bluuebunny/crossref_metadata_2025 huggingface dataset:
Methods for Line Shapes in Plasmas in the Presence of External Electric Fields
Authors: Alexiou Spiros
Published: May 2021

Line broadening is usually dominated by interactions of an atomic system with a stochastic, random medium. When, in addition to the random medium, a non-random field (such as a laser) is applied, the line profile may be modified in significant ways. The present work discusses these modifications and the methods to deal with them.
Blood Glucose Level Forecasting on Type-1-Diabetes Subjects during Physical Activity: A Comparative Analysis of Different Learning Techniques
Authors: De Paoli Benedetta , D’Antoni Federico , Merone Mario , Pieralice Silvia , Piemonte Vincenzo , Pozzilli Paolo
Published: May 2021

Background: Type 1 Diabetes Mellitus (T1DM) is a widespread chronic disease in industrialized countries. Preventing blood glucose levels from exceeding the euglycaemic range would reduce the incidence of diabetes-related complications and improve the quality of life of subjects with T1DM. As a consequence, in the last decade, many Machine Learning algorithms aiming to forecast future blood glucose levels have been proposed. Despite the excellent performance they obtained, the prediction of abrupt changes in blood glucose values produced during physical activity (PA) is still one of the main challenges. Methods: A Jump Neural Network was developed in order to overcome the issue of predicting blood glucose values during PA. Three learning configurations were developed and tested: offline training, online training, and online training with reinforcement. All configurations were tested on six subjects suffering from T1DM that held regular PA (three aerobic and three anaerobic) and exploited Continuous Glucose Monitoring (CGM). Results: The forecasting performance was evaluated in terms of the Root-Mean-Squared-Error (RMSE), according to a paradigm of Precision Medicine. Conclusions: The online learning configurations performed better than the offline configuration in total days but not on the only CGM associated with the PA; thus, the results do not justify the increased computational burden because the improvement was not significant.
Restoration of Vitamin D Levels Improves Endothelial Function and Increases TASK-Like K+ Currents in Pulmonary Arterial Hypertension Associated with Vitamin D Deficiency
Authors: Callejo Maria , Morales-Cano Daniel , Mondejar-Parreño Gema , Barreira Bianca , Esquivel-Ruiz Sergio , Olivencia Miguel Angel , Moreno Laura , Cogolludo Angel , Perez-Vizcaino Francisco
Published: May 2021

Background: Vitamin D (vitD) deficiency is highly prevalent in patients with pulmonary arterial hypertension (PAH). Moreover, PAH-patients with lower levels of vitD have worse prognosis. We hypothesize that recovering optimal levels of vitD in an animal model of PAH previously depleted of vitD improves the hemodynamics, the endothelial dysfunction and the ionic remodeling. Methods: Male Wistar rats were fed a vitD-free diet for five weeks and then received a single dose of Su5416 (20 mg/Kg) and were exposed to vitD-free diet and chronic hypoxia (10% O2) for three weeks to induce PAH. Following this, vitD deficient rats with PAH were housed in room air and randomly divided into two groups: (a) continued on vitD-free diet or (b) received an oral dose of 100,000 IU/Kg of vitD plus standard diet for three weeks. Hemodynamics, pulmonary vascular remodeling, pulmonary arterial contractility, and K+ currents were analyzed. Results: Recovering optimal levels of vitD improved endothelial function, measured by an increase in the endothelium-dependent vasodilator response to acetylcholine. It also increased the activity of TASK-1 potassium channels. However, vitD supplementation did not reduce pulmonary pressure and did not ameliorate pulmonary vascular remodeling and right ventricle hypertrophy. Conclusions: Altogether, these data suggest that in animals with PAH and severe deficit of vitD, restoring vitD levels to an optimal range partially improves some pathophysiological features of PAH.
Perspectives of Microscopy Methods for Morphology Characterisation of Extracellular Vesicles from Human Biofluids
Authors: Malenica Mladenka , Vukomanović Marija , Kurtjak Mario , Masciotti Valentina , dal Zilio Simone , Greco Silvio , Lazzarino Marco , Krušić Vedrana , Perčić Marko , Jelovica Badovinac Ivana , Wechtersbach Karmen , Vidović Ivona , Baričević Vanja , Valić Srećko , Lučin Pero , Kojc Nika , Grabušić Kristina
Published: May 2021

Extracellular vesicles (EVs) are nanometric membranous structures secreted from almost every cell and present in biofluids. Because EV composition reflects the state of its parental tissue, EVs possess an enormous diagnostic/prognostic potential to reveal pathophysiological conditions. However, a prerequisite for such usage of EVs is their detailed characterisation, including visualisation which is mainly achieved by atomic force microscopy (AFM) and electron microscopy (EM). Here we summarise the EV preparation protocols for AFM and EM bringing out the main challenges in the imaging of EVs, both in their natural environment as biofluid constituents and in a saline solution after EV isolation. In addition, we discuss approaches for EV imaging and identify the potential benefits and disadvantages when different AFM and EM methods are applied, including numerous factors that influence the morphological characterisation, standardisation, or formation of artefacts. We also demonstrate the effects of some of these factors by using cerebrospinal fluid as an example of human biofluid with a simpler composition. Here presented comparison of approaches to EV imaging should help to estimate the current state in morphology research of EVs from human biofluids and to identify the most efficient pathways towards the standardisation of sample preparation and microscopy modes.
Melanoma Cell State-Specific Responses to TNFα
Authors: Lim Su Yin , Alavi Sara , Ming Zizhen , Shklovskaya Elena , Fung Carina , Stewart Ashleigh , Rizos Helen
Published: May 2021

