration
Authors: Eikmans Michael , D. H. Anholts Jacqueline , Blijleven Laura , Meuleman Tess , van Beelen Els , van der Hoorn Marie-Louise P. , Claas Frans H. J.
Published: June 2020

About 10–15% of couples who want to conceive suffer from subfertility, while in 30% of these cases, a male factor plays a role. Levels of particular microRNAs in seminal plasma, including those involved in spermatogenesis, may serve as an indicative parameter for subfertility. We first optimized a protocol for acquiring microRNAs from seminal plasma. Next, using a test-validation strategy in a male cohort, we aimed to identify microRNAs of which the levels are related to semen motility and concentration. By qPCR, 742 microRNAs were profiled in three normozoospermic samples, three seminal samples with a low semen motility (asthenozoospermia), and three with a low semen concentration (oligozoospermia). MicroRNAs showing significant differences between groups were further validated in a second cohort consisting of 40 samples with normozoospermia (control group), 47 samples with asthenozoospermia, and 19 samples with oligozoospermia (of which 74% also low motility). Highest microRNA yields were obtained with the Biofluids RNA extraction kit, with inclusion of MS2 RNA carrier and proteinase K treatment to the protocol, and when 50 µL of seminal plasma was used as input. Exosome isolation prior to RNA extraction did not lead to enhanced yields. In the test cohort, 236 microRNAs could be detected, of which 54 microRNAs showed a difference between groups. Five microRNAs were analyzed in the validation cohort. MiR-34b-5p levels in the control group were significantly higher compared to the asthenozoospermia group (p < 0.05) and compared to the oligozoospermia group (p < 0.001). We optimized microRNA acquirement from seminal plasma and identified microRNA levels in relation to semen concentration and motility. As recent human and mouse studies show that the miR-34 family is a marker of low semen concentration and is crucial in spermatogenesis, seminal plasma miR-34b-5p may represent a suitable candidate to study further as a marker of male subfertility.
Chrysosplenol d, a Flavonol from Artemisia annua, Induces ERK1/2-Mediated Apoptosis in Triple Negative Human Breast Cancer Cells
Authors: Lang Sophia J. , Schmiech Michael , Hafner Susanne , Paetz Christian , Werner Katharina , El Gaafary Menna , Schmidt Christoph Q. , Syrovets Tatiana , Simmet Thomas
Published: June 2020

Triple negative human breast cancer (TNBC) is an aggressive cancer subtype with poor prognosis. Besides the better-known artemisinin, Artemisia annua L. contains numerous active compounds not well-studied yet. High-performance liquid chromatography coupled with diode-array and mass spectrometric detection (HPLC-DAD-MS) was used for the analysis of the most abundant compounds of an Artemisia annua extract exhibiting toxicity to MDA-MB-231 TNBC cells. Artemisinin, 6,7-dimethoxycoumarin, arteannuic acid were not toxic to any of the cancer cell lines tested. The flavonols chrysosplenol d and casticin selectively inhibited the viability of the TNBC cell lines, MDA-MB-231, CAL-51, CAL-148, as well as MCF7, A549, MIA PaCa-2, and PC-3. PC-3 prostate cancer cells exhibiting high basal protein kinase B (AKT) and no ERK1/2 activation were relatively resistant, whereas MDA-MB-231 cells with high basal ERK1/2 and low AKT activity were more sensitive to chrysosplenol d treatment. In vivo, chrysosplenol d and casticin inhibited MDA-MB-231 tumor growth on chick chorioallantoic membranes. Both compounds induced mitochondrial membrane potential loss and apoptosis. Chrysosplenol d activated ERK1/2, but not other kinases tested, increased cytosolic reactive oxygen species (ROS) and induced autophagy in MDA-MB-231 cells. Lysosomal aberrations and toxicity could be antagonized by ERK1/2 inhibition. The Artemisia annua flavonols chrysosplenol d and casticin merit exploration as potential anticancer therapeutics.
Epigenetic Landscape in Pancreatic Ductal Adenocarcinoma: On the Way to Overcoming Drug Resistance?
Authors: Ciernikova Sona , Earl Julie , García Bermejo María Laura , Stevurkova Viola , Carrato Alfredo , Smolkova Bozena
Published: June 2020

