bluuebunny/crossref_metadata_2025 huggingface dataset:
The Incidence and Intensity of Postendodontic Pain and Flareup in Single and Multiple Visit Root Canal Treatments: A Systematic Review and Meta-Analysis
Authors: Vishwanathaiah Satish , Maganur Prabhadevi C , Khanagar Sanjeev B , Chohan Hitesh , Testarelli Luca , Mazzoni Alessandro , Gupta Archana A , Raj A. Thirumal , Bhandi Shilpa , Mehta Deepak , Patil Shankargouda
Published: April 2021

To assess the incidence and intensity of postendodontic pain and flareup in single and multiple visit root canal treatment (RCT) and determine if the difference between the two is significant, a search of PubMed, Medline, Embase, Cochrane, Scopus and Web of science was conducted. The grey literature was searched using Google Scholar and Saudi digital library. Randomised controlled trials evaluating the incidence and intensity of postendodontic pain and flareup published in English from 1 January 2000 to 15 April 2020 were searched. The PRISMA protocol was followed to select the articles. A random effects model was used for the meta-analysis of the data in the included studies. Twenty-one articles were included in the review. Three compared both the incidence and the intensity, while the rest compared either one of the parameters. Most studies used both hand-driven and rotary instruments and irrigated with sodium hypochlorite. Twelve studies used an intracanal medicament. Although individual studies showed discordant treatment outcomes, the meta-analysis did not reveal any significant difference in the incidence or the intensity of the postendodontic flareup between the single and multiple visit RCT groups. Single or a multiple visit root canal treatment is not an independent determinant for the risk of postendodontic pain or a flareup.
Correlation between Myocardial Function and Electric Current Pulsatility of the Sputnik Left Ventricular Assist Device: In-Vitro Study
Authors: Telyshev Dmitry V. , Pugovkin Alexander A. , Ephimov Ivan A. , Markov Aleksandr , Leonhardt Steffen , Walter Marian , Karimov Jamshid H. , Selishchev Sergey V.
Published: April 2021

This study assesses the electric current parameters and reports on the analysis of the associated degree of myocardial function during left ventricular assist device (LVAD) support. An assumption is made that there is a correlation between cardiac output and the pulsatility index of the pump electric current. The experimental study is carried out using the ViVitro Pulse Duplicator System with Sputnik LVAD connected. Cardiac output and cardiac power output are used as a measure of myocardial function. Different heart rates (59, 73, 86 bpm) and pump speeds (7600–8400 rpm in 200 rpm steps) are investigated. In our methodology, ventricular stroke volumes in the range of 30–80 mL for each heart rate at a certain pump speed were used to simulate different levels of contractility. The correlation of the two measures of myocardial function and proposed pulsatility index was confirmed using different correlation coefficients (values ≥ 0.91). Linear and quadratic models for cardiac output and cardiac power output versus pulsatility index were obtained using regression analysis of measured data. Coefficients of determination for CO and CPO models were in the ranges of 0.914–0.982 and 0.817–0.993, respectively. Study findings suggest that appropriate interpretation of parameters could potentially serve as a valuable clinical tool to assess myocardial therapy using LVAD infrastructure.
Mobile Robot Self-Localization Using Omnidirectional Vision with Feature Matching from Real and Virtual Spaces
Authors: Lin Huei-Yung , He Chien-Hsing
Published: April 2021

This paper presents a novel self-localization technique for mobile robots based on image feature matching from omnidirectional vision. The proposed method first constructs a virtual space with synthetic omnidirectional imaging to simulate a mobile robot equipped with an omnidirectional vision system in the real world. In the virtual space, a number of vertical and horizontal lines are generated according to the structure of the environment. They are imaged by the virtual omnidirectional camera using the catadioptric projection model. The omnidirectional images derived from the virtual and real environments are then used to match the synthetic lines and real scene edges. Finally, the pose and trajectory of the mobile robot in the real world are estimated by the efficient perspective-n-point (EPnP) algorithm based on the line feature matching. In our experiments, the effectiveness of the proposed self-localization technique was validated by the navigation of a mobile robot in a real world environment.
Design and Demonstration of a Flying-Squirrel-Inspired Jumping Robot with Two Modes
Authors: Zhao Fei , Wang Wei , Wyrwa Justyna , Zhang Jingtao , Du Wenxin , Zhong Pengyu
Published: April 2021