Immune checkpoint inhibitors that target the programmed cell death protein 1 (PD1) pathway have revolutionized the treatment of patients with advanced metastatic melanoma. PD1 inhibitors reinvigorate exhausted tumor-reactive T cells, thus restoring anti-tumor immunity. Tumor necrosis factor alpha (TNFα) is abundantly expressed as a consequence of T cell activation and can have pleiotropic effects on melanoma response and resistance to PD1 inhibitors. In this study, we examined the influence of TNFα on markers of melanoma dedifferentiation, antigen presentation and immune inhibition in a panel of 40 melanoma cell lines. We report that TNFα signaling is retained in all melanomas but the downstream impact of TNFα was dependent on the differentiation status of melanoma cells. We show that TNFα is a poor inducer of antigen presentation molecules HLA-ABC and HLA-DR but readily induces the PD-L2 immune checkpoint in melanoma cells. Our results suggest that TNFα promotes dynamic changes in melanoma cells that may favor immunotherapy resistance.
let-7 microRNAs: Their Role in Cerebral and Cardiovascular Diseases, Inflammation, Cancer, and Their Regulation
Authors: Bernstein David L. , Jiang Xinpei , Rom Slava
Published: May 2021

The let-7 family is among the first microRNAs found. Recent investigations have indicated that it is highly expressed in many systems, including cerebral and cardiovascular systems. Numerous studies have implicated the aberrant expression of let-7 members in cardiovascular diseases, such as stroke, myocardial infarction (MI), cardiac fibrosis, and atherosclerosis as well as in the inflammation related to these diseases. Furthermore, the let-7 microRNAs are involved in development and differentiation of embryonic stem cells in the cardiovascular system. Numerous genes have been identified as target genes of let-7, as well as a number of the let-7’ regulators. Further studies are necessary to identify the gene targets and signaling pathways of let-7 in cardiovascular diseases and inflammatory processes. The bulk of the let-7’ regulatory proteins are well studied in development, proliferation, differentiation, and cancer, but their roles in inflammation, cardiovascular diseases, and/or stroke are not well understood. Further knowledge on the regulation of let-7 is crucial for therapeutic advances. This review focuses on research progress regarding the roles of let-7 and their regulation in cerebral and cardiovascular diseases and associated inflammation.
Limited Substrate Specificity of PS/γ-Secretase Is Supported by Novel Multiplexed FRET Analysis in Live Cells
Authors: Houser Mei C. Q. , Turchyna Yuliia , Perrin Florian , Chibnik Lori , Berezovska Oksana , Maesako Masato
Published: May 2021

Presenilin (PS)/γ-secretase is an aspartyl protease that processes a wide range of transmembrane proteins such as the amyloid precursor protein (APP) and Notch1, playing essential roles in normal biological events and diseases. However, whether there is a substrate preference for PS/γ-secretase processing in cells is not fully understood. Structural studies of PS/γ-secretase enfolding a fragment of APP or Notch1 showed that the two substrates engage the protease in broadly similar ways, suggesting the limited substrate specificity of PS/γ-secretase. In the present study, we developed a new multiplexed imaging platform that, for the first time, allowed us to quantitatively monitor how PS/γ-secretase processes two different substrates (e.g., APP vs. Notch1) in the same cell. In this assay, we utilized the recently reported, spectrally compatible visible and near-infrared (NIR)-range Förster resonance energy transfer (FRET) biosensors that permit quantitative recording of PS/γ-secretase activity in live cells. Here, we show that, overall, PS/γ-secretase similarly cleaves Notch1 N100, wild-type APP C99, and familial Alzheimer’s disease (FAD)-linked APP C99 mutants in Chinese hamster ovary (CHO) cells, which further supports the limited PS/γ-secretase substrate specificity. On the other hand, a cell-by-cell basis analysis demonstrates a certain degree of variability in substrate recognition and processing by PS/γ-secretase among different cells. Our new multiplexed FRET assay could be a useful tool to better understand how PS/γ-secretase processes its multiple substrates in normal and disease conditions in live, intact cells.
¡Hola! Nice to Meet You: Language Mixing and Biographical Information Processing
Authors: Antón Eneko , Duñabeitia Jon Andoni
Published: May 2021

In bilingual communities, social interactions take place in both single- and mixed-language contexts. Some of the information shared in multilingual conversations, such as interlocutors’ personal information, is often required in consequent social encounters. In this study, we explored whether the autobiographical information provided in a single-language context is better remembered than in an equivalent mixed-language situation. More than 400 Basque-Spanish bilingual (pre) teenagers were presented with new persons who introduced themselves by either using only Spanish or only Basque, or by inter-sententially mixing both languages. Different memory measures were collected immediately after the initial exposure to the new pieces of information (immediate recall and recognition) and on the day after (delayed recall and recognition). In none of the time points was the information provided in a mixed-language fashion worse remembered than that provided in a strict one-language context. Interestingly, the variability across participants in their sociodemographic and linguistic variables had a negligible impact on the effects. These results are discussed considering their social and educational implications for bilingual communities.
Revision of Commonly Accepted Warburg Mechanism of Cancer Development: Redox-Sensitive Mitochondrial Cytochromes in Breast and Brain Cancers by Raman Imaging
Authors: Abramczyk Halina , Surmacki Jakub Maciej , Brozek-Pluska Beata , Kopec Monika
Published: May 2021