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive solid malignancies due to the rapid rate of metastasis and high resistance to currently applied cancer therapies. The complex mechanism underlying the development and progression of PDAC includes interactions between genomic, epigenomic, and signaling pathway alterations. In this review, we summarize the current research findings on the deregulation of epigenetic mechanisms in PDAC and the influence of the epigenome on the dynamics of the gene expression changes underlying epithelial–mesenchymal transition (EMT), which is responsible for the invasive phenotype of cancer cells and, therefore, their metastatic potential. More importantly, we provide an overview of the studies that uncover potentially actionable pathways. These studies provide a scientific basis to test epigenetic drug efficacy in synergy with other anticancer therapies in future clinical trials, in order to reverse acquired therapy resistance. Thus, epigenomics has the potential to generate relevant new knowledge of both a biological and clinical impact. Moreover, the potential, hurdles, and challenges of predictive biomarker discoveries will be discussed, with a special focus on the promise of liquid biopsies.
Endometrial Decidualization: The Primary Driver of Pregnancy Health
Authors: Ng Shu-Wing , Norwitz Gabriella A. , Pavlicev Mihaela , Tilburgs Tamara , Simón Carlos , Norwitz Errol R.
Published: June 2020

Interventions to prevent pregnancy complications have been largely unsuccessful. We suggest this is because the foundation for a healthy pregnancy is laid prior to the establishment of the pregnancy at the time of endometrial decidualization. Humans are one of only a few mammalian viviparous species in which decidualization begins during the latter half of each menstrual cycle and is therefore independent of the conceptus. Failure to adequately prepare (decidualize) the endometrium hormonally, biochemically, and immunologically in anticipation of the approaching blastocyst—including the downregulation of genes involved in the pro- inflammatory response and resisting tissue invasion along with the increased expression of genes that promote angiogenesis, foster immune tolerance, and facilitate tissue invasion—leads to abnormal implantation/placentation and ultimately to adverse pregnancy outcome. We hypothesize, therefore, that the primary driver of pregnancy health is the quality of the soil, not the seed.
Fatty Acid Diets: Regulation of Gut Microbiota Composition and Obesity and Its Related Metabolic Dysbiosis
Authors: Machate David Johane , Figueiredo Priscila Silva , Marcelino Gabriela , Guimarães Rita de Cássia Avellaneda , Hiane Priscila Aiko , Bogo Danielle , Pinheiro Verônica Assalin Zorgetto , Oliveira Lincoln Carlos Silva de , Pott Arnildo
Published: June 2020

Long-term high-fat dietary intake plays a crucial role in the composition of gut microbiota in animal models and human subjects, which affect directly short-chain fatty acid (SCFA) production and host health. This review aims to highlight the interplay of fatty acid (FA) intake and gut microbiota composition and its interaction with hosts in health promotion and obesity prevention and its related metabolic dysbiosis. The abundance of the Bacteroidetes/Firmicutes ratio, as Actinobacteria and Proteobacteria species are associated with increased SCFA production, reported high-fat diet rich in medium-chain fatty acids (MCFAs), monounsaturated fatty acids (MUFAs), and n–3 polyunsaturated fatty acids (PUFAs) as well as low-fat diets rich in long-chain fatty acids (LCFAs). SCFAs play a key role in health promotion and prevention and, reduction and reversion of metabolic syndromes in the host. Furthermore, in this review, we discussed the type of fatty acids and their amount, including the administration time and their interplay with gut microbiota and its results about health or several metabolic dysbioses undergone by hosts.
Vitamin E Blocks Connexin Hemichannels and Prevents Deleterious Effects of Glucocorticoid Treatment on Skeletal Muscles
Authors: Balboa Elisa , Saavedra Fujiko , Cea Luis A. , Ramírez Valeria , Escamilla Rosalba , Vargas Aníbal A. , Regueira Tomás , Sáez Juan C.
Published: June 2020

