bluuebunny/crossref_metadata_2025 huggingface dataset:
Sensorimotor Research Utilising Immersive Virtual Reality: A Pilot Study with Children and Adults with Autism Spectrum Disorders
Authors: Valori Irene , Bayramova Rena , McKenna-Plumley Phoebe E. , Farroni Teresa
Published: April 2020

When learning and interacting with the world, people with Autism Spectrum Disorders (ASD) show compromised use of vision and enhanced reliance on body-based information. As this atypical profile is associated with motor and social difficulties, interventions could aim to reduce the potentially isolating reliance on the body and foster the use of visual information. To this end, head-mounted displays (HMDs) have unique features that enable the design of Immersive Virtual Realities (IVR) for manipulating and training sensorimotor processing. The present study assesses feasibility and offers some early insights from a new paradigm for exploring how children and adults with ASD interact with Reality and IVR when vision and proprioception are manipulated. Seven participants (five adults, two children) performed a self-turn task in two environments (Reality and IVR) for each of three sensory conditions (Only Proprioception, Only Vision, Vision + Proprioception) in a purpose-designed testing room and an HMD-simulated environment. The pilot indicates good feasibility of the paradigm. Preliminary data visualisation suggests the importance of considering inter-individual variability. The participants in this study who performed worse with Only Vision and better with Only Proprioception seemed to benefit from the use of IVR. Those who performed better with Only Vision and worse with Only Proprioception seemed to benefit from Reality. Therefore, we invite researchers and clinicians to consider that IVR may facilitate or impair individuals depending on their profiles.
Sirtuins’ Deregulation in Bladder Cancer: SIRT7 Is Implicated in Tumor Progression through Epithelial to Mesenchymal Transition Promotion
Authors: Monteiro-Reis Sara , Lameirinhas Ana , Miranda-Gonçalves Vera , Felizardo Diana , Dias Paula C. , Oliveira Jorge , Graça Inês , Gonçalves Céline S. , Costa Bruno M. , Henrique Rui , Jerónimo Carmen
Published: April 2020

Sirtuins are emerging players in cancer biology and other age-related disorders, and their putative role in bladder cancer (BlCa) remains elusive. Further understanding of disease biology may allow for generation of more effective pathway-based biomarkers and targeted therapies. Herein, we aimed to illuminate the role of sirtuins’ family in BlCa and evaluate their potential as disease biomarkers and therapeutic targets. SIRT1-7 transcripts and protein levels were evaluated in a series of primary BlCa and normal bladder mucosa tissues. SIRT7 knockdown was performed through lentiviral transduction in MGHU3, 5637 and J82 cells and its functional role was assessed. SIRT1, 2, 4 and 5 expression levels were significantly lower in BlCa, whereas SIRT6 and 7 were overexpressed, and these results were corroborated by TCGA cohort analysis. SIRT7 transcript levels were significantly decreased in muscle-invasive vs. papillary BlCa. In vitro studies showed that SIRT7 downregulation promoted cells migration and invasion. Accordingly, increased EMT markers expression and decreased E-Cadherin (CDH1) was observed in those BlCa cells. Moreover, increased EZH2 expression and H3K27me3 deposition in E-Cadherin promoter was found in sh-SIRT7 cells. We demonstrated that sirtuins are globally deregulated in BlCa, and specifically SIRT7 downregulation is implicated in EMT, fostering BlCa invasiveness through EZH2-CDH1 axis.
Solving the Time- and Frequency-Multiplexed Problem of Constrained Radiofrequency Induced Hyperthermia
Authors: Kuehne Andre , Oberacker Eva , Waiczies Helmar , Niendorf Thoralf
Published: April 2020

Targeted radiofrequency (RF) heating induced hyperthermia has a wide range of applications, ranging from adjunct anti-cancer treatment to localized release of drugs. Focal RF heating is usually approached using time-consuming nonconvex optimization procedures or approximations, which significantly hampers its application. To address this limitation, this work presents an algorithm that recasts the problem as a semidefinite program and quickly solves it to global optimality, even for very large (human voxel) models. The target region and a desired RF power deposition pattern as well as constraints can be freely defined on a voxel level, and the optimum application RF frequencies and time-multiplexed RF excitations are automatically determined. 2D and 3D example applications conducted for test objects containing pure water (rtarget = 19 mm, frequency range: 500–2000 MHz) and for human brain models including brain tumors of various size (r1 = 20 mm, r2 = 30 mm, frequency range 100–1000 MHz) and locations (center, off-center, disjoint) demonstrate the applicability and capabilities of the proposed approach. Due to its high performance, the algorithm can solve typical clinical problems in a few seconds, making the presented approach ideally suited for interactive hyperthermia treatment planning, thermal dose and safety management, and the design, rapid evaluation, and comparison of RF applicator configurations.
YM155-Adapted Cancer Cell Lines Reveal Drug-Induced Heterogeneity and Enable the Identification of Biomarker Candidates for the Acquired Resistance Setting
Authors: Michaelis Martin , Wass Mark N. , Reddin Ian , Voges Yvonne , Rothweiler Florian , Hehlgans Stephanie , Cinatl Jaroslav , Mernberger Marco , Nist Andrea , Stiewe Thorsten , Rödel Franz , Cinatl Jindrich
Published: April 2020

