bluuebunny/crossref_metadata_2025 huggingface dataset:
Vibration Reduction in Ballasted Track Using Ballast Mat: Numerical and Experimental Evaluation by Wheelset Drop Test
Authors: Hou Bowen , Wang Di , Wang Bingbing , Chen Xingyu , Pombo João
Published: February 2022

Ballast mats are considered as an effective solution for reducing vehicle-induced vibrations. However, the research on the vibration characteristics of each part of the ballasted track with a ballast mat is limited. In this study, the ballast mat vibration reduction effects are evaluated by numerical and experimental analysis using wheelset drop tests. A three-dimensional model consisting of a wheel, track and the contact between them is built using a rigid–flexible coupling method. The accuracy of the numerical model is verified by comparison with the finite element model in terms of the track receptance and phase angle. Comparisons show that the proposed model is in good agreement with the finite element model, which allows validating the flexible-body model. Moreover, the track dynamic performance in the presence and absence of the ballast mat is studied with the wheelset drop tests in both time and frequency domains. The results from the wheelset drop excitation tests show that the use of the ballast mat decreases the mid- and high-frequency track vibration by 13–17 dB but increases the low-frequency track vibration by 5–15 dB.
Word Sense Disambiguation Using Clustered Sense Labels
Authors: Park Jeong Yeon , Shin Hyeong Jin , Lee Jae Sung
Published: February 2022

Sequence labeling models for word sense disambiguation have proven highly effective when the sense vocabulary is compressed based on the thesaurus hierarchy. In this paper, we propose a method for compressing the sense vocabulary without using a thesaurus. For this, sense definitions in a dictionary are converted into sentence vectors and clustered into the compressed senses. First, the very large set of sense vectors is partitioned for less computational complexity, and then it is clustered hierarchically with awareness of homographs. The experiment was done on the English Senseval and Semeval datasets and the Korean Sejong sense annotated corpus. This process demonstrated that the performance greatly increased compared to that of the uncompressed sense model and is comparable to that of the thesaurus-based model.
UV Protection in the Cornea: Failure and Rescue
Authors: Volatier Thomas , Schumacher Björn , Cursiefen Claus , Notara Maria
Published: February 2022

Ultraviolet (UV) irradiation induces DNA lesions in all directly exposed tissues. In the human body, two tissues are chronically exposed to UV: the skin and the cornea. The most frequent UV-induced DNA lesions are cyclobutane pyrimidine dimers (CPDs) that can lead to apoptosis or induce tumorigenesis. Lacking the protective pigmentation of the skin, the transparent cornea is particularly dependent on nucleotide excision repair (NER) to remove UV-induced DNA lesions. The DNA damage response also triggers intracellular autophagy mechanisms to remove damaged material in the cornea; these mechanisms are poorly understood despite their noted involvement in UV-related diseases. Therapeutic solutions involving xenogenic DNA-repair enzymes such as T4 endonuclease V or photolyases exist and are widely distributed for dermatological use. The corneal field lacks a similar set of tools to address DNA-lesions in photovulnerable patients, such as those with genetic disorders or recently transplanted tissue.
What We Know about Sting-Related Deaths? Human Fatalities Caused by Hornet, Wasp and Bee Stings in Europe (1994–2016)
Authors: Feás Xesús , Vidal Carmen , Remesar Susana
Published: February 2022

Epidemiology of Hymenopteran-related deaths in Europe, based on official registers from WHO Mortality Database (Cause Code of Death: X23), are presented. Over a 23-year period (1994–2016), a total of 1691 fatalities were recorded, mostly occurring in Western (42.8%) and Eastern (31.9%) Europe. The victims tended to concentrate in: Germany (n = 327; 1998–2015), France (n = 211; 2000–2014) and Romania (n = 149; 1999–2016). The majority of deaths occurred in males (78.1%) between 25–64 years (66.7%), and in an “unspecified place” (44.2%). The highest X23MR (mortality rate) were recorded in countries from Eastern Europe (0.35) followed by Western (0.28), Northern (0.23) and Southern Europe (0.2). The countries with the highest and lowest mean X23MR were Estonia (0.61), Austria (0.6) and Slovenia (0.55); and Ireland (0.05), United Kingdom (0.06) and the Netherlands (0.06), respectively. The X23 gender ratio (X23GR; male/female) of mortality varied from a minimum of 1.4 for Norway to a maximum of 20 for Slovenia. Country-by-country data show that the incidence of insect-sting mortality is low and more epidemiological data at the regional level is needed to improve our understanding of this incidence. With the expansion of non-native Hymenopteran species across Europe, allergists should be aware that their community’s exposures are continually changing
Increased TRPV1 Channels and FosB Protein Expression Are Associated with Chronic Epileptic Seizures and Anxiogenic-like Behaviors in a Preclinical Model of Temporal Lobe Epilepsy
Authors: Lazarini-Lopes Willian , Silva-Cardoso Gleice Kelli , Leite-Panissi Christie Ramos Andrade , Garcia-Cairasco Norberto
Published: February 2022