Glucocorticoids are frequently used as anti-inflammatory and immunosuppressive agents. However, high doses and/or prolonged use induce undesired secondary effects such as muscular atrophy. Recently, de novo expression of connexin43 and connexin45 hemichannels (Cx43 HCs and Cx45 HCs, respectively) has been proposed to play a critical role in the mechanism underlying myofiber atrophy induced by dexamethasone (Dex: a synthetic glucocorticoid), but their involvement in specific muscle changes promoted by Dex remains poorly understood. Moreover, treatments that could prevent the undesired effects of glucocorticoids on skeletal muscles remain unknown. In the present work, a 7-day Dex treatment in adult mice was found to induce weight loss and skeletal muscle changes including expression of functional Cx43/Cx45 HCs, elevated atrogin immunoreactivity, atrophy, oxidative stress and mitochondrial dysfunction. All these undesired effects were absent in muscles of mice simultaneously treated with Dex and vitamin E (VitE). Moreover, VitE was found to rapidly inhibit the activity of Cx HCs in freshly isolated myofibers of Dex treated mice. Exposure to alkaline pH induced free radical generation only in HeLa cells expressing Cx43 or Cx45 where Ca2+ was present in the extracellular milieu, response that was prevented by VitE. Besides, VitE and two other anti-oxidant compounds, Tempol and Resveratrol, were found to inhibit Cx43 HCs in HeLa cells transfectants. Thus, we propose that in addition to their intrinsic anti-oxidant potency, some antioxidants could be used to reduce expression and/or opening of Cx HCs and consequently reduce the undesired effect of glucocorticoids on skeletal muscles.
IGF-1 Deficiency Rescue and Intracellular Calcium Blockade Improves Survival and Corresponding Mechanisms in a Mouse Model of Acute Kidney Injury
Authors: Wasnik Samiksha , Tang Xiaolei , Bi Hongzheng , Abdipour Amir , E. Carreon Edmundo , Sutjiadi Brian , Lyu Justin , Zhang Jintao , Wilson Sean , Baylink David J.
Published: June 2020

This study was undertaken to test two therapies for acute kidney injury (AKI) prevention, IGF-1, which is renal protective, and BTP-2, which is a calcium entry (SOCE) inhibitor. We utilized lipopolysaccharide (LPS) IP, as a systemic model of AKI and studied in five groups of animals. Three experiments showed that at 7 days: (1) LPS significantly reduced serum IGF-1 and intramuscular IGF-I in vivo gene therapy rescued this deficiency. (2) Next, at the 7-day time point, our combination therapy, compared to the untreated group, caused a significant increase in survival, which was noteworthy because all of the untreated animals died in 72 h. (3) The four pathways associated with inflammation, including (A) increase in cytosolic calcium, (B) elaboration of proinflammatory cytokines, (C) impairment of vascular integrity, and (D) cell injury, were adversely affected in renal tissue by LPS, using a sublethal dose of LPS. The expression of several genes was measured in each of the above pathways. The combined therapy of IGF-1 and BTP-2 caused a favorable gene expression response in all four pathways. Our current study was an AKI study, but these pathways are also involved in other types of severe inflammation, including sepsis, acute respiratory distress syndrome, and probably severe coronavirus infection.
p53-PHLDA3-Akt Network: The Key Regulators of Neuroendocrine Tumorigenesis
Authors: Chen Yu , Ohki Rieko
Published: June 2020

