bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic Signature of the Standardized Uptake Value in 18F-Fluorodeoxyglucose Positron Emission Tomography in Breast Cancer
Authors: Kim Seon-Kyu , Ahn Sung Gwe , Mun Jeong-Yeon , Jeong Mi-So , Bae Soong June , Lee Ju-Seog , Jeong Joon , Leem Sun-Hee , Chu In-Sun
Published: February 2020

The standardized uptake value (SUV), an indicator of the degree of glucose uptake in 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), has been used for predicting the clinical behavior of malignant tumors. However, its characteristics have been insufficiently explored at the genomics level. Here, we aim to identify genomic signatures reflecting prognostic SUV characteristics in breast cancer (BRC). Through integrative genomic profiling of 3710 BRC patients, including 254 patients who underwent preoperative FDG-PET, we identified an SUV signature, which showed independent clinical utility for predicting BRC prognosis (hazard ratio [HR] 1.27, 95% confidence interval [CI] = 1.12 to 1.45, p = 2.23 × 10−4). The risk subgroups classified by the signature exhibited mutually exclusive mutation patterns of TP53 and PIK3CA and showed significantly different responsiveness to immunotherapy. Experimental assays revealed that a signaling axis defined by TP53–FOXM1 and its downstream effectors in glycolysis–gluconeogenesis, including LDHA, might be important mediators in the FDG-PET process. Our molecular characterizations support an understanding of glucose metabolism and poor prognosis in BRC with a high SUV, utilizable in clinical practice to assist other diagnostic tools.
Lipid–Saporin Nanoparticles for the Intracellular Delivery of Cytotoxic Protein to Overcome ABC Transporter-Mediated Multidrug Resistance In Vitro and In Vivo
Authors: Zhang Guan-Nan , Gupta Pranav , Wang Ming , Barbuti Anna Maria , Ashby Charles R. , Zhang Yun-Kai , Zeng Leli , Xu Qiaobing , Fan Ying-Fang , Chen Zhe-Sheng
Published: February 2020

Although the judicious use of anticancer drugs that target one or more receptor tyrosine kinases constitutes an effective strategy to attenuate tumor growth, drug resistance is commonly encountered in cancer patients. The ATP-binding cassette transporters are one of the major contributors to the development of multidrug resistance as their overexpression significantly decreases the intracellular concentration and thus, the efficacy of certain anticancer drugs. Therefore, the development of treatment strategies that would not be susceptible to efflux or excretion by specific ABC transporters could overcome resistance to treatment. Here, we investigated the anticancer efficacy of saporin, a ribosome-inactivating protein. Since saporin has poor permeability across the cell membrane, it was encapsulated in a lipid-based nanoparticle system (EC16-1) that effectively delivered the formulation (EC16-1/saporin) intracellularly and produced anti-cancer efficacy. EC16-1/saporin, at nanomolar concentrations, significantly inhibited the cellular proliferation of parental and ABCB1- and ABCG2-overexpressing cancer cells. EC16-1/saporin did not significantly alter the subcellular localization of ABCB1 and ABCG2. In addition, EC16-1/saporin induced apoptosis in parental and ABCB1- and ABCG2-overexpressing cancer cells. In a murine model system, EC16-1/saporin significantly inhibited the tumor growth in mice xenografted with parental and ABCB1- and ABCG2-overexpressing cancer cells. Our findings suggest that the EC16-1/saporin combination could potentially be a novel therapeutic treatment in patients with parental or ABCB1- and ABCG2-positive drug-resistant cancers.
Protein Tyrosine Phosphatase-1B Inhibition Disrupts IL13Rα2-Promoted Invasion and Metastasis in Cancer Cells
Authors: Bartolomé Rubén A. , Martín-Regalado Ángela , Jaén Marta , Zannikou Markella , Zhang Peng , de los Ríos Vivian , Balyasnikova Irina V. , Casal J. Ignacio
Published: February 2020

Background: Interleukin 13 receptor alpha 2 subunit (IL13Rα2) is overexpressed in glioblastoma (GBM), metastatic colorectal cancer (CRC) and ovarian cancer (OC). Here, we investigated the IL13Rα2 interactome searching for novel targets in cancer invasion and metastasis. Methods: The interactome of IL13Rα2 was determined in GBM by using a proteomic analysis and then validated in CRC and OC. Cell signaling was investigated using siRNA interference, protein tyrosine phosphatase-1B (PTP1B) inhibitors and Western blot analysis. Animal models of GBM and metastatic CRC were used for testing PTP1B inhibitors. Results: PTP1B was identified and validated as a mediator of IL13Rα2 signaling. An in silico analysis revealed that PTP1B overexpression is associated with lower overall survival of patients in the three types of cancer. PTP1B silencing or treatment with Claramine, a PTP1B inhibitor, caused a significant decrease in IL-13-mediated adhesion, migration and invasion of IL13Rα2-expressing cancer cells by inhibiting the dephosphorylation of Src Tyr530 and consequently, the phosphorylation of Src Tyr419, AKT and ERK1/2. In addition, Claramine inhibited EGF-mediated activation of EGFR Tyr1068. In vivo treatment with Claramine caused a total inhibition of liver metastasis in mice inoculated with CRC cells and a significant increase in the survival of mice bearing intracranial GBM patient-derived xenografts. Conclusions: We have uncovered that IL13 signaling through IL13Rα2 requires PTP1B activity and therefore, PTP1B inhibition represents a promising therapeutic strategy in multiple types of cancer, including glioblastoma.
The c-Myc/AKT1/TBX3 Axis Is Important to Target in the Treatment of Embryonal Rhabdomyosarcoma
Authors: Sims Danica , Maranyane Hapiloe Mabaruti , Damerell Victoria , Govender Dhirendra , Isaacs Ashwin W. , Peres Jade , Prince Sharon
Published: February 2020