We used Raman imaging to monitor changes in the redox state of the mitochondrial cytochromes in ex vivo human brain and breast tissues, surgically resected specimens of human tissues and in vitro human brain cells of normal astrocytes (NHA), astrocytoma (CRL-1718), glioblastoma (U87-MG) and medulloblastoma (Daoy), and human breast cells of normal cells (MCF 10A), slightly malignant cells (MCF7) and highly aggressive cells (MDA-MB-231) by means of Raman microspectroscopy at 532 nm. We visualized localization of cytochromes by Raman imaging in the major organelles in cancer cells. We demonstrated that the “redox state Raman marker” of the ferric low-spin heme in cytochrome c at 1584 cm−1 can serve as a sensitive indicator of cancer aggressiveness. We compared concentration of reduced cytochrome c and the grade of cancer aggressiveness in cancer tissues and single cells and specific organelles in cells: nucleous, mitochondrium, lipid droplets, cytoplasm and membrane. We found that the concentration of reduced cytochrome c becomes abnormally high in human brain tumors and breast cancers in human tissues. Our results reveal the universality of Raman vibrational characteristics of mitochondrial cytochromes in metabolic regulation in cancers that arise from epithelial breast cells and brain glial cells.
Cholesterol-Induced Metabolic Reprogramming in Breast Cancer Cells Is Mediated via the ERRα Pathway
Authors: Ghanbari Faegheh , Fortier Anne-Marie , Park Morag , Philip Anie
Published: May 2021

The molecular mechanism underlying the metabolic reprogramming associated with obesity and high blood cholesterol levels is poorly understood. We previously reported that cholesterol is an endogenous ligand of the estrogen-related receptor alpha (ERRα). Using functional assays, metabolomics, and genomics, here we show that exogenous cholesterol alters the metabolic pathways in estrogen receptor-positive (ER+) and triple-negative breast cancer (TNBC) cells, and that this involves increased oxidative phosphorylation (OXPHOS) and TCA cycle intermediate levels. In addition, cholesterol augments aerobic glycolysis in TNBC cells although it remains unaltered in ER+ cells. Interestingly, cholesterol does not alter the metabolite levels of glutaminolysis, one-carbon metabolism, or the pentose phosphate pathway, but increases the NADPH levels and cellular proliferation, in both cell types. Importantly, we show that the above cholesterol-induced modulations of the metabolic pathways in breast cancer cells are mediated via ERRα. Furthermore, analysis of the ERRα metabolic gene signature of basal-like breast tumours of overweight/obese versus lean patients, using the GEO database, shows that obesity may modulate ERRα gene signature in a manner consistent with our in vitro findings with exogenous cholesterol. Given the close link between high cholesterol levels and obesity, our findings provide a mechanistic explanation for the association between cholesterol/obesity and metabolic reprogramming in breast cancer patients.
Accuracy of Machine Learning Algorithms for the Classification of Molecular Features of Gliomas on MRI: A Systematic Literature Review and Meta-Analysis
Authors: van Kempen Evi J. , Post Max , Mannil Manoj , Kusters Benno , ter Laan Mark , Meijer Frederick J. A. , Henssen Dylan J. H. A.
Published: May 2021

Treatment planning and prognosis in glioma treatment are based on the classification into low- and high-grade oligodendroglioma or astrocytoma, which is mainly based on molecular characteristics (IDH1/2- and 1p/19q codeletion status). It would be of great value if this classification could be made reliably before surgery, without biopsy. Machine learning algorithms (MLAs) could play a role in achieving this by enabling glioma characterization on magnetic resonance imaging (MRI) data without invasive tissue sampling. The aim of this study is to provide a performance evaluation and meta-analysis of various MLAs for glioma characterization. Systematic literature search and meta-analysis were performed on the aggregated data, after which subgroup analyses for several target conditions were conducted. This study is registered with PROSPERO, CRD42020191033. We identified 724 studies; 60 and 17 studies were eligible to be included in the systematic review and meta-analysis, respectively. Meta-analysis showed excellent accuracy for all subgroups, with the classification of 1p/19q codeletion status scoring significantly poorer than other subgroups (AUC: 0.748, p = 0.132). There was considerable heterogeneity among some of the included studies. Although promising results were found with regard to the ability of MLA-tools to be used for the non-invasive classification of gliomas, large-scale, prospective trials with external validation are warranted in the future.
Focus on the Complex Interconnection between Cancer, Narcolepsy and Other Neurodegenerative Diseases: A Possible Case of Orexin-Dependent Inverse Comorbidity
Authors: Mogavero Maria P. , Silvani Alessandro , DelRosso Lourdes M. , Salemi Michele , Ferri Raffaele
Published: May 2021

Conditions such as Alzheimer’s (AD) and Parkinson’s diseases (PD) are less prevalent in cancer survivors and, overall, cancer is less prevalent in subjects with these neurodegenerative disorders. This seems to suggest that a propensity towards one type of disease may decrease the risk of the other. In addition to epidemiologic data, there is also evidence of a complex biological interconnection, with genes, proteins, and pathways often showing opposite dysregulation in cancer and neurodegenerative diseases. In this narrative review, we focus on the possible role played by orexin signaling, which is altered in patients with narcolepsy type 1 and in those with AD and PD, and which has been linked to β-amyloid brain levels and inflammation in mouse models and to cancer in cell lines. Taken together, these lines of evidence depict a possible case of inverse comorbidity between cancer and neurodegenerative disorders, with a role played by orexins. These considerations suggest a therapeutic potential of orexin modulation in diverse pathologies such as narcolepsy, neurodegenerative disorders, and cancer.
Therapeutics Targeting the Core Apoptotic Machinery
Authors: Hamilton Claudia , Fox Jennifer P. , Longley Daniel B. , Higgins Catherine A.
Published: May 2021

