bluuebunny/crossref_metadata_2025 huggingface dataset:
Chimeric Antigen Receptor Cell Therapy: Overcoming Obstacles to Battle Cancer
Authors: Petty Amy J. , Heyman Benjamin , Yang Yiping
Published: April 2020

Chimeric antigen receptors (CAR) are fusion proteins engineered from antigen recognition, signaling, and costimulatory domains that can be used to reprogram T cells to specifically target tumor cells expressing specific antigens. Current CAR-T cell technology utilizes the patient’s own T cells to stably express CARs and has achieved exciting clinical success in the past few years. However, current CAR-T cell therapy still faces several challenges, including suboptimal persistence and potency, impaired trafficking to solid tumors, local immunosuppression within the tumor microenvironment and intrinsic toxicity associated with CAR-T cells. This review focuses on recent strategies to improve the clinical efficacy of CAR-T cell therapy and other exciting CAR approaches currently under investigation, including CAR natural killer (NK) and NKT cell therapies.
Plasma and Tissue Specific miRNA Expression Pattern and Functional Analysis Associated to Colorectal Cancer Patients
Authors: Cojocneanu Roxana , Braicu Cornelia , Raduly Lajos , Jurj Ancuta , Zanoaga Oana , Magdo Lorand , Irimie Alexandru , Muresan Mihai-Stefan , Ionescu Calin , Grigorescu Mircea , Berindan-Neagoe Ioana
Published: April 2020

An increasing number of studies suggest the implication of microRNAs (miRNAs) in colorectal (CRC) carcinogenesis and disease progression. Nevertheless, the basic mechanism is not yet clear. We determined plasma miRNA expression levels using Agilent microarray technology followed by overlapping with The Cancer Genome Atlas (TCGA) tissue data and a qRT-PCR validation step and analysis of the altered miRNA signatures to emphasize new mechanistic insights. For TGCA dataset, we identified 156 altered miRNAs (79 downregulated and 77 upregulated) in colorectal tissue samples versus normal tissue. The microarray experiment is based on 16 control samples, 38 CRC plasma samples from colorectal cancer patients who have not undergone chemotherapy, and 17 chemo-treated samples. In the case of the analysis of CRC cancer versus healthy control we identified 359 altered miRNAs (214 downregulated and 60 upregulated), considering as the cutoff value a fold-change of ±1.5 and p < 0.01. An additional microarray analysis was performed on plasma from untreated colorectal cancer (n = 38) and chemotherapy-treated colorectal cancer patients (n = 17), which revealed 15 downregulated miRNAs and 53 upregulated miRNAs, demonstrating that the plasma miRNA pattern is affected by chemotherapy and emphasizing important regulators of drug resistance mechanisms. For the validation of the microarray data, we selected a panel of 4 miRNAs from the common miRNA signatures for colon and rectal cancer (miR-642b-3p, miR-195-5p and miR-4741). At the tissue level, the expression levels were in agreement with those observed in colorectal plasma. miR-1228-3p, the top upregulated miRNA in CRC, was chosen to be validated on tissue and plasma samples, as it was demonstrated to be downregulated at tissue level in our patient cohort. This was confirmed by TCGA data and was one example of ta ranscript that has a different expression level between tumor tissue and plasma. Developing more efficient investigation methods will help explain the mechanisms responsible for miRNAs released in biofluids, which is the most upregulated transcript in colorectal plasma samples and which can function as a prediction tool within the oncological field.
Combination Treatment with Cold Physical Plasma and Pulsed Electric Fields Augments ROS Production and Cytotoxicity in Lymphoma
Authors: Wolff Christina M. , Kolb Juergen F. , Weltmann Klaus-Dieter , von Woedtke Thomas , Bekeschus Sander
Published: April 2020

New approaches in oncotherapy rely on the combination of different treatments to enhance the efficacy of established monotherapies. Pulsed electric fields (PEFs) are an established method (electrochemotherapy) for enhancing cellular drug uptake while cold physical plasma is an emerging and promising anticancer technology. This study aimed to combine both technologies to elucidate their cytotoxic potential as well as the underlying mechanisms of the effects observed. An electric field generator (0.9–1.0 kV/cm and 100-μs pulse duration) and an atmospheric pressure argon plasma jet were employed for the treatment of lymphoma cell lines as a model system. PEF but not plasma treatment induced cell membrane permeabilization. Additive cytotoxicity was observed for the metabolic activity and viability of the cells while the sequence of treatment in the combination played only a minor role. Intriguingly, a parallel combination was more effective compared to a 15-min pause between both treatment regimens. A combination effect was also found for lipid peroxidation; however, none could be observed in the cytosolic and mitochondrial reactive oxygen species (ROS) production. The supplementation with either antioxidant, a pan-caspase-inhibitor or a ferroptosis inhibitor, all partially rescued lymphoma cells from terminal cell death, which contributes to the mechanistic understanding of this combination treatment.
Administration of Nicotinamide Mononucleotide (NMN) Reduces Metabolic Impairment in Male Mouse Offspring from Obese Mothers
Authors: Uddin Golam M. , Youngson Neil A. , Chowdhury Sabiha S. , Hagan Christopher , Sinclair David A. , Morris Margaret J.
Published: April 2020