p53 is a well-known tumor suppressor gene and one of the most extensively studied genes in cancer research. p53 functions largely as a transcription factor and can trigger a variety of antiproliferative programs via induction of its target genes. We identified PHLDA3 as a p53 target gene and found that its protein product is a suppressor of pancreatic neuroendocrine tumors (PanNETs) and a repressor of Akt function. PHLDA3 is frequently inactivated by loss of heterozygosity (LOH) and methylation in human PanNETs, and LOH at the PHLDA3 gene locus correlates with PanNET progression and poor prognosis. In addition, in PHLDA3-deficient mice, pancreatic islet cells proliferate abnormally and acquire resistance to apoptosis. In this article, we briefly review the roles of p53 and Akt in human neuroendocrine tumors (NETs) and describe the relationship between the p53-PHLDA3 and Akt pathways. We also discuss the role of PHLDA3 as a tumor suppressor in various NETs and speculate on the possibility that loss of PHLDA3 function may be a useful prognostic marker for NET patients indicating particular drug therapies. These results suggest that targeting the downstream PHLDA3-Akt pathway might provide new therapies to treat NETs.
Tau Gene Deletion Does Not Influence Axonal Regeneration and Retinal Neuron Survival in the Injured Mouse Visual System
Authors: Rodriguez Léa , Joly Sandrine , Mdzomba Julius Baya , Pernet Vincent
Published: June 2020

In the present study, we hypothesized that the microtubule-associated protein Tau may influence retinal neuron survival and axonal regeneration after optic nerve injury. To test this hypothesis, the density of retinal ganglion cells was evaluated by immunostaining retinal flat-mounts for RNA-binding protein with multiple splicing (RBPMS) two weeks after optic nerve micro-crush lesion in Tau-deprived (Tau knock-out (KO)) and wild-type (WT) mice. Axon growth was determined on longitudinal sections of optic nerves after anterograde tracing. Our results showed that the number of surviving retinal ganglion cells and growing axons did not significantly vary between WT and Tau KO animals. Moreover, sustained activation of the neuronal growth program with ciliary neurotrophic factor (CNTF) resulted in a similar increase in surviving neurons and in growing axons in WT and Tau KO mice. Taken together, our data suggest that Tau does not influence axonal regeneration or neuronal survival.
Staying out or Going in? The Interplay between Type 3 and Type 5 Secretion Systems in Adhesion and Invasion of Enterobacterial Pathogens
Authors: Whelan Rachel , McVicker Gareth , Leo Jack C.
Published: June 2020

Enteric pathogens rely on a variety of toxins, adhesins and other virulence factors to cause infections. Some of the best studied pathogens belong to the Enterobacterales order; these include enteropathogenic and enterohemorrhagic Escherichia coli, Shigella spp., and the enteropathogenic Yersiniae. The pathogenesis of these organisms involves two different secretion systems, a type 3 secretion system (T3SS) and type 5 secretion systems (T5SSs). The T3SS forms a syringe-like structure spanning both bacterial membranes and the host cell plasma membrane that translocates toxic effector proteins into the cytoplasm of the host cell. T5SSs are also known as autotransporters, and they export part of their own polypeptide to the bacterial cell surface where it exerts its function, such as adhesion to host cell receptors. During infection with these enteropathogens, the T3SS and T5SS act in concert to bring about rearrangements of the host cell cytoskeleton, either to invade the cell, confer intracellular motility, evade phagocytosis or produce novel structures to shelter the bacteria. Thus, in these bacteria, not only the T3SS effectors but also T5SS proteins could be considered “cytoskeletoxins” that bring about profound alterations in host cell cytoskeletal dynamics and lead to pathogenic outcomes.
Influence of Implant Material and Surface on Mode and Strength of Cell/Matrix Attachment of Human Adipose Derived Stromal Cell
Authors: Jung Susanne , Bohner Lauren , Hanisch Marcel , Kleinheinz Johannes , Sielker Sonja
Published: June 2020