Rhabdomyosarcoma is a highly aggressive malignant cancer that arises from skeletal muscle progenitor cells and is the third most common solid tumour in children. Despite significant advances, rhabdomyosarcoma still presents a therapeutic challenge, and while targeted therapy has shown promise, there are limited options because the molecular drivers of rhabdomyosarcoma are poorly understood. We previously reported that the T-box transcription factor 3 (TBX3), which has been identified as a druggable target in many cancers, is overexpressed in rhabdomyosarcoma patient samples and cell lines. To identify new molecular therapeutic targets to treat rhabdomyosarcoma, this study investigates the potential oncogenic role(s) for TBX3 and the factors responsible for upregulating it in this cancer. To this end, rhabdomyosarcoma cell culture models in which TBX3 was either stably knocked down or overexpressed were established and the impact on key hallmarks of cancer were examined using growth curves, soft agar and scratch motility assays, as well as tumour-forming ability in nude mice. Our data show that TBX3 promotes substrate-dependent and -independent proliferation, migration and tumour formation. We further reveal that TBX3 is upregulated by c-Myc transcriptionally and AKT1 post-translationally. This study identifies c-Myc/AKT1/TBX3 as an important axis that could be targeted for the treatment of rhabdomyosarcoma.
Obesity Promotes Cooperation of Cancer Stem-Like Cells and Macrophages to Enhance Mammary Tumor Angiogenesis
Authors: Hillers-Ziemer Lauren E. , McMahon Rachel Q. , Hietpas Margaret , Paderta Gretchen , LeBeau Jennelle , McCready Jessica , Arendt Lisa M.
Published: February 2020

Obesity is correlated with worsened prognosis and treatment resistance in breast cancer. Macrophage-targeted therapies are currently in clinical trials, however, little is known about how obesity may impact treatment efficacy. Within breast adipose tissue, obesity leads to chronic, macrophage-driven inflammation, suggesting that obese breast cancer patients may benefit from these therapies. Using a high fat diet model of obesity, we orthotopically transplanted cancer cell lines into the mammary glands of obese and lean mice. We quantified changes in tumor invasiveness, angiogenesis and metastasis, and examined the efficacy of macrophage depletion to diminish tumor progression in obese and lean mice. Mammary tumors from obese mice grew significantly faster, were enriched for cancer stem-like cells (CSCs) and were more locally invasive and metastatic. Tumor cells isolated from obese mice demonstrated enhanced expression of stem cell-related pathways including Sox2 and Notch2. Despite more rapid growth, mammary tumors from obese mice had reduced necrosis, higher blood vessel density, and greater macrophage recruitment. Depletion of macrophages in obese tumor-bearing mice resulted in increased tumor necrosis, reduced endothelial cells, and enhanced recruitment of CD8+ T cells compared to IgG-treated controls. Macrophages may be an important clinical target to improve treatment options for obese breast cancer patients.
A Novel pH-Tunable Secondary Conformation Containing Mixed Micellar System in Anticancer Treatment
Authors: Shih Fu-Ying , Jiang Wen-Ping , Lin Xiaojie , Kuo Sheng-Chu , Huang Guan-Jhong , Hou Yu-Chi , Chang Chih-Shiang , Liu Yang , Chiang Yi-Ting
Published: February 2020

In this study, for the first time, we precisely assembled the poly-γ-benzyl-l-glutamate and an amphiphilic copolymer d-α-tocopherol polyethylene glycol succinate into a mixed micellar system for the embedment of the anticancer drug doxorubicin. Importantly, the intracellular drug-releasing behaviors could be controlled by changing the secondary structures of poly-γ-benzyl-l-glutamate via the precise regulation of the buffer’s pH value. Under neutral conditions, the micellar architectures were stabilized by both α-helix secondary structures and the microcrystalline structures. Under acidic conditions (pH 4.0), the interior structures transformed into a coil state with a disordered alignment, inducing the release of the loaded drug. A remarkable cytotoxicity of the Dox-loaded mixed micelles was exhibited toward human lung cancer cells in vitro. The internalizing capability into the cancer cells, as well as the intracellular drug-releasing behaviors, were also identified and observed. The secondary structures containing Dox-loaded mixed micelles had an outstanding antitumor efficacy in human lung cancer A549 cells-bearing nude mice, while little toxicities occurred or interfered with the hepatic or renal functions after the treatments. Thus, these pH-tunable α-helix-containing mixed micelles are innovative and promising for controlled intracellular anticancer drug delivery.
Adjuvant Therapy in Adrenocortical Carcinoma: Reflections and Future Directions
Authors: Bedrose Sara , Daher Marilyne , Altameemi Lina , Habra Mouhammed Amir
Published: February 2020

Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with high risk of recurrence despite macroscopically complete surgical resection. The main predictors of ACC recurrence include advanced disease stage, incomplete surgical resection, cortisol production, certain genetic alterations, and high proliferation rate (Ki-67 proliferation index). Mitotane has been the mainstay adjuvant therapy of ACC. However, the use of mitotane is based on retrospective and occasionally conflicting evidence. As mitotane levels can take a few months before reaching therapeutic levels, there is an emerging practice of combining platinum-based chemotherapy with mitotane in the adjuvant setting. Retrospective data indicate that radiotherapy is an option for select patients, particularly those with positive resection margins. There are multiple knowledge gaps in selecting patients for adjuvant therapy. It is of great importance to establish risk calculators to predict recurrence and to implement molecular profiling of ACC to guide adjuvant therapy. The role of immunotherapy in metastatic ACC is emerging and if deemed efficacious, then future studies will be needed to ascertain the role of adjuvant immunotherapy in ACC.
Inflammation-Modulating Hydrogels for Osteoarthritis Cartilage Tissue Engineering
Authors: Koh Rachel H. , Jin Yinji , Kim Jisoo , Hwang Nathaniel S.
Published: February 2020

Osteoarthritis (OA) is the most common form of the joint disease associated with age, obesity, and traumatic injury. It is a disabling degenerative disease that affects synovial joints and leads to cartilage deterioration. Despite the prevalence of this disease, the understanding of OA pathophysiology is still incomplete. However, the onset and progression of OA are heavily associated with the inflammation of the joint. Therefore, studies on OA treatment have sought to intra-articularly deliver anti-inflammatory drugs, proteins, genes, or cells to locally control inflammation in OA joints. These therapeutics have been delivered alone or increasingly, in delivery vehicles for sustained release. The use of hydrogels in OA treatment can extend beyond the delivery of anti-inflammatory components to have inherent immunomodulatory function via regulating immune cell polarization and activity. Currently, such immunomodulatory biomaterials are being developed for other applications, which can be translated into OA therapy. Moreover, anabolic and proliferative levels of OA chondrocytes are low, except initially, when chondrocytes temporarily increase anabolism and proliferation in response to structural changes in their extracellular environment. Therefore, treatments need to restore matrix protein synthesis and proliferation to healthy levels to reverse OA-induced damage. In conjugation with injectable and/or adhesive hydrogels that promote cartilage tissue regeneration, immunomodulatory tissue engineering solutions will have robust potential in OA treatment. This review describes the disease, its current and future immunomodulatory therapies as well as cartilage-regenerative injectable and adhesive hydrogels.
Purity Determines the Effect of Extracellular Vesicles Derived from Mesenchymal Stromal Cells
Authors: Forteza-Genestra Maria Antònia , Antich-Rosselló Miquel , Calvo Javier , Gayà Antoni , Monjo Marta , Ramis Joana Maria
Published: February 2020

Extracellular vesicles (EVs) have been recently identified as vital components of cell-based therapies based on the observation that conditioned media from cultured stromal cells reproduce some of the beneficial effects of intact cells. In order to obtain clinically active EVs derived from Mesenchymal Stromal Cells (MSCs) different procedures have been reported in the literature. Usually, non-confluent cells are incubated with culture medium for 48 h either with EV-depleted Fetal Bovine Serum (FBS) or without FBS. Our aim was to compare the effects of EVs isolated by ultracentrifugation from human umbilical cord MSC conditioned media obtained using these two conditions: with EV-depleted FBS (UC) or without FBS (UCw/o) on the mRNA expression levels of extracellular matrix related genes using the mouse chondrogenic cell line ATDC-5. We observed a deleterious effect on chondrogenic cells treated with UCw/o, showing higher mRNA expression levels of different metalloproteinases and decorin (Dcn) and lower collagen (Col1a1 and Col2a1) and aggrecan (Acan) mRNA levels. To elucidate whether this deleterious effect was induced by the EVs or by any proteins co-purified in the EV pellet, we used size exclusion chromatography (SEC) to further purify the EV pellet, obtaining an EV enriched fraction (EV or EVw/o) and a protein enriched fraction (Prot or Protw/o). Our results pointed that the negative effect on the chondrogenic cell line was due to the contaminant proteins coisolated with the EVs by ultracentrifugation and not from the EVs themselves. Thus, these results highlight the importance of working with well purified EV preparations to specifically achieve their therapeutic effect.
SIRT1 Protects the Heart from ER Stress-Induced Injury by Promoting eEF2K/eEF2-Dependent Autophagy
Authors: Pires Da Silva Julie , Monceaux Kevin , Guilbert Arnaud , Gressette Mélanie , Piquereau Jérôme , Novotova Marta , Ventura-Clapier Renée , Garnier Anne , Lemaire Christophe
Published: February 2020

Many recent studies have demonstrated the involvement of endoplasmic reticulum (ER) stress in the development of cardiac diseases and have suggested that modulation of ER stress response could be cardioprotective. Previously, we demonstrated that the deacetylase Sirtuin 1 (SIRT1) attenuates ER stress response and promotes cardiomyocyte survival. Here, we investigated whether and how autophagy plays a role in SIRT1-afforded cardioprotection against ER stress. The results revealed that protective autophagy was initiated before cell death in response to tunicamycin (TN)-induced ER stress in cardiac cells. SIRT1 inhibition decreased ER stress-induced autophagy, whereas its activation enhanced autophagy. In response to TN- or isoproterenol-induced ER stress, mice deficient for SIRT1 exhibited suppressed autophagy along with exacerbated cardiac dysfunction. At the molecular level, we found that in response to ER stress (i) the extinction of eEF2 or its kinase eEF2K not only reduced autophagy but further activated cell death, (ii) inhibition of SIRT1 inhibited the phosphorylation of eEF2, (iii) eIF2α co-immunoprecipitated with eEF2K, and (iv) knockdown of eIF2α reduced the phosphorylation of eEF2. Our results indicate that in response to ER stress, SIRT1 activation promotes cardiomyocyte survival by enhancing autophagy at least through activation of the eEF2K/eEF2 pathway.
Phosphorylation-Dependent Differences in CXCR4-LASP1-AKT1 Interaction between Breast Cancer and Chronic Myeloid Leukemia
Authors: Butt Elke , Stempfle Katrin , Lister Lorenz , Wolf Felix , Kraft Marcella , Herrmann Andreas B. , Viciano Cristina Perpina , Weber Christian , Hochhaus Andreas , Ernst Thomas , Hoffmann Carsten , Zernecke Alma , Frietsch Jochen J.
Published: February 2020