Maternal obesity impacts offspring metabolism. We sought to boost mitochondrial energy metabolism using the nicotinamide adenine dinucleotide (NAD+) precursor nicotinamide mononucleotide (NMN) to treat metabolic impairment induced by maternal and long-term post weaning over-nutrition. Male offspring of lean or obese mothers, fed chow or high fat diet (HFD) for 30 weeks post-weaning, were given NMN injection, starting at 31 weeks of age, daily for 3 weeks before sacrifice. Glucose tolerance was tested at 10, 29 and 32 weeks of age to measure short and long term effects of post-weaning HFD, and NMN treatment. Plasma insulin and triglycerides, liver triglycerides and expression of mitochondrial metabolism-related genes were measured at 34 weeks. Impaired glucose tolerance due to maternal and post weaning HFD was significantly improved by only 8 days of NMN treatment. Furthermore, in offspring of obese mothers hepatic lipid accumulation was reduced due to NMN treatment by 50% and 23% in chow and HFD fed offspring respectively. Hepatic genes involved in fat synthesis, transport and uptake were reduced, while those involved in fatty acid oxidation were increased by NMN. Overall this finding suggests short term administration of NMN could be a therapeutic approach for treating metabolic disease due to maternal and post weaning over-nutrition, even in late adulthood.
The Brain–Skin Connection and the Pathogenesis of Psoriasis: A Review with a Focus on the Serotonergic System
Authors: Martins Ana M. , Ascenso Andreia , Ribeiro Helena M. , Marto Joana
Published: April 2020

Psoriasis is a common non-communicable chronic immune-mediated skin disease, affecting approximately 125 million people in the world. Its pathogenesis results from a combination of genetic and environmental factors. The pathogenesis of psoriasis seems to be driven by the interaction between innate immune cells, adaptive immune cells and keratinocytes, in a process mediated by cytokines (including interleukins (IL)-6, IL-17 and IL-22, interferon and tumor necrosis factor) and other signaling molecules. This leads to an inflammatory process with increased proliferation of epidermal cells, neo-angiogenesis and infiltration of dendritic cells in the skin. Dysfunctional de novo glucocorticoid synthesis in psoriatic keratinocytes and the skin microbiome have also been suggested as mediators in the pathogenesis of this disease. To understand psoriasis, it is essential to comprehend the processes underlying the skin immunity and neuroendocrinology. This review paper focuses on the skin as a neuroendocrine organ and summarizes what is known about the skin immune system, the brain–skin connection and the role played by the serotonergic system in skin. Subsequently, the alterations of neuroimmune processes and of the serotonergic system in psoriatic skin are discussed, as well as, briefly, the genetic basis of psoriasis.
Zebrafish Microenvironment Elevates EMT and CSC-Like Phenotype of Engrafted Prostate Cancer Cells
Authors: Chen Lanpeng , Boleslaw Olszewski Maciej , Kruithof-de Julio Marianna , Snaar-Jagalska B. Ewa
Published: April 2020

To visually and genetically trace single-cell dynamics of human prostate cancer (PCa) cells at the early stage of metastasis, a zebrafish (ZF) xenograft model was employed. The phenotypes of intravenously transplanted fluorescent cells were monitored by high-resolution, single-cell intravital confocal and light-sheet imaging. Engrafted osteotropic, androgen independent PCa cells were extravasated from caudle vein, invaded the neighboring tissue, proliferated and formed experimental metastases around caudal hematopoietic tissue (CHT) in four days. Gene expression comparison between cells in culture and in CHT revealed that engrafted PCa cells responded to the ZF microenvironment by elevating expression of epithelial–mesenchymal transition (EMT) and stemness markers. Next, metastatic potentials of ALDHhi cancer stem-like cells (CSCs) and ALDHlow non-CSCs were analyzed in ZF. Engraftment of CSCs induced faster metastatic onset, however after six days both cell subpopulations equally responded to the ZF microenvironment, resulting in the same increase of stemness genes expression including Nanog, Oct-4 and Cripto. Knockdown of Cripto significantly reduced the vimentin/E-cadherin ratio in engrafted cells, indicating that Cripto is required for transduction of the microenvironment signals from the ZF niche to increase mesenchymal potential of cells. Targeting of either Cripto or EMT transcriptional factors Snail 1 and Zeb1 significantly suppressed metastatic growth. These data indicated that zebrafish microenvironment governed the CSC/EMT plasticity of human PCa cells promoting metastasis initiation.
Recent Advances and Future Perspectives of In Vivo Targeted Delivery of Genome-Editing Reagents to Germ cells, Embryos, and Fetuses in Mice
Authors: Sato Masahiro , Takabayashi Shuji , Akasaka Eri , Nakamura Shingo
Published: April 2020

The recently discovered clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (Cas9) systems that occur in nature as microbial adaptive immune systems are considered an important tool in assessing the function of genes of interest in various biological systems. Thus, development of efficient and simple methods to produce genome-edited (GE) animals would accelerate research in this field. The CRISPR/Cas9 system was initially employed in early embryos, utilizing classical gene delivery methods such as microinjection or electroporation, which required ex vivo handling of zygotes before transfer to recipients. Recently, novel in vivo methods such as genome editing via oviductal nucleic acid delivery (GONAD), improved GONAD (i-GONAD), or transplacental gene delivery for acquiring genome-edited fetuses (TPGD-GEF), which facilitate easy embryo manipulation, have been established. Studies utilizing these techniques employed pregnant female mice for direct introduction of the genome-editing components into the oviduct or were dependent on delivery via tail-vein injection. In mice, embryogenesis occurs within the oviducts and the uterus, which often hampers the genetic manipulation of embryos, especially those at early postimplantation stages (days 6 to 8), owing to a thick surrounding layer of tissue called decidua. In this review, we have surveyed the recent achievements in the production of GE mice and have outlined the advantages and disadvantages of the process. We have also referred to the past achievements in gene delivery to early postimplantation stage embryos and germ cells such as primordial germ cells and spermatogonial stem cells, which will benefit relevant research.
Human γδ TCR Repertoires in Health and Disease
Authors: Fichtner Alina Suzann , Ravens Sarina , Prinz Immo
Published: April 2020