Survivin is a drug target and its suppressant YM155 a drug candidate mainly investigated for high-risk neuroblastoma. Findings from one YM155-adapted subline of the neuroblastoma cell line UKF-NB-3 had suggested that increased ABCB1 (mediates YM155 efflux) levels, decreased SLC35F2 (mediates YM155 uptake) levels, decreased survivin levels, and TP53 mutations indicate YM155 resistance. Here, the investigation of 10 additional YM155-adapted UKF-NB-3 sublines only confirmed the roles of ABCB1 and SLC35F2. However, cellular ABCB1 and SLC35F2 levels did not indicate YM155 sensitivity in YM155-naïve cells, as indicated by drug response data derived from the Cancer Therapeutics Response Portal (CTRP) and the Genomics of Drug Sensitivity in Cancer (GDSC) databases. Moreover, the resistant sublines were characterized by a remarkable heterogeneity. Only seven sublines developed on-target resistance as indicated by resistance to RNAi-mediated survivin depletion. The sublines also varied in their response to other anti-cancer drugs. In conclusion, cancer cell populations of limited intrinsic heterogeneity can develop various resistance phenotypes in response to treatment. Therefore, individualized therapies will require monitoring of cancer cell evolution in response to treatment. Moreover, biomarkers can indicate resistance formation in the acquired resistance setting, even when they are not predictive in the intrinsic resistance setting.
Crosstalk between Prostate Cancer Cells and Tumor-Associated Fibroblasts Enhances the Malignancy by Inhibiting the Tumor Suppressor PLZF
Authors: Noh Kum Hee , Jeong Ae Jin , Lee Haeri , Lee Song-Hee , Yi Eunhee , Chang Pahn-Shick , Kwak Cheol , Ye Sang-Kyu
Published: April 2020

Although prostate cancer is clinically manageable during the early stages of progression, metastatic progression severely compromises the prognosis and leads to mortality. Constitutive activation of STAT3 has been connected to prostate cancer malignancy, and abolishing the STAT3 activity may diminish tumor growth and metastasis. However, its suppressor genes and pathways have not been well established. In this study, we show that promyelocytic leukemia zinc finger (PLZF) has a putative tumor-suppressor function in prostate cancer by inhibiting phosphorylation of STAT3. Compared with a benign prostate, high-grade prostate cancer patient tissue was negatively correlated with PLZF expression. PLZF depletion accelerated proliferation and survival, migration, and invasion in human prostate cancer cells. Mechanistically, we demonstrated a novel role of PLZF as the transcriptional regulator of the tyrosine phosphatase SHP-1 that inhibits the oncogenic JAKs–STAT3 pathway. These results suggest that the collapse of PLZF expression by the CCL3 derived from fibroblasts accelerates the cell migration and invasion properties of prostate cancer cells. Our results suggest that increasing PLZF could be an attractive strategy for suppressing prostate cancer metastasis as well as for tumor growth.
Mevalonate Pathway Enzyme HMGCS1 Contributes to Gastric Cancer Progression
Authors: Wang I-Han , Huang Tzu-Ting , Chen Ji-Lin , Chu Li-Wei , Ping Yueh-Hsin , Hsu Kai-Wen , Huang Kuo-Hung , Fang Wen-Liang , Lee Hsin-Chen , Chen Chian-Feng , Liao Chen-Chung , Hsieh Rong-Hong , Yeh Tien-Shun
Published: April 2020

The 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) is a potential regulatory node in the mevalonate pathway that is frequently dysregulated in tumors. This study found that HMGCS1 expression is upregulated in stomach adenocarcinoma samples of patients and tumorspheres of gastric cancer cells. HMGCS1 elevates the expression levels of the pluripotency genes Oct4 and SOX-2 and contributes to tumorsphere formation ability in gastric cancer cells. HMGCS1 also promotes in vitro cell growth and progression and the in vivo tumor growth and lung metastasis of gastric cancer cells. After blocking the mevalonate pathway by statin and dipyridamole, HMGCS1 exerts nonmetabolic functions in enhancing gastric cancer progression. Furthermore, the level and nuclear translocation of HMGCS1 in gastric cancer cells are induced by serum deprivation. HMGCS1 binds to and activates Oct4 and SOX-2 promoters. HMGCS1 also enhances the integrated stress response (ISR) and interacts with the endoplasmic reticulum (ER) stress transducer protein kinase RNA-like endoplasmic reticulum kinase (PERK). Our results reveal that HMGCS1 contributes to gastric cancer progression in both metabolic and nonmetabolic manners.
Scientific Rationale for Combined Immunotherapy with PD-1/PD-L1 Antibodies and VEGF Inhibitors in Advanced Hepatocellular Carcinoma
Authors: Kudo Masatoshi
Published: April 2020

A successful phase III trial for the combination of atezolizumab and bevacizumab (the IMbrave150 trial) in advanced hepatocellular carcinoma has recently been reported. This is groundbreaking because nivolumab and pembrolizumab, both programmed cell death-1 (PD-1) antibodies, have failed to show efficacy as first- and second-line therapeutics, respectively, in phase III clinical trials. Immunotherapy with a combination of atezolizumab and bevacizumab resulted in better survival than treatment with sorafenib for the first time since sorafenib was approved in 2007. The high efficacy of the combination of PD-1/programmed death ligand 1 (PD-L1) and vascular endothelial growth factor (VEGF) antibodies is not only due to their additive effects on tumor growth, but also to their reprogramming of the immunosuppressive microenvironment into an immunostimulatory microenvironment. These results were confirmed in a phase Ib trial that showed significantly longer progression-free survival in the atezolizumab plus bevacizumab group than in patients that received atezolizumab alone. These results demonstrate that immunotherapy with a combination of PD-1/PD-L1 and VEGF inhibitors is effective and may result in a reprogramming of the tumor microenvironment. The results of an ongoing phase III trial of a PD-1 antibody in combination with the VEGF receptor tyrosine kinase inhibitor (TKI) are highly anticipated.
ATR Inhibition Potentiates PARP Inhibitor Cytotoxicity in High Risk Neuroblastoma Cell Lines by Multiple Mechanisms
Authors: Southgate Harriet E. D. , Chen Lindi , Tweddle Deborah A. , Curtin Nicola J.
Published: April 2020