A fundamental step for cell growth and differentiation is the cell adhesion. The purpose of this study was to determine the adhesion of different cell lineages, adipose derived stromal cells, osteoblasts, and gingival fibroblast to titanium and zirconia dental implants with different surface treatments. Primary cells were cultured on smooth/polished surfaces (titanium with a smooth surface texture (Ti-PT) and machined zirconia (ZrO2-M)) and on rough surfaces (titanium with a rough surface texture (Ti-SLA) and zirconia material (ZrO2-ZLA)). Alterations in cell morphology (f-actin staining and SEM) and in expression of the focal adhesion marker were analysed after 1, 7, and 14 days. Statistical analysis was performed by one-way ANOVA with a statistical significance at p = 0.05. Cell morphology and cytoskeleton were strongly affected by surface texture. Actin beta and vimentin expressions were higher on rough surfaces (p < 0.01). Vinculin and FAK expressions were significant (p < 0.05) and increased over time. Fibronectin and laminin expressions were significant (p < 0.01) and did not alter over time. Strength of cell/material binding is influenced by surface structure and not by material. Meanwhile, the kind of cell/material binding is regulated by cell type and implant material.
Ablation of the miRNA Cluster 24 Has Profound Effects on Extracellular Matrix Protein Abundance in Cartilage
Authors: Georgieva Veronika S. , Etich Julia , Bluhm Björn , Zhu Mengjie , Frie Christian , Wilson Richard , Zaucke Frank , Bateman John , Brachvogel Bent
Published: June 2020

MicroRNAs (miRNAs) regulate cartilage differentiation and contribute to the onset and progression of joint degeneration. These small RNA molecules may affect extracellular matrix organization (ECM) in cartilage, but for only a few miRNAs has this role been defined in vivo. Previously, we showed that cartilage-specific genetic ablation of the Mirc24 cluster in mice leads to impaired cartilage development due to increased RAF/MEK/ERK pathway activation. Here, we studied the expression of the cluster in cartilage by LacZ reporter gene assays and determined its role for extracellular matrix homeostasis by proteome and immunoblot analysis. The cluster is expressed in prehypertrophic/hypertrophic chondrocytes of the growth plate and we now show that the cluster is also highly expressed in articular cartilage. Cartilage-specific loss of the cluster leads to increased proteoglycan 4 and matrix metallopeptidase 13 levels and decreased aggrecan and collagen X levels in epiphyseal cartilage. Interestingly, these changes are linked to a decrease in SRY-related HMG box-containing (SOX) transcription factors 6 and 9, which regulate ECM production in chondrocytes. Our data suggests that the Mirc24 cluster is important for ECM homoeostasis and the expression of transcriptional regulators of matrix production in cartilage.
Epigenetic Modifiers as Potential Therapeutic Targets in Diabetic Kidney Disease
Authors: Martinez-Moreno Julio M. , Fontecha-Barriuso Miguel , Martin-Sanchez Diego , Guerrero-Mauvecin Juan , Goma-Garces Elena , Fernandez-Fernandez Beatriz , Carriazo Sol , Sanchez-Niño Maria D. , Ramos Adrian M. , Ruiz-Ortega Marta , Ortiz Alberto , Sanz Ana B.
Published: June 2020

Diabetic kidney disease is one of the fastest growing causes of death worldwide. Epigenetic regulators control gene expression and are potential therapeutic targets. There is functional interventional evidence for a role of DNA methylation and the histone post-translational modifications—histone methylation, acetylation and crotonylation—in the pathogenesis of kidney disease, including diabetic kidney disease. Readers of epigenetic marks, such as bromodomain and extra terminal (BET) proteins, are also therapeutic targets. Thus, the BD2 selective BET inhibitor apabetalone was the first epigenetic regulator to undergo phase-3 clinical trials in diabetic kidney disease with an endpoint of kidney function. The direct therapeutic modulation of epigenetic features is possible through pharmacological modulators of the specific enzymes involved and through the therapeutic use of the required substrates. Of further interest is the characterization of potential indirect effects of nephroprotective drugs on epigenetic regulation. Thus, SGLT2 inhibitors increase the circulating and tissue levels of β-hydroxybutyrate, a molecule that generates a specific histone modification, β-hydroxybutyrylation, which has been associated with the beneficial health effects of fasting. To what extent this impact on epigenetic regulation may underlie or contribute to the so-far unclear molecular mechanisms of cardio- and nephroprotection offered by SGLT2 inhibitors merits further in-depth studies.
Dietary Fat and Cancer—Which Is Good, Which Is Bad, and the Body of Evidence
Authors: Bojková Bianka , Winklewski Pawel J. , Wszedybyl-Winklewska Magdalena
Published: June 2020