The jumping–gliding robot is a kind of locomotion platform with the capabilities to jump on the ground and glide through the air. The jumping of this robot has to juggle the requirements of initial velocity and posture for entry to gliding and progressing on the ground. Inspired by flying squirrels, we proposed the concept of flexible wing-limb blending platform and designed a robot with two jumping modes. The robot can takeoff with different speeds and stances, and adjust aerial posture using the swing of forelimbs. To the best of our knowledge, this is the first miniature and bio-inspired jumping robot that can autonomically change the speeds and stances when takeoff. Experimental results show that the robot can takeoff at about 3 m/s and pitch angle of 0° in the mode of jumping for gliding and adjust the pitch angle at the top to 0°~10° by actuating the forelimbs swing according to the requirement of gliding. In the mode of jumping for progress, the robot can takeoff at about 2 m/s with a pitch angle of 20° and then intermittently jump with a distance of 0.37 m of once jump and an average progress speed of 0.2 m/s. The robot presented in this paper lays the foundation for the development of flexible wing-limb blending platform, which is capable of jumping and gliding.
Quantum Biotech and Internet of Virus Things: Towards a Theoretical Framework
Authors: Padhi Prafulla Kumar , Charrua-Santos Feranando
Published: April 2021

Quantumization, the process of converting information into quantum (qubit) format, is a key enabler for propelling a new and distinct infrastructure in the pharmaceutical space. Quantum messenger RNA (QmRNA) technology, an indispensable constituent of quantum biotech (QB), is a compelling alternative to conventional vaccine methods because of its capacity for rapid development, high efficacy, and low-cost manufacturing to combat infectious diseases. Internet of Virus Things (IoVT), a biological version of Internet of Things (IoT), comprises applications to fight against pandemics and provides effective vaccine administration. The integration of QB and IoVT constitutes the QBIoVT system to advance the prospect of QmRNA vaccine discovery within a few days. This research disseminates the QBIoVT system paradigm, including architectural aspects, priority areas, challenges, applications, and QmRNA research engine design to accelerate QmRNA vaccines discovery. A comprehensive review of the literature was accomplished, and a context-centered methodology was applied to the QBIoVT paradigm forensic investigations to impel QmRNA vaccine discovery. Based on the above rumination, the principal motive for this study was to develop a novel QBIoVT theoretical framework which has not been produced through earlier theories. The proposed framework shall inspire future QBIoVT system research activities to improve pandemics detection and protection.
The Environmental Effects of the April 2020 Wildfires and the Cs-137 Re-Suspension in the Chernobyl Exclusion Zone: A Multi-Hazard Threat
Authors: Baró Rocío , Maurer Christian , Brioude Jerome , Arnold Delia , Hirtl Marcus
Published: April 2021