Background: High risk neuroblastoma (HR-NB) is one the most difficult childhood cancers to cure. These tumours frequently present with DNA damage response (DDR) defects including loss or mutation of key DDR genes, oncogene-induced replication stress (RS) and cell cycle checkpoint dysfunction. Aim: To identify biomarkers of sensitivity to inhibition of Ataxia telangiectasia and Rad3 related (ATR), a DNA damage sensor, and poly (ADP-ribose) polymerase (PARP), which is required for single strand break repair. We also hypothesise that combining ATR and PARP inhibition is synergistic. Methods: Single agent sensitivity to VE-821 (ATR inhibitor) and olaparib (PARP inhibitor), and the combination, was determined using cell proliferation and clonogenic assays, in HR-NB cell lines. Basal expression of DDR proteins, including ataxia telangiectasia mutated (ATM) and ATR, was assessed using Western blotting. CHK1S345 and H2AXS129 phosphorylation was assessed using Western blotting to determine ATR activity and RS, respectively. RS and homologous recombination repair (HRR) activity was also measured by γH2AX and Rad51 foci formation using immunofluorescence. Results: MYCN amplification and/or low ATM protein expression were associated with sensitivity to VE-821 (p < 0.05). VE-821 was synergistic with olaparib (CI value 0.04–0.89) independent of MYCN or ATM status. Olaparib increased H2AXS129 phosphorylation which was further increased by VE-821. Olaparib-induced Rad51 foci formation was reduced by VE-821 suggesting inhibition of HRR. Conclusion: RS associated with MYCN amplification, ATR loss or PARP inhibition increases sensitivity to the ATR inhibitor VE-821. These findings suggest a potential therapeutic strategy for the treatment of HR-NB.
Are Pathogenic Germline Variants in Metastatic Melanoma Associated with Resistance to Combined Immunotherapy?
Authors: Amaral Teresa , Schulze Martin , Sinnberg Tobias , Nieser Maike , Martus Peter , Battke Florian , Garbe Claus , Biskup Saskia , Forschner Andrea
Published: April 2020

Background: Combined immunotherapy has significantly improved survival of patients with advanced melanoma, but there are still patients that do not benefit from it. Early biomarkers that indicate potential resistance would be highly relevant for these patients. Methods: We comprehensively analyzed tumor and blood samples from patients with advanced melanoma, treated with combined immunotherapy and performed descriptive and survival analysis. Results: Fifty-nine patients with a median follow-up of 13 months (inter quartile range (IQR) 11–15) were included. Interestingly, nine patients were found to have pathogenic or likely pathogenic (P/LP) germline variants in one of these genes: BRCA2, POLE, WRN, FANCI, CDKN2A, BAP1, PALB2 and RAD54B. Most of them are involved in DNA repair mechanisms. Patients with P/LP germline variants had a significantly shorter progression-free survival (PFS) and melanoma specific survival (MSS) compared to patients without P/LP germline variants (HR = 2.16; 95% CI: 1.01–4.64; p = 0.048 and HR = 3.21; 95% CI: 1.31–7.87; p = 0.011, respectively). None of the patients with a P/LP germline variant responded to combined immunotherapy. In the multivariate Cox-regression analysis, presence of a P/LP germline variant, S100B and lactate dehydrogenase (LDH) remained independently significant factors for MSS (p = 0.036; p = 0.044 and p = 0.001, respectively). Conclusions: The presence of P/LP germline variants was associated with resistance to combined immunotherapy in our cohort. As genes involved in DNA repair mechanisms are also involved in lymphocyte development and T-cell differentiation, a P/LP germline variant in these genes may preclude an antitumor immune response.
The Role of Deubiquitinating Enzymes in Hematopoiesis and Hematological Malignancies
Authors: Sarodaya Neha , Karapurkar Janardhan , Kim Kye-Seong , Hong Seok-Ho , Ramakrishna Suresh
Published: April 2020

Hematopoietic stem cells (HSCs) are responsible for the production of blood cells throughout the human lifespan. Single HSCs can give rise to at least eight distinct blood-cell lineages. Together, hematopoiesis, erythropoiesis, and angiogenesis coordinate several biological processes, i.e., cellular interactions during development and proliferation, guided migration, lineage programming, and reprogramming by transcription factors. Any dysregulation of these processes can result in hematological disorders and/or malignancies. Several studies of the molecular mechanisms governing HSC maintenance have demonstrated that protein regulation by the ubiquitin proteasomal pathway is crucial for normal HSC function. Recent studies have shown that reversal of ubiquitination by deubiquitinating enzymes (DUBs) plays an equally important role in hematopoiesis; however, information regarding the biological function of DUBs is limited. In this review, we focus on recent discoveries about the physiological roles of DUBs in hematopoiesis, erythropoiesis, and angiogenesis and discuss the DUBs associated with common hematological disorders and malignancies, which are potential therapeutic drug targets.
Aberrant Expression of Androgen Receptor Associated with High Cancer Risk and Extrathyroidal Extension in Papillary Thyroid Carcinoma
Authors: Chou Chen-Kai , Chi Shun-Yu , Chou Fong-Fu , Huang Shun-Chen , Wang Jia-He , Chen Chueh-Chen , Kang Hong-Yo
Published: April 2020