Therapeutic targeting of the apoptotic pathways for the treatment of cancer is emerging as a valid and exciting approach in anti-cancer therapeutics. Accumulating evidence demonstrates that cancer cells are typically “addicted” to a small number of anti-apoptotic proteins for their survival, and direct targeting of these proteins could provide valuable approaches for directly killing cancer cells. Several approaches and agents are in clinical development targeting either the intrinsic mitochondrial apoptotic pathway or the extrinsic death receptor mediated pathways. In this review, we discuss the main apoptosis pathways and the key molecular targets which are the subject of several drug development approaches, the clinical development of these agents and the emerging resistance factors and combinatorial treatment approaches for this class of agents with existing and emerging novel targeted anti-cancer therapeutics.
The Endless Sources of Hepatocellular Carcinoma Heterogeneity
Authors: Barcena-Varela Marina , Lujambio Amaia
Published: May 2021

Hepatocellular carcinoma (HCC) represents a global health problem. The incidence keeps increasing and current therapeutic options confer limited benefits to the patients. Tumor heterogeneity plays a central role in this context, limiting the availability of predictive biomarkers and complicating the criteria used to choose the most suitable therapeutic option. HCC heterogeneity occurs at different levels: within the population (inter-patient heterogeneity) and within tumors from the same patient (intra-patient and intra-tumor heterogeneity). Experts in the field have made many efforts to classify the patients based on clinicopathological characteristics and molecular signatures; however, there is still much work ahead to be able to integrate the extra-tumor heterogeneity that emerges from the complexity of the tumor microenvironment, which plays a critical role in the pathogenesis of the disease and therapy responses. In this review, we summarize tumor intrinsic and extrinsic sources of heterogeneity of the most common etiologies of HCC and summarize the most recent discoveries regarding the evolutionary trajectory of liver cancer cells and the influence of tumor-extrinsic factors such as the microbiome and the host immune system. We further highlight the potential of novel high-throughput methodologies to contribute to a better understanding of this devastating disease and to the improvement of the clinical management of patients.
The Effect of MoS2 Active Site Dispersion on Suppression of Polycondensation Reactions during Heavy Oil Hydroconversion
Authors: Kadiev Khusain M. , Maximov Anton L. , Kadieva Malkan Kh.
Published: May 2021

In this work, the composition, structural and morphological features, and particle size of the active phase of the catalyst (MoS2), synthesized in-situ during the heavy oil hydroconversion performed in continuous flow reactor on lab-scale pilot flow unit at T = 450 °C, P = 6.0–9.0 MPa, V = 1.0 h−1, H2/feed = 1000 nL/L, catalyst concentration C (Mo) = 0.01–0.08%wt have been studied. It has been shown that MoS2 formed during hydroconversion is represented by nanosized particles stabilized by polycondensation products as a result of strong adsorption and aggregation with the components of the hydroconversion reaction medium. The influence of morphological characteristics of catalyst nanoparticles on the feed conversion, the yield of gaseous and liquid products, and the quality of distillate fractions, as well as the yield of polycondensation products, have been studied. It has been established that an increase in MoS2 active site dispersion, both due to a decreased plate length and lower stacking numbers in MoS2 cluster, enhances hydroconversion effectivity, particularly, in suppressing polycondensation reactions.
MSC Manufacturing for Academic Clinical Trials: From a Clinical-Grade to a Full GMP-Compliant Process
Authors: Lechanteur Chantal , Briquet Alexandra , Bettonville Virginie , Baudoux Etienne , Beguin Yves
Published: May 2021

Following European regulation 1394/2007, mesenchymal stromal cell (MSCs) have become an advanced therapy medicinal product (ATMP) that must be produced following the good manufacturing practice (GMP) standards. We describe the upgrade of our existing clinical-grade MSC manufacturing process to obtain GMP certification. Staff organization, premises/equipment qualification and monitoring, raw materials management, starting materials, technical manufacturing processes, quality controls, and the release, thawing and infusion were substantially reorganized. Numerous studies have been carried out to validate cultures and demonstrate the short-term stability of fresh or thawed products, as well their stability during long-term storage. Detailed results of media simulation tests, validation runs and early MSC batches are presented. We also report the validation of a new variant of the process aiming to prepare fresh MSCs for the treatment of specific lesions of Crohn’s disease by local injection. In conclusion, we have successfully ensured the adaptation of our clinical-grade MSC production process to the GMP requirements. The GMP manufacturing of MSC products is feasible in the academic setting for a limited number of batches with a significant cost increase, but moving to large-scale production necessary for phase III trials would require the involvement of industrial partners.
Aberrant B Cell Receptor Signaling in Naïve B Cells from Patients with Idiopathic Pulmonary Fibrosis
Authors: Neys Stefan F. H. , Heukels Peter , van Hulst Jennifer A. C. , Rip Jasper , Wijsenbeek Marlies S. , Hendriks Rudi W. , Corneth Odilia B. J.
Published: May 2021