This paper demonstrates the environmental impacts of the wildfires occurring at the beginning of April 2020 in and around the highly contaminated Chernobyl Exclusion Zone (CEZ). Due to the critical fire location, concerns arose about secondary radioactive contamination potentially spreading over Europe. The impact of the fire was assessed through the evaluation of fire plume dispersion and re-suspension of the radionuclide Cs-137, whereas, to assess the smoke plume effect, a WRF-Chem simulation was performed and compared to Tropospheric Monitoring Instrument (TROPOMI) satellite columns. The results show agreement of the simulated black carbon and carbon monoxide plumes with the plumes as observed by TROPOMI, where pollutants were also transported to Belarus. From an air quality and health perspective, the wildfires caused extremely bad air quality over Kiev, where the WRF-Chem model simulated mean values of PM2.5 up to 300 µg/m3 (during the first fire outbreak) over CEZ. The re-suspension of Cs-137 was assessed by a Bayesian inverse modelling approach using FLEXPART as the atmospheric transport model and Ukraine observations, yielding a total release of 600 ± 200 GBq. The increase in both smoke and Cs-137 emissions was only well correlated on the 9 April, likely related to a shift of the focus area of the fires. From a radiological point of view even the highest Cs-137 values (average measured or modelled air concentrations and modelled deposition) at the measurement site closest to the Chernobyl Nuclear Power Plant, i.e., Kiev, posed no health risk.
Comparative Numerical Study of PM2.5 in Exit-and-Entrance Areas Associated with Transboundary Transport over China, Japan, and Korea
Authors: Kim Cheol-Hee , Meng Fan , Kajino Mizuo , Lim Jaehyun , Tang Wei , Lee Jong-Jae , Kiriyama Yusuke , Woo Jung-Hun , Sato Keiichi , Kitada Toshihiro , Minoura Hiroaki , Kim Jiyoung , Lee Kyoung-Bin , Roh Soona , Jo Hyun-Young , Jo Yu-Jin
Published: April 2021

We report the results of year-long PM2.5 (particulate matter less than 2.5 µm in diameter) simulations over Northeast Asia for the base year of 2013 under the framework of the Long-range Transboundary Air Pollutants in Northeast Asia (LTP) project. LTP is a tripartite project launched by China, Japan, and Korea for cooperative monitoring and modeling of the long-range transport (LRT) of air pollutants. In the modeling aspect in the LTP project, each country’s modeling group employs its own original air quality model and options. The three regional air quality models employed by the modeling groups are WRF-CAMx, NHM-RAQM2, and WRF-CMAQ. PM2.5 concentrations were simulated in remote exit-and-entrance areas associated with the LRT process over China, Japan, and Korea. The results showed apparent bias that remains unexplored due to a series of uncertainties from emission estimates and inherent model limitations. The simulated PM10 levels at seven remote exit-and-entrance sites were underestimated with the normalized mean bias of 0.4 ± 0.2. Among the four chemical components of PM2.5 (SO42−, NO3−, organic carbon (OC), and elemental carbon (EC)), the largest inter-model variability was in OC, with the second largest discrepancy in NO3−. Our simulation results also indicated that under considerable SO42− levels, favorable environments for ammonium nitrate formation were found in exit-and-entrance areas between China and Korea, and gas-aerosol partitioning for semi-volatile species of ammonium nitrate could be fully achieved prior to arrival at the entrance areas. Other chemical characteristics, including NO3−/SO42− and OC/EC ratios, are discussed to diagnose the LRT characteristics of PM2.5 in exit-and-entrance areas associated with transboundary transport over China, Japan, and Korea.
Flight Data-Based Wind Disturbance and Air Data Estimation
Authors: Gao Zhenxing , Wang Haofeng , Xiang Zhiwei , Wang Debao
Published: April 2021

The instantaneous wind field and air data, including true airspeed, angle of attack, angle of sideslip, cannot be measured and recorded accurately in wind disturbance. A new air data and wind field estimation method is proposed based on flight data in this study. Since the wind field is the horizontal prevailing wind added by turbulence, the slowly time-varying prevailing wind and small-scale turbulence are described by the exponentially correlated stochastic wind model and von Karman turbulence model, respectively. The system update equation of air data is built based on inertial measurements instead of the complex aerodynamic and aero-engine model of aircraft. Benefitted by the post-analysis characteristics of flight data, a forward–backward filtering algorithm was designed to improve the estimation accuracy. Simulation results indicate that the forward–backward filter integrated with the von Karman turbulence model can reduce the estimation error and ensure filtering stability. A further test with actual flight data shows that the forward–backward filter is not only able to track the wide-range change in prevailing wind but also reduce the adverse effects of uncertain disturbance on estimation accuracy.
Some Fixed Point Results in b-Metric Spaces and b-Metric-Like Spaces with New Contractive Mappings
Authors: Jain Kapil , Kaur Jatinderdeep
Published: April 2021