The T cell receptor (TCR) repertoires of γδ T cells are very different to those of αβ T cells. While the theoretical TCR repertoire diversity of γδ T cells is estimated to exceed the diversity of αβ T cells by far, γδ T cells are still understood as more invariant T cells that only use a limited set of γδ TCRs. Most of our current knowledge of human γδ T cell receptor diversity builds on specific monoclonal antibodies that discriminate between the two major subsets, namely Vδ2+ and Vδ1+ T cells. Of those two subsets, Vδ2+ T cells seem to better fit into a role of innate T cells with semi-invariant TCR usage, as compared to an adaptive-like biology of some Vδ1+ subsets. Yet, this distinction into innate-like Vδ2+ and adaptive-like Vδ1+ γδ T cells does not quite recapitulate the full diversity of γδ T cell subsets, ligands and interaction modes. Here, we review how the recent introduction of high-throughput TCR repertoire sequencing has boosted our knowledge of γδ T cell repertoire diversity beyond Vδ2+ and Vδ1+ T cells. We discuss the current understanding of clonal composition and the dynamics of human γδ TCR repertoires in health and disease.
The Many Facets of CD38 in Lymphoma: From Tumor–Microenvironment Cell Interactions to Acquired Resistance to Immunotherapy
Authors: Calabretta Eleonora , Carlo-Stella Carmelo
Published: April 2020

The CD38 antigen is expressed in several hematological malignancies, and the anti-CD38 monoclonal antibodies Daratumumab and Isatuximab have an established role in the therapy of multiple myeloma. However, data on the therapeutic utility of CD38 targeting in other lymphoid malignancies are limited. In chronic lymphocytic leukemia, the prognostic significance of CD38 expression is well accepted, and preclinical studies on the use of Daratumumab in monotherapy or combination therapy have demonstrated considerable efficacy. In other lymphoproliferative disorders, preclinical and clinical data have not been as compelling; however, CD38 overexpression likely contributes to resistance to checkpoint inhibitors, prompting numerous clinical trials in Hodgkin and non-Hodgkin lymphoma to investigate whether blocking CD38 enhances the efficacy of checkpoint inhibitors. Furthermore, due to its widespread expression in hematological tumors, CD38 represents an attractive target for cellular therapies such as CAR-T cells. The present review discusses current knowledge of CD38 expression and its implications in various lymphoid malignancies. Furthermore, it addresses current and future therapeutic perspectives, with a particular emphasis on the significance of CD38 interaction with immune cells of the tumor microenvironment. Lastly, results of ongoing studies using anti-CD38 antibodies will be reviewed.
Breakthrough Technologies Reshape the Ewing Sarcoma Molecular Landscape
Authors: Salguero-Aranda Carmen , Amaral Ana Teresa , Olmedo-Pelayo Joaquín , Diaz-Martin Juan , Álava Enrique de
Published: April 2020

Ewing sarcoma is a highly aggressive round cell mesenchymal neoplasm, most often occurring in children and young adults. At the molecular level, it is characterized by the presence of recurrent chromosomal translocations. In the last years, next-generation technologies have contributed to a more accurate diagnosis and a refined classification. Moreover, the application of these novel technologies has highlighted the relevance of intertumoral and intratumoral molecular heterogeneity and secondary genetic alterations. Furthermore, they have shown evidence that genomic features can change as the tumor disseminates and are influenced by treatment as well. Similarly, next-generation technologies applied to liquid biopsies will significantly impact patient management by allowing the early detection of relapse and monitoring response to treatment. Finally, the use of these novel technologies has provided data of great value in order to discover new druggable pathways. Thus, this review provides concise updates on the latest progress of these breakthrough technologies, underscoring their importance in the generation of key knowledge, prognosis, and potential treatment of Ewing Sarcoma.
Autophagy Modulators Profoundly Alter the Astrocyte Cellular Proteome
Authors: Sher Affan Ali , Gao Ang , Coombs Kevin M.
Published: April 2020

Autophagy is a key cellular process that involves constituent degradation and recycling during cellular development and homeostasis. Autophagy also plays key roles in antimicrobial host defense and numerous pathogenic organisms have developed strategies to take advantage of and/or modulate cellular autophagy. Several pharmacologic compounds, such as BafilomycinA1, an autophagy inducer, and Rapamycin, an autophagy inhibitor, have been used to modulate autophagy, and their effects upon notable autophagy markers, such as LC3 protein lipidation and Sequestosome-1/p62 alterations are well defined. We sought to understand whether such autophagy modulators have a more global effect upon host cells and used a recently developed aptamer-based proteomic platform (SOMAscan®) to examine 1305 U-251 astrocytic cell proteins after the cells were treated with each compound. These analyses, and complementary cytokine array analyses of culture supernatants after drug treatment, revealed substantial perturbations in the U-251 astrocyte cellular proteome. Several proteins, including cathepsins, which have a role in autophagy, were differentially dysregulated by the two drugs as might be expected. Many proteins, not previously known to be involved in autophagy, were significantly dysregulated by the compounds, and several, including lactadherin and granulins, were up-regulated by both drugs. These data indicate that these two compounds, routinely used to help dissect cellular autophagy, have much more profound effects upon cellular proteins.
Impaired Metabolic Flexibility in the Osteoarthritis Process: A Study on Transmitochondrial Cybrids
Authors: Dalmao-Fernández Andrea , Lund Jenny , Hermida-Gómez Tamara , Vazquez-Mosquera María E , Rego-Pérez Ignacio , Blanco Francisco J. , Fernández-Moreno Mercedes
Published: April 2020