Epilepsies are neurological disorders characterized by chronic seizures and their related neuropsychiatric comorbidities, such as anxiety. The Transient Receptor Potential Vanilloid type-1 (TRPV1) channel has been implicated in the modulation of seizures and anxiety-like behaviors in preclinical models. Here, we investigated the impact of chronic epileptic seizures in anxiety-like behavior and TRPV1 channels expression in a genetic model of epilepsy, the Wistar Audiogenic Rat (WAR) strain. WARs were submitted to audiogenic kindling (AK), a preclinical model of temporal lobe epilepsy (TLE) and behavioral tests were performed in the open-field (OF), and light-dark box (LDB) tests 24 h after AK. WARs displayed increased anxiety-like behavior and TRPV1R expression in the hippocampal CA1 area and basolateral amygdala nucleus (BLA) when compared to control Wistar rats. Chronic seizures increased anxiety-like behaviors and TRPV1 and FosB expression in limbic and brainstem structures involved with epilepsy and anxiety comorbidity, such as the hippocampus, superior colliculus, and periaqueductal gray matter. Therefore, these results highlight previously unrecognized alterations in TRPV1 expression in brain structures involved with TLE and anxiogenic-like behaviors in a genetic model of epilepsy, the WAR strain, supporting an important role of TRPV1 in the modulation of neurological disorders and associated neuropsychiatric comorbidities.
Neuron–Microglia Contacts Govern the PGE2 Tolerance through TLR4-Mediated de Novo Protein Synthesis
Authors: Kuo Hsing-Chun , Lee Kam-Fai , Chen Shiou-Lan , Chiu Shu-Chen , Lee Li-Ya , Chen Wan-Ping , Chen Chin-Chu , Chu Chun-Hsien
Published: February 2022

Cellular and molecular mechanisms of the peripheral immune system (e.g., macrophage and monocyte) in programming endotoxin tolerance (ET) have been well studied. However, regulatory mechanism in development of brain immune tolerance remains unclear. The inducible COX-2/PGE2 axis in microglia, the primary innate immune cells of the brain, is a pivotal feature in causing inflammation and neuronal injury, both in acute excitotoxic insults and chronic neurodegenerative diseases. This present study investigated the regulatory mechanism of PGE2 tolerance in microglia. Multiple reconstituted primary brain cells cultures, including neuron–glial (NG), mixed glial (MG), neuron-enriched, and microglia-enriched cultures, were performed and consequently applied to a treatment regimen for ET induction. Our results revealed that the levels of COX-2 mRNA and supernatant PGE2 in NG cultures, but not in microglia-enriched and MG cultures, were drastically reduced in response to the ET challenge, suggesting that the presence of neurons, rather than astroglia, is required for PGE2 tolerance in microglia. Furthermore, our data showed that neural contact, instead of its soluble factors, is sufficient for developing microglial PGE2 tolerance. Simultaneously, this finding determined how neurons regulated microglial PGE2 tolerance. Moreover, by inhibiting TLR4 activation and de novo protein synthesis by LPS-binding protein (LBP) manipulation and cycloheximide, our data showed that the TLR4 signal and de novo protein synthesis are necessary for microglia to develop PGE2 tolerance in NG cells under the ET challenge. Altogether, our findings demonstrated that neuron–microglia contacts are indispensable in emerging PGE2 tolerance through the regulation of TLR4-mediated de novo protein synthesis.
Non-Destructive Monitoring via Electrochemical NADH Detection in Murine Cells
Authors: Lee Ju Kyung , Suh Han Na , Yoon Sung Hoon , Lee Kyu Hong , Ahn Sae Young , Kim Hyung Jin , Kim Sang Hee
Published: February 2022

Nicotinamide adenine dinucleotide (NADH) is an important cofactor involved in metabolic redox reactions in living cells. The detection of NADH in living animal cells is a challenge. We developed a one-step monitoring method for NADH via an electrocatalytic reaction that uses a surface-modified, screen-printed electrode (SPE) having a redox active monolayer 4′-mercapto-N-phenlyquinone diamine (NPQD) formed by a self-assembled monolayer (SAM) of an aromatic thiol, 4-aminothiophenol (4-ATP). This electrode has a limit of detection (LOD) of 0.49 μM and a sensitivity of 0.0076 ± 0.0006 μM/μA in cell culture media, which indicates that it retains its selectivity. The applicability of this NADH sensor was demonstrated for the first time by cell viability monitoring via NADH-sensing in cell culture supernatants.
Design and Optimisation of Elliptical-Shaped Planar Hall Sensor for Biomedical Applications
Authors: Uddin Shah Mukim , Sayad Abkar , Chan Jianxiong , Skafidas Efstratios , Kwan Patrick
Published: February 2022

The magnetic beads detection-based immunoassay, also called magneto-immunoassay, has potential applications in point-of-care testing (POCT) due to its unique advantage of minimal background interference from the biological sample and associated reagents. While magnetic field detection technologies are well established for numerous applications in the military, as well as in geology, archaeology, mining, spacecraft, and mobile phones, adaptation into magneto-immunoassay is yet to be explored. The magnetic field biosensors under development tend to be multilayered and require an expensive fabrication process. A low-cost and affordable biosensing platform is required for an effective point-of-care diagnosis in a resource-limited environment. Therefore, we evaluated a single-layered magnetic biosensor in this study to overcome this limitation. The shape-induced magnetic anisotropy-based planar hall effect sensor was recently developed to detect a low-level magnetic field, but was not explored for medical application. In this study, the elliptical-shaped planar hall effect (EPHE) sensor was designed, fabricated, characterized, and optimized for the magneto-immunoassay, specifically. Nine sensor variants were designed and fabricated. A customized measurement setup incorporating a lock-in amplifier was used to quantify 4.5 µm magnetic beads in a droplet. The result indicated that the single-domain behaviour of the magnetic film and larger sensing area with a thinner magnetic film had the highest sensitivity. The developed sensor was tested with a range of magnetic bead concentrations, demonstrating a limit of detection of 200 beads/μL. The sensor performance encourages employing magneto-immunoassay towards developing a low-cost POCT device in the future.
Microbial Fuel Cell Based on Nitrogen-Fixing Rhizobium anhuiense Bacteria
Authors: Žalnėravičius Rokas , Paškevičius Algimantas , Samukaitė-Bubnienė Urtė , Ramanavičius Simonas , Vilkienė Monika , Mockevičienė Ieva , Ramanavičius Arūnas
Published: February 2022