The aim of our paper is to present a new class of functions and to define some new contractive mappings in b-metric spaces. We establish some fixed point results for these new contractive mappings in b-metric spaces. Furthermore, we extend our main result in the framework of b-metric-like spaces. Some consequences of main results are also deduced. We present some examples to illustrate and support our results. We provide an application to solve simultaneous linear equations. In addition, we present some open problems.
Non-Standard Discrete RothC Models for Soil Carbon Dynamics
Authors: Diele Fasma , Marangi Carmela , Martiradonna Angela
Published: April 2021

Soil Organic Carbon (SOC) is one of the key indicators of land degradation. SOC positively affects soil functions with regard to habitats, biological diversity and soil fertility; therefore, a reduction in the SOC stock of soil results in degradation, and it may also have potential negative effects on soil-derived ecosystem services. Dynamical models, such as the Rothamsted Carbon (RothC) model, may predict the long-term behaviour of soil carbon content and may suggest optimal land use patterns suitable for the achievement of land degradation neutrality as measured in terms of the SOC indicator. In this paper, we compared continuous and discrete versions of the RothC model, especially to achieve long-term solutions. The original discrete formulation of the RothC model was then compared with a novel non-standard integrator that represents an alternative to the exponential Rosenbrock–Euler approach in the literature.
Insight into Liver lncRNA and mRNA Profiling at Four Developmental Stages in Ningxiang Pig
Authors: Gong Yan , Zhang Yuebo , Li Biao , Xiao Yu , Zeng Qinghua , Xu Kang , Duan Yehui , He Jianhua , Ma Haiming
Published: April 2021

Ningxiang pigs, a fat-type pig, are native to Ningxiang County in Hunan Province, with thousands of years of breeding history. This study aims to explore the expression profiles and functional networks on messenger RNAs (mRNAs) and long non-coding RNAs (lncRNAs) in the liver. Liver tissue of Ningxiang piglets was collected at 30, 90, 150, and 210 days after birth (four development stages), and the mRNA and lncRNA expression was profiled. Compared to mRNA and lncRNA expression profiles, most differentially expressed mRNAs (DEmRNAs) were upregulated at 30 days; however, most DElncRNAs were downregulated at 210 days. Via Short Time-series Expression Miner (STEM) analysis and weighted gene co-expression network analysis (WGCNA), a complex interaction between mRNAs and lncRNAs was identified, indicating that lncRNAs may be a critical regulatory element for mRNAs. One module of genes in particular (module profile 4) was related to fibril organization, vasculogenesis, GTPase activator activity, and regulation of kinase activity. The mRNAs and lncRNAs in module profile 4 had a similar pattern of expression, indicating that they have functional and regulatory relationships. Only CAV1, PACSIN2, and CDC42 in the particular mRNA profile 4 were the target genes of lncRNAs in that profile, which shows the possible regulatory relationship between lncRNAs and mRNAs. The expression of these genes and lncRNAs in profile 4 was the highest at 30 days, and it is believed that these RNAs may play a critical role during the suckling period in order to meet the dietary requirements of piglets. In the lncRNA–mRNA co-expression network, the identified gene hubs and associated lncRNAs were shown to be involved in saccharide, lipid, and glucose metabolism, which may play an important role in the development and health of the liver. This result will lead to further investigation of liver lncRNA functions at various stages of development in Ningxiang pigs.
A Retrospective Analysis of the COVID-19 Pandemic Evolution in Italy
Authors: Fochesato Anna , Simoni Giulia , Reali Federico , Giordano Giulia , Domenici Enrico , Marchetti Luca
Published: April 2021