Osteoarthritis (OA) is the most frequent joint disease; however, the etiopathogenesis is still unclear. Chondrocytes rely primarily on glycolysis to meet cellular energy demand, but studies implicate impaired mitochondrial function in OA pathogenesis. The relationship between mitochondrial dysfunction and OA has been established. The aim of the study was to examine the differences in glucose and Fatty Acids (FA) metabolism, especially with regards to metabolic flexibility, in cybrids from healthy (N) or OA donors. Glucose and FA metabolism were studied using D-[14C(U)]glucose and [1-14C]oleic acid, respectively. There were no differences in glucose metabolism among the cybrids. Osteoarthritis cybrids had lower acid-soluble metabolites, reflecting incomplete FA β-oxidation but higher incorporation of oleic acid into triacylglycerol. Co-incubation with glucose and oleic acid showed that N but not OA cybrids increased their glucose metabolism. When treating with the mitochondrial inhibitor etomoxir, N cybrids still maintained higher glucose oxidation. Furthermore, OA cybrids had higher oxidative stress response. Combined, this indicated that N cybrids had higher metabolic flexibility than OA cybrids. Healthy donors maintained the glycolytic phenotype, whereas OA donors showed a preference towards oleic acid metabolism. Interestingly, the results indicated that cybrids from OA patients had mitochondrial impairments and reduced metabolic flexibility compared to N cybrids.
Lamin Mutations Cause Increased YAP Nuclear Entry in Muscle Stem Cells
Authors: Owens Daniel J. , Fischer Martina , Jabre Saline , Moog Sophie , Mamchaoui Kamel , Butler-Browne Gillian , Coirault Catherine
Published: April 2020

Mutations in the LMNA gene, encoding the nuclear envelope A-type lamins, are responsible for muscular dystrophies, the most severe form being the LMNA-related congenital muscular dystrophy (L-CMD), with severe defects in myonucleus integrity. We previously reported that L-CMD mutations compromise the ability of muscle stem cells to modulate the yes-associated protein (YAP), a pivotal factor in mechanotransduction and myogenesis. Here, we investigated the intrinsic mechanisms by which lamins influence YAP subcellular distribution, by analyzing different conditions affecting the balance between nuclear import and export of YAP. In contrast to wild type (WT) cells, LMNADK32 mutations failed to exclude YAP from the nucleus and to inactivate its transcriptional activity at high cell density, despite activation of the Hippo pathway. Inhibiting nuclear pore import abolished YAP nuclear accumulation in confluent mutant cells, thus showing persistent nuclear import of YAP at cell confluence. YAP deregulation was also present in congenital myopathy related to nesprin-1 KASH mutation, but not in cells expressing the LMNAH222P mutation, the adult form of lamin-related muscle dystrophy with reduced nuclear deformability. In conclusion, our data showed that L-CMD mutations increased YAP nuclear localization via an increased nuclear import and implicated YAP as a pathogenic contributor in muscle dystrophies caused by nuclear envelop defects.
Extracellular Vesicles in NAFLD/ALD: From Pathobiology to Therapy
Authors: Hernández Alejandra , Arab Juan Pablo , Reyes Daniela , Lapitz Ainhoa , Moshage Han , Bañales Jesús M. , Arrese Marco
Published: April 2020

In recent years, knowledge on the biology and pathobiology of extracellular vesicles (EVs) has exploded. EVs are submicron membrane-bound structures secreted from different cell types containing a wide variety of bioactive molecules (e.g., proteins, lipids, and nucleic acids (coding and non-coding RNA) and mitochondrial DNA). EVs have important functions in cell-to-cell communication and are found in a wide variety of tissues and body fluids. Better delineation of EV structures and advances in the isolation and characterization of their cargo have allowed the diagnostic and therapeutic implications of these particles to be explored. In the field of liver diseases, EVs are emerging as key players in the pathogenesis of both nonalcoholic liver disease (NAFLD) and alcoholic liver disease (ALD), the most prevalent liver diseases worldwide, and their complications, including development of hepatocellular carcinoma. In these diseases, stressed/damaged hepatocytes release large quantities of EVs that contribute to the occurrence of inflammation, fibrogenesis, and angiogenesis, which are key pathobiological processes in liver disease progression. Moreover, the specific molecular signatures of released EVs in biofluids have allowed EVs to be considered as promising candidates to serve as disease biomarkers. Additionally, different experimental studies have shown that EVs may have potential for therapeutic use as a liver-specific delivery method of different agents, taking advantage of their hepatocellular uptake through interactions with specific receptors. In this review, we focused on the most recent findings concerning the role of EVs as new structures mediating autocrine and paracrine intercellular communication in both ALD and NAFLD, as well as their potential use as biomarkers of disease severity and progression. Emerging therapeutic applications of EVs in these liver diseases were also examined, along with the potential for successful transition from bench to clinic.
Oncofetal Chondroitin Sulfate: A Putative Therapeutic Target in Adult and Pediatric Solid Tumors
Authors: Khazamipour Nastaran , Al-Nakouzi Nader , Oo Htoo Zarni , Ørum-Madsen Maj , Steino Anne , Sorensen Poul H , Daugaard Mads
Published: April 2020