In this study, the nitrogen-fixing, Gram-negative soil bacteria Rhizobium anhuiense was successfully utilized as the main biocatalyst in a bacteria-based microbial fuel cell (MFC) device. This research investigates the double-chambered, H-type R. anhuiense-based MFC that was operated in modified Norris medium (pH = 7) under ambient conditions using potassium ferricyanide as an electron acceptor in the cathodic compartment. The designed MFC exhibited an open-circuit voltage (OCV) of 635 mV and a power output of 1.07 mW m−2 with its maximum power registered at 245 mV. These values were further enhanced by re-feeding the anode bath with 25 mM glucose, which has been utilized herein as the main carbon source. This substrate addition led to better performance of the constructed MFC with a power output of 2.59 mW m−2 estimated at an operating voltage of 281 mV. The R. anhuiense-based MFC was further developed by improving the charge transfer through the bacterial cell membrane by applying 2-methyl-1,4-naphthoquinone (menadione, MD) as a soluble redox mediator. The MD-mediated MFC device showed better performance, resulting in a slightly higher OCV value of 683 mV and an almost five-fold increase in power density to 4.93 mW cm−2. The influence of different concentrations of MD on the viability of R. anhuiense bacteria was investigated by estimating the optical density at 600 nm (OD600) and comparing the obtained results with the control aliquot. The results show that lower concentrations of MD, ranging from 1 to 10 μM, can be successfully used in an anode compartment in which R. anhuiense bacteria cells remain viable and act as a main biocatalyst for MFC applications.
Functional Analysis of Zebrafish socs4a: Impacts on the Notochord and Sensory Function
Authors: Trengove Monique , Wyett Ruby , Liongue Clifford , Ward Alister C.
Published: February 2022

The suppressor of cytokine signaling (SOCS) proteins play important roles in cytokine and growth factor signaling, where they act principally as negative feedback regulators, particularly of the downstream signal transducer and activator of transcription (STAT) transcription factors. This critical mode of regulation impacts on both development and homeostasis. However, understanding of the function of SOCS4 remains limited. To address this, we investigated one of the zebrafish SOCS4 paralogues, socs4a, analyzing its expression and the consequences of its ablation. The socs4a gene had a dynamic expression profile during zebrafish embryogenesis, with initial ubiquitous expression becoming restricted to sensory ganglion within the developing nervous system. The knockdown of zebrafish socs4a revealed novel roles in notochord development, as well as the formation of a functional sensory system.
Spatial Correlation Network and Driving Effect of Carbon Emission Intensity in China’s Construction Industry
Authors: Wang Zhenshuang , Zhou Yanxin , Zhao Ning , Wang Tao , Zhang Zhongsheng
Published: February 2022

To explore the spatial network structure characteristics and driving effects of carbon emission intensity in China’s construction industry, this paper measures the carbon emission data of China’s construction industry in various provinces from 2006 to 2017 and then combines the modified gravity model and social network analysis method to deeply analyze the spatially associated network structure characteristics and driving effects of the carbon emission intensity in China’s construction industry. The results show that the regional differences of the carbon emissions of the construction industry are significant, and the carbon emission intensity of the construction industry shows a fluctuating trend. The overall network of carbon emission intensity shows an obvious “core-edge” state, and the hierarchical network structure is gradually broken. Economically developed provinces generally play a leading role in the network and play an intermediary role to guide other provinces to develop together with them. Among the network blocks, most of the blocks play the role of “brokers”. The block with the leading economic development has a strong influence on the other blocks. The increase in network density and the decrease in network hierarchy and network efficiency will reduce the construction carbon emission intensity.
Development of Organ-Preserving Radiation Therapy in Gastric Marginal Zone Lymphoma
Authors: Rolf Daniel , Reinartz Gabriele , Rehn Stephan , Kittel Christopher , Eich Hans Theodor
Published: February 2022

Gastric marginal zone lymphoma (gMZL) of mucosa-associated lymphoid tissue (MALT) may persist even after H. pylori eradication, or it can be primarily Helicobacter pylori (H. pylori) independent. For patients without the successful eradication of lymphoma, or with progressive disease, treatment options have historically included partial or total gastrectomy. Presently, in these instances, curative radiation therapy (RT) is the current standard of care. This review emphasizes the historically changing role of radiation therapy in gMZL, progressing from large-volume RT without surgery, to localized RT, on its own, as a curative organ-preserving treatment. This overview shows the substantial progress in radiation therapy during the recent two to three decades, from high-dose, large-field techniques to low-dose, localized target volumes based on advanced imaging, three-dimensional treatment planning, and advanced treatment delivery techniques. RT has evolved from very large extended field techniques (EF) with prophylactic treatment of the whole abdomen and the supradiaphragmatic lymph nodes, applying doses between 30 and 50 Gy, to involved-field RT (IF), to the current internationally recommended involved site radiation therapy (ISRT) with a radiation dose of 24–30 Gy in gMZL. Stage-adapted RT is a highly effective and safe treatment with excellent overall survival rates and very rare acute or late treatment-related toxicities, as shown not only in retrospective studies, but also in large prospective multicenter studies, such as those conducted by the German Study Group on Gastrointestinal Lymphoma (DSGL). Further de-escalation of the radiation treatments with low-dose 20 Gy, as well as ultra-low-dose 4 Gy radiation therapy, is under investigation within ongoing prospective clinical trials of the International Lymphoma Radiation Oncology Group (ILROG) and of the German Lymphoma Alliance (GLA).
HSA-Binding Prodrugs-Based Nanoparticles Endowed with Chemo and Photo-Toxicity against Breast Cancer
Authors: Rapozzi Valentina , Moret Francesca , Menilli Luca , Guerrini Andrea , Tedesco Daniele , Naldi Marina , Bartolini Manuela , Gani Mariachiara , Zorzet Sonia , Columbaro Marta , Milani Celeste , Martini Cecilia , Ferroni Claudia , Varchi Greta
Published: February 2022