Late 2019 saw the outbreak of COVID-19, a respiratory disease caused by the new coronavirus SARS-CoV-2, which rapidly turned into a pandemic, killing more than 2.77 million people and infecting more than 126 million as of late March 2021. Daily collected data on infection cases and hospitalizations informed decision makers on the ongoing pandemic emergency, enabling the design of diversified countermeasures, from behavioral policies to full lockdowns, to curb the virus spread. In this context, mechanistic models could represent valuable tools to optimize the timing and stringency of interventions, and to reveal non-trivial properties of the pandemic dynamics that could improve the design of suitable guidelines for future epidemics. We performed a retrospective analysis of the Italian epidemic evolution up to mid-December 2020 to gain insight into the main characteristics of the original strain of SARS-CoV-2, prior to the emergence of new mutations and the vaccination campaign. We defined a time-varying optimization procedure to calibrate a refined version of the SIDARTHE (Susceptible, Infected, Diagnosed, Ailing, Recognized, Threatened, Healed, Extinct) model and hence accurately reconstruct the epidemic trajectory. We then derived additional features of the COVID-19 pandemic in Italy not directly retrievable from reported data, such as the estimate of the day zero of infection in late November 2019 and the estimate of the spread of undetected infection. The present analysis contributes to a better understanding of the past pandemic waves, confirming the importance of epidemiological modeling to support an informed policy design against epidemics to come.
Differential Expression of the Tetraspanin CD9 in Normal and Leukemic Stem Cells
Authors: Lahlil Rachid , Scrofani Maurice , Aries Anne , Hénon Philippe , Drénou Bernard
Published: April 2021

CD9 plays a crucial role in cellular growth, mobility, and signal transduction, as well as in hematological malignancy. In myeloid neoplasms, CD9 is involved in the altered interactions between leukemic and stromal cells. However, apart from its role in CD34+ progenitors and myeloid and megakaryocytic differentiation, its function in normal and leukemic pluripotent cells has not yet been determined. Very small embryonic-like stem cells (VSELs) are promising pluripotent stem cells found in adult tissues that can be developed for safe and efficient regenerative medicine. VSELs express different surface receptors of the highest importance in cell functioning, including CD9, and can be effectively mobilized after organ injury or in leukemic patients. In the present study, we observed that CD9 is among the most expressed receptors in VSELs under steady-state conditions; however, once the VSELs are expanded, CD9+ VSELs decrease and are more apoptotic. CD9– VSELs had no proliferative improvement in vitro compared to those that were CD9+. Interestingly, the addition of SDF-1 induced CD9 expression on the surface of VSELs, as observed by flow cytometry, and improved their migration. In addition, we observed, in the phenotypically identical VSELs present in the peripheral blood of patients with myeloproliferative neoplasms, compared to healthy subjects, a significantly higher number of CD9+ cells. However, in their hematopoietic stem cell (HSC) counterparts, the expression remained comparable. These results indicate that, likewise, in progenitors and mature cells, CD9 may play an important function in normal and malignant VSELs. This could explain the refractoriness observed by some groups of expanded stem cells to repairing efficiently damaged tissue when used as a source in cell therapies. Understanding the function of the CD9 receptor in normal and malignant CD34+ and VSELs, along with its relationship with the CXCR4/SDF-1 pathway, will enable advances in the field of adult pluripotent cell usage in regenerative medicine and in their role in leukemia.
Naphthalimide-Containing BP100 Leads to Higher Model Membranes Interactions and Antimicrobial Activity
Authors: Carretero Gustavo Penteado Battesini , Saraiva Greice Kelle Viegas , Rodrigues Magali Aparecida , Kiyota Sumika , Bemquerer Marcelo Porto , Chaimovich Hernan , Cuccovia Iolanda Midea
Published: April 2021