Solid tumors remain a major challenge for targeted therapeutic intervention strategies such as antibody-drug conjugates and immunotherapy. At a minimum, clear and actionable solid tumor targets have to comply with the key biological requirement of being differentially over-expressed in solid tumors and metastasis, in contrast to healthy organs. Oncofetal chondroitin sulfate is a cancer-specific secondary glycosaminoglycan modification to proteoglycans expressed in a variety of solid tumors and metastasis. Normally, this modification is found to be exclusively expressed in the placenta, where it is thought to facilitate normal placental implantation during pregnancy. Informed by this biology, oncofetal chondroitin sulfate is currently under investigation as a broad and specific target in solid tumors. Here, we discuss oncofetal chondroitin sulfate as a potential therapeutic target in childhood solid tumors in the context of current knowhow obtained over the past five years in adult cancers.
CRISPR/Cas9-Mediated Genome Editing Reveals Oosp Family Genes are Dispensable for Female Fertility in Mice
Authors: Abbasi Ferheen , Kodani Mayo , Emori Chihiro , Kiyozumi Daiji , Mori Masashi , Fujihara Yoshitaka , Ikawa Masahito
Published: April 2020

There are over 200 genes that are predicted to be solely expressed in the oocyte and ovary, and thousands more that have expression patterns in the female reproductive tract. Unfortunately, many of their physiological functions, such as their roles in oogenesis or fertilization, have yet to be elucidated. Previous knockout (KO) mice studies have proven that many of the genes that were once thought to be essential for fertility are dispensable in vivo. Therefore, it is extremely important to confirm the roles of all genes before spending immense time studying them in vitro. To do this, our laboratory analyzes the functions of ovary and oocyte-enriched genes in vivo through generating CRISPR/Cas9 KO mice and examining their fertility. In this study, we have knocked out three Oosp family genes (Oosp1, Oosp2, and Oosp3) that have expression patterns linked to the female reproductive system and found that the triple KO (TKO) mutant mice generated exhibited decreased prolificacy but were not infertile; thus, these genes may potentially be dispensable for fertility. We also generated Cd160 and Egfl6 KO mice and found these genes are individually dispensable for female fertility. KO mice with no phenotypic data are seldom published, but we believe that this information must be shared to prevent unnecessary experimentation by other laboratories.
Decreased Metabolic Flexibility in Skeletal Muscle of Rat Fed with a High-Fat Diet Is Recovered by Individual CLA Isomer Supplementation via Converging Protective Mechanisms
Authors: Trinchese Giovanna , Cavaliere Gina , Cimmino Fabiano , Catapano Angela , Carta Gianfranca , Pirozzi Claudio , Murru Elisabetta , Lama Adriano , Meli Rosaria , Bergamo Paolo , Banni Sebastiano , Mollica Maria Pina
Published: April 2020

Energy balance, mitochondrial dysfunction, obesity, and insulin resistance are disrupted by metabolic inflexibility while therapeutic interventions are associated with improved glucose/lipid metabolism in skeletal muscle. Conjugated linoleic acid mixture (CLA) exhibited anti-obesity and anti-diabetic effects; however, the modulatory ability of its isomers (cis9, trans11, C9; trans10, cis12, C10) on the metabolic flexibility in skeletal muscle remains to be demonstrated. Metabolic inflexibility was induced in rat by four weeks of feeding with a high-fat diet (HFD). At the end of this period, the beneficial effects of C9 or C10 on body lipid content, energy expenditure, pro-inflammatory cytokines, glucose metabolism, and mitochondrial efficiency were examined. Moreover, oxidative stress markers, fatty acids, palmitoyletanolamide (PEA), and oleyletanolamide (OEA) contents along with peroxisome proliferator-activated receptors-alpha (PPARα), AKT, and adenosine monophosphate-activated protein kinase (AMPK) expression were evaluated in skeletal muscle to investigate the underlying biochemical mechanisms. The presented results indicate that C9 intake reduced mitochondrial efficiency and oxidative stress and increased PEA and OEA levels more efficiently than C10 while the anti-inflammatory activity of C10, and its regulatory efficacy on glucose homeostasis are associated with modulation of the PPARα/AMPK/pAKT signaling pathway. Our results support the idea that the dissimilar efficacy of C9 and C10 against the HFD-induced metabolic inflexibility may be consequential to their ability to activate different molecular pathways.
Circulating Pro- and Anti-Inflammatory Metabolites and Its Potential Role in Rheumatoid Arthritis Pathogenesis
Authors: Coras Roxana , Murillo-Saich Jessica , Guma Monica
Published: April 2020