The serine/threonine protein kinase AKT1 is a downstream target of the chemokine receptor 4 (CXCR4), and both proteins play a central role in the modulation of diverse cellular processes, including proliferation and cell survival. While in chronic myeloid leukemia (CML) the CXCR4 is downregulated, thereby promoting the mobilization of progenitor cells into blood, the receptor is highly expressed in breast cancer cells, favoring the migratory capacity of these cells. Recently, the LIM and SH3 domain protein 1 (LASP1) has been described as a novel CXCR4 binding partner and as a promoter of the PI3K/AKT pathway. In this study, we uncovered a direct binding of LASP1, phosphorylated at S146, to both CXCR4 and AKT1, as shown by immunoprecipitation assays, pull-down experiments, and immunohistochemistry data. In contrast, phosphorylation of LASP1 at Y171 abrogated these interactions, suggesting that both LASP1 phospho-forms interact. Finally, findings demonstrating different phosphorylation patterns of LASP1 in breast cancer and chronic myeloid leukemia may have implications for CXCR4 function and tyrosine kinase inhibitor treatment.
Transactivation of miR-202-5p by Steroidogenic Factor 1 (SF1) Induces Apoptosis in Goat Granulosa Cells by Targeting TGFβR2
Authors: Ding Qiang , Jin Miaohan , Wang Yaoyue , Liu Jiao , Kalds Peter , Wang Ying , Yang Yuxin , Wang Xiaolong , Chen Yulin
Published: February 2020

MicroRNAs play key roles during ovary development, with emerging evidence suggesting that miR-202-5p is specifically expressed in female animal gonads. Granulosa cells (GCs) are somatic cells that are closely related to the development of female gametes in mammalian ovaries. However, the biological roles of miR-202-5p in GCs remain unknown. Here, we show that miR-202-5p is specifically expressed in GCs and accumulates in extracellular vesicles (EVs) from large growth follicles in goat ovaries. In vitro assays showed that miR-202-5p induced apoptosis and suppressed the proliferation of goat GCs. We further revealed that miR-202-5p is a functional miRNA that targets the transforming growth factor-beta type II receptor (TGFβR2). MiR-202-5p attenuated TGF-β/SMAD signaling through the degradation of TGFβR2 at both the mRNA and protein level, decreasing p-SMAD3 levels in GCs. Moreover, we verified that steroidogenic factor 1 (SF1) is a transcriptional factor that binds to the promoters of miR-202 and cytochrome P450 family 19 subfamily A member 1 (CYP19A1) through luciferase reporter and chromatin immunoprecipitation (ChIP) assays. That contributed to positive correlation between miR-202-5p and CYP19A1 expression and estradiol (E2) release. Furthermore, SF1 repressed TGFβR2 and p-SMAD3 levels in GCs through the transactivation of miR-202-5p. Taken together, these results suggest a mechanism by which miR-202-5p regulates canonical TGF-β/SMAD signaling through targeting TGFβR2 in GCs. This provides insight into the transcriptional regulation of miR-202 and CYP19A1 during goat ovarian follicular development.
Extracellular Vesicles Derived from Induced Pluripotent Stem Cells Promote Renoprotection in Acute Kidney Injury Model
Authors: Collino Federica , Lopes Jarlene A. , Tapparo Marta , Tortelote Giovane G. , Kasai-Brunswick Taís H. , Lopes Gustavo M.C. , Almeida Douglas B. , Skovronova Renata , Wendt Camila H. C. , Miranda Kildare R. de , Bussolati Benedetta , Vieyra Adalberto , Lindoso Rafael Soares
Published: February 2020

Induced pluripotent stem cells (iPSC) have been the focus of several studies due to their wide range of application, including in cellular therapy. The use of iPSC in regenerative medicine is limited by their tumorigenic potential. Extracellular vesicles (EV) derived from stem cells have been shown to support renal recovery after injury. However, no investigation has explored the potential of iPSC-EV in the treatment of kidney diseases. To evaluate this potential, we submitted renal tubule cells to hypoxia-reoxygenation injury, and we analyzed cell death rate and changes in functional mitochondria mass. An in vivo model of ischemia-reperfusion injury was used to evaluate morphological and functional alterations. Gene array profile was applied to investigate the mechanism involved in iPSC-EV effects. In addition, EV derived from adipose mesenchymal cells (ASC-EV) were also used to compare the potential of iPSC-EV in support of tissue recovery. The results showed that iPSC-EV were capable of reducing cell death and inflammatory response with similar efficacy than ASC-EV. Moreover, iPSC-EV protected functional mitochondria and regulated several genes associated with oxidative stress. Taken together, these results show that iPSC can be an alternative source of EV in the treatment of different aspects of kidney disease.
Characterizing the Retinal Phenotype in the High-Fat Diet and Western Diet Mouse Models of Prediabetes
Authors: Asare-Bediako Bright , Noothi Sunil , Li Calzi Sergio , Athmanathan Baskaran , Vieira Cristiano , Adu-Agyeiwaah Yvonne , Dupont Mariana , Jones Bryce , Wang Xiaoxin , Chakraborty Dibyendu , Levi Moshe , Nagareddy Prabhakara , Grant Maria
Published: February 2020