Exploiting the tumor environment features (EPR effect, elevated glutathione, reactive oxygen species levels) might allow attaining a selective and responsive carrier capable of improving the therapeutic outcome. To this purpose, the in situ covalent binding of drugs and nanoparticles to circulating human serum albumin (HSA) might represent a pioneering approach to achieve an effective strategy. This study describes the synthesis, in vitro and in vivo evaluation of bioresponsive HSA-binding nanoparticles (MAL-PTX2S@Pba), co-delivering two different paclitaxel (PTX) prodrugs and the photosensitizer pheophorbide a (Pba), for the combined photo- and chemo-treatment of breast cancer. Stable and reproducible MAL-PTX2S@Pba nanoparticles with an average diameter of 82 nm and a PTX/Pba molar ratio of 2.5 were obtained by nanoprecipitation. The in vitro 2D combination experiments revealed that MAL-PTX2S@Pba treatment induces a strong inhibition of cell viability of MDA-MB-231, MCF7 and 4T1 cell lines, whereas 3D experiments displayed different trends: while MAL-PTX2S@Pba effectiveness was confirmed against MDA-MB-231 spheroids, the 4T1 model exhibited marked resistance. Lastly, despite using a low PTX-PDT regimen (e.g., 8.16 mg/Kg PTX and 2.34 mg/Kg Pba), our formulation showed to foster primary tumor reduction and curb lung metastases growth in 4T1 tumor-bearing mice, thus setting the basis for further preclinical validations.
The PRP19 Ubiquitin Ligase, Standing at the Cross-Roads of mRNA Processing and Genome Stability
Authors: Idrissou Mouhamed , Maréchal Alexandre
Published: February 2022

mRNA processing factors are increasingly being recognized as important regulators of genome stability. By preventing and resolving RNA:DNA hybrids that form co-transcriptionally, these proteins help avoid replication–transcription conflicts and thus contribute to genome stability through their normal function in RNA maturation. Some of these factors also have direct roles in the activation of the DNA damage response and in DNA repair. One of the most intriguing cases is that of PRP19, an evolutionarily conserved essential E3 ubiquitin ligase that promotes mRNA splicing, but also participates directly in ATR activation, double-strand break resection and mitosis. Here, we review historical and recent work on PRP19 and its associated proteins, highlighting their multifarious cellular functions as central regulators of spliceosome activity, R-loop homeostasis, DNA damage signaling and repair and cell division. Finally, we discuss open questions that are bound to shed further light on the functions of PRP19-containing complexes in both normal and cancer cells.
Prediction Model for Pancreatic Cancer—A Population-Based Study from NHIRD
Authors: Lee Hsiu-An , Chen Kuan-Wen , Hsu Chien-Yeh
Published: February 2022

(1) Background: Cancer has been the leading cause of death in Taiwan for 39 years, and among them, pancreatic cancer has been ranked seventh in the top ten cancer mortality rates for the past three years. While the incidence rate of pancreatic cancer is ranked at the bottom of the top 10 cancers, the survival rate is very low. Pancreatic cancer is one of the more difficult cancers to detect early due to the lack of early diagnostic tools. Early screening is important for the treatment of pancreatic cancer. Only a few studies have designed predictive models for pancreatic cancer. (2) Methods: The Taiwan Health Insurance Database was used in this study, covering over 99% of the population in Taiwan. The subset sample was not significantly different from the original NHIRD sample. A machine learning approach was used to develop a predictive model for pancreatic cancer disease. Four models, including logistic regression, deep neural networks, ensemble learning, and voting ensemble were used in this study. The ROC curve and a confusion matrix were used to evaluate the accuracy of the pancreatic cancer prediction models. (3) Results: The AUC of the LR model was higher than the other three models in the external testing set for all three of the factor combinations. Sensitivity was best measured by the stacking model for the first factor combinations, and specificity was best measured by the DNN model for the second factor combination. The result of the model that used only nine factors (third factor combinations) was equal to the other two factor combinations. The AUC of the previous models for the early assessment of pancreatic cancer ranged from approximately 0.57 to 0.71. The AUC of this study was higher than that of previous studies and ranged from 0.71 to 0.76, which provides higher accuracy. (4) Conclusions: This study compared the performances of LR, DNN, stacking, and voting models for pancreatic cancer prediction and constructed a pancreatic cancer prediction model with accuracy higher than that of previous studies. This predictive model will improve awareness of the risk of pancreatic cancer and give patients with pancreatic cancer a simpler tool for early screening in the golden period when the disease can still be eradicated.
Interleukin-6 Is a Circulating Prognostic Biomarker for Hepatocellular Carcinoma Patients Treated with Combined Immunotherapy
Authors: Myojin Yuta , Kodama Takahiro , Sakamori Ryotaro , Maesaka Kazuki , Matsumae Takayuki , Sawai Yoshiyuki , Imai Yasuharu , Ohkawa Kazuyoshi , Miyazaki Masanori , Tanaka Satoshi , Mita Eiji , Tawara Seiichi , Yakushijin Takayuki , Nozaki Yasutoshi , Hagiwara Hideki , Tahata Yuki , Yamada Ryoko , Hikita Hayato , Tatsumi Tomohide , Takehara Tetsuo
Published: February 2022