In a large variety of organisms, antimicrobial peptides (AMPs) are primary defenses against pathogens. BP100 (KKLFKKILKYL-NH2), a short, synthetic, cationic AMP, is active against bacteria and displays low toxicity towards eukaryotic cells. BP100 acquires a α-helical conformation upon interaction with membranes and increases membrane permeability. Despite the volume of information available, the action mechanism of BP100, the selectivity of its biological effects, and possible applications are far from consensual. Our group synthesized a fluorescent BP100 analogue containing naphthalimide linked to its N-terminal end, NAPHT-BP100 (Naphthalimide-AAKKLFKKILKYL-NH2). The fluorescence properties of naphthalimides, especially their spectral sensitivity to microenvironment changes, are well established, and their biological activities against transformed cells and bacteria are known. Naphthalimide derived compounds are known to interact with DNA disturbing related processes as replication and transcription, and used as anticancer agents due to this property. A wide variety of techniques were used to demonstrate that NAPHT-BP100 bound to and permeabilized zwitterionic POPC and negatively charged POPC:POPG liposomes and, upon interaction, acquired a α-helical structure. Membrane surface high peptide/lipid ratios triggered complete permeabilization of the liposomes in a detergent-like manner. Membrane disruption was driven by charge neutralization, lipid aggregation, and bilayer destabilization. NAPHT-BP100 also interacted with double-stranded DNA, indicating that this peptide could also affect other cellular processes besides causing membrane destabilization. NAPHT-BP100 showed increased antibacterial and hemolytic activities, compared to BP100, and may constitute an efficient antimicrobial agent for dermatological use. By conjugating BP100 and naphthalimide DNA binding properties, NAPHT-BP100 bound to a large extent to the bacterial membrane and could more efficiently destabilize it. We also speculate that peptide could enter the bacteria cell and interact with its DNA in the cytoplasm.
Neuroprotective Herbs for the Management of Alzheimer’s Disease
Authors: Gregory Julie , Vengalasetti Yasaswi V. , Bredesen Dale E. , Rao Rammohan V.
Published: April 2021

Background—Alzheimer’s disease (AD) is a multifactorial, progressive, neurodegenerative disease that is characterized by memory loss, personality changes, and a decline in cognitive function. While the exact cause of AD is still unclear, recent studies point to lifestyle, diet, environmental, and genetic factors as contributors to disease progression. The pharmaceutical approaches developed to date do not alter disease progression. More than two hundred promising drug candidates have failed clinical trials in the past decade, suggesting that the disease and its causes may be highly complex. Medicinal plants and herbal remedies are now gaining more interest as complementary and alternative interventions and are a valuable source for developing drug candidates for AD. Indeed, several scientific studies have described the use of various medicinal plants and their principal phytochemicals for the treatment of AD. This article reviews a subset of herbs for their anti-inflammatory, antioxidant, and cognitive-enhancing effects. Methods—This article systematically reviews recent studies that have investigated the role of neuroprotective herbs and their bioactive compounds for dementia associated with Alzheimer’s disease and pre-Alzheimer’s disease. PubMed Central, Scopus, and Google Scholar databases of articles were collected, and abstracts were reviewed for relevance to the subject matter. Conclusions—Medicinal plants have great potential as part of an overall program in the prevention and treatment of cognitive decline associated with AD. It is hoped that these medicinal plants can be used in drug discovery programs for identifying safe and efficacious small molecules for AD.
EPLIN Expression in Gastric Cancer and Impact on Prognosis and Chemoresistance
Authors: Gong Wenjing , Zeng Jianyuan , Ji Jiafu , Jia Yongning , Jia Shuqin , Sanders Andrew J. , Jiang Wen G.
Published: April 2021

