bluuebunny/crossref_metadata_2025 huggingface dataset:
Liquid–Liquid Phase Separation Enhances TDP-43 LCD Aggregation but Delays Seeded Aggregation
Authors: Pakravan Donya , Michiels Emiel , Bratek-Skicki Anna , De Decker Mathias , Van Lindt Joris , Alsteens David , Derclaye Sylvie , Van Damme Philip , Schymkowitz Joost , Rousseau Frederic , Tompa Peter , Van Den Bosch Ludo
Published: April 2021

Aggregates of TAR DNA-binding protein (TDP-43) are a hallmark of several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Although TDP-43 aggregates are an undisputed pathological species at the end stage of these diseases, the molecular changes underlying the initiation of aggregation are not fully understood. The aim of this study was to investigate how phase separation affects self-aggregation and aggregation seeded by pre-formed aggregates of either the low-complexity domain (LCD) or its short aggregation-promoting regions (APRs). By systematically varying the physicochemical conditions, we observed that liquid–liquid phase separation (LLPS) promotes spontaneous aggregation. However, we noticed less efficient seeded aggregation in phase separating conditions. By analyzing a broad range of conditions using the Hofmeister series of buffers, we confirmed that stabilizing hydrophobic interactions prevail over destabilizing electrostatic forces. RNA affected the cooperativity between LLPS and aggregation in a “reentrant” fashion, having the strongest positive effect at intermediate concentrations. Altogether, we conclude that conditions which favor LLPS enhance the subsequent aggregation of the TDP-43 LCD with complex dependence, but also negatively affect seeding kinetics.
Atherosclerotic Plaque Fissuration and Clinical Outcomes in Pre-Diabetics vs. Normoglycemics Patients Affected by Asymptomatic Significant Carotid Artery Stenosis at 2 Years of Follow-Up: Role of microRNAs Modulation: The ATIMIR Study
Authors: Sardu Celestino , Modugno Pietro , Castellano Gaetano , Scisciola Lucia , Barbieri Michelangela , Petrella Lella , Fanelli Mara , Macchia Gabriella , Caradonna Eugenio , Massetti Massimo , Paolisso Giuseppe , Marfella Raffaele
Published: April 2021

Atherosclerotic plaque instability and rupture in patients with asymptomatic carotid artery stenosis (ACAS) is a leading cause of major adverse cardiac events (MACE). This could be mainly evidenced in patients with pre-diabetes. Indeed, the altered glucose homeostasis and insulin resistance could cause over-inflammation of atherosclerotic plaque, favoring its conversion to unstable phenotype with rupture and MACE. Notably, metformin therapy reducing the metabolic distress and the inflammatory burden could reduce MACE in ACAS patients with pre-diabetes. In this setting, the microRNAs (miRs) could be used as molecular biomarkers of atherosclerosis progression, plaque rupture, and worse prognosis in normoglycemics (NG) versus pre-diabetics metformin users (PDMU) versus pre-diabetics non-metformin users (PDNMU). However, our study aimed to investigate a wide miRNA panel in peripheral blood exosomes from patients with ACAS divided in NG versus PDMU versus PDNMU, and to associate the circulating miRNA expression profiles with MACE at 2 years of follow-up after endarterectomy. The study included 234 patients with ACAS divided into NG (n = 125), PDNMU (n = 73), and PDMU (n = 36). The miRs’ expression profiles of circulating exosomes were determined at baseline and at 2 years of follow-up by Affymetrix microarrays from the patients’ plasma samples from any study cohort. Then we collected and analyzed MACE at 2 years of follow-up in NG versus PDMU versus PDNMU. Prediabetics versus NG had over-inflammation (p < 0.05) and over expressed miR-24 and miR-27 at baseline. At 2 years of follow-up, PDNMU versus NG, PDMU versus NG, and PDNMU versus PDMU over-expressed inflammatory markers and miR-24, miR-27, miR-100, miR-126, and miR-133 (p < 0.05). Finally, at the end of follow-up, we observed a significant difference about MACE comparing PDNMU versus NG (n = 27 (36.9%) versus n = 8 (6.4%); p < 0.05), PDNMU versus PDMU (n = 27 (36.9%) versus n = 6 (16.6%); p < 0.05); and PDMU versus NG (n = 6 (16.6%) versus n = 8 (6.4%); p < 0.05). Admission glucose values (HR (hazard ratio) 1.020, CI (confidence of interval) 95% (1.001–1.038), p = 0.029), atheromatous carotid plaque (HR 5.373, CI 95% (1.251–11.079), p = 0.024), and miR-24 (HR 3.842, CI 95% (1.768–19.222), p = 0.011) predicted MACE at 2 years of follow-up. Specific circulating miRs could be over-expressed in pre-diabetics and specifically in PDNMU versus PDMU after endarterectomy. MiR24, hyperglycemia, and atheromatous plaque could predict MACE at 2 years of follow-up.
Amyloid-Mediated Mechanisms of Membrane Disruption
Authors: Sciacca Michele F. M. , La Rosa Carmelo , Milardi Danilo
Published: April 2021