Idiopathic pulmonary fibrosis (IPF) is a chronic and ultimately fatal disease in which an impaired healing response to recurrent micro-injuries is thought to lead to fibrosis. Recent findings hint at a role for B cells and autoimmunity in IPF pathogenesis. We previously reported that circulating B cells from a fraction of patients, compared with healthy controls, express increased levels of the signaling molecule Bruton’s tyrosine kinase (BTK). However, it remains unclear whether B cell receptor (BCR) signaling is altered in IPF. Here, we show that the response to BCR stimulation is enhanced in peripheral blood B cells from treatment-naïve IPF patients. We observed increased anti-immunoglobulin-induced phosphorylation of BTK and its substrate phospholipase Cγ2 (PLCγ2) in naïve but not in memory B cells of patients with IPF. In naïve B cells of IPF patients enhanced BCR signaling correlated with surface expression of transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) but not B cell activating factor receptor (BAFFR), both of which provide pro-survival signals. Interestingly, treatment of IPF patients with nintedanib, a tyrosine kinase inhibitor with anti-fibrotic and anti-inflammatory activity, induced substantial changes in BCR signaling. These findings support the involvement of B cells in IPF pathogenesis and suggest that targeting BCR signaling has potential value as a treatment option.
Loss of Motor Protein MYO1C Causes Rhodopsin Mislocalization and Results in Impaired Visual Function
Authors: Solanki Ashish K. , Biswal Manas R. , Walterhouse Stephen , Martin René , Kondkar Altaf A. , Knölker Hans-Joachim , Rahman Bushra , Arif Ehtesham , Husain Shahid , Montezuma Sandra R. , Nihalani Deepak , Lobo Glenn Prazere
Published: May 2021

Unconventional myosins, linked to deafness, are also proposed to play a role in retinal cell physiology. However, their direct role in photoreceptor function remains unclear. We demonstrate that systemic loss of the unconventional myosin MYO1C in mice, specifically causes rhodopsin mislocalization, leading to impaired visual function. Electroretinogram analysis of Myo1c knockout (Myo1c-KO) mice showed a progressive loss of photoreceptor function. Immunohistochemistry and binding assays demonstrated MYO1C localization to photoreceptor inner and outer segments (OS) and identified a direct interaction of rhodopsin with MYO1C. In Myo1c-KO retinas, rhodopsin mislocalized to rod inner segments (IS) and cell bodies, while cone opsins in OS showed punctate staining. In aged mice, the histological and ultrastructural examination of the phenotype of Myo1c-KO retinas showed progressively shorter photoreceptor OS. These results demonstrate that MYO1C is important for rhodopsin localization to the photoreceptor OS, and for normal visual function.
Complex Roles of Neutrophils during Arboviral Infections
Authors: Muralidharan Abenaya , Reid St Patrick
Published: May 2021

Arboviruses are known to cause large-scale epidemics in many parts of the world. These arthropod-borne viruses are a large group consisting of viruses from a wide range of families. The ability of their vector to enhance viral pathogenesis and transmission makes the development of treatments against these viruses challenging. Neutrophils are generally the first leukocytes to be recruited to a site of infection, playing a major role in regulating inflammation and, as a result, viral replication and dissemination. However, the underlying mechanisms through which neutrophils control the progression of inflammation and disease remain to be fully understood. In this review, we highlight the major findings from recent years regarding the role of neutrophils during arboviral infections. We discuss the complex nature of neutrophils in mediating not only protection, but also augmenting disease pathology. Better understanding of neutrophil pathways involved in effective protection against arboviral infections can help identify potential targets for therapeutics.
RETRACTED: EFA6 in Axon Regeneration, as a Microtubule Regulator and as a Guanine Nucleotide Exchange Factor
Authors: Gonzalez Gilberto , Chen Lizhen
Published: May 2021

Axon regeneration after injury is a conserved biological process that involves a large number of molecular pathways, including rapid calcium influx at injury sites, retrograde injury signaling, epigenetic transition, transcriptional reprogramming, polarized transport, and cytoskeleton reorganization. Despite the numerous efforts devoted to understanding the underlying cellular and molecular mechanisms of axon regeneration, the search continues for effective target molecules for improving axon regeneration. Although there have been significant historical efforts towards characterizing pro-regenerative factors involved in axon regeneration, the pursuit of intrinsic inhibitors is relatively recent. EFA6 (exchange factor for ARF6) has been demonstrated to inhibit axon regeneration in different organisms. EFA6 inhibition could be a promising therapeutic strategy to promote axon regeneration and functional recovery after axon injury. This review summarizes the inhibitory role on axon regeneration through regulating microtubule dynamics and through affecting ARF6 (ADP-ribosylation factor 6) GTPase-mediated integrin transport.
Comment on Celentano et al. Suitability of a Progenitor Cell-Enriching Device for In Vitro Applications. Coatings 2021, 11, 146
Authors: Astarita Carlo , Trovato Letizia , Graziano Antonio
Published: May 2021

The intent of this letter is to comment on an article entitled “Suitability of a Progenitor Cell-Enriching Device for In Vitro Applications” [...]
Indoor–Outdoor Detection in Mobile Networks Using Quantum Machine Learning Approaches
Authors: Phillipson Frank , Wezeman Robert S. , Chiscop Irina
Published: May 2021