A high-fat diet (HFD) induces changes in gut microbiota leading to activation of pro-inflammatory pathways, and obesity, as a consequence of overnutrition, exacerbates inflammation, a known risk factor not only for cancer. However, experimental data showed that the composition of dietary fat has a greater impact on the pathogenesis of cancer than the total fat content in isocaloric diets. Similarly, human studies did not prove that a decrease in total fat intake is an effective strategy to combat cancer. Saturated fat has long been considered as harmful, but the current consensus is that moderate intake of saturated fatty acids (SFAs), including palmitic acid (PA), does not pose a health risk within a balanced diet. In regard to monounsaturated fat, plant sources are recommended. The consumption of plant monounsaturated fatty acids (MUFAs), particularly from olive oil, has been associated with lower cancer risk. Similarly, the replacement of animal MUFAs with plant MUFAs decreased cancer mortality. The impact of polyunsaturated fatty acids (PUFAs) on cancer risk depends on the ratio between ω-6 and ω-3 PUFAs. In vivo data showed stimulatory effects of ω-6 PUFAs on tumour growth while ω-3 PUFAs were protective, but the results of human studies were not as promising as indicated in preclinical reports. As for trans FAs (TFAs), experimental data mostly showed opposite effects of industrially produced and natural TFAs, with the latter being protective against cancer progression, but human data are mixed, and no clear conclusion can be made. Further studies are warranted to establish the role of FAs in the control of cell growth in order to find an effective strategy for cancer prevention/treatment.
Mouse Tumor Models for Advanced Cancer Immunotherapy
Authors: Chulpanova Daria S. , Kitaeva Kristina V. , Rutland Catrin S. , Rizvanov Albert A. , Solovyeva Valeriya V.
Published: June 2020

Recent advances in the development of new methods of cancer immunotherapy require the production of complex cancer animal models that reliably reflect the complexity of the tumor and its microenvironment. Mice are good animals to create tumor models because they are low cost, have a short reproductive cycle, exhibit high tumor growth rates, and can be easily genetically modified. However, the obvious problem of these models is the high failure rate observed in human clinical trials after promising results obtained in mouse models. In order to increase the reliability of the results obtained in mice, the tumor model should reflect the heterogeneity of the tumor, contain components of the tumor microenvironment, in particular immune cells, to which the action of immunotherapeutic drugs are directed. This review discusses the current immunocompetent and immunocompromised mouse models of human tumors that are used to evaluate the effectiveness of immunotherapeutic agents, in particular chimeric antigen receptor (CAR) T-cells and immune checkpoint inhibitors.
Antiphospholipid Antibodies and Autoimmune Haemolytic Anaemia: A Systematic Review and Meta-Analysis
Authors: Ames Paul R.J. , Merashli Mira , Bucci Tommaso , Pastori Daniele , Pignatelli Pasquale , Arcaro Alessia , Gentile Fabrizio
Published: June 2020