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that affects synovial joints, leading to inflammation, joint destruction, loss of function, and disability. Although recent pharmaceutical advances have improved the treatment of RA, patients often inquire about dietary interventions to improve RA symptoms, as they perceive pain and/or swelling after the consumption or avoidance of certain foods. There is evidence that some foods have pro- or anti-inflammatory effects mediated by diet-related metabolites. In addition, recent literature has shown a link between diet-related metabolites and microbiome changes, since the gut microbiome is involved in the metabolism of some dietary ingredients. But diet and the gut microbiome are not the only factors linked to circulating pro- and anti-inflammatory metabolites. Other factors including smoking, associated comorbidities, and therapeutic drugs might also modify the circulating metabolomic profile and play a role in RA pathogenesis. This article summarizes what is known about circulating pro- and anti-inflammatory metabolites in RA. It also emphasizes factors that might be involved in their circulating concentrations and diet-related metabolites with a beneficial effect in RA.
Cholesterol Homeostasis Modulates Platinum Sensitivity in Human Ovarian Cancer
Authors: Criscuolo Daniela , Avolio Rosario , Calice Giovanni , Laezza Chiara , Paladino Simona , Navarra Giovanna , Maddalena Francesca , Crispo Fabiana , Pagano Cristina , Bifulco Maurizio , Landriscina Matteo , Matassa Danilo Swann , Esposito Franca
Published: April 2020

Despite initial chemotherapy response, ovarian cancer is the deadliest gynecologic cancer, due to frequent relapse and onset of drug resistance. To date, there is no affordable diagnostic/prognostic biomarker for early detection of the disease. However, it has been recently shown that high grade serous ovarian cancers show peculiar oxidative metabolism, which is in turn responsible for inflammatory response and drug resistance. The molecular chaperone TRAP1 plays pivotal roles in such metabolic adaptations, due to the involvement in the regulation of mitochondrial respiration. Here, we show that platinum-resistant ovarian cancer cells also show reduced cholesterol biosynthesis, and mostly rely on the uptake of exogenous cholesterol for their needs. Expression of FDPS and OSC, enzymes involved in cholesterol synthesis, are decreased both in drug-resistant cells and upon TRAP1 silencing, whereas the expression of LDL receptor, the main mediator of extracellular cholesterol uptake, is increased. Strikingly, treatment with statins to inhibit cholesterol synthesis reduces cisplatin-induced apoptosis, whereas silencing of LIPG, an enzyme involved in lipid metabolism, or withdrawal of lipids from the culture medium, increases sensitivity to the drug. These results suggest caveats for the use of statins in ovarian cancer patients and highlights the importance of lipid metabolism in ovarian cancer treatment.
Hepatitis B Virus HBx Protein Mediates the Degradation of Host Restriction Factors through the Cullin 4 DDB1 E3 Ubiquitin Ligase Complex
Authors: Minor Marissa M. , Hollinger F. Blaine , McNees Adrienne L. , Jung Sung Yun , Jain Antrix , Hyser Joseph M. , Bissig Karl-Dimiter , Slagle Betty L.
Published: April 2020

The hepatitis B virus (HBV) regulatory HBx protein is required for infection, and its binding to cellular damaged DNA binding protein 1 (DDB1) is critical for this function. DDB1 is an adaptor protein for the cullin 4A Really Interesting New Gene (RING) E3 ubiquitin ligase (CRL4) complex and functions by binding cellular DDB1 cullin associated factor (DCAF) receptor proteins that recruit substrates for ubiquitination and degradation. We compared the proteins found in the CRL4 complex immunoprecipitated from uninfected versus HBV-infected hepatocytes from human liver chimeric mice for insight into mechanisms by which HBV and the cell interact within the CRL4 complex. Consistent with its role as a viral DCAF, HBx was found in the HBV CRL4 complexes. In tissue culture transfection experiments, we showed that HBx expression led to decreased levels of known restriction factor structural maintenance of chromosomes protein 6 (SMC6) and putative restriction factors stromal interaction molecule 1 (STIM1, zinc finger E-box binding homeobox 2 (ZEB2), and proteasome activator subunit 4 (PSME4). Moreover, silencing of these proteins led to increased HBV replication in the HepG2-sodium taurocholate cotransporting polypeptide (NTCP) infection model. We also identified cellular DCAF receptors in CRL4 complexes from humanized mice. Increasing amounts of HBx did not reveal competitive DCAF binding to cullin4 (CUL4)-DDB1 in plasmid-transfected cells. Our results suggest a model in which HBx benefits virus replication by directly or indirectly degrading multiple cellular restriction factors.
Rho GTPase Regulators and Effectors in Autism Spectrum Disorders: Animal Models and Insights for Therapeutics
Authors: Guo Daji , Yang Xiaoman , Shi Lei
Published: April 2020

The Rho family GTPases are small G proteins that act as molecular switches shuttling between active and inactive forms. Rho GTPases are regulated by two classes of regulatory proteins, guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Rho GTPases transduce the upstream signals to downstream effectors, thus regulating diverse cellular processes, such as growth, migration, adhesion, and differentiation. In particular, Rho GTPases play essential roles in regulating neuronal morphology and function. Recent evidence suggests that dysfunction of Rho GTPase signaling contributes substantially to the pathogenesis of autism spectrum disorder (ASD). It has been found that 20 genes encoding Rho GTPase regulators and effectors are listed as ASD risk genes by Simons foundation autism research initiative (SFARI). This review summarizes the clinical evidence, protein structure, and protein expression pattern of these 20 genes. Moreover, ASD-related behavioral phenotypes in animal models of these genes are reviewed, and the therapeutic approaches that show successful treatment effects in these animal models are discussed.
Role of Connexins 30, 36, and 43 in Brain Tumors, Neurodegenerative Diseases, and Neuroprotection
Authors: Sánchez Oscar F. , Rodríguez Andrea V. , Velasco-España José M. , Murillo Laura C. , Sutachan Jhon-Jairo , Albarracin Sonia-Luz
Published: April 2020