Male gender is a risk factor for mortality in patients with papillary thyroid carcinoma (PTC). This study investigated the impact of androgen receptor (AR) gene expression on the clinical features and progression of PTC. The levels of AR mRNA and protein in frozen, formalin-fixed, paraffin-embedded tissue samples from PTC and adjacent normal thyroid tissue were assessed by quantitative real-time polymerase chain reaction and immunohistochemical staining, respectively, and the relationships between AR expression and clinical features were analyzed. The thyroid cancer cell lines, BCPAP and TPC-1, were used to evaluate the effects of AR on the regulation of cell migration, and key epithelial–mesenchymal transition (EMT) markers. AR mRNA expression was significantly higher in normal thyroid tissue from men than women. The sex difference in AR mRNA expression diminished during PTC tumorigenesis, as AR mRNA expression levels were lower in PTC than normal thyroid tissues from both men and women. AR mRNA expression was significantly decreased in PTC patients with higher risk and in those with extrathyroidal extension. Overexpression of AR in BCPAP cells decreased cell migration and repressed the EMT process by down-regulating mRNA expression of N-cadherin, Snail1, Snail2, Vimentin, and TWIST1 and up-regulating E-cadherin gene expression. These results suggest that suppression of the androgen–AR axis may lead to aggressive tumor behavior in patients with PTC.
Comparative Application of BioID and TurboID for Protein-Proximity Biotinylation
Authors: May Danielle G. , Scott Kelsey L. , Campos Alexandre R. , Roux Kyle J.
Published: April 2020

BioID is a well-established method for identifying protein–protein interactions and has been utilized within live cells and several animal models. However, the conventional labeling period requires 15–18 h for robust biotinylation which may not be ideal for some applications. Recently, two new ligases termed TurboID and miniTurbo were developed using directed evolution of the BioID ligase and were able to produce robust biotinylation following a 10 min incubation with excess biotin. However, there is reported concern about inducibility of biotinylation, cellular toxicity, and ligase stability. To further investigate the practical applications of TurboID and ascertain strengths and weaknesses compared to BioID, we developed several stable cell lines expressing BioID and TurboID fusion proteins and analyzed them via immunoblot, immunofluorescence, and biotin-affinity purification-based proteomics. For TurboID we observed signs of protein instability, persistent biotinylation in the absence of exogenous biotin, and an increase in the practical labeling radius. However, TurboID enabled robust biotinylation in the endoplasmic reticulum lumen compared to BioID. Induction of biotinylation could be achieved by combining doxycycline-inducible expression with growth in biotin depleted culture media. These studies should help inform investigators utilizing BioID-based methods as to the appropriate ligase and experimental protocol for their particular needs.
Tubulin Resists Degradation by Cereblon-Recruiting PROTACs
Authors: Gasic Ivana , Groendyke Brian J. , Nowak Radosław P. , Yuan J. Christine , Kalabathula Joann , Fischer Eric S. , Gray Nathanael S. , Mitchison Timothy J.
Published: April 2020

Dysregulation of microtubules and tubulin homeostasis has been linked to developmental disorders, neurodegenerative diseases, and cancer. In general, both microtubule-stabilizing and destabilizing agents have been powerful tools for studies of microtubule cytoskeleton and as clinical agents in oncology. However, many cancers develop resistance to these agents, limiting their utility. We sought to address this by developing a different kind of agent: tubulin-targeted small molecule degraders. Degraders (also known as proteolysis-targeting chimeras (PROTACs)) are compounds that recruit endogenous E3 ligases to a target of interest, resulting in the target’s degradation. We developed and examined several series of α- and β-tubulin degraders, based on microtubule-destabilizing agents. Our results indicate, that although previously reported covalent tubulin binders led to tubulin degradation, in our hands, cereblon-recruiting PROTACs were not efficient. In summary, while we consider tubulin degraders to be valuable tools for studying the biology of tubulin homeostasis, it remains to be seen whether the PROTAC strategy can be applied to this target of high clinical relevance.
The Spindle Assembly Checkpoint Functions during Early Development in Non-Chordate Embryos
Authors: Chenevert Janet , Roca Marianne , Besnardeau Lydia , Ruggiero Antonella , Nabi Dalileh , McDougall Alex , Copley Richard R. , Christians Elisabeth , Castagnetti Stefania
Published: April 2020

In eukaryotic cells, a spindle assembly checkpoint (SAC) ensures accurate chromosome segregation, by monitoring proper attachment of chromosomes to spindle microtubules and delaying mitotic progression if connections are erroneous or absent. The SAC is thought to be relaxed during early embryonic development. Here, we evaluate the checkpoint response to lack of kinetochore-spindle microtubule interactions in early embryos of diverse animal species. Our analysis shows that there are two classes of embryos, either proficient or deficient for SAC activation during cleavage. Sea urchins, mussels, and jellyfish embryos show a prolonged delay in mitotic progression in the absence of spindle microtubules from the first cleavage division, while ascidian and amphioxus embryos, like those of Xenopus and zebrafish, continue mitotic cycling without delay. SAC competence during early development shows no correlation with cell size, chromosome number, or kinetochore to cell volume ratio. We show that SAC proteins Mad1, Mad2, and Mps1 lack the ability to recognize unattached kinetochores in ascidian embryos, indicating that SAC signaling is not diluted but rather actively silenced during early chordate development.
Modulation of mTORC1 Signaling Pathway by HIV-1
Authors: Akbay Burkitkan , Shmakova Anna , Vassetzky Yegor , Dokudovskaya Svetlana
Published: April 2020