Communication networks are managed more and more by using artificial intelligence. Anomaly detection, network monitoring and user behaviour are areas where machine learning offers advantages over more traditional methods. However, computer power is increasingly becoming a limiting factor in machine learning tasks. The rise of quantum computers may be helpful here, especially where machine learning is one of the areas where quantum computers are expected to bring an advantage. This paper proposes and evaluates three approaches for using quantum machine learning for a specific task in mobile networks: indoor–outdoor detection. Where current quantum computers are still limited in scale, we show the potential the approaches have when larger systems become available.
Investigation of 1064-nm Pumped Type II SPDC in Potassium Niobate for Generation of High Spectral Purity Photon Pairs
Authors: Lee Donghwa , Kim Ilhwan , Lee Kwang Jo
Published: May 2021

The generation and detection of nonclassical light of about 2 μm has good potential in an emerging field of high-sensitivity metrology, especially gravitational wave detection, as well as free-space quantum communication. A pair of photons is generated through a spontaneous parametric down-conversion (SPDC) process in a nonlinear optic crystal, which can be properly entangled in a spatial region where two beams with each polarization overlap or in a Sagnac-loop interferometer configuration. We investigated theoretically and numerically Type II SPDC in a potassium niobate (KNbO3, KN) crystal, which is useful as a material platform for generating photon pairs of high spectral purity in the 2-μm range. The technique is based on the frequency degenerate SPDC under Type II extended phase matching (EPM). We described the EPM characteristics of KN and showed that it is practically feasible for a 1064-nm pumped SPDC under moderate temperature conditions. The effective nonlinear optic coefficient of KN is at least four-times larger than those of other crystals using the Type II EPM approach, which implies a significant improvement in SPDC efficiency. The joint spectral analysis showed that a pair of photons can be generated with a high purity of 0.995 through proper pump filtering.
Eastern Canadian Gastrointestinal Cancer Consensus Conference 2019
Authors: Gotfrit Joanna , Goodwin Rachel , Asmis Timothy , Hyde Angela J. , Alcindor Thierry , Aubin Francine , Berry Scott , Bossé Dominick , Brown Colin , Burkes Ronald , Burnell Margot , Colwell Bruce , Corbett Jessica , Craswell Jeff , Daaboul Nathalie , Doherty Mark , Fleming D. A. Barry , Galvis Luisa , Goel Rakesh , Harb Mohammed , Jeyakumar Alwin , Jonker Derek , Kennedy Erin , Lock Michael , Mahmud Aamer , McCrea Patrick H. , Nair Vimoj , Nassabein Rami , Nessim Carolyn , Ramjeesingh Ravi , Raza Muhammad , Saliba Wissam , Samimi Satareh , Singh Simron , Snow Stephanie , Tehfé Mustapha , Thirlwell Michael , Valdes Mario , Welch Stephen , Vickers Michael
Published: May 2021

The annual Eastern Canadian Gastrointestinal Cancer Consensus Conference 2019 was held in Morell, Prince Edward Island, 19–21 September 2019. Experts in medical oncology, radiation oncology, and surgical oncology who are involved in the management of patients with gastrointestinal malignancies participated in presentations and discussion sessions for the purpose of developing the recommendations presented here. This consensus statement addresses multiple topics in the management of anal, colorectal, biliary tract, and gastric cancers, including: radiotherapy and systemic therapy for localized and advanced anal cancer; watch and wait strategy for the management of rectal cancer; role of testing for dihydropyrimidine dehydrogenase (DPD) deficiency prior to commencement of fluoropyrimidine therapy; radiotherapy and systemic therapy in the adjuvant and unresectable settings for biliary tract cancer; and radiotherapy and systemic therapy in the perioperative setting for early-stage gastric cancer.
TP53 Abnormalities and MMR Preservation in 5 Cases of Proliferating Trichilemmal Tumours
Authors: Martín-Sanz Raquel , Sayagués José María , García-Cano Pilar , Azcue-Mayorga Mikel , Parra-Pérez María del Carmen , Pacios-Pacios María Ángeles , Piqué-Durán Enric , Feito Jorge
Published: May 2021

Proliferating trichilemmal tumours (PTT) are defined by a benign squamous cell proliferation inside a trichilemmal cystic (TC) cavity. A possible explanation of this proliferative phenomenon within the cyst may be molecular alterations in genes associated to cell proliferation, which can be induced by ultraviolet radiation. Among other genes, alterations on TP53 and DNA mismatch repair proteins (MMR) may be involved in the cellular proliferation observed in PTT. Based on this assumption, but also taking into account the close relationship between the sebaceous ducts and the external root sheath where TC develop, a MMR, a p53 expression assessment and a TP53 study were performed in a series of 5 PTT cases, including a giant one. We failed to demonstrate a MMR disorder on studied PTT, but we agree with previous results suggesting increased p53 expression in these tumours, particularly in proliferative areas. TP53 alteration was confirmed with FISH technique, demonstrating TP53 deletion in most cells.
Diagnostic Yield and Cost-Effectiveness of “Dynamic” Exome Analysis in Epilepsy with Neurodevelopmental Disorders: A Tertiary-Center Experience in Northern Italy
Authors: Varesio Costanza , Gana Simone , Asaro Alessia , Ballante Elena , Cabini Raffaella Fiamma , Tartara Elena , Bagnaschi Michela , Pasca Ludovica , Valente Marialuisa , Orcesi Simona , Cereda Cristina , Veggiotti Pierangelo , Borgatti Renato , Valente Enza Maria , De Giorgis Valentina
Published: May 2021