Atezolizumab/bevacizumab (Atezo/Bev) combination therapy has become a front-line therapy for advanced hepatocellular carcinoma (HCC), but approximately 20% of patients are nonresponders. We investigated circulating biomarkers to predict therapeutic outcomes. We performed simultaneous measurement of 34 proteins using a multiplex bead-based immunoassay in baseline plasma from 34 patients who underwent Atezo/Bev therapy as first- or second-line treatment. Logistic regression analysis showed that plasma IL-6 and interferon alpha (IFNα) levels were significant predictors of non-responders (odds ratio of 13.33 and FDR p = 0.021 for IL-6 and IFNα). The progression-free survival (PFS) and overall survival (OS) of patients with high IL-6 levels were significantly shorter than those of patients with low IL-6 levels. Next, we measured baseline plasma IL-6 levels in 64 HCC patients who underwent Atezo/Bev therapy by ELISA. The IL-6-high group showed higher female ratio, AST levels, tumor markers, Child–Pugh score, and vascular invasion ratio. The PFS and OS of the IL-6-high group were significantly shorter than those of the IL-6-low group. Multivariate Cox proportional hazards analysis showed that IL-6 level and age were independent risk factors for disease progression (hazard ratio of 2.785 and p = 0.015 for IL-6, and hazard ratio 0.306 and p = 0.03 for age). In conclusion, circulating IL-6 levels are a novel prognostic biomarker for advanced HCC patients who undergo combined immunotherapy.
Inducing Biomechanical Heterogeneity in Brain Tumor Modeling by MR Elastography: Effects on Tumor Growth, Vascular Density and Delivery of Therapeutics
Authors: Harkos Constantinos , Svensson Siri Fløgstad , Emblem Kyrre E. , Stylianopoulos Triantafyllos
Published: February 2022

The purpose of this study is to develop a methodology that incorporates a more accurate assessment of tissue mechanical properties compared to current mathematical modeling by use of biomechanical data from magnetic resonance elastography. The elastography data were derived from five glioblastoma patients and a healthy subject and used in a model that simulates tumor growth, vascular changes due to mechanical stresses and delivery of therapeutic agents. The model investigates the effect of tumor-specific biomechanical properties on tumor anisotropic growth, vascular density heterogeneity and chemotherapy delivery. The results showed that including elastography data provides a more realistic distribution of the mechanical stresses in the tumor and induces anisotropic tumor growth. Solid stress distribution differs among patients, which, in turn, induces a distinct functional vascular density distribution—owing to the compression of tumor vessels—and intratumoral drug distribution for each patient. In conclusion, incorporating elastography data results in a more accurate calculation of intratumoral mechanical stresses and enables a better mathematical description of subsequent events, such as the heterogeneous development of the tumor vasculature and intrapatient variations in tumor perfusion and delivery of drugs.
Dissecting miRNA–Gene Networks to Map Clinical Utility Roads of Pharmacogenomics-Guided Therapeutic Decisions in Cardiovascular Precision Medicine
Authors: Chatzopoulou Fani , Kyritsis Konstantinos A. , Papagiannopoulos Christos I. , Galatou Eleftheria , Mittas Nikolaos , Theodoroula Nikoleta F. , Papazoglou Andreas S. , Karagiannidis Efstratios , Chatzidimitriou Maria , Papa Anna , Sianos Georgios , Angelis Lefteris , Chatzidimitriou Dimitrios , Vizirianakis Ioannis S.
Published: February 2022

MicroRNAs (miRNAs) create systems networks and gene-expression circuits through molecular signaling and cell interactions that contribute to health imbalance and the emergence of cardiovascular disorders (CVDs). Because the clinical phenotypes of CVD patients present a diversity in their pathophysiology and heterogeneity at the molecular level, it is essential to establish genomic signatures to delineate multifactorial correlations, and to unveil the variability seen in therapeutic intervention outcomes. The clinically validated miRNA biomarkers, along with the relevant SNPs identified, have to be suitably implemented in the clinical setting in order to enhance patient stratification capacity, to contribute to a better understanding of the underlying pathophysiological mechanisms, to guide the selection of innovative therapeutic schemes, and to identify innovative drugs and delivery systems. In this article, the miRNA–gene networks and the genomic signatures resulting from the SNPs will be analyzed as a method of highlighting specific gene-signaling circuits as sources of molecular knowledge which is relevant to CVDs. In concordance with this concept, and as a case study, the design of the clinical trial GESS (NCT03150680) is referenced. The latter is presented in a manner to provide a direction for the improvement of the implementation of pharmacogenomics and precision cardiovascular medicine trials.
MG132 Induces Progerin Clearance and Improves Disease Phenotypes in HGPS-like Patients’ Cells
Authors: Harhouri Karim , Cau Pierre , Casey Frank , Guedenon Koffi Mawuse , Doubaj Yassamine , Van Maldergem Lionel , Mejia-Baltodano Gerardo , Bartoli Catherine , De Sandre-Giovannoli Annachiara , Lévy Nicolas
Published: February 2022