Mammalian target of rapamycin complex 1 (mTORC1) is a master regulator of cellular proliferation and survival which controls cellular response to different stresses, including viral infection. HIV-1 interferes with the mTORC1 pathway at every stage of infection. At the same time, the host cells rely on the mTORC1 pathway and autophagy to fight against virus replication and transmission. In this review, we will provide the most up-to-date picture of the role of the mTORC1 pathway in the HIV-1 life cycle, latency and HIV-related diseases. We will also provide an overview of recent trends in the targeting of the mTORC1 pathway as a promising strategy for HIV-1 eradication.
Microbial Alterations and Risk Factors of Breast Cancer: Connections and Mechanistic Insights
Authors: Parida Sheetal , Sharma Dipali
Published: April 2020

Breast cancer-related mortality remains high worldwide, despite tremendous advances in diagnostics and therapeutics; hence, the quest for better strategies for disease management, as well as the identification of modifiable risk factors, continues. With recent leaps in genomic technologies, microbiota have emerged as major players in most cancers, including breast cancer. Interestingly, microbial alterations have been observed with some of the established risk factors of breast cancer, such as obesity, aging and periodontal disease. Higher levels of estrogen, a risk factor for breast cancer that cross-talks with other risk factors such as alcohol intake, obesity, parity, breastfeeding, early menarche and late menopause, are also modulated by microbial dysbiosis. In this review, we discuss the association between known breast cancer risk factors and altered microbiota. An important question related to microbial dysbiosis and cancer is the underlying mechanisms by which alterations in microbiota can support cancer progression. To this end, we review the involvement of microbial metabolites as effector molecules, the modulation of the metabolism of xenobiotics, the induction of systemic immune modulation, and altered responses to therapy owing to microbial dysbiosis. Given the association of breast cancer risk factors with microbial dysbiosis and the multitude of mechanisms altered by dysbiotic microbiota, an impaired microbiome is, in itself, an important risk factor.
Cardiomyocyte-Specific Deletion of Orai1 Reveals Its Protective Role in Angiotensin-II-Induced Pathological Cardiac Remodeling
Authors: Segin Sebastian , Berlin Michael , Richter Christin , Medert Rebekka , Flockerzi Veit , Worley Paul , Freichel Marc , Camacho Londoño Juan E.
Published: April 2020

Pathological cardiac remodeling correlates with chronic neurohumoral stimulation and abnormal Ca2+ signaling in cardiomyocytes. Store-operated calcium entry (SOCE) has been described in adult and neonatal murine cardiomyocytes, and Orai1 proteins act as crucial ion-conducting constituents of this calcium entry pathway that can be engaged not only by passive Ca2+ store depletion but also by neurohumoral stimuli such as angiotensin-II. In this study, we, therefore, analyzed the consequences of Orai1 deletion for cardiomyocyte hypertrophy in neonatal and adult cardiomyocytes as well as for other features of pathological cardiac remodeling including cardiac contractile function in vivo. Cellular hypertrophy induced by angiotensin-II in embryonic cardiomyocytes from Orai1-deficient mice was blunted in comparison to cells from litter-matched control mice. Due to lethality of mice with ubiquitous Orai1 deficiency and to selectively analyze the role of Orai1 in adult cardiomyocytes, we generated a cardiomyocyte-specific and temporally inducible Orai1 knockout mouse line (Orai1CM–KO). Analysis of cardiac contractility by pressure-volume loops under basal conditions and of cardiac histology did not reveal differences between Orai1CM–KO mice and controls. Moreover, deletion of Orai1 in cardiomyocytes in adult mice did not protect them from angiotensin-II-induced cardiac remodeling, but cardiomyocyte cross-sectional area and cardiac fibrosis were enhanced. These alterations in the absence of Orai1 go along with blunted angiotensin-II-induced upregulation of the expression of Myoz2 and a lack of rise in angiotensin-II-induced STIM1 and Orai3 expression. In contrast to embryonic cardiomyocytes, where Orai1 contributes to the development of cellular hypertrophy, the results obtained from deletion of Orai1 in the adult myocardium reveal a protective function of Orai1 against the development of angiotensin-II-induced cardiac remodeling, possibly involving signaling via Orai3/STIM1-calcineurin-NFAT related pathways.
The Role of Crosstalk between AR3 and E2F1 in Drug Resistance in Prostate Cancer Cells
Authors: Xu Jin , Yang Xi , Deshmukh Dhanraj , Chen Hegang , Fang Shengyun , Qiu Yun
Published: April 2020