We sought to delineate the retinal features associated with the high-fat diet (HFD) mouse, a widely used model of obesity. C57BL/6 mice were fed either a high-fat (60% fat; HFD) or low-fat (10% fat; LFD) diet for up to 12 months. The effect of HFD on body weight and insulin resistance were measured. The retina was assessed by electroretinogram (ERG), fundus photography, permeability studies, and trypsin digests for enumeration of acellular capillaries. The HFD cohort experienced hypercholesterolemia when compared to the LFD cohort, but not hyperglycemia. HFD mice developed a higher body weight (60.33 g vs. 30.17g, p < 0.0001) as well as a reduced insulin sensitivity index (9.418 vs. 62.01, p = 0.0002) compared to LFD controls. At 6 months, retinal functional testing demonstrated a reduction in a-wave and b-wave amplitudes. At 12 months, mice on HFD showed evidence of increased retinal nerve infarcts and vascular leakage, reduced vascular density, but no increase in number of acellular capillaries compared to LFD mice. In conclusion, the HFD mouse is a useful model for examining the effect of prediabetes and hypercholesterolemia on the retina. The HFD-induced changes appear to occur slower than those observed in type 2 diabetes (T2D) models but are consistent with other retinopathy models, showing neural damage prior to vascular changes.
The Histone Code of Senescence
Authors: Paluvai Harikrishnareddy , Di Giorgio Eros , Brancolini Claudio
Published: February 2020

Senescence is the end point of a complex cellular response that proceeds through a set of highly regulated steps. Initially, the permanent cell-cycle arrest that characterizes senescence is a pro-survival response to irreparable DNA damage. The maintenance of this prolonged condition requires the adaptation of the cells to an unfavorable, demanding and stressful microenvironment. This adaptation is orchestrated through a deep epigenetic resetting. A first wave of epigenetic changes builds a dam on irreparable DNA damage and sustains the pro-survival response and the cell-cycle arrest. Later on, a second wave of epigenetic modifications allows the genomic reorganization to sustain the transcription of pro-inflammatory genes. The balanced epigenetic dynamism of senescent cells influences physiological processes, such as differentiation, embryogenesis and aging, while its alteration leads to cancer, neurodegeneration and premature aging. Here we provide an overview of the most relevant histone modifications, which characterize senescence, aging and the activation of a prolonged DNA damage response.
The Cell Cycle Checkpoint System MAST(L)-ENSA/ARPP19-PP2A is Targeted by cAMP/PKA and cGMP/PKG in Anucleate Human Platelets
Authors: Kumm Elena J. , Pagel Oliver , Gambaryan Stepan , Walter Ulrich , Zahedi René P. , Smolenski Albert , Jurk Kerstin
Published: February 2020

The cell cycle is controlled by microtubule-associated serine/threonine kinase-like (MASTL), which phosphorylates the cAMP-regulated phosphoproteins 19 (ARPP19) at S62 and 19e/α-endosulfine (ENSA) at S67and converts them into protein phosphatase 2A (PP2A) inhibitors. Based on initial proteomic data, we hypothesized that the MASTL-ENSA/ARPP19-PP2A pathway, unknown until now in platelets, is regulated and functional in these anucleate cells. We detected ENSA, ARPP19 and various PP2A subunits (including seven different PP2A B-subunits) in proteomic studies of human platelets. ENSA-S109/ARPP19–S104 were efficiently phosphorylated in platelets treated with cAMP- (iloprost) and cGMP-elevating (NO donors/riociguat) agents. ENSA-S67/ARPP19-S62 phosphorylations increased following PP2A inhibition by okadaic acid (OA) in intact and lysed platelets indicating the presence of MASTL or a related protein kinase in human platelets. These data were validated with recombinant ENSA/ARPP19 and phospho-mutants using recombinant MASTL, protein kinase A and G. Both ARPP19 phosphorylation sites S62/S104 were dephosphorylated by platelet PP2A, but only S62-phosphorylated ARPP19 acted as PP2A inhibitor. Low-dose OA treatment of platelets caused PP2A inhibition, diminished thrombin-stimulated platelet aggregation and increased phosphorylation of distinct sites of VASP, Akt, p38 and ERK1/2 MAP kinases. In summary, our data establish the entire MASTL(like)–ENSA/ARPP19–PP2A pathway in human platelets and important interactions with the PKA, MAPK and PI3K/Akt systems.
The Impact of Cigarette Smoking on Risk of Rheumatoid Arthritis: A Narrative Review
Authors: Ishikawa Yuki , Terao Chikashi
Published: February 2020

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and subsequent proliferation of synovial tissues, which eventually leads to cartilage and bone destruction without effective treatments. Anti-citrullinated cyclic peptide/protein antibody (ACPA) and rheumatoid factor (RF) are two main characteristic autoantibodies found in RA patients and are associated with unfavorable disease outcomes. Although etiologies and causes of the disease have not been fully clarified yet, it is likely that interactive contributions of genetic and environmental factors play a main role in RA pathology. Previous works have demonstrated several genetic and environmental factors as risks of RA development and/or autoantibody productions. Among these, cigarette smoking and HLA-DRB1 are the well-established environmental and genetic risks, respectively. In this narrative review, we provide a recent update on genetic contributions to RA and the environmental risks of RA with a special focus on cigarette smoking and its impacts on RA pathology. We also describe gene–environmental interaction in RA pathogenesis with an emphasis on cigarette smoking and HLA-DRB1.
Extra Virgin Olive Oil Polyphenols: Modulation of Cellular Pathways Related to Oxidant Species and Inflammation in Aging
Authors: Serreli Gabriele , Deiana Monica
Published: February 2020