Gap junction (GJ) channels and their connexins (Cxs) are complex proteins that have essential functions in cell communication processes in the central nervous system (CNS). Neurons, astrocytes, oligodendrocytes, and microglial cells express an extraordinary repertory of Cxs that are important for cell to cell communication and diffusion of metabolites, ions, neurotransmitters, and gliotransmitters. GJs and Cxs not only contribute to the normal function of the CNS but also the pathological progress of several diseases, such as cancer and neurodegenerative diseases. Besides, they have important roles in mediating neuroprotection by internal or external molecules. However, regulation of Cx expression by epigenetic mechanisms has not been fully elucidated. In this review, we provide an overview of the known mechanisms that regulate the expression of the most abundant Cxs in the central nervous system, Cx30, Cx36, and Cx43, and their role in brain cancer, CNS disorders, and neuroprotection. Initially, we focus on describing the Cx gene structure and how this is regulated by epigenetic mechanisms. Then, the posttranslational modifications that mediate the activity and stability of Cxs are reviewed. Finally, the role of GJs and Cxs in glioblastoma, Alzheimer’s, Parkinson’s, and Huntington’s diseases, and neuroprotection are analyzed with the aim of shedding light in the possibility of using Cx regulators as potential therapeutic molecules.
Characterization of Pediatric Seizures in the Commonwealth of the Northern Mariana Islands
Authors: Yogesh Ahana , Taylor Michael , Chang Mary P.
Published: April 2020

Saipan is a United States (US) territory Western Pacific island where little recent data exists regarding epidemiology, clinical presentation, and standard of care for pediatric seizures. This paper characterizes these features in Saipan’s pediatric population with comparisons to mainland US. This is a retrospective chart review of all pediatric patients with a history of seizures at the island’s only hospital and major private neurology clinic over a 10-year period. Variables regarding demographics, presentation, diagnosis, and treatment were collected. A total of 144 patients were included, with 101 patients diagnosed with febrile seizures and 31 patients diagnosed with non-febrile seizures. Age at first presentation peaked at 1 year old overall. The most common identified etiology of epilepsy was found to be hypoxic injury (39%), hemorrhagic injury (10%), cerebral malformation (6%), and brain mass (6%). Simple versus complex classification of febrile seizures, etiologies, and first-line treatment for non-febrile seizures were comparable to the mainland US. Electroencephalogram (EEG) was not used consistently in diagnosis. The findings from this study demonstrate that clinical presentations of pediatric seizures in Saipan are comparable to those in the mainland US.
Modeling of Erosion Response of Cold-Sprayed In718-Ni Composite Coating Using Full Factorial Design
Authors: Verna Elisa , Biagi Roberto , Kazasidis Marios , Galetto Maurizio , Bemporad Edoardo , Lupoi Rocco
Published: April 2020

In this work, the cold-spray technique was used to deposit Inconel 718–nickel (1:1) composite coatings on stainless steel substrate. A general full factorial design was adopted to identify the statistically significant operating variables, i.e., impingement angle, erodent size, and feed rate on the coating erosion response. Erodent feed rate, impingement angle, and the interaction between impingement angle and erodent size were identified as the highly significant variables on the erosion rate. Then, a model correlating the identified variables with the erosion rate was derived. The best combination of control variables for minimum erosion loss with respect to erodent feed rate, erodent size, and impingement angle was 2 mg/min, 60 μm, and 90°, respectively. To analyze the erosion mechanism, the erodent samples were finally observed using Scanning Electron Microscope (SEM).
THz Pulsed Imaging in Biomedical Applications
Authors: D’Arco Annalisa , Di Fabrizio Marta , Dolci Valerio , Petrarca Massimo , Lupi Stefano
Published: April 2020

Recent advances in technology have allowed the production and the coherent detection of sub-ps pulses of terahertz (THz) radiation. Therefore, the potentialities of this technique have been readily recognized for THz spectroscopy and imaging in biomedicine. In particular, THz pulsed imaging (TPI) has rapidly increased its applications in the last decade. In this paper, we present a short review of TPI, discussing its basic principles and performances, and its state-of-the-art applications on biomedical systems.
Optimized Corrosion Performance of AISI 1345 Steel in Hydrochloric Acid Through Thermo-Mechanical Cyclic Annealing Processes
Authors: Hafeez Muhammad Arslan , Inam Aqil , Hassan Misbah Ul , Umer Malik Adeel , Usman Muhammad , Hanif Asad
Published: April 2020