The relationship between antiphospholipid antibodies (aPL) and autoimmune haemolytic anaemia (AIHA) has never been systematically addressed. The aim of this study is to assess the link between aPL and AIHA in adult systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). This study performed an EMBASE/PubMed search from inception to June 2019 and meta-analysis using Peto’s odds ratios. The pooled prevalence (PP) of IgG/IgM anticardiolipin (aCL) and lupus anticoagulant (LA) was greater in AIHA +ve than AIHA −ve patients (34.7% vs. 27.6%, p = 0.03; 33.3% vs. 21.8%, p < 0.0001; 20.9% vs. 8.3%, p = 0.01). The PP of AIHA was greater in: (1) IgG and IgM aCL +ve than −ve patients (21.8% vs. 11.1%, p = 0.001 and 18.7% vs. 6.3%, p < 0.0001), (2) in SLE related APS than in primary APS patients (22.8% vs. 3.9% p < 0.0001), (3) in APS +ve than APS −ve SLE patients (23.2% vs. 8.4%, p = 0.01), and (4) in thrombotic APS than non-thrombotic APS/SLE patients (26.8% vs. 10%, p = 0.03). The PP of IgG/IgM aCL and LA was greater in DAT +ve than DAT −ve patients (42.4% vs. 12.8%, p < 0.0001; 26.2% vs. 12.8%, p = 0.03 and 29.2% vs. 15.7%, p = 0.004 respectively). It was found that AIHA prevalence is maximal in SLE with aPL/APS, low-moderate in SLE without aPL and minimal in PAPS. Moreover, AIHA is rightly included among the classification criteria for SLE but not for APS/aPL. The significance of an isolated DAT positivity remains unclear in this setting
A Process Model for Component-Based Model-Driven Software Development
Authors: Umran Alrubaee Afrah , Cetinkaya Deniz , Liebchen Gernot , Dogan Huseyin
Published: June 2020

Developing high quality, reliable and on time software systems is challenging due to the increasing size and complexity of these systems. Traditional software development approaches are not suitable for dealing with such challenges, so several approaches have been introduced to increase the productivity and reusability during the software development process. Two of these approaches are Component-Based Software Engineering (CBSE) and Model-Driven Software Development (MDD) which focus on reusing pre-developed code and using models throughout the development process respectively. There are many research studies that show the benefits of using software components and model-driven approaches. However, in many cases the development process is either ad-hoc or not well-defined. This paper proposes a new software development process model that merges CBSE and MDD principles to facilitate software development. The model is successfully tested by applying it to the development of an e-learning system as an exemplar case study.
Dew Computing and Asymmetric Security Framework for Big Data File Sharing
Authors: Suwansrikham Parinya , Kun She , Hayat Shaukat , Jackson Jehoiada
Published: June 2020

Due to the advancement of technology, devices generate huge working files at a rapid rate. These data, which are of considerable scale and are created very fast, can be called big data. Keeping such files in one storage device is impossible. Therefore, a large file size is recommended for storage in a cloud storage service. Although this concept is a solution to solve the storage problem, it still faces challenges in terms of reliability and security. The main issues are the unreliability of single cloud storage when its service is down, and the risk of insider attack from the storage service. Therefore, this paper proposes a file sharing scheme that increases both the reliability of the file fragments using a multi-cloud storage system and decreases the risk from insider attack. The dew computing concept is used as a contributor to the file-sharing scheme. The working file is split into fragments. Each fragment is deployed to cloud storage services, one fragment per one cloud provider manner. The dew server controls users’ access and monitors the availability of fragments. Finally, we verify the proposed scheme in aspects of the downloading performance, and security.
Android Collusion: Detecting Malicious Applications Inter-Communication through SharedPreferences
Authors: Casolare Rosangela , Martinelli Fabio , Mercaldo Francesco , Santone Antonella
Published: June 2020

The Android platform is currently targeted by malicious writers, continuously focused on the development of new types of attacks to extract sensitive and private information from our mobile devices. In this landscape, one recent trend is represented by the collusion attack. In a nutshell this attack requires that two or more applications are installed to perpetrate the malicious behaviour that is split in more than one single application: for this reason anti-malware are not able to detect this attack, considering that they analyze just one application at a time and that the single colluding application does not exhibit any malicious action. In this paper an approach exploiting model checking is proposed to automatically detect whether two applications exhibit the ability to perform a collusion through the SharedPreferences communication mechanism. We formulate a series of temporal logic formulae to detect the collusion attack from a model obtained by automatically selecting the classes candidate for the collusion, obtained by two heuristics we propose. Experimental results demonstrate that the proposed approach is promising in collusion application detection: as a matter of fact an accuracy equal to 0.99 is obtained by evaluating 993 Android applications.
Attention-Based SeriesNet: An Attention-Based Hybrid Neural Network Model for Conditional Time Series Forecasting
Authors: Cheng Yepeng , Liu Zuren , Morimoto Yasuhiko
Published: June 2020

Traditional time series forecasting techniques can not extract good enough sequence data features, and their accuracies are limited. The deep learning structure SeriesNet is an advanced method, which adopts hybrid neural networks, including dilated causal convolutional neural network (DC-CNN) and Long-short term memory recurrent neural network (LSTM-RNN), to learn multi-range and multi-level features from multi-conditional time series with higher accuracy. However, they didn’t consider the attention mechanisms to learn temporal features. Besides, the conditioning method for CNN and RNN is not specific, and the number of parameters in each layer is tremendous. This paper proposes the conditioning method for two types of neural networks, and respectively uses the gated recurrent unit network (GRU) and the dilated depthwise separable temporal convolutional networks (DDSTCNs) instead of LSTM and DC-CNN for reducing the parameters. Furthermore, this paper presents the lightweight RNN-based hidden state attention module (HSAM) combined with the proposed CNN-based convolutional block attention module (CBAM) for time series forecasting. Experimental results show our model is superior to other models from the viewpoint of forecasting accuracy and computation efficiency.
Effectiveness of the Execution and Prevention of Metric-Based Adversarial Attacks on Social Network Data †
Authors: Parulian Nikolaus Nova , Lu Tiffany , Mishra Shubhanshu , Avram Mihai , Diesner Jana
Published: June 2020

Observed social networks are often considered as proxies for underlying social networks. The analysis of observed networks oftentimes involves the identification of influential nodes via various centrality measures. This paper brings insights from research on adversarial attacks on machine learning systems to the domain of social networks by studying strategies by which an adversary can minimally perturb the observed network structure to achieve their target function of modifying the ranking of a target node according to centrality measures. This can represent the attempt of an adversary to boost or demote the degree to which others perceive individual nodes as influential or powerful. We study the impact of adversarial attacks on targets and victims, and identify metric-based security strategies to mitigate such attacks. We conduct a series of controlled experiments on synthetic network data to identify attacks that allow the adversary to achieve their objective with a single move. We then replicate the experiments with empirical network data. We run our experiments on common network topologies and use common centrality measures. We identify a small set of moves that result in the adversary achieving their objective. This set is smaller for decreasing centrality measures than for increasing them. For both synthetic and empirical networks, we observe that larger networks are less prone to adversarial attacks than smaller ones. Adversarial moves have a higher impact on cellular and small-world networks, while random and scale-free networks are harder to perturb. Also, empirical networks are harder to attack than synthetic networks. Using correlation analysis on our experimental results, we identify how combining measures with low correlation can aid in reducing the effectiveness of adversarial moves. Our results also advance the knowledge about the robustness of centrality measures to network perturbations. The notion of changing social network data to yield adversarial outcomes has practical implications, e.g., for information diffusion on social media, influence and power dynamics in social systems, and developing solutions to improving network security.
MoLaBSS: Server-Specific Add-On Biometric Security Layer Model to Enhance the Usage of Biometrics
Authors: Singh Bhanu , Singh Nirvisha
Published: June 2020

With high-paced growth in biometrics, and its easy availability to capture various biometric features, it is emerging as one of the most valuable technologies for multifactor authentication to verify a user’s identity, for data security. Organizations encourage their members to use biometrics, but they are hesitant to use them due to perceived security risks. Because of its low usage rate, many medium and small segment organizations find it unfeasible to deploy robust biometric systems. We propose a server-specific add-on biometric security layer model (MoLaBSS) to enhance confidence in the usage of biometrics. We tested this model via a biometric mobile app, and the survey showed a favorable response of 80%. The innovative mobile app was tested for its usability and got a score of more than 71%. For test tool reliability, we examined the equal error rate (EER) of the app and got a reasonably low score of 6%. The results show good potential of this framework to enhance users’ confidence level in the usage of biometrics. Higher usage rates may make deployment of biometrics more cost-effective for many organizations to decrease their information security risk.