Epithelial protein lost in neoplasm (EPLIN) has been implicated as a suppressor of cancer progression. The current study explored EPLIN expression in clinical gastric cancer and its association with chemotherapy resistance. EPLIN transcript expression, in conjunction with patient clinicopathological information and responsiveness to neoadjuvant chemotherapy (NAC), was explored in two gastric cancer cohorts collected from the Beijing Cancer Hospital. Kaplan-Meier survival analysis was undertaken to explore EPLIN association with patient survival. Reduced EPLIN expression was associated with significant or near significant reductions of overall, disease-free, first progression or post-progression survival in the larger host cohort and Kaplan Meier plotter datasets. In the larger cohort EPLIN expression was significantly higher in the combined T1 + T2 gastric cancer group compared to the T3 + T4 group and identified to be an independent prognostic factor of disease-free survival and overall survival by multivariate analysis. In the smaller, NAC cohort, EPLIN expression was found to be significantly lower in tumour tissues than in paratumour tissues. EPLIN expression was significantly associated with responsiveness to chemotherapy which contributes to overall survival. Together, EPLIN appears to be a prognostic factor and may be associated with patient sensitivity to NAC.
Conformational Plasticity-Rigidity Axis of the Coagulation Factor VII Zymogen Elucidated by Atomistic Simulations of the N-Terminally Truncated Factor VIIa Protease Domain
Authors: Madsen Jesper J. , Olsen Ole H.
Published: April 2021

The vast majority of coagulation factor VII (FVII), a trypsin-like protease, circulates as the inactive zymogen. Activated FVII (FVIIa) is formed upon proteolytic activation of FVII, where it remains in a zymogen-like state and it is fully activated only when bound to tissue factor (TF). The catalytic domains of trypsin-like proteases adopt strikingly similar structures in their fully active forms. However, the dynamics and structures of the available corresponding zymogens reveal remarkable conformational plasticity of the protease domain prior to activation in many cases. Exactly how ligands and cofactors modulate the conformational dynamics and function of these proteases is not entirely understood. Here, we employ atomistic simulations of FVIIa (and variants hereof, including a TF-independent variant and N-terminally truncated variants) to provide fundamental insights with atomistic resolution into the plasticity-rigidity interplay of the protease domain conformations that appears to govern the functional response to proteolytic and allosteric activation. We argue that these findings are relevant to the FVII zymogen, whose structure has remained elusive despite substantial efforts. Our results shed light on the nature of FVII and demonstrate how conformational dynamics has played a crucial role in the evolutionary adaptation of regulatory mechanisms that were not present in the ancestral trypsin. Exploiting this knowledge could lead to engineering of protease variants for use as next-generation hemostatic therapeutics.
Emerging Role of C5 Complement Pathway in Peripheral Neuropathies: Current Treatments and Future Perspectives
Authors: Giorgio Cristina , Zippoli Mara , Cocchiaro Pasquale , Castelli Vanessa , Varrassi Giustino , Aramini Andrea , Allegretti Marcello , Brandolini Laura , Cesta Maria Candida
Published: April 2021

The complement system is a key component of innate immunity since it plays a critical role in inflammation and defense against common pathogens. However, an inappropriate activation of the complement system is involved in numerous disorders, including peripheral neuropathies. Current strategies for neuropathy-related pain fail to achieve adequate pain relief, and although several therapies are used to alleviate symptoms, approved disease-modifying treatments are unavailable. This urgent medical need is driving the development of therapeutic agents for this condition, and special emphasis is given to complement-targeting approaches. Recent evidence has underscored the importance of complement component C5a and its receptor C5aR1 in inflammatory and neuropathic pain, indicating that C5a/C5aR1 axis activation triggers a cascade of events involved in pathophysiology of peripheral neuropathy and painful neuro-inflammatory states. However, the underlying pathophysiological mechanisms of this signaling in peripheral neuropathy are not fully known. Here, we provide an overview of complement pathways and major components associated with dysregulated complement activation in peripheral neuropathy, and of drugs under development targeting the C5 system. C5/C5aR1 axis modulators could represent a new strategy to treat complement-related peripheral neuropathies. Specifically, we describe novel C5aR allosteric modulators, which may potentially become new tools in the therapeutic armory against neuropathic pain.
Fas-Fas Ligand Interplay in the Periphery of Salivary Gland Carcinomas as a New Checkpoint Predictor for Disease Severity and Immunotherapy Response
Authors: Strizova Zuzana , Kuchar Martin , Capkova Linda , Komarc Martin , Skrivan Jiri , Bartunkova Jirina , Plzak Jan , Smrz Daniel
Published: April 2021