The thermo-mechanical treatments and cyclic annealing processes have the potential of optimizing the corrosion performance of carbon steels in corrosive environments. Herein, an attempt has been made to optimize the corrosion performance of AISI 1345 steel in hydrochloric acid by thermo-mechanical cyclic annealing treatments. AISI 1345 steel was produced and cast in the laboratory and subjected to three types of thermo-mechanical cyclic annealing treatments (TMCA). The first TMCA treatment comprised hot rolling at 1050 °C followed by oil quenching and single austenitizing at 900 °C followed by furnace cooling (TMSA). The second and the third TMCA treatments involved similar hot rolling processes with double austenitizing and furnace cooling (TMDA) and triple austenitizing and furnace cooling (TMTA) processes. Microstructure analysis showed that dual-phase (retained austenite + pearlite) microstructure was achieved after all TMCA treatments with an exception of secondary phase particles precipitation after TMSA treatment. Maximum fractions of retained austenite and minimum fractions of pearlite were achieved after TMTA treatment. Highly refined microstructure of size 26.7 µm was achieved after TMDA treatment whereas; TMSA treatment offered coarse grained microstructure of size 254 µm. Electrochemical analysis was performed in 5 vol% HCl solution using Tafel scan technique. Results revealed that both TMDA and TMTA treatments caused three-fold reduction in corrosion rates (3.025, 2.771 mpy) compared to non-treated steel sample. After 168 h of immersion corrosion analysis in 5 vol% HCl solution, the surface of TMTA treated sample was observed to be partially covered with a very thin, crack-free oxide layer exhibiting minimum oxygen (8.16%) percentage. These features indicated that the TMTA treated sample underwent a very low-intensity minor corrosion attack of HCl solution and exhibited the best immersion corrosion performance among all samples. Electrochemical and immersion corrosion analysis results were in good agreement.
Defect Related Emission in Calcium Hydroxide: The Controversial Band at 780 cm−1
Authors: Pisu Francesca , Chiriu Daniele , Ricci Pier , Carbonaro Carlo
Published: April 2020

Calcium hydroxide, a crystal involved in the cycle of calcination and carbonation of calcium oxide, finds several applications from cultural heritage to the dentistry branch or to the construction industry. When excited at 1064 nm, Raman spectra of calcium hydroxide show a broad composite band peaked at about 780 cm−1, corresponding to 1170 nm. Since it is not observed with visible excitation, the origin of this band is debated, being assigned to some pre-existent luminescent impurities or some structural defect of the lime formed after the synthesis of the material. To shed light on the formation of this band, we synthetised the lime paste starting from pure calcite powders. The obtained fresh Ca(OH)2 samples did not show any band in the investigated range, irrespective of the laser excitation applied. A detailed analysis of the excitation and emission spectra in the near infrared region did not show the 1170 nm band, supporting the hypothesis of a post-synthesis origin. Thus, we carried out thermal treatments at different temperatures (90–500 °C) and under different environments (in air or under nitrogen flux) on synthesised fresh Ca(OH)2 powders. We also investigated the time evolution of the samples, monitoring the Raman spectra over 90 days after a specific treatment. The collected data support the hypothesis of a defect-related luminescence centre, whose formation depends on the temperature and environment of the treatment, which appears as a preferential site for the carbonation process of the calcium hydroxide. These results can be useful in the field of Cultural Heritage for dating purposes, and to determine the conservation state of Ca(OH)2 containing relics to prevent the possible activation of degradation processes.
Wildlife Diversity and Relative Abundance Among a Variety of Adjacent Protected Areas in the Northern Talamanca Mountains of Costa Rica
Authors: Sáenz-Bolaños Carolina , Fuller Todd K. , Carrillo J. Eduardo
Published: April 2020

Protected areas are intended to achieve the long-term conservation of nature, but not all such areas are equal in their effectiveness because of their varying regulation of human activities. In Costa Rica, we assessed mammal and bird species presence and relative abundance in three protected areas in the northern Talamanca Mountains. In this humid tropical forest area, we placed camera traps in an adjacent national park, forest reserve, and indigenous territories, each with a different mix of human activities. In 10,120 trap nights, we obtained 6181 independent photos of mostly mammals (34 species other than humans) and birds (34 species). Species with greater abundance or only occurrence in the national park were mammals and birds commonly hunted outside of the park, large carnivores rarely documented in other areas, and poachers. Species found more often outside of the park were medium-sized mammals, some birds, and domestic mammals. We conclude that even in the same ecological area, varying regulations related to type of protected area have significant effects on some mammal and bird species abundances and occurrences, and thus need to be considered when assessing the overall effectiveness of protection as a conservation strategy.
The Construction of a Mock-Up Test Building and a Statistical Analysis of the Data Acquired to Evaluate the Power Generation Performance of Photovoltaic Modules
Authors: Lee Seung-Joon , Kim Kyu-Jin , Kim Da-Sol , Ryu Eui-Hwan , Lee Jae
Published: April 2020

Traditionally, studies on the power generation performance analysis of the photovoltaic (PV) modules used in building-integrated PV (BIPV) systems have been based on computer simulations and actual experiments with constraints, resulting in the results being inaccurate and limited. This paper proposes a two-step analysis method that results in a more versatile and reliable means of analysis. The steps are: (1) construction of a mock-up test building in the form of BIPV systems and the collection of a massive amount of operational data for one year; and (2) a statistical analysis of the acquired data using Minitab software (Version: 17, Manufacturer: Minitab Inc., State College, PA, USA) to examine the power generation performance. The constructed BIPV mock-up applies design elements such as material types (c-Si and a-Si) and various directions and angles for different module installations. Prior to the analysis, the reliability of the large database (DB) constructed from the acquired data is statistically validated. Then, from the statistical correlation analysis of the DB, several plots that visualize the performance characteristics governed by design elements, including contour plots that show the region of higher performance, are generated. Further, a regression model equation for power generation performance is derived and verified. The results of this study will be useful in determining whether a BIPV system should be adopted in a building’s architectural design and, subsequently, selecting design element values for an actual BIPV system.