Background: Drug resistance is one of the most prevalent causes of death in advanced prostate cancer patients. Combination therapies that target cancer cells via different mechanisms to overcome resistance have gained increased attention in recent years. However, the optimal drug combinations and the underlying mechanisms are yet to be fully explored. Aim and methods: The aim of this study is to investigate drug combinations that inhibit the growth of drug-resistant cells and determine the underlying mechanisms of their actions. In addition, we also established cell lines that are resistant to combination treatments and tested new compounds to overcome the phenomenon of double drug-resistance. Results: Our results show that the combination of enzalutamide (ENZ) and docetaxel (DTX) effectively inhibit the growth of prostate cancer cells that are resistant to either drug alone. The downregulation of transcription factor E2F1 plays a crucial role in cellular inhibition in response to the combined therapy. Notably, we found that the androgen receptor (AR) variant AR3 (a.k.a. AR-V7), but not AR full length (AR-FL), positively regulates E2F1 expression in these cells. E2F1 in turn regulates AR3 and forms a positive regulatory feedforward loop. We also established double drug-resistant cell lines that are resistant to ENZ+DTX combination therapy and found that the expression of both AR3 and E2F1 was restored in these cells. Furthermore, we identified that auranofin, an FDA-approved drug for the treatment of rheumatoid arthritis, overcame drug resistance and inhibited the growth of drug-resistant prostate cancer cells both in vitro and in vivo. Conclusion and significance: This proof-of-principle study demonstrates that targeting the E2F1/AR3 feedforward loop via a combination therapy or a multi-targeting drug could circumvent castration resistance in prostate cancer.
Special Issue on “Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis”
Authors: Weiskirchen Ralf
Published: April 2020

This Special issue contains 48 contributions highlighting novel findings and current concepts in basic and clinical liver fibrosis research. These articles emphasize issues on pathogenesis, cellular mediators, modulators, molecular pathways, disease-specific therapies, scoring systems, as well as novel preclinical animal models for the study of liver fibrogenesis. This editorial aims to briefly summarize the content of these papers.
The Effect of Ti-6Al-4V Alloy Surface Structure on the Adhesion and Morphology of Unidirectional Freeze-Coated Gelatin
Authors: Pal Snehashis , Peršin Zdenka , Vuherer Tomaž , Drstvenšek Igor , Kokol Vanja
Published: April 2020

The modification of a metal implant surface with a biomimetic coating of bone-like anisotropic and graded porosity structures to improve its biological anchorage with the surrounding bone tissue at implanting, is still a high challenge. In this paper, we present an innovative way of a gelatin (GEL) dip-coating on Ti-6Al-4V substrates of different square-net surface textures by the unidirectional deep-freezing process at simultaneous cross-linking using carbodiimide chemistry. Different concentrations of GEL solution were used to study the changes in morphology, density, and mechanical properties of the coatings. In addition, the surface free energy and polarity of Ti-6Al-4V substrate surfaces and GEL solutions have been evaluated to assess the wetting properties at the substrate interfaces, and to describe the adhesion of GEL macromolecules with their surfaces, being supported by mechanical pull-out testing. The results indicate that the coating’s morphology depends primarily on the Ti-6Al-4V substrate’s surface texture and second, on the concentration of GEL, which further influences their adhesion properties, orientation, morphological arrangement, as well as compression strength. The substrate with a 300 × 300 μm2 texture resulted in a highly adhered GEL coating with ≥80% porosity, interconnected and well-aligned pores of 75–200 μm, required to stimulate the bone ingrowth, mechanically and histologically.
Symbolic Computation to Solving an Irrational Equation on Based Symmetric Polynomials Method
Authors: Ochkov Valery , Vasileva Inna , Nori Massimiliano , Orlov Konstantin , Nikulchev Evgeny
Published: April 2020

In this article, we examine the use of symmetry groups for modeling applied problems through computer symbolic calculus. We consider the problem of solving radical equations symbolically using computer mathematical packages. We propose some methods to obtain a correct analytical solution for this class of equations by means of the Mathcad package. The application of symmetric polynomials is proposed to ensure a correct approach to the solution. Issues on the solvability based on the physical sense of a problem are discussed. Common errors in solving radical equations related to the specificity of the computer usage are analyzed. Provable electrical and geometrical problems are illustrated as example.
A Comprehensive Study of a New 1.75 Hydrate of Ciprofloxacin Salicylate: SCXRD Structure Determination, Solid Characterization, Water Stability, Solubility, and Dissolution Study
Authors: Nugrahani Ilma , Tjengal Billgerd , Gusdinar Tutus , Horikawa Ayano , Uekusa Hidehiro
Published: April 2020

One problem that often arises during the formulation of a dosage form is the solubility and dissolution of the active ingredients. This problem arises in ciprofloxacin, which is a BCS class IV fluoroquinolone antibiotic. A pseudopolymorph is a kind of polymorph in which the number of hydrates is different. In this study, a new pseudopolymorph comprised of ciprofloxacin and salicylic acid was found, namely the salt ciprofloxacin salicylate 1.75 hydrate form. This new solid phase was analyzed by Fourier-transform infrared spectroscope (FTIR), Raman spectroscopy, and thermal analysis and proven by Powder X-ray Diffractometry (PXRD) analysis. The crystal structure was successfully determined by Single Crystal X-ray Diffractometry (SCXRD) analysis. It was found that the piperazinyl group of ciprofloxacin is protonated by H+ from the carboxylic group of salicylic acid. In the unit cell, two ciprofloxacin and two salicylic acid molecules were independent with four water molecules, in which one water molecule had 0.5 occupancy due to inversion symmetry. Interestingly, this hydrate crystal dehydrated by grinding for 105 minutes forms an anhydrous crystalline phase, which was analyzed with FTIR, Raman spectroscopy, thermal analysis, and PXRD. The solubility and dissolution tests were carried out using UV-Visible spectrophotometry and a multiple linear regression method. This new hydrate solid phase has a better profile than the original ciprofloxacin crystal, according to the solubility and dissolution tests.
An Adaptive Multi-Target Jamming Waveform Design Based on Power Minimization
Authors: Gao Jing , Wu Rihan , Zhang Jinde
Published: April 2020