Salivary gland carcinomas (SGCs) are extremely morphologically heterogeneous, and treatment options for this disease are limited. Immunotherapy with immune checkpoint inhibitors (ICIs) represents a revolutionary treatment approach. However, SGCs remain largely resistant to this therapy. An increasing body of evidence suggests that resistance to ICI therapy is modulated by the Fas (CD95)–Fas ligand (FasL, CD178) interplay between tumor cells and immune cells. In this study, we examined the Fas–FasL interplay between tumor cells and tumor-infiltrating immune cells (TIICs) in the center and periphery of SGCs from 62 patients. We found that the Fas-expressing tumor cells accumulated in the center of SGC tumors with increasing tumor stage. Furthermore, this accumulation occurred regardless of the presence of TIICs expressing high levels of FasL. On the contrary, a loss of Fas-expressing TIICs with increasing tumor stage was found in the tumor periphery, whereas FasL expression in tumor cells in the tumor periphery correlated with tumor stage. These data suggest that SGC cells are resistant to FasL-induced apoptosis by TIICs but could utilize FasL to eliminate these cells in high-stage tumors to provide resistance to immunotherapy.
Melting Curve Analysis of Aptachains: Adenosine Detection with Internal Calibration
Authors: Lu Chenze , Saint-Pierre Christine , Gasparutto Didier , Roupioz Yoann , Ravelet Corinne , Peyrin Eric , Buhot Arnaud
Published: April 2021

Small molecules are ubiquitous in nature and their detection is relevant in various domains. However, due to their size, sensitive and selective probes are difficult to select and the detection methods are generally indirect. In this study, we introduced the use of melting curve analysis of aptachains based on split-aptamers for the detection of adenosine. Aptamers, short oligonucleotides, are known to be particularly efficient probes compared to antibodies thanks to their advantageous probe/target size ratio. Aptachains are formed from dimers with dangling ends followed by the split-aptamer binding triggered by the presence of the target. The high melting temperature of the dimers served as a calibration for the detection/quantification of the target based on the height and/or temperature shift of the aptachain melting peak.
Association between Functional Brain Network Metrics and Surgeon Performance and Distraction in the Operating Room
Authors: Shafiei Somayeh B. , Jing Zhe , Attwood Kristopher , Iqbal Umar , Arman Sena , Hussein Ahmed A. , Durrani Mohammad , Guru Khurshid
Published: April 2021

Objective: The aim of this work was to examine (electroencephalogram) EEG features that represent dynamic changes in the functional brain network of a surgical trainee and whether these features can be used to evaluate a robot assisted surgeon’s (RAS) performance and distraction level in the operating room. Materials and Methods: Electroencephalogram (EEG) data were collected from three robotic surgeons in an operating room (OR) via a 128-channel EEG headset with a frequency of 500 samples/second. Signal processing and network neuroscience algorithms were applied to the data to extract EEG features. The SURG-TLX and NASA-TLX metrics were subjectively evaluated by a surgeon and mentor at the end of each task. The scores given to performance and distraction metrics were used in the analyses here. Statistical test data were utilized to select EEG features that have a significant relationship with surgeon performance and distraction while carrying out a RAS surgical task in the OR. Results: RAS surgeon performance and distraction had a relationship with the surgeon’s functional brain network metrics as recorded throughout OR surgery. We also found a significant negative Pearson correlation between performance and the distraction level (−0.37, p-value < 0.0001). Conclusions: The method proposed in this study has potential for evaluating RAS surgeon performance and the level of distraction. This has possible applications in improving patient safety, surgical mentorship, and training.
Small Molecules in the Treatment of Squamous Cell Carcinomas: Focus on Indirubins
Authors: Schäfer Mirijam , Semmler Marie Luise , Bernhardt Thoralf , Fischer Tobias , Kakkassery Vinodh , Ramer Robert , Hein Martin , Bekeschus Sander , Langer Peter , Hinz Burkhard , Emmert Steffen , Boeckmann Lars
Published: April 