The olive-oil-centered Mediterranean diet has been associated with extended life expectancy and a reduction in the risk of age-related degenerative diseases. Extra virgin olive oil (EVOO) itself has been proposed to promote a “successful aging”, being able to virtually modulate all the features of the aging process, because of its great monounsaturated fatty acids content and its minor bioactive compounds, the polyphenols above all. Polyphenols are mostly antioxidant and anti-inflammatory compounds, able to modulate abnormal cellular signaling induced by pro-inflammatory stimuli and oxidative stress, as that related to NF-E2-related factor 2 (Nrf-2) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), which have been identified as important modulators of age-related disorders and aging itself. This review summarizes existing literature about the interaction between EVOO polyphenols and NF-κB and Nrf-2 signaling pathways. Reported studies show the ability of EVOO phenolics, mainly hydroxytyrosol and tyrosol, to activate Nrf-2 signaling, inducing a cellular defense response and to prevent NF-κB activation, thus suppressing the induction of a pro-inflammatory phenotype. Literature data, although not exhaustive, indicate as a whole that EVOO polyphenols may significantly help to modulate the aging process, so tightly connected to oxidative stress and chronic inflammation.
Technical Considerations in Ex Vivo Human Regulatory T Cell Migration and Suppression Assays
Authors: Irekeola Ahmad Adebayo , E. A. R. Engku Nur Syafirah , Mat Lazim Norhafiza , Mohamud Rohimah , Yean Chan Yean , Shueb Rafidah Hanim
Published: February 2020

Regulatory T cells (Tregs) are renowned for maintaining homeostasis and self-tolerance through their ability to suppress immune responses. For over two decades, Tregs have been the subject of intensive research. The immunosuppressive and migratory potentials of Tregs have been exploited, especially in the areas of cancer, autoimmunity and vaccine development, and many assay protocols have since been developed. However, variations in assay conditions in different studies, as well as covert experimental factors, pose a great challenge to the reproducibility of results. Here, we focus on human Tregs derived from clinical samples and highlighted caveats that should be heeded when conducting Tregs suppression and migration assays. We particularly delineated how factors such as sample processing, choice of reagents and equipment, optimization and other experimental conditions could introduce bias into the assay, and we subsequently proffer recommendations to enhance reliability and reproducibility of results. It is hoped that prioritizing these factors will reduce the tendencies of generating false and misleading results, and thus, help improve our understanding and interpretation of Tregs functional studies.
TLR2 Signaling Pathway Combats Streptococcus uberis Infection by Inducing Mitochondrial Reactive Oxygen Species Production
Authors: Li Bin , Wan Zhixin , Wang Zhenglei , Zuo Jiakun , Xu Yuanyuan , Han Xiangan , Phouthapane Vanhnaseng , Miao Jinfeng
Published: February 2020

Mastitis caused by Streptococcus uberis (S. uberis) is a common and difficult-to-cure clinical disease in dairy cows. In this study, the role of Toll-like receptors (TLRs) and TLR-mediated signaling pathways in mastitis caused by S. uberis was investigated using mouse models and mammary epithelial cells (MECs). We used S. uberis to infect mammary glands of wild type, TLR2−/− and TLR4−/− mice and quantified the adaptor molecules in TLR signaling pathways, proinflammatory cytokines, tissue damage, and bacterial count. When compared with TLR4 deficiency, TLR2 deficiency induced more severe pathological changes through myeloid differentiation primary response 88 (MyD88)-mediated signaling pathways during S. uberis infection. In MECs, TLR2 detected S. uberis infection and induced mitochondrial reactive oxygen species (mROS) to assist host in controlling the secretion of inflammatory factors and the elimination of intracellular S. uberis. Our results demonstrated that TLR2-mediated mROS has a significant effect on S. uberis-induced host defense responses in mammary glands as well as in MECs.
Thermal Stability of CrWN Glass Molding Coatings after Vacuum Annealing
Authors: Huang Xinfang , Xie Zhiwen , Li Kangsen , Chen Qiang , Chen Yongjun , Gong Feng
Published: February 2020

CrWN glass molding coatings were deposited by plasma enhanced magnetron sputtering (PEMS). The microstructure and thermal stability of these coatings were investigated by X-ray diffraction, X-ray photoelectron spectroscopy, scanning electron microscope, transmission electron microscope, atomic force microscope and nanoindentation tests. The as-deposited coating exhibited an aggravated lattice expansion resulting in a constant hardness enhancement. The vacuum annealing induced surface coarsening and the spinodal decomposition of the coating accompanied by the formation of nm-sized c-CrN, c-W2N, and h-WN domains. The annealed coating with low W content had mainly a face-centered cubic (f.c.c) matrix, strain fields caused by lattice mismatch caused hardness enhancement. Following an increase in W content, the annealed coating showed a mixed face-centered cubic (f.c.c) and hexagonal close-packed (h.c.p) matrix. The large volume fraction of h-WN phases seriously weakened the coating strengthening effect and caused an obvious drop in hardness.
Hydrothermal Synthesis of Cobalt Ruthenium Sulfides as Promising Pseudocapacitor Electrode Materials
Authors: Bolagam Ravi , Um Sukkee
Published: February 2020