With increasing complexity of electronic warfare environments, smart jammers are beginning to play an important role. This study investigates a method of power minimization-based jamming waveform design in the presence of multiple targets, in which the performance of a radar system can be degraded according to the jammers’ different tasks. By establishing an optimization model, the power consumption of the designed jamming spectrum is minimized. The jamming spectrum with power control is constrained by a specified signal-to-interference-plus-noise ratio (SINR) or mutual information (MI) requirement. Considering that precise characterizations of the radar-transmitted spectrum are rare in practice, a single-robust jamming waveform design method is proposed. Furthermore, recognizing that the ground jammer is not integrated with the target, a double-robust jamming waveform design method is studied. Simulation results show that power minimization-based single-robust jamming spectra can maximize the power-saving performance of smart jammers in the local worst-case scenario. Moreover, double-robust jamming spectra can minimize the power consumption in the global worst-case scenario and provide useful guidance for the waveform design of ground jammers.
Image Restoration Using Fixed-Point-Like Methods for New TVL1 Variational Problems
Authors: Yun Jae Heon , Lim Hyo Jin
Published: April 2020

In this paper, we first propose two TVL1 variational problems for restoring images degraded by blurring and impulse noise, and then we propose two fixed-point-like methods, using proximal operators, for solving the new proposed TVL1 problems. Numerical experiments for several test images blurred by Gaussian kernel and corrupted by salt-and-pepper impulse noise are provided to demonstrate the efficiency and reliability of the proposed fixed-point-like methods. Numerical results show that two fixed-point-like methods for solving the new TVL1 variational problems perform very well in both PSNR (Peak signal-to-noise ratio) values and CPU time as compared with the fixed-point-like methods for solving two existing TVL1 variational problems.
Plug-In Electric Bus Depot Charging with PV and ESS and Their Impact on LV Feeder
Authors: Arif Syed Muhammad , Lie Tek Tjing , Seet Boon Chong , Ahsan Syed Muhammad , Khan Hassan Abbas
Published: April 2020

Plug-in electric buses (PEBs) are a promising alternative to conventional buses to provide a sustainable, economical, and efficient mode of transportation. However, electrification of public transportation leads to a phenomenon of peak load that impacts the stability of low voltage (LV) feeders. In this context, the effective integration of an energy storage system (ESS) and photovoltaic (PV) in a bus depot charging ecosystem can lead to i) peak load reduction and ii) charging cost reduction with low carbon emission. Therefore, a limited PEB charge scheduling algorithm is proposed for: i) bus depot operator (BDO) profit maximization and ii) grid stability enhancement considering the constraints of PEB charging and grids. A mixed integer linear programming (MILP) model for BDO profit maximization has been formulated and analyzed using IBM ILOG studio with CPLEX solver. Simulation has been performed for SkyBus electric fleet using real-world data such as actual bus arrival and departure schedules under diverse traffic, number of passengers, trip duration, daily load profile, solar radiation profile, and benchmark storage price. The charging impact of PEBs was tested on one of the distribution feeders in Auckland, New Zealand. The BDO generates revenue by performing energy trading among PV, ESS, PEBs, and buildings after incorporating capital investment, operation and maintenance, and depreciation costs.
Long-Term Environmental Monitoring in an Arctic Lake Polluted by Metals under Climate Change
Authors: Zubova Elena M. , Kashulin Nikolay A. , Dauvalter Vladimir A. , Denisov Dmitry B. , Valkova Svetlana A. , Vandysh Oksana I. , Slukovskii Zakhar I. , Terentyev Peter M. , Cherepanov Alexander A.
Published: April 2020

Lake Kuetsjarvi (in the lower reaches of the Pasvik River, Murmansk Region, Russia) in the border area between Russia and Norway, is one of the most polluted water reservoirs in the European Arctic. The operation of the Pechenganikel Smelter located on its shores has led to the extremely high concentrations of heavy metals observed in the waters and sediments of the lake. Long-term comprehensive studies of the ecosystem of Lake Kuetsjarvi have made it possible to identify the response of its components to the global and regional change in the environment and climate as a whole, resulting in increased water toxicity and eutrophication, reduction in the number of stenobiont species of aquatic organisms against the background of an increase in the number of eurybiontic and invasive species. Modern communities of Lake Kuetsjarvi are the result of a combination of long-term changes in the abiotic environment and biotic interactions. Heavy-metal pollution of Lake Kuetsjarvi, observed since the 1930s, has led to the formation of a community that is resistant to this type of impact and supports large populations of adapted species. Adaptations of communities to the dynamics of the environmental conditions that their members are exposed to include changes in the species composition, quantitative indicators, ratios between individual taxonomic groups, and the population structure. The development of sympatric forms that differ in the ecological niches they occupy, morphology, and life cycle strategies, including the transition to a short-cycle survival strategy, allows whitefish to remain the dominant species and maintain high population numbers. Unlike the organismal level, responses to medium-term environmental changes on the population and community level are less specific and characterized by stronger inertia.
Impact of Genotype, Environment, and Malting Conditions on the Antioxidant Activity and Phenolic Content in US Malting Barley
Authors: Zhou Bing , Jin Zhao , Schwarz Paul , Li Yin
Published: April 2020