Background: The advent of next-generation sequencing (NGS) techniques in clinical practice led to a significant advance in gene discovery. We aimed to describe diagnostic yields of a “dynamic” exome-based approach in a cohort of patients with epilepsy associated with neurodevelopmental disorders. Methods: We conducted a retrospective, observational study on 72 probands. All patients underwent a first diagnostic level of a 135 gene panel, a second of 297 genes for inconclusive cases, and finally, a whole-exome sequencing for negative cases. Diagnostic yields at each step and cost-effectiveness were the objects of statistical analysis. Results: Overall diagnostic yield in our cohort was 37.5%: 29% of diagnoses derived from the first step analysis, 5.5% from the second step, and 3% from the third. A significant difference emerged between the three diagnostic steps (p < 0.01), between the first and second (p = 0.001), and the first and third (p << 0.001). The cost-effectiveness plane indicated that our exome-based “dynamic” approach was better in terms of cost savings and higher diagnostic rate. Conclusions: Our findings suggested that “dynamic” NGS techniques applied to well-phenotyped individuals can save both time and resources. In patients with unexplained epilepsy comorbid with NDDs, our approach might maximize the number of diagnoses achieved.
Feasibility and Implementation of Ex Vivo Fluorescence Confocal Microscopy for Diagnosis of Oral Leukoplakia: Preliminary Study
Authors: Shavlokhova Veronika , Flechtenmacher Christa , Sandhu Sameena , Vollmer Michael , Vollmer Andreas , Pilz Maximilian , Hoffmann Jürgen , Ristow Oliver , Engel Michael , Freudlsperger Christian
Published: May 2021

Background: Oral leukoplakia is a potentially malignant lesion with a clinical impression similar to different benign and malignant lesions. Ex vivo fluorescence confocal microscopy is a developing approach for a rapid “chairside” detection of oral lesions with a cellular-level resolution. A possible application of interest is a quick differentiation of benign oral pathology from normal or cancerous tissue. The aim of this study was to analyze the sensitivity and specificity of ex vivo fluorescence confocal microscopy (FCM) for detecting oral leukoplakia and to compare confocal images with gold-standard histopathology. Methods: Imaging of 106 submosaics of 27 oral lesions was performed using an ex vivo fluorescence confocal microscope immediately after excision. Every confocal image was qualitatively assessed for presence or absence of leukoplakia by an expert reader of confocal images. The results were compared to conventional histopathology with H&E staining. Results: Leukoplakia was detected with an overall sensitivity of 96.3%, specificity of 92.3%, positive predictive value of 93%, and negative predictive value of 96%. Conclusion: The results demonstrate the potential of ex vivo confocal microscopy in fresh tissue for rapid real-time assessment of oral pathologies.
HPV-Negative Cervical Cancer: A Narrative Review
Authors: Arezzo Francesca , Cormio Gennaro , Loizzi Vera , Cazzato Gerardo , Cataldo Viviana , Lombardi Claudio , Ingravallo Giuseppe , Resta Leonardo , Cicinelli Ettore
Published: May 2021

Cervical cancer (CC) is the fourth most frequent cancer in women worldwide. HPV infection is associated with the majority of CC cases, but a small proportion of CCs actually test negative for HPV. The prevalence of HPV among CC histotypes is very different. It has been suggested that HPV-negative CC may represent a biologically distinct subset of tumors, relying on a distinct pathogenetic pathway and carrying a poorer prognosis, than HPV-positive CCs. Although, the discordance in terms of sensitivity and specificity between different HPV tests as well as the potential errors in sampling and storing tissues may be considered as causes of false-negative results. The identification of HPV-negative CCs is essential for their correct management. The aim of this narrative review is to summarize the clinical and pathological features of this variant. We also discuss the pitfalls of different HPV tests possibly leading to classification errors.
Detection of Bone Marrow Edema in Patients with Osteoid Osteoma Using Three-Material Decomposition with Dual-Layer Spectral CT
Authors: Gassert Florian T. , Hammel Johannes , Hofmann Felix C. , Neumann Jan , von Schacky Claudio E. , Gassert Felix G. , Pfeiffer Daniela , Pfeiffer Franz , Makowski Marcus R. , Woertler Klaus , Gersing Alexandra S. , Schwaiger Benedikt J.
Published: May 2021

The aim of this study is to assess whether perifocal bone marrow edema (BME) in patients with osteoid osteoma (OO) can be accurately detected on dual-layer spectral CT (DLCT) with three-material decomposition. To that end, 18 patients with OO (25.33 ± 12.44 years; 7 females) were pairwise-matched with 18 patients (26.72 ± 9.65 years; 9 females) admitted for suspected pathologies other than OO in the same anatomic location but negative imaging findings. All patients were examined with DLCT and MRI. DLCT data was decomposed into hydroxyapatite and water- and fat-equivalent volume fraction maps. Two radiologists assessed DLCT-based volume fraction maps for the presence of perifocal BME, using a Likert scale (1 = no edema; 2 = likely no edema; 3 = likely edema; 4 = edema). Accuracy, sensitivity, and specificity for the detection of BME on DLCT were analyzed using MR findings as standard of reference. For the detection of BME in patients with OO, DLCT showed a sensitivity of 0.92, a specificity of 0.94, and an accuracy of 0.92 for both radiologists. Interreader agreement for the assessment of BME with DLCT was substantial (weighted κ = 0.78; 95% CI, 0.59, 0.94). DLCT with material-specific volume fraction maps allowed accurate detection of BME in patients with OO. This may spare patients additional examinations and facilitate the diagnosis of OO.
The Prognostic Importance of Right Ventricular Longitudinal Strain in Patients with Cardiomyopathies, Connective Tissue Diseases, Coronary Artery Disease, and Congenital Heart Diseases
Authors: Tadic Marijana , Kersten Johannes , Nita Nicoleta , Schneider Leonhard , Buckert Dominik , Gonska Birgid , Scharnbeck Dominik , Dahme Tilman , Imhof Armin , Belyavskiy Evgeny , Cuspidi Cesare , Rottbauer Wolfgang
Published: May 2021