Protein aggregation and amyloid formation are pathogenic events underlying the development of an increasingly large number of human diseases named “proteinopathies”. Abnormal accumulation in affected tissues of amyloid β (Aβ) peptide, islet amyloid polypeptide (IAPP), and the prion protein, to mention a few, are involved in the occurrence of Alzheimer’s (AD), type 2 diabetes mellitus (T2DM) and prion diseases, respectively. Many reports suggest that the toxic properties of amyloid aggregates are correlated with their ability to damage cell membranes. However, the molecular mechanisms causing toxic amyloid/membrane interactions are still far to be completely elucidated. This review aims at describing the mutual relationships linking abnormal protein conformational transition and self-assembly into amyloid aggregates with membrane damage. A cross-correlated analysis of all these closely intertwined factors is thought to provide valuable insights for a comprehensive molecular description of amyloid diseases and, in turn, the design of effective therapies.
Gel-Like Human Mimicking Phantoms: Realization Procedure, Dielectric Characterization and Experimental Validations on Microwave Wearable Body Sensors
Authors: Costanzo Sandra , Cioffi Vincenzo , Qureshi Adil Masoud , Borgia Antonio
Published: April 2021

A simple and low-cost procedure for gel-like time-durable biological phantoms is presented in this work. Easily accessible materials are adopted, which are able to provide a flexible and controllable method to rapidly realize different kind of tissues. The proposed technique is applied to fabricate various tissue-mimicking phantoms, namely skin, muscle, blood and fat. Their effectiveness is first tested by performing dielectric characterization on a wide frequency range, from 500 MHz up to 5 GHz, and validating the measured dielectric parameters (dielectric constant and conductivity) by comparison with reference models in the literature. Then, a multi-layer phantom simulating the human arm is realized, and a wearable body sensor is adopted to prove the perfect agreement of the biometric response achieved in the presence of the fabricated phantom and that provided by a real human arm.
Frontal Transcranial Direct Current Stimulation as a Potential Treatment of Parkinson’s Disease-Related Fatigue
Authors: Zaehle Tino
Published: April 2021

In contrast to motor symptoms, non-motor symptoms in Parkinson’s disease (PD) are often poorly recognized and inadequately treated. Fatigue is one of the most common non-motor symptoms in PD and affects a broad range of everyday activities, causes disability, and substantially reduces the quality of life. It occurs at every stage of PD, and once present, it often persists and worsens over time. PD patients attending the 2013 World Parkinson Congress voted fatigue as the leading symptom in need of further research. However, despite its clinical significance, little progress has been made in understanding the causes of Parkinson’s disease-related fatigue (PDRF) and developing effective treatment options, which argues strongly for a greater effort. Transcranial direct current stimulation (tDCS) is a technique to non-invasively modulate cortical excitability by delivering low electrical currents to the cerebral cortex. In the past, it has been consistently evidenced that tDCS has the ability to induce neuromodulatory changes in the motor, sensory, and cognitive domains. Importantly, recent data present tDCS over the frontal cortex as an effective therapeutic option to treat fatigue in patients suffering from multiple sclerosis (MS). The current opinion paper reviews recent data on PDRF and the application of tDCS for the treatment of fatigue in neuropsychiatric disorders to further develop an idea of using frontal anodal tDCS as a potential therapeutic strategy to alleviate one of the most common and severe non-motor symptoms of PD.
Extracellular Dopamine Levels in Nucleus Accumbens after Chronic Stress in Rats with Persistently High vs. Low 50-kHz Ultrasonic Vocalization Response
Authors: Kõiv Kadri , Tiitsaar Kai , Laugus Karita , Harro Jaanus
Published: April 2021

Fifty-kHz ultrasonic vocalizations (USVs) in response to an imitation of rough-and-tumble play (‘tickling’) have been associated with positive affective states and rewarding experience in the rat. This USV response can be used as a measure of inter-individual differences in positive affect. We have previously shown that rats with persistently low positive affectivity are more vulnerable to the effects of chronic variable stress (CVS). To examine whether these differential responses are associated with dopaminergic neurotransmission in the nucleus accumbens (NAc), juvenile male Wistar rats were categorized as of high or low positive affectivity (HC and LC, respectively), and after reaching adulthood, extracellular dopamine (DA) levels in the NAc shell were measured using in vivo microdialysis after three weeks of CVS. Baseline levels of DA were compared as well as the response to K+-induced depolarization and the effect of glial glutamate transporter EAAT2 inhibition by 4 mM l-trans-pyrrolidine-2,4-dicarboxylate (PDC). DA baseline levels were higher in control LC-rats, and stress significantly lowered the DA content in LC-rats. An interaction of stress and affectivity appeared in response to depolarization where stress increased the DA output in HC-rats whereas it decreased it in LC-rats. These results show that NAc-shell DA is differentially regulated in response to stress in animals with high and low positive affect.
German Language Adaptation of the NAVS (NAVS-G) and of the NAT (NAT-G): Testing Grammar in Aphasia
Authors: Ditges Ruth , Barbieri Elena , Thompson Cynthia K. , Weintraub Sandra , Weiller Cornelius , Mesulam Marek-Marsel , Kümmerer Dorothee , Schröter Nils , Musso Mariacristina
Published: April 2021

Grammar provides the framework for understanding and producing language. In aphasia, an acquired language disorder, grammatical deficits are diversified and widespread. However, the few assessments for testing grammar in the German language do not consider current linguistic, psycholinguistic, and functional imaging data, which have been shown to be crucial for effective treatment. This study developed German language versions of the Northwestern Assessment of Verbs and Sentences (NAVS-G) and the Northwestern Anagram Test (NAT-G) to examine comprehension and production of verbs, controlling for the number and optionality of verb arguments, and sentences with increasing syntactic complexity. The NAVS-G and NAT-G were tested in 27 healthy participants, 15 right hemispheric stroke patients without aphasia, and 15 stroke patients with mild to residual aphasia. Participants without aphasia showed near-perfect performance, with the exception of (object) relative sentences, where accuracy was associated with educational level. In each patient with aphasia, deficits in more than one subtest were observed. The within and between population-groups logistic mixed regression analyses identified significant impairments in processing syntactic complexity at the verb and sentence levels. These findings indicate that the NAVS-G and NAT-G have potential for testing grammatical competence in (German) stroke patients.
PGC1α Loss Promotes Lung Cancer Metastasis through Epithelial-Mesenchymal Transition
Authors: Oh Taek-In , Lee Mingyu , Lee Yoon-Mi , Kim Geon-Hee , Lee Daekee , You Jueng Soo , Kim Sun Ha , Choi Minyoung , Jang Hyonchol , Park Yeong-Min , Shin Hyun-Woo , Shin Dong Hoon , Lim Ji-Hong
Published: April 2021