The phenolic content and antioxidant potential of malting barley are important in brewing. The objective of our study was to investigate the effects of barley genotype, growing environment, and malting conditions on the total phenolic content and antioxidant activities of malting barley grown in North America. Eight barley cultivars grown at three locations over three years were used. For the malting study, a single barley cultivar, separated into different kernel size fractions, was germinated for various periods of time and then processed by kilning or freeze-drying. Total phenolic content (TPC) and some of the antioxidant activities, including DPPH, ABTS, and superoxide anion radical scavenging activities, reducing power, and iron (II) chelating activity, were significantly impacted by the barley genotype, growth environment, and their interactions. The TPC and most antioxidant activities were also influenced by malting conditions and were generally higher in the malted barleys of the thin kernel size fraction, four-day germination, and in samples processed by kilning, when compared to the plumper kernel size fractions, one and two days of germination, and freeze-dried samples, respectively. There were interactions between malting parameters, and stepwise regression analysis was used to suggest the contribution of each parameter to the TPC and antioxidant activities.
Brewing Quality of Hop Varieties Cultivated in Central Italy Based on Multivolatile Fingerprinting and Bitter Acid Content
Authors: Mozzon Massimo , Foligni Roberta , Mannozzi Cinzia
Published: April 2020

The brewing value of hops is mainly affected by the content and composition of humulones (α-acids) and essential oil. Interest in hop plantations is increasing more and more in Italy, in parallel with the rising number of microbreweries and brewpubs, which are strongly oriented towards local production chains. In this context, a selection of 15 international hop varieties were grown, under the same conditions, in an experimental field in the Marche region, Central Italy, with the aim of assessing their suitability for beer production. A multivariate analysis approach to experimental data showed a high content of α- and b-acids and myrcene in the Centennial, Brewer’s Gold, Sterling, Cascade, Nugget, and Columbus varieties; a consistently lower percentages of humulones and a predominance of sesquiterpene hydrocarbons in the cultivars Mount Hood, Northern Brewer, Northdown, Galena, Willamette, and Fuggle; and a desirable high α-acids content and a sesquiterpene-type aroma in cultivars Chinook, Yeoman, and Hallertau. Further studies are needed to assess the environmental adaptability and the yield performance of hop plants in the pedoclimatic conditions of the Central Italy hills.
Dark Matter Dogma: A Study of 214 Galaxies
Authors: Sipols Alan , Pavlovich Alex
Published: April 2020

The aim of this paper is to test the need for non-baryonic dark matter in the context of galactic rotation and the apparent difference between distributions of galactic mass and luminosity. We present a set of rotation curves and 3.6 μm surface brightness profiles for a diverse sample of 214 galaxies. Using rotation curves as the sole input into our Newtonian disk model, we compute non-parametric radial profiles of surface mass density. All profiles exhibit lower density than parametric models with dark halos and provide a superior fit with observed rotation curves. Assuming all dynamical mass is in main-sequence stars, we estimate radial distributions of characteristic star mass implied by the corresponding pairs of density and brightness profiles. We find that for 132 galaxies or 62% of the sample, the relation between density and brightness can be fully explained by a radially declining stellar mass gradient. Such idealized stellar population fitting can also largely address density and brightness distributions of the remaining 82 galaxies, but their periphery shows, on average, 14 M⊙/pc2 difference between total density and light-constrained stellar density. We discuss how this density gap can be interpreted, by considering a low-luminosity baryonic matter, observational uncertainties, and visibility cutoffs for red dwarf populations. Lastly, we report tight correlation between radial density and brightness trends, and the discovered flattening of surface brightness profiles—both being evidence against dark matter. Our findings make non-baryonic dark matter unnecessary in the context of galactic rotation.
Telomere and Centromere Staining Followed by M-FISH Improves Diagnosis of Chromosomal Instability and Its Clinical Utility
Authors: M’kacher Radhia , Colicchio Bruno , Borie Claire , Junker Steffen , Marquet Valentine , Heidingsfelder Leonhard , Soehnlen Kevin , Najar Wala , Hempel William M. , Oudrhiri Noufissa , Wilhelm-Murer Nadège , Miguet Marguerite , Arnoux Micheline , Ferrapie Catherine , Kerbrat Wendy , Plesch Andreas , Dieterlen Alain , Girinsky Theodore , Voisin Philippe , Deschenes Georges , Tabet Anne-Claude , Yardin Catherine , Bennaceur-Griscelli Annelise , Fenech Michael , Carde Patrice , Jeandidier Eric
Published: April 2020

Dicentric chromosomes are a relevant marker of chromosomal instability. Their appearance is associated with telomere dysfunction, leading to cancer progression and a poor clinical outcome. Here, we present Telomere and Centromere staining followed by M-FISH (TC+M-FISH) for improved detection of telomere dysfunction and the identification of dicentric chromosomes in cancer patients and various genetic syndromes. Significant telomere length shortening and significantly higher frequencies of telomere loss and deletion were found in the peripheral lymphocytes of patients with cancer and genetic syndromes relative to similar age-matched healthy donors. We assessed our technique against conventional cytogenetics for the detection of dicentric chromosomes by subjecting metaphase preparations to both approaches. We identified dicentric chromosomes in 28/50 cancer patients and 21/44 genetic syndrome patients using our approach, but only 7/50 and 12/44, respectively, using standard cytogenetics. We ascribe this discrepancy to the identification of the unique configuration of dicentric chromosomes. We observed significantly higher frequencies of telomere loss and deletion in patients with dicentric chromosomes (p < 10−4). TC+M-FISH analysis is superior to classical cytogenetics for the detection of chromosomal instability. Our approach is a relatively simple but useful tool for documenting telomere dysfunction and chromosomal instability with the potential to become a standard additional diagnostic tool in medical genetics and the clinic.