Progeroid syndromes (PS), including Hutchinson-Gilford Progeria Syndrome (HGPS), are premature and accelerated aging diseases, characterized by clinical features mimicking physiological aging. Most classical HGPS patients carry a de novo point mutation within exon 11 of the LMNA gene encoding A-type lamins. This mutation activates a cryptic splice site, leading to the production of a truncated prelamin A, called prelamin A ∆50 or progerin, that accumulates in HGPS cell nuclei and is a hallmark of the disease. Some patients with PS carry other LMNA mutations and are named “HGPS-like” patients. They produce progerin and/or other truncated prelamin A isoforms (∆35 and ∆90). We previously found that MG132, a proteasome inhibitor, induced progerin clearance in classical HGPS through autophagy activation and splicing regulation. Here, we show that MG132 induces aberrant prelamin A clearance and improves cellular phenotypes in HGPS-like patients’ cells other than those previously described in classical HGPS. These results provide preclinical proof of principle for the use of a promising class of molecules toward a potential therapy for children with HGPS-like or classical HGPS.
Tocotrienol in Pre-Eclampsia Prevention: A Mechanistic Analysis in Relation to the Pathophysiological Framework
Authors: Mahdy Zaleha Abdullah , Chin Kok-Yong , Nik-Ahmad-Zuky Nik Lah , Kalok Aida , Abdul Rahman Rahana
Published: February 2022

The pathophysiology of pre-eclampsia involves two major pathways, namely systemic oxidative stress and subsequent generalised inflammatory response, which eventually culminates in endothelial cell injury and the syndrome of pre-eclampsia with multi-organ dysfunction. Aspirin has been used to reduce the risk of pre-eclampsia, but it only possesses anti-inflammatory properties without any antioxidant effect. Hence, it can only partially alleviate the problem. Tocotrienols are a unique form of vitamin E with strong antioxidant and anti-inflammatory properties that can be exploited as a preventive agent for pre-eclampsia. Many preclinical models showed that tocotrienol can also prevent hypertension and ischaemic/reperfusion injury, which are the two main features in pre-eclampsia. This review explores the mechanism of action of tocotrienol in relation to the pathophysiology of pre-eclampsia. In conclusion, the study provides sufficient justification for the establishment of a large clinical trial to thoroughly assess the capability of tocotrienol in preventing pre-eclampsia.
Diagnosis, Prognosis and Treatment of Canine Cutaneous and Subcutaneous Mast Cell Tumors
Authors: de Nardi Andrigo Barboza , dos Santos Horta Rodrigo , Fonseca-Alves Carlos Eduardo , de Paiva Felipe Noleto , Linhares Laís Calazans Menescal , Firmo Bruna Fernanda , Ruiz Sueiro Felipe Augusto , de Oliveira Krishna Duro , Lourenço Silvia Vanessa , De Francisco Strefezzi Ricardo , Brunner Carlos Henrique Maciel , Rangel Marcelo Monte Mor , Jark Paulo Cesar , Castro Jorge Luiz Costa , Ubukata Rodrigo , Batschinski Karen , Sobral Renata Afonso , da Cruz Natália Oyafuso , Nishiya Adriana Tomoko , Fernandes Simone Crestoni , dos Santos Cunha Simone Carvalho , Gerardi Daniel Guimarães , Challoub Guilherme Sellera Godoy , Biondi Luiz Roberto , Laufer-Amorim Renee , de Oliveira Paes Paulo Ricardo , Lavalle Gleidice Eunice , Huppes Rafael Ricardo , Grandi Fabrizio , de Carvalho Vasconcellos Carmen Helena , dos Anjos Denner Santos , Luzo Ângela Cristina Malheiros , Matera Julia Maria , Vozdova Miluse , Dagli Maria Lucia Zaidan
Published: February 2022

Mast cell tumors (MCTs) are hematopoietic neoplasms composed of mast cells. It is highly common in dogs and is extremely important in the veterinary oncology field. It represents the third most common tumor subtype, and is the most common malignant skin tumor in dogs, corresponding to 11% of skin cancer cases. The objective of this critical review was to present the report of the 2nd Consensus meeting on the Diagnosis, Prognosis, and Treatment of Canine Cutaneous and Subcutaneous Mast Cell Tumors, which was organized by the Brazilian Association of Veterinary Oncology (ABROVET) in August 2021. The most recent information on cutaneous and subcutaneous mast cell tumors in dogs is presented and discussed.
Potential Therapeutic Effects of PPAR Ligands in Glioblastoma
Authors: Basilotta Rossella , Lanza Marika , Casili Giovanna , Chisari Giulia , Munao Stefania , Colarossi Lorenzo , Cucinotta Laura , Campolo Michela , Esposito Emanuela , Paterniti Irene
Published: February 2022

Glioblastoma (GB), also known as grade IV astrocytoma, represents the most aggressive form of brain tumor, characterized by extraordinary heterogeneity and high invasiveness and mortality. Thus, a great deal of interest is currently being directed to investigate a new therapeutic strategy and in recent years, the research has focused its attention on the evaluation of the anticancer effects of some drugs already in use for other diseases. This is the case of peroxisome proliferator-activated receptors (PPARs) ligands, which over the years have been revealed to possess anticancer properties. PPARs belong to the nuclear receptor superfamily and are divided into three main subtypes: PPAR-α, PPAR-β/δ, and PPAR-γ. These receptors, once activated by specific natural or synthetic ligands, translocate to the nucleus and dimerize with the retinoid X receptors (RXR), starting the signal transduction of numerous genes involved in many physiological processes. PPARs receptors are activated by specific ligands and participate principally in the preservation of homeostasis and in lipid and glucose metabolism. In fact, synthetic PPAR-α agonists, such as fibrates, are drugs currently in use for the clinical treatment of hypertriglyceridemia, while PPAR-γ agonists, including thiazolidinediones (TZDs), are known as insulin-sensitizing drugs. In this review, we will analyze the role of PPARs receptors in the progression of tumorigenesis and the action of PPARs agonists in promoting, or not, the induction of cell death in GB cells, highlighting the conflicting opinions present in the literature.
Feasibility of Real-Time Central Surgical Review for Patients with Advanced-Stage Hepatoblastoma in the JPLT3 Trial
Authors: Hishiki Tomoro , Honda Shohei , Takama Yuichi , Inomata Yukihiro , Okajima Hideaki , Hoshino Ken , Suzuki Tatsuya , Souzaki Ryota , Wada Motoshi , Kasahara Mureo , Mizuta Koichi , Oue Takaharu , Yokoi Akiko , Kazama Takuro , Komatsu Shugo , Saeki Isamu , Miyazaki Osamu , Takimoto Tetsuya , Ida Kohmei , Watanabe Kenichiro , Hiyama Eiso
Published: February 2022