PGC1α oppositely regulates cancer metastasis in melanoma, breast, and pancreatic cancer; however, little is known about its impact on lung cancer metastasis. Transcriptome and in vivo xenograft analysis show that a decreased PGC1α correlates with the epithelial–mesenchymal transition (EMT) and lung cancer metastasis. The deletion of a single Pgc1α allele in mice promotes bone metastasis of KrasG12D-driven lung cancer. Mechanistically, PGC1α predominantly activates ID1 expression, which interferes with TCF4-TWIST1 cooperation during EMT. Bioinformatic and clinical studies have shown that PGC1α and ID1 are downregulated in lung cancer, and correlate with a poor survival rate. Our study indicates that TCF4-TWIST1-mediated EMT, which is regulated by the PGC1α-ID1 transcriptional axis, is a potential diagnostic and therapeutic target for metastatic lung cancer.
Benign Tumors in Long-Term Survivors of Retinoblastoma
Authors: van Hoefen Wijsard Milo , Schonfeld Sara J. , van Leeuwen Flora E. , Moll Annette C. , Fabius Armida W. , Abramson David H. , Seddon Johanna M. , Francis Jasmine H. , Tucker Margaret A. , Kleinerman Ruth A. , Morton Lindsay M.
Published: April 2021

Hereditary retinoblastoma survivors have substantially increased risk of subsequent malignant neoplasms (SMNs). The risk of benign neoplasms, a substantial cause of morbidity, is unclear. We calculated the cumulative incidence of developing benign tumors at 60 years following retinoblastoma diagnosis among 1128 hereditary (i.e., bilateral retinoblastoma or unilateral with family history, mutation testing was not available) and 924 nonhereditary retinoblastoma survivors diagnosed during 1914–2006 at two US medical centers with follow-up through 2016. Using Cox proportional hazards regression, we compared benign tumor risk by hereditary status and evaluated the association between benign tumors and SMNs. There were 100 benign tumors among 73 hereditary survivors (cumulative incidence = 17.6%; 95% confidence interval [CI] = 12.9–22.8%) and 22 benign tumors among 16 nonhereditary survivors (cumulative incidence = 3.9%; 95%CI = 2.2–6.4%), corresponding to 4.9-fold (95%CI = 2.8–8.4) increased risk for hereditary survivors. The cumulative incidence after hereditary retinoblastoma was highest for lipoma among males (14.0%; 95%CI = 7.7–22.1%) and leiomyoma among females (8.9%; 95%CI = 5.2–13.8%). Among hereditary survivors, having a prior SMN was associated with 3.5-fold (95%CI = 2.0–6.1) increased risk of developing a benign tumor; the reciprocal risk for developing an SMN after a benign tumor was 1.8 (95%CI = 1.1–2.9). These large-scale, long-term data demonstrate an increased risk for benign tumors after hereditary versus nonhereditary retinoblastoma. If confirmed, the association between benign tumors and SMNs among hereditary patients may have implications for long-term surveillance.
Activated Regulatory T-Cells, Dysfunctional and Senescent T-Cells Hinder the Immunity in Pancreatic Cancer
Authors: Sivakumar Shivan , Abu-Shah Enas , Ahern David J. , Arbe-Barnes Edward H. , Jainarayanan Ashwin K. , Mangal Nagina , Reddy Srikanth , Rendek Aniko , Easton Alistair , Kurz Elke , Silva Michael , Soonawalla Zahir , Heij Lara R. , Bashford-Rogers Rachael , Middleton Mark R. , Dustin Michael L.
Published: April 2021

Pancreatic cancer has one of the worst prognoses of any human malignancy and leukocyte infiltration is a major prognostic marker of the disease. As current immunotherapies confer negligible survival benefits, there is a need to better characterise leukocytes in pancreatic cancer to identify better therapeutic strategies. In this study, we analysed 32 human pancreatic cancer patients from two independent cohorts. A multi-parameter mass-cytometry analysis was performed on 32,000 T-cells from eight patients. Single-cell RNA sequencing dataset analysis was performed on a cohort of 24 patients. Multiplex immunohistochemistry imaging and spatial analysis were performed to map immune infiltration into the tumour microenvironment. Regulatory T-cell populations demonstrated highly immunosuppressive states with high TIGIT, ICOS and CD39 expression. CD8+ T-cells were found to be either in senescence or an exhausted state. The exhausted CD8 T-cells had low PD-1 expression but high TIGIT and CD39 expression. These findings were corroborated in an independent pancreatic cancer single-cell RNA dataset. These data suggest that T-cells are major players in the suppressive microenvironment of pancreatic cancer. Our work identifies multiple novel therapeutic targets that should form the basis for rational design of a new generation of clinical trials in pancreatic ductal adenocarcinoma.
SIO: A Spatioimageomics Pipeline to Identify Prognostic Biomarkers Associated with the Ovarian Tumor Microenvironment
Authors: Zhu Ying , Ferri-Borgogno Sammy , Sheng Jianting , Yeung Tsz-Lun , Burks Jared K. , Cappello Paola , Jazaeri Amir A. , Kim Jae-Hoon , Han Gwan Hee , Birrer Michael J. , Mok Samuel C. , Wong Stephen T. C.
Published: April 2021