In this paper, we report the successful synthesis of cobalt ruthenium sulfides by a facile hydrothermal method. The structural aspects of the as-prepared cobalt ruthenium sulfides were characterized using X-ray diffraction, X-ray photoelectron spectroscopy, and Raman spectroscopy. All the prepared materials exhibited nanocrystal morphology. The electrochemical performance of the ternary metal sulfides was investigated by cyclic voltammetry (CV), galvanostatic charge-discharge (GCD), and electrochemical impedance spectroscopy techniques. Noticeably, the optimized ternary metal sulfide electrode exhibited good specific capacitances of 95 F g−1 at 5 mV s−1 and 75 F g−1 at 1 A g−1, excellent rate capability (48 F g−1 at 5 A g−1), and superior cycling stability (81% capacitance retention after 1000 cycles). Moreover, this electrode demonstrated energy densities of 10.5 and 6.7 Wh kg−1 at power densities of 600 and 3001.5 W kg−1, respectively. These attractive properties endow proposed electrodes with significant potential for high-performance energy storage devices.
Stable and Metastable Patterns in Chromonic Nematic Liquid Crystal Droplets Forced with Static and Dynamic Magnetic Fields
Authors: Ignés-Mullol Jordi , Mora Marc , Martínez-Prat Berta , Vélez-Cerón Ignasi , Herrera R. , Sagués Francesc
Published: February 2020

Spherical confinement of nematic liquid crystals leads to the formation of equilibrium director field configurations that include point and line defects. Driving these materials with flows or dynamic fields often results in the formation of alternative metastable states. In this article, we study the effect of magnetic field alignment, both under static and dynamic conditions, of nematic gems (nematic droplets in coexistence with the isotropic phase) and emulsified nematic droplets of a lyotropic chromonic liquid crystal. We use a custom polarizing optical microscopy assembly that incorporates a permanent magnet whose strength and orientation can be dynamically changed. By comparing simulated optical patterns with microscopy images, we measure an equilibrium twisted bipolar pattern within nematic gems that is only marginally different from the one reported for emulsified droplets. Both systems evolve to concentric configurations upon application of a static magnetic field, but behave very differently when the field is rotated. While the concentric texture within the emulsified droplets is preserved and only displays asynchronous oscillations for high rotating speeds, the nematic gems transform into a metastable untwisted bipolar configuration that is memorized by the system when the field is removed. Our results demonstrate the importance of boundary conditions in determining the dynamic behavior of confined liquid crystals even for configurations that share similar equilibrium bulk structures.
Experimental Investigation on Heat Transfer of Supercritical Water Flowing in the Subchannel with Grid Spacer in Supercritical Water-Cooled Reactor
Authors: Wang Weishu , Guo Lingwei , Zhu Ge , Zhu Xiaojing , Bi Qincheng
Published: February 2020

Experimental investigations on the heat transfer performance of supercritical water flowing in the subchannel of supercritical water-cooled reactor (SCWR) simulated by a triangular channel were conducted at pressures of 23–28 MPa, mass flow rates of 700–1300 kg·m−2·s−1, and inner wall surface heat fluxes of 200–600 kW·m−2. An 8 mm diameter fuel rod with a 1.4 pitch to diameter ratio was used. The effects of pressure, mass flow rate, and heat flux on the heat transfer performance under the resistance of a standard grid spacer were analyzed. Experimental results showed the significant positive influence of the grid spacer on the supercritical water in the subchannel. Moreover, in the presence of the grid spacer, the parameters influenced the heat transfer with different degrees of strengthening reaction. In view of the phenomenon in the tests, the rule of the supercritical heat transfer was further revealed by the comparison between empirical formulas and experimental data. This paper mainly studied the positioning grid function and the fluid flow characteristics downstream of the subchannel under the influence of the standard grid spacer and the impact mechanism of each parameter on the whole heat transfer process coefficient.
Rural Household Livelihood and Tree Plantation Dependence in the Central Mountainous Region of Hainan Island, China: Implications for Poverty Alleviation
Authors: Li Ruida , Zheng Hua , Zhang Cuiping , Keeler Bonnie , Samberg Leah H. , Li Cong , Polasky Stephen , Ni Yongming , Ouyang Zhiyun
Published: February 2020

Plantations support local economies and rural livelihoods in many mountainous regions, where poverty and a fragile environment are often interlinked. Managing plantations sustainably and alleviating poverty is a major challenge. This study reports on the findings of a household livelihood survey in the central mountainous region of Hainan Island, a global biodiversity hotspot. The survey aimed to identify rural household livelihoods, strategies to lift rural households out of poverty and potential environmental consequences of different livelihood strategies. Households were divided into five groups based on their main source of income: plantations, crops, livestock, local off-farm income and remittances. Plantations were the main source of income for 74% of households and provided 46% of the total income. Plantation land area, planting diverse tree species and intercropping were significantly associated with higher income. Reallocating land by family size could increase the proportion of households above the poverty line in the plantation group from 51.3% to 85.3%, while making only 3.3% of households worse off. Lower income households tended to apply more chemicals to plantations, which suggests that they create more strain on the environment. Improving household income through dynamically allocating plantation land and diversifying planted species could therefore be beneficial both socially and environmentally. Our results emphasize the importance of dynamic plantation land allocation and diverse plantation planting in poverty alleviation and environmental sustainability.
Unveiling the Diversity of Tree Growth Patterns in Boreal Old-Growth Forests Reveals the Richness of Their Dynamics
Authors: Martin Maxence , Krause Cornélia , Fenton Nicole J. , Morin Hubert
Published: February 2020