In the JPLT3 study, a real-time central surgical reviewing (CSR) system was employed aimed at facilitating early referral of candidates for liver transplantation (LTx) to centers with pediatric LTx services. The expected consequence was surgery, including LTx, conducted at the appropriate time in all cases. This study aimed to review the effect of CSR on institutional surgical decisions in cases enrolled in the JPLT3 study. Real-time CSR was performed in cases in which complex surgeries were expected, using images obtained after two courses of preoperative chemotherapy. Using the cloud-based remote image viewing system, an expert panel consisting of pediatric and transplant surgeons reviewed the images and commented on the expected surgical strategy or the necessity of transferring the patient to a transplant unit. The results were summarized and reported to the treating institutions. A total of 41 reviews were conducted for 35 patients, and 16 cases were evaluated as possible candidates for LTx, with the treating institutions being advised to consult a transplant center. Most of the reviewed cases promptly underwent definitive liver surgeries, including LTx per protocol.
Applying Bibliometric Techniques: Studying Interdisciplinarity in Higher Education Curriculum
Authors: Herzog Patricia Snell , Ai Jin , Ashton Julia
Published: February 2022

Bibliometric methods are relevant for a range of applications and disciplines. The majority of existing scholarship investigating citation and reference patterns focuses on studying research impact. This article presents a new approach to studying the curriculum using bibliometric methods. Through a review of existing definitions and measures of interdisciplinary research and standardization procedures for comparing disciplinary citations, three measures were considered: variety, balance and dissimilarity. Bibliometric algorithms for assessing these measures were adopted and modified for a curriculum context, and three interdisciplinary programs were investigated that span undergraduate and graduate degrees. Data objects were course syllabi, and required references were coded for disciplinary affiliations. The results indicated that—despite purportedly pursuing a singular goal in the same academic unit—the programs employed distinct citation patterns. Variety was highest in the master’s program, and balance was highest in the doctoral program. Dissimilarity was highest in the doctoral program, yet a novel technique for disambiguating disciplinary composition was implemented to improve interpretation. The analysis yielded unexpected findings, which underscore the value of a systematic approach in advancing beyond discourse by harnessing bibliometric techniques to reveal underlying curricula structure. This study contributed a well-grounded bibliometric method that can be replicated in future studies.
Single-Island Endemism despite Repeated Dispersal in Caribbean Micrathena (Araneae: Araneidae): An Updated Phylogeographic Analysis
Authors: Shapiro Lily , Binford Greta J. , Agnarsson Ingi
Published: February 2022

Island biogeographers have long sought to elucidate the mechanisms behind biodiversity genesis. The Caribbean presents a unique stage on which to analyze the diversification process, due to the geologic diversity among the islands and the rich biotic diversity with high levels of island endemism. The colonization of such islands may reflect geologic heterogeneity through vicariant processes and/ or involve long-distance overwater dispersal. Here, we explore the phylogeography of the Caribbean and proximal mainland spiny orbweavers (Micrathena, Araneae), an American spider lineage that is the most diverse in the tropics and is found throughout the Caribbean. We specifically test whether the vicariant colonization via the contested GAARlandia landbridge (putatively emergent 33–35 mya), long-distance dispersal (LDD), or both processes best explain the modern Micrathena distribution. We reconstruct the phylogeny and test biogeographic hypotheses using a ‘target gene approach’ with three molecular markers (CO1, ITS-2, and 16S rRNA). Phylogenetic analyses support the monophyly of the genus but reject the monophyly of Caribbean Micrathena. Biogeographical analyses support five independent colonizations of the region via multiple overwater dispersal events, primarily from North/Central America, although the genus is South American in origin. There is no evidence for dispersal to the Greater Antilles during the timespan of GAARlandia. Our phylogeny implies greater species richness in the Caribbean than previously known, with two putative species of M. forcipata that are each single-island endemics, as well as deep divergences between the Mexican and Floridian M. sagittata. Micrathena is an unusual lineage among arachnids, having colonized the Caribbean multiple times via overwater dispersal after the submergence of GAARlandia. On the other hand, single-island endemism and undiscovered diversity are nearly universal among all but the most dispersal-prone arachnid groups in the Caribbean.
Low-Grade Serous Carcinoma of the Ovary: The Current Status
Authors: Babaier Abdulaziz , Mal Hanan , Alselwi Waleed , Ghatage Prafull
Published: February 2022