Right ventricular (RV) systolic function represents an important independent predictor of adverse outcomes in many cardiovascular (CV) diseases. However, conventional parameters of RV systolic function (tricuspid annular plane excursion (TAPSE), RV myocardial performance index (MPI), and fractional area change (FAC)) are not always able to detect subtle changes in RV function. New evidence indicates a significantly higher predictive value of RV longitudinal strain (LS) over conventional parameters. RVLS showed higher sensitivity and specificity in the detection of RV dysfunction in the absence of RV dilatation, apparent wall motion abnormalities, and reduced global RV systolic function. Additionally, RVLS represents a significant and independent predictor of adverse outcomes in patients with dilated cardiomyopathy (CMP), hypertrophic CMP, arrhythmogenic RV CMP, and amyloidosis, but also in patients with connective tissue diseases and patients with coronary artery disease. Due to its availability, echocardiography remains the main imaging tool for RVLS assessment, but cardiac magnetic resonance (CMR) also represents an important additional imaging tool in RVLG assessment. The findings from the large studies support the routine evaluation of RVLS in the majority of CV patients, but this has still not been adopted in daily clinical practice. This clinical review aims to summarize the significance and predictive value of RVLS in patients with different types of cardiomyopathies, tissue connective diseases, and coronary artery disease.
Improving Learner-Computer Interaction through Intelligent Learning Material Delivery Using Instructional Design Modeling
Authors: Troussas Christos , Krouska Akrivi , Sgouropoulou Cleo
Published: May 2021

This paper describes an innovative and sophisticated approach for improving learner-computer interaction in the tutoring of Java programming through the delivery of adequate learning material to learners. To achieve this, an instructional theory and intelligent techniques are combined, namely the Component Display Theory along with content-based filtering and multiple-criteria decision analysis, with the intention of providing personalized learning material and thus, improving student interaction. Until now, the majority of the research efforts mainly focus on adapting the presentation of learning material based on students’ characteristics. As such, there is free space for researching issues like delivering the appropriate type of learning material, in order to maintain the pedagogical affordance of the educational software. The blending of instructional design theories and sophisticated techniques can offer a more personalized and adaptive learning experience to learners of computer programming. The paper presents a fully operating intelligent educational software. It merges pedagogical and technological approaches for sophisticated learning material delivery to students. Moreover, it was used by undergraduate university students to learn Java programming for a semester during the COVID-19 lockdown. The findings of the evaluation showed that the presented way for delivering the Java learning material surpassed other approaches incorporating merely instructional models or intelligent tools, in terms of satisfaction and knowledge acquisition.
Learning from Problem-Based Projects in Cross-Disciplinary Student Teams
Authors: Ellingsen Pål , Tonholm Trude , Johansen Frode Ramstad , Andersson Gunnar
Published: May 2021

This paper explores how Engineering students and Work and Welfare students reflect upon their own engagement in a one-week cross-disciplinary project. To develop a better understanding of what unfolds during these activities we collected data through anonymous surveys two consecutive years. Data from these 141 respondents were analysed using a learning history approach and are presented as narratives. Results show major disruptions and conflicts driving the student projects, exposing inviting confrontations, social identity threats, managing diversity, and friction of ideas. Whereas this in many cases led to new and better project solutions, these real-world experiences raise awareness of the need for tools and methods for training students. The aim of the paper is to learn from students’ experiences through narrative distance, and fill a gap in the literature between problem-based learning (PBL) and the learning history method. Discussing different experiences of cross-disciplinary teamwork through the explanations of these theories, we also lay out potential questions for future research on the topic.
Young People’s Views on Food Hygiene and Food Safety: A Multicentre Qualitative Study
Authors: Syeda Rowshonara , Touboul Lundgren Pia , Kasza Gyula , Truninger Monica , Brown Carla , Lacroix-Hugues Virginie , Izsó Tekla , Teixeira Paula , Eley Charlotte , Ferré Noémie , Kunszabo Atilla , Nunes Cristina , Hayes Catherine , Gennimata Dimitra , Szakos Dávid , McNulty Cliodna Ann Miriam
Published: May 2021

Foodborne diseases are a global burden, are preventable, and young people are a key population for behaviour change as they gain autonomy. This study aimed to explore young people’s needs across several European countries in relation to learning about and implementing food hygiene and food safety. Qualitative focus groups and interviews were conducted in rural and city regions across England, France, Hungary and Portugal. Data were collected to attain data saturation, transcribed, thematically analysed, and mapped to the Theoretical Domains Framework. Twenty-five out of 84 schools approached (29.8%) participated, with data collected from 156 11–18-year-old students. Students had good knowledge of personal hygiene but did not always follow hygiene rules due to forgetfulness, lack of facilities or lack of concern for consequences. Students had limited understanding of foodborne microbes, underestimated the risks and consequences of foodborne illness and perceived the “home” environment as the safest. Young people preferred interactive educational methods. Addressing gaps in young people’s food safety knowledge is essential to improve their lack of concern towards foodborne illness and motivate them to follow food hygiene and safety behaviours consistently. Findings have been used to develop educational resources to address gaps in knowledge, skills, attitudes and beliefs.