Stromal and immune cells in the tumor microenvironment (TME) have been shown to directly affect high-grade serous ovarian cancer (HGSC) malignant phenotypes, however, how these cells interact to influence HGSC patients’ survival remains largely unknown. To investigate the cell-cell communication in such a complex TME, we developed a SpatioImageOmics (SIO) pipeline that combines imaging mass cytometry (IMC), location-specific transcriptomics, and deep learning to identify the distribution of various stromal, tumor and immune cells as well as their spatial relationship in TME. The SIO pipeline automatically and accurately segments cells and extracts salient cellular features to identify biomarkers, and multiple nearest-neighbor interactions among tumor, immune, and stromal cells that coordinate to influence overall survival rates in HGSC patients. In addition, SIO integrates IMC data with microdissected tumor and stromal transcriptomes from the same patients to identify novel signaling networks, which would lead to the discovery of novel survival rate-modulating mechanisms in HGSC patients.
The Incidence of Epstein-Barr Virus-Positive Diffuse Large B-Cell Lymphoma: A Systematic Review and Meta-Analysis
Authors: Hwang Jisun , Suh Chong Hyun , Won Kim Kyung , Kim Ho Sung , Armand Philippe , Huang Raymond Y. , Guenette Jeffrey P.
Published: April 2021

The worldwide prevalence of Epstein-Barr virus-positive (EBV+) diffuse large B-cell lymphoma (DLBCL) is undetermined. There is no clearly defined cut-off for EBV-encoded RNA (EBER) positivity in tumor cells by in-situ hybridization. The purpose of this study was to establish the proportions of EBV+ DLBCL patients and influence of the different cut-offs for EBER positivity, geographical location, and age on the prevalence of EBV+ DLBCL. PubMed and EMBASE were searched for studies published up to May 28, 2020 that reported proportions of EBER positivity in immunocompetent and de novo DLBCL patients. The pooled proportions were computed by an inverse variance method for calculating the weights and the DerSimonian–Laird method. Multiple subgroup analyses were conducted to explore any heterogeneity. Thirty-one studies (8249 patients) were included. The pooled proportion of EBV+ DLBCL was 7.9% (95% CI, 6.2–10.0%) with significant heterogeneity among studies (p < 0.001). The prevalence of EBV+ DLBCL was significantly higher in Asia and South America compared with Western countries (p < 0.01). The cut-offs for EBER positivity (10%, 20%, 50%) and patients’ age (≥50 years vs. <50 years) did not significantly affect the prevalence (p ≥ 0.10). EBV+ DLBCL is rare with a pooled proportion of 7.9% in patients with DLBCL and the geographic heterogeneity was confirmed.
CO2-Induced Fibrous Zn Catalyst Promotes Electrochemical Reduction of CO2 to CO
Authors: Guo Mengquan , Li Xiangxiang , Huang Yuxin , Li Linfa , Li Jixiao , Lu Yiren , Xu Yanhong , Zhang Lihong
Published: April 2021

The electrochemical reduction of CO2 is a promising strategy to achieve efficient conversion and utilization. In this paper, a series of Zn catalysts were prepared by electrodeposition in different atmospheric conditions (N2, CO2, H2, CO). A fibrous Zn catalyst (Zn-CO2) exhibits high electrochemical activity and stability. The Zn-CO2 catalyst shows 73.0% faradaic efficiency of CO at −1.2 V vs. RHE and the selectivity of CO almost did not change over 6 h in −1.2 V vs. RHE. The excellent selectivity and stability is attributed to the novel fibrous morphology, which increases the electrochemical active surface area. X-ray diffraction (XRD) results show that Zn-CO2 catalyst has a higher proportion of Zn (101) crystal planes, which is considered to be conducive to the production of CO. The search further demonstrates the importance of morphology control for the preparation of highly active and stable catalysts.
UV/Vis-Based Persulphate Activation for p-Nitrophenol Degradation
Authors: Dubois Valentin , Rodrigues Carmen S. D. , Alves Ana S. P. , Madeira Luis M.
Published: April 2021

In the present work, the degradation of p-nitrophenol (PNP) and its mineralization by a UV/Vis-based persulphate activation process was investigated. Firstly, a screening of processes as direct photolysis, persulphate alone and persulphate activated by radiation was performed. The incidence of radiation demonstrated to have an important role in the oxidant activation, allowing to achieve the highest PNP and total organic carbon (TOC) removals. The maximum PNP oxidation (100%) and mineralization (61.6%)—both after 2 h of reaction time—were reached when using T = 70 °C, (S2O82−) = 6.4 g/L and I = 500 W/m2. The influence of radiation type (ultraviolet/visible, visible or simulated solar light) was also evaluated, being found that the source with the highest emission of ultraviolet radiation (UV/visible) allowed to achieve the best oxidation efficiency; however, solar radiation also reached very-good performance. According to quenching experiments, the sulphate radical is key in the activated persulphate oxidation process, but the hydroxyl radical also plays an important role.
Alteration of Tissue Marking Dyes Depends on Used Chromogen during Immunohistochemistry
Authors: Kiefer Selina , Huber Julia , Füllgraf Hannah , Sörensen Kristin , Csanadi Agnes , Stillger Maren Nicole , Werner Martin , Schaefer Hans-Eckart , Bronsert Peter , Aumann Konrad
Published: April 2021

Pathological biopsy protocols require tissue marking dye (TMD) for orientation. In some cases (e.g., close margin), additional immunohistochemical analyses can be necessary. Therefore, the correlation between the applied TMD during macroscopy and the examined TMD during microscopy is crucial for the correct orientation, the residual tumour status and the subsequent therapeutic regime. In this context, our group observed colour changes during routine immunohistochemistry. Tissue specimens were marked with various TMD and processed by two different methods. TMD (blue, red, black, yellow and green) obtained from three different providers (A, B and C, and Whiteout/Tipp-Ex®) were used. Immunohistochemistry was performed manually via stepwise omission of reagents to identify the colour changing mechanism. Blue colour from provider A changed during immunohistochemistry into black, when 3,3′-Diaminobenzidine-tetrahydrochloride-dihydrate (DAB) and H2O2 was applied as an immunoperoxidase-based terminal colour signal. No other applied reagents, nor tissue texture or processing showed any influence on the colour. The remaining colours from provider A and the other colours did not show any changes during immunohistochemistry. Our results demonstrate an interesting and important pitfall in routine immunohistochemistry-based diagnostics that pathologists should be aware of. Furthermore, the chemical rationale behind the observed misleading colour change is discussed.
Zebrafish Models of Autosomal Recessive Ataxias
Authors: Quelle-Regaldie Ana , Sobrido-Cameán Daniel , Barreiro-Iglesias Antón , Sobrido María Jesús , Sánchez Laura
Published: April 2021

Autosomal recessive ataxias are much less well studied than autosomal dominant ataxias and there are no clearly defined systems to classify them. Autosomal recessive ataxias, which are characterized by neuronal and multisystemic features, have significant overlapping symptoms with other complex multisystemic recessive disorders. The generation of animal models of neurodegenerative disorders increases our knowledge of their cellular and molecular mechanisms and helps in the search for new therapies. Among animal models, the zebrafish, which shares 70% of its genome with humans, offer the advantages of being small in size and demonstrating rapid development, making them optimal for high throughput drug and genetic screening. Furthermore, embryo and larval transparency allows to visualize cellular processes and central nervous system development in vivo. In this review, we discuss the contributions of zebrafish models to the study of autosomal recessive ataxias characteristic phenotypes, behavior, and gene function, in addition to commenting on possible treatments found in these models. Most of the zebrafish models generated to date recapitulate the main features of recessive ataxias.
Lumican Inhibits In Vivo Melanoma Metastasis by Altering Matrix-Effectors and Invadopodia Markers
Authors: Karamanou Konstantina , Franchi Marco , Proult Isabelle , Rivet Romain , Vynios Demitrios , Brézillon Stéphane
Published: April 2021

It was reported that lumican inhibits the activity of metalloproteinase MMP-14 and melanoma cell migration in vitro and in vivo. Moreover, Snail triggers epithelial-to-mesenchymal transition and the metastatic potential of cancer cells. Therefore, the aim of this study was to examine the effect of lumican on Mock and Snail overexpressing melanoma B16F1 cells in vivo. Lung metastasis was analyzed after intravenous injections of Mock-B16F1 and Snail-B16F1 cells in Lum+/+ and Lum−/− mice. At day 14, mice were sacrificed, and lungs were collected. The number of lung metastatic nodules was significantly higher in mice injected with Snail-B16F1 cells as compared to mice injected with Mock-B16F1 cells confirming the pro-metastatic effect of Snail. This effect was stronger in Lum−/− mice as compared to Lum+/+, suggesting that endogenous lumican of wild-type mice significantly inhibits metastasis to lungs. Scanning electron and confocal microscopy investigations demonstrated that lumican inhibits the development of elongated cancer cell phenotypes which are known to develop invadopodia releasing MMPs. Moreover, lumican was shown to affect the expression of cyclin D1, cortactin, vinculin, hyaluronan synthase 2, heparanase, MMP-14 and the phosphorylation of FAK, AKT, p130 Cas and GSK3α/β. Altogether, these data demonstrated that lumican significantly inhibits lung metastasis in vivo, as well as cell invasion in vitro, suggesting that a lumican-based strategy targeting Snail-induced metastasis could be useful for melanoma treatment.
Effects of a 6 Week Low-Dose Combined Resistance and Endurance Training on T Cells and Systemic Inflammation in the Elderly
Authors: Despeghel Michael , Reichel Thomas , Zander Johannes , Krüger Karsten , Weyh Christopher
Published: April 2021

With increasing age, the immune system undergoes a remodeling process, affecting the shift of T cell subpopulations and the development of chronic low-grade inflammation. Clinically, this is characterized by increased susceptibility to infections or development of several diseases. Since lifestyle factors can play a significant role in reducing the hallmarks of immune aging and inflammation, we investigated the effect of a 6 week low-dose combined resistance and endurance training program. Forty participants (70.3 ± 5.0 years) were randomly assigned to either a training (TG) or control group (CG) and performed a controlled low-threshold and care-oriented 6-week-long combined resistance and endurance training program. Changes in anthropometrics as well as strength capacity were measured. In subgroups of TG and CG, T cells and their subpopulations (CD4+, CD8+, naïve, central, effector memory, T-EMRA) were analyzed by flow cytometry. The changes of various plasma cytokines, chemokines, growth factors and adipokines were analyzed by luminex assays. The exercise program was followed by an increase in strength capacities. Participants of TG showed an increase of the CD4+/CD8+ T cell ratio over time (p < 0.05). Significant decreases in systemic levels of interleukin (IL-) 6, IL-8, IL-10 and vascular endothelial growth factor (VEGF) (p < 0.05) were observed for participants of TG over time. Even short-term and low-threshold training can reduce some of the hallmarks of immune aging in elderly and thus could be beneficial to stimulate immunity. The specific characteristics of the program make it easily accessible to older people, who may benefit in the longer term in terms of their immunocompetence.
Dissecting FGF Signalling to Target Cellular Crosstalk in Pancreatic Cancer
Authors: Carter Edward P. , Coetzee Abigail S. , Tomas Bort Elena , Wang Qiaoying , Kocher Hemant M. , Grose Richard P.
Published: April 2021

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis with a 5 year survival rate of less than 8%, and is predicted to become the second leading cause of cancer-related death by 2030. Alongside late detection, which impacts upon surgical treatment, PDAC tumours are challenging to treat due to their desmoplastic stroma and hypovascular nature, which limits the effectiveness of chemotherapy and radiotherapy. Pancreatic stellate cells (PSCs), which form a key part of this stroma, become activated in response to tumour development, entering into cross-talk with cancer cells to induce tumour cell proliferation and invasion, leading to metastatic spread. We and others have shown that Fibroblast Growth Factor Receptor (FGFR) signalling can play a critical role in the interactions between PDAC cells and the tumour microenvironment, but it is clear that the FGFR signalling pathway is not acting in isolation. Here we describe our current understanding of the mechanisms by which FGFR signalling contributes to PDAC progression, focusing on its interaction with other pathways in signalling networks and discussing the therapeutic approaches that are being developed to try and improve prognosis for this terrible disease.
The F-Actin-Binding MPRIP Forms Phase-Separated Condensates and Associates with PI(4,5)P2 and Active RNA Polymerase II in the Cell Nucleus
Authors: Balaban Can , Sztacho Martin , Blažíková Michaela , Hozák Pavel
Published: April 2021

Here, we provide evidence for the presence of Myosin phosphatase rho-interacting protein (MPRIP), an F-actin-binding protein, in the cell nucleus. The MPRIP protein binds to Phosphatidylinositol 4,5-bisphosphate (PIP2) and localizes to the nuclear speckles and nuclear lipid islets which are known to be involved in transcription. We identified MPRIP as a component of RNA Polymerase II/Nuclear Myosin 1 complex and showed that MPRIP forms phase-separated condensates which are able to bind nuclear F-actin fibers. Notably, the fibrous MPRIP preserves its liquid-like properties and reforms the spherical shaped condensates when F-actin is disassembled. Moreover, we show that the phase separation of MPRIP is driven by its long intrinsically disordered region at the C-terminus. We propose that the PIP2/MPRIP association might contribute to the regulation of RNAPII transcription via phase separation and nuclear actin polymerization.
Associations between Free Sugar and Sugary Beverage Intake in Early Childhood and Adult NAFLD in a Population-Based UK Cohort
Authors: Sekkarie Ahlia , Welsh Jean A. , Northstone Kate , Stein Aryeh D. , Ramakrishnan Usha , Vos Miriam B.
Published: April 2021

(1) Background: High sugar intake is prevalent among children and is associated with non-alcoholic fatty liver disease (NAFLD). The purpose of this study is to determine if a high intake of free sugars and sugary beverages (SB) in childhood is associated with NAFLD in adulthood; (2) Methods: At 24 years, 3095 participants were assessed for severe hepatic steatosis (controlled attenuation parameter >280 dB/m) and had dietary data collected via a food frequency questionnaire at age three years. Multiple logistic regression models adjusted for total energy intake, potential confounders, and a mediator (offspring body mass index (BMI) at 24 years); (3) Results: Per quintile increase of free sugar intake association with severe hepatic steatosis at 24 years after adjusting for total energy was odds ratio (OR):1.07 (95% CL: 0.99–1.17). Comparing the lowest vs. the highest free sugar consumers, the association was OR:1.28 (95% CL: 0.88–1.85) and 1.14 (0.72, 1.82) after full adjustment. The OR for high SB consumption (>2/day) compared to <1/day was 1.23 (95% CL: 0.82–1.84) and OR: 0.98 (95% CL: 0.60–1.60) after full adjustment; (4) Conclusions: High free sugar and SB intake at three years were positively but weakly associated with severe hepatic steatosis at 24 years. These associations were completely attenuated after adjusting for confounders and 24-year BMI.
Assessment of Post-Stroke Consequences in Pediatric Ischemic Stroke in the Context of Neuroimaging Results—Experience from a Single Medical Center
Authors: Kopyta Ilona , Sarecka-Hujar Beata , Raczkiewicz Dorota , Gruszczyńska Katarzyna , Machnikowska-Sokołowska Magdalena
Published: April 2021

Arterial ischemic stroke (AIS) in children is a rare condition; its frequency is estimated at 0.58 to 7.9 new onsets in 100,000 children per year. The knowledge on risk factors, clinical outcomes and consequences of pediatric AIS is increasing. However, there are still many unknowns in the field. The aim of the study was to analyze the clinical presentation of pediatric AIS and its consequences according to the neuroimaging results and location of ischemia. The research was retrospective and observational. The analyzed group consisted of 75 AIS children (32 girls, 43 boys), whereby the age of the patients ranged from 9 months to 18 years at stroke onset. All the patients were diagnosed and treated in one tertiary center. The most frequent stroke subtype was total anterior circulation infarct (TACI) with most common ischemic focus location in temporal lobe and vascular pathology in middle cerebral artery (MCA). The location of ischemic focus in the brain correlated with post-stroke outcomes: intellectual delay and epilepsy, hemiparesis corresponded to the location of vascular pathology. A correlation found between ischemic lesion location and vascular pathology with post-stroke consequences in pediatric AIS may be important information and helpful in choosing proper early therapy. The expected results should lead to lesser severity of late post-stroke outcomes.
A Novel Quinoxaline-Rhodamine Conjugate for a Simple and Efficient Detection of Hydrogen Sulphate Ion
Authors: Sahu Sutapa , Sikdar Yeasin , Bag Riya , Maiti Dilip K. , Cerón-Carrasco José P. , Goswami Sanchita
Published: April 2021

This work presents the development of a quinoxaline and rhodamine conjugate system that acts as a colorimetric chemosensor for hydrogen sulfate (HSO4−) ions in methanol media. This sensor has been characterized both theoretically and experimentally. The detection limits for HSO4− are small as 0.71 µM and 3.8 µM for the absorption and emission experiments, respectively. The effectiveness of the probe in recognizing HSO4− both in gel and solid phase is evaluated as well. Thus, this works presents a simple strategy to detect the environmental HSO4− pollutant event at tiny concentrations.
Mechanical Properties of CaO–Al2O3–SiO2 Glass-Ceramics Precipitating Hexagonal CaAl2Si2O8 Crystals
Authors: Maeda Kei , Akatsuka Kosho , Okuma Gaku , Yasumori Atsuo
Published: April 2021

Fracture behavior via a flexural test for a newly found CaO–Al2O3–SiO2 (CAS) glass-ceramic (GC) was compared with that of enstatite GC and mica GC, which are well-known GCs with high-fracture toughness and machinability, respectively. By focusing on the nonelastic load–displacement curves, CAS GC was characterized as a less brittle material similar to machinable mica GC, compared with enstatite GC, which showed higher fracture toughness, KIC. The microcrack toughening mechanism in CAS GC was supported by the nondestructive observation of microcracks around the Vickers indentation using the X-ray microcomputed tomography technique. The CAS GC also showed higher transparency than mica GC due to its low crystallinity. Moreover, the precursor glass had easy formability due to its low-liquidus temperature.
A Structural Study of 0.06LiNbO3-0.94K0.5Na0.5NbO3 from Neutron Total Scattering Analysis
Authors: Kong J. , Liu J. , Marlton F. , Jørgensen M. R. V. , Pramanick A.
Published: April 2021

The structure of ferroelectric 0.06LiNbO3-0.94K0.5Na0.5NbO3 (KNNL6) was investigated by the neutron total scattering method in the temperature range of 290–773 K. The Rietveld analysis using the powder neutron diffraction data in the range of 290–773 K indicates transition from a two-phase (monoclinic and tetragonal) mixture at room temperature to tetragonal and cubic phases at higher temperatures. However, characterization of the local structure by the pair distribution function (PDF) method indicates that the local structure (r ≲ 10 Å) stays monoclinic over the same temperature range. Besides, the local oxygen octahedral distortion exhibits smaller changes with temperature than what is observed for the long-range average structure.
Bryophyte Diversity along an Elevational Gradient on Pico Island (Azores, Portugal)
Authors: Coelho Márcia C. M. , Gabriel Rosalina , Hespanhol Helena , Borges Paulo A. V. , Ah-Peng Claudine
Published: April 2021

The study of elevational patterns is a valuable method for inferring the influence of the climate and other variables in the regional distributions of species. Bryophytes are ideal for revealing different environmental patterns in elevational studies, since they occur from sea level to above the tree line. Taking advantage of the long elevational transect of Pico Island and the use of standardized survey methods, our main aims were: (1) to identify and characterize the alpha and beta diversities of bryophytes across the full elevational gradient (12 sites of native vegetation, ranging from 10 to 2200 m above sea level [a.s.l.]); (2) to detect the ecological factors driving bryophyte composition; (3) to identify bryophytes’ substrate specificity; and (4) to check the presence of rare and endemic species. The identification of 878 microplots yielded 141 species (71 liverworts and 70 mosses), almost half of those known to occur on Pico Island. The bryophyte species richness followed a parabolic unimodal pattern with a mid-elevation peak, where the richest native forests occur. A canonical correspondence analysis (CCA) of the bryophyte composition and explanatory variables revealed the effect of the elevation, precipitation, disturbance, richness of vascular plants and bark pH in explaining bryophyte compositions at regional levels. Very few species of bryophytes showed substrate specificity. Pico Island’s elevational gradient could be an asset for studying long-term changes in bryophyte species composition and alpha diversity under global change.
The Enigmatic Emerging Role of the C-Maf Inducing Protein in Cancer
Authors: Ollero Mario , Sahali Dil
Published: April 2021

The C-Maf-Inducing protein (CMIP) was first described as overexpressed in T cell subpopulations of idiopathic nephrotic syndrome (INS) patients. Later, it was found concomitantly upregulated in podocytes. CMIP expression has also been reported in several types of cancer, including blood malignancies and solid tumors, in many cases accompanied by nephrotic syndrome. In addition to these observations, the duality of CMIP overexpression in the kidney and INS lesions, has been extensively reported as one of the adverse effects of anticancer therapy based on anti-receptor tyrosine kinase drugs. As a consequence, a growing body of evidence points at CMIP as playing a role in cancer. This includes its reciprocal regulatory ties with NF-κB and WT1, and the more recent reports showing an involvement in regulatory circuits in cancer cells. The ensemble of the current information justifies to propose CMIP as an important piece of the puzzle of biological systems involved in cancer and other diseases and its potential as a target.
Electromyography-Guided Adjustment of an Occlusal Appliance: Effect on Pain Perceptions Related with Temporomandibular Disorders. A Controlled Clinical Study
Authors: Tecco Simona , Quinzi Vincenzo , Nota Alessandro , Giovannozzi Alessandro , Abed Maria Rosaria , Marzo Giuseppe
Published: April 2021

Background: The purpose of this study is to evaluate the effect of an electromyography-guided adjustment of an occlusal appliance on the management of Temporomandibular disorder-related pain. Methods: Data from 40 adult patients (20 males and 20 females), who underwent treatment with occlusal appliances, were recorded. A total of 20 appliances were adjusted according to electromyographic data (group 1), while the others were adjusted by a clinical conventional procedure (group 2). Muscle pain to palpation, pain during articular movements and headache were recorded by a VAS score (from 0 to 100) before the beginning of treatment (T0), at T1 (4 weeks) and T2 (8 weeks). Results: Results showed a reduction of pain in both groups, with a better trend for group 1, where better results were achieved at T1 and maintained stability at T2, with an improved mean value regarding all parameters studied. After 8 weeks, only small recurrences started to occur in muscle pain to palpation in group 2. Conclusions: An occlusal appliance seems to be able to achieve a clinical improvement of Temporomandibular disorder (TMD)-related pain and headache, independently from the adjustment procedure adopted. However, the use of a surface electromyographic activity of masticatory muscles (sEMG) device as an aid in the calibration procedure seems to allow a better trend because the improvement of symptoms was obtained before, after the first four weeks, with an improvement in percentages of all the variables investigated. While the conventional procedure obtained later the improvement.
A Systematic Review on the Correlations between Left Atrial Strain and Cardiovascular Outcomes in Chronic Kidney Disease Patients
Authors: Tanasa Ana , Burlacu Alexandru , Popa Cristina , Kanbay Mehmet , Brinza Crischentian , Macovei Liviu , Crisan-Dabija Radu , Covic Adrian
Published: April 2021

Left atrial strain (LASr) represents a relatively new but promising technique for left atrial and left ventricle function evaluation. LASr was strongly linked to myocardial fibrosis and endocardial thickness, suggesting the utility of LASr in subclinical cardiac dysfunction detection. As CKD negatively impacts cardiovascular risk and mortality, underlying structural and functional abnormalities of cardiac remodeling are widely investigated. LASr could be used in LV diastolic dysfunction grading with an excellent discriminatory power. Our objectives were to assess the impact and existing correlations between LASr and cardiovascular outcomes, as reported in clinical trials, including patients with CKD. We searched PubMed, Web of Science, Embase, and the Cochrane Central Register of Controlled Trials for full-text papers. As reported in clinical studies, LASr was associated with adverse cardiovascular outcomes, including cardiovascular death and major adverse cardiovascular events (HR 0.89, 95% CI, 0.84–0.93, p < 0.01), paroxysmal atrial fibrillation (OR 0.847, 95% CI, 0.760–0.944, p = 0.003), reduced exercise capacity (AUC 0.83, 95% CI, 0.78–0.88, p < 0.01), diastolic dysfunction (p < 0.05), and estimated pulmonary capillary wedge pressure (p < 0.001). Despite limitations attributed to LA deformation imaging (image quality, inter-observer variability, software necessity, learning curve), LASr constitutes a promising marker for cardiovascular events prediction and risk evaluation in patients with CKD.
Dynamic Analyses of Contagion Risk and Module Evolution on the SSE A-Shares Market Based on Minimum Information Entropy
Authors: Chen Muzi , Wang Yuhang , Wu Boyao , Huang Difang
Published: April 2021

The interactive effect is significant in the Chinese stock market, exacerbating the abnormal market volatilities and risk contagion. Based on daily stock returns in the Shanghai Stock Exchange (SSE) A-shares, this paper divides the period between 2005 and 2018 into eight bull and bear market stages to investigate interactive patterns in the Chinese financial market. We employ the Least Absolute Shrinkage and Selection Operator (LASSO) method to construct the stock network, compare the heterogeneity of bull and bear markets, and further use the Map Equation method to analyse the evolution of modules in the SSE A-shares market. Empirical results show that (1) the connected effect is more significant in bear markets than bull markets and gives rise to abnormal volatilities in the stock market; (2) a system module can be found in the network during the first four stages, and the industry aggregation effect leads to module differentiation in the last four stages; (3) some stocks have leading effects on others throughout eight periods, and medium- and small-cap stocks with poor financial conditions are more likely to become risk sources, especially in bear markets. Our conclusions are beneficial to improving investment strategies and making regulatory policies.
Early Childhood Science Education from 0 to 6: A Literature Review
Authors: O’Connor Gillian , Fragkiadaki Glykeria , Fleer Marilyn , Rai Prabhat
Published: April 2021

Over the past three decades, our understanding of science learning in early childhood has improved exponentially and today we have a strong empirically based understanding of science experiences for children aged three to six years. However, our understanding of science learning as it occurs for children from birth to three years, is limited. We do not know enough about how scientific thinking develops across the first years of life. Identifying what we do know about science experiences for our youngest learners within the birth to three period specifically, is critical. This paper reviews the literature, and for the first time includes children in the birth to three period. The results are contextualised through a broader review of early childhood science education for children aged from birth to six years. Findings illustrated that the empirical research on science concept formation in the early years, has focused primarily, on children aged three to six years. The tendency of research to examine the process of concept formation in the birth to three period is also highlighted. A lack of empirical understanding of science concept formation in children from birth to three is evident. The eminent need for research in science in infancy–toddlerhood is highlighted.