Low-grade serous carcinoma (LGSC) of the ovary is a rare histological subtype of epithelial ovarian carcinoma. It has distinct clinical behavior and a specific molecular profile. Compared with high-grade serous carcinoma, this tumor presents at a younger age, has an indolent course, and is associated with prolonged survival. LGSC can arise de novo or originate following a serous borderline tumor (SBT). Pathological differentiation between LGSC and other ovarian carcinoma histological subtypes is fundamental. Several factors might influence the overall outcome, such as the age at diagnosis, current smoking, elevated body mass index, mutational status, hormonal receptors’ expression, and Ki-67 proliferation index. Surgery is the main treatment option in LGSC, and efforts must be maximized to achieve a microscopic residual in metastatic disease. Despite being relatively chemo-resistant, adjuvant platinum-based chemotherapy remains the standard of care in LGSC. Hormonal maintenance therapy after adjuvant chemotherapy results in improved outcomes. Treatment options for disease recurrence include secondary cytoreductive surgery, chemotherapy, hormonal therapy, targeted therapy, and clinical trials. Advancements in genomic studies and targeted therapies are expected to change the treatment landscape in LGSC.
A Multi-Technique Approach to Exploring the Main Influences of Information Exchange Monitoring Tolerance
Authors: Homocianu Daniel
Published: February 2022

The privacy and security of online transactions and information exchange has always been a critical issue of e-commerce. However, there is a certain level of tolerance (a share of 36%) when it comes to so-called governments’ rights to monitor electronic mail messages and other information exchange as resulting from the answers of respondents from 51 countries in the latest wave (2017–2020) of the World Values Survey. Consequently, the purpose of this study is to discover the most significant influences associated with this type of tolerance and even causal relationships. The variables have been selected and analyzed in many rounds (Adaptive Boosting, LASSO, mixed-effects modeling, and different regressions) with the aid of a private cloud. The results confirmed most hypotheses regarding the overwhelming role of trust, public surveillance acceptance, and some attitudes indicating conscientiousness, altruistic behavior, and gender discrimination acceptance in models with good-to-excellent classification accuracy. A generated prediction nomogram included 10 ten most resilient influences. Another one contained only 5 of these 10 that acted more as determinants resisting reverse causality checks. In addition, some sociodemographic controls indicated significant variables afferent to the highest education level attained, settlement size, and marital status. The paper’s novelty stands on many robust techniques supporting randomly and nonrandomly cross-validated and fully reproducible results based on a large amount and variety of evidence. The findings also represent a step forward in research related to privacy and security issues in e-commerce.
Smish: A Novel Activation Function for Deep Learning Methods
Authors: Wang Xueliang , Ren Honge , Wang Achuan
Published: February 2022

Activation functions are crucial in deep learning networks, given that the nonlinear ability of activation functions endows deep neural networks with real artificial intelligence. Nonlinear nonmonotonic activation functions, such as rectified linear units, Tan hyperbolic (tanh), Sigmoid, Swish, Mish, and Logish, perform well in deep learning models; however, only a few of them are widely used in mostly all applications due to their existing inconsistencies. Inspired by the MB-C-BSIF method, this study proposes Smish, a novel nonlinear activation function, expressed as f(x)=x·tanh[ln(1+sigmoid(x))], which could overcome other activation functions with good properties. Logarithmic operations are first used to reduce the range of sigmoid(x). The value is then calculated using the tanh operator. Inputs are ultimately used to multiply the previous value, thus exhibiting negative output regularization. Experiments show that Smish tends to operate more efficiently than Logish, Mish, and other activation functions on EfficientNet models with open datasets. Moreover, we evaluated the performance of Smish in various deep learning models and the parameters of its function f(x)=αx·tanh[ln(1+sigmoid(βx))], and where α = 1 and β = 1, Smish was found to exhibit the highest accuracy. The experimental results show that with Smish, the EfficientNetB3 network exhibits a Top-1 accuracy of 84.1% on the CIFAR-10 dataset; the EfficientNetB5 network has a Top-1 accuracy of 99.89% on the MNIST dataset; and the EfficientnetB7 network has a Top-1 accuracy of 91.14% on the SVHN dataset. These values are superior to those obtained using other state-of-the-art activation functions, which shows that Smish is more suitable for complex deep learning models.
Genomics-Enabled Management of Genetic Resources in Radiata Pine
Authors: Klápště Jaroslav , Ismael Ahmed , Paget Mark , Graham Natalie J. , Stovold Grahame T. , Dungey Heidi S. , Slavov Gancho T.
Published: February 2022

Traditional tree improvement is cumbersome and costly. Our main objective was to assess the extent to which genomic data can currently accelerate and improve decision making in this field. We used diameter at breast height (DBH) and wood density (WD) data for 4430 tree genotypes and single-nucleotide polymorphism (SNP) data for 2446 tree genotypes. Pedigree reconstruction was performed using a combination of maximum likelihood parentage assignment and matching based on identity-by-state (IBS) similarity. In addition, we used best linear unbiased prediction (BLUP) methods to predict phenotypes using SNP markers (GBLUP), recorded pedigree information (ABLUP), and single-step “blended” BLUP (HBLUP) combining SNP and pedigree information. We substantially improved the accuracy of pedigree records, resolving the inconsistent parental information of 506 tree genotypes. This led to substantially increased predictive ability (i.e., by up to 87%) in HBLUP analyses compared to a baseline from ABLUP. Genomic prediction was possible across populations and within previously untested families with moderately large training populations (N = 800–1200 tree genotypes) and using as few as 2000–5000 SNP markers. HBLUP was generally more effective than traditional ABLUP approaches, particularly after dealing appropriately with pedigree uncertainties. Our study provides evidence that genome-wide marker data can significantly enhance tree improvement. The operational implementation of genomic selection has started in radiata pine breeding in New Zealand, but further reductions in DNA extraction and genotyping costs may be required to realise the full potential of this approach.