Research Highlights: Radial growth patterns of trees growing in old-growth boreal forests in eastern Canada can be grouped into a small number of simple patterns that are specific to different old-growth forest types or successional stages. Background and Objectives: Identifying the main radial growth trends in old-growth forests could help to develop silvicultural treatments that mimic the complex dynamics of old-growth forests. Therefore, this study aimed to identify the main radial growth patterns and determine how their frequencies change during forest succession in old-growth forests, focusing on boreal landscapes in eastern Canada. Materials and Methods: We used dendrochronological data sampled from 21 old-growth stands in the province of Quebec, Canada. Tree-ring chronologies were simplified into chronologies of equal length to retain only primary growth trends. We used k-means clustering to identify individual growth patterns and the difference in growth-pattern frequency within the studied stands. We then used non-parametric analyses of variance to compare tree or stand characteristics among the clusters. Results: We identified six different growth patterns corresponding to four old-growth forest types, from stands at the canopy breakup stage to true old-growth stands (i.e., when all the pioneer cohort had disappeared). Secondary disturbances of low or moderate severity drove these growth patterns. Overall, the growth patterns were relatively simple and could be generally separated into two main phases (e.g., a phase of limited radial increment size due to juvenile suppression and a phase of increased radial increment size following a growth release). Conclusions: The complexity of old-growth forest dynamics was observed mainly at the stand level, not at the tree level. The growth patterns observed in true old-growth forests were similar to those observed following partial or stem-selection cuts in boreal stands; thus, these silvicultural treatments may be effective in mimicking old-growth dynamics.
Extending Aging of Beef Longissimus Lumborum From 21 to 84 Days Postmortem Influences Consumer Eating Quality
Authors: Garmyn Andrea , Hardcastle Nicholas , Polkinghorne Rod , Lucherk Loni , Miller Mark
Published: February 2020

Our objective was to determine the effect of extending postmortem aging from 21 to 84 days on consumer eating quality of beef longissimus lumborum. Strip loins were collected from 108 carcasses. The longissimus lumborum muscle was isolated from strip loins and assigned to one of ten postmortem aging periods from 21 to 84 days (7-day increments) and balanced within four anatomical positions within the muscle. Consumer evaluations for tenderness, juiciness, flavor, and overall liking were conducted using untrained consumer sensory panels consisting of 1080 individual consumers, in accordance with the Meat Standards Australia protocols. These scores were then used to calculate an overall eating quality (MQ4) score. Postmortem aging had no effect (P > 0.05) on tenderness, but juiciness, flavor liking, overall liking, and MQ4 declined (P < 0.05) as aging period increased. Samples aged 21 to 42 days were most preferred having greater (P < 0.05) overall liking and greater (P < 0.05) MQ4 scores than samples aged 70 to 84 days postmortem. These results suggest that longissimus lumborum samples should not be wet-aged longer than 63 days to prevent potential negative eating experiences for consumers; however, altering storage conditions, specifically reducing temperature, could potentially allow for longer chilled storage without such negative effects on flavor and overall liking.
Whole-Genome k-mer Topic Modeling Associates Bacterial Families
Authors: Borrayo Ernesto , May-Canche Isaias , Paredes Omar , Morales J. Alejandro , Romo-Vázquez Rebeca , Vélez-Pérez Hugo
Published: February 2020

Alignment-free k-mer-based algorithms in whole genome sequence comparisons remain an ongoing challenge. Here, we explore the possibility to use Topic Modeling for organism whole-genome comparisons. We analyzed 30 complete genomes from three bacterial families by topic modeling. For this, each genome was considered as a document and 13-mer nucleotide representations as words. Latent Dirichlet allocation was used as the probabilistic modeling of the corpus. We where able to identify the topic distribution among analyzed genomes, which is highly consistent with traditional hierarchical classification. It is possible that topic modeling may be applied to establish relationships between genome’s composition and biological phenomena.
Evolution of the Small Family of Alternative Splicing Modulators Nuclear Speckle RNA-Binding Proteins in Plants
Authors: Lucero Leandro , Bazin Jeremie , Rodriguez Melo Johan , Ibañez Fernando , Crespi Martín D. , Ariel Federico
Published: February 2020

RNA-Binding Protein 1 (RBP1) was first identified as a protein partner of the long noncoding RNA (lncRNA) ENOD40 in Medicago truncatula, involved in symbiotic nodule development. RBP1 is localized in nuclear speckles and can be relocalized to the cytoplasm by the interaction with ENOD40. The two closest homologs to RBP1 in Arabidopsis thaliana were called Nuclear Speckle RNA-binding proteins (NSRs) and characterized as alternative splicing modulators of specific mRNAs. They can recognize in vivo the lncRNA ALTERNATIVE SPLICING COMPETITOR (ASCO) among other lncRNAs, regulating lateral root formation. Here, we performed a phylogenetic analysis of NSR/RBP proteins tracking the roots of the family to the Embryophytes. Strikingly, eudicots faced a reductive trend of NSR/RBP proteins in comparison with other groups of flowering plants. In Medicago truncatula and Lotus japonicus, their expression profile during nodulation and in specific regions of the symbiotic nodule was compared to that of the lncRNA ENOD40, as well as to changes in alternative splicing. This hinted at distinct and specific roles of each member during nodulation, likely modulating the population of alternatively spliced transcripts. Our results establish the basis to guide future exploration of NSR/RBP function in alternative splicing regulation in different developmental contexts along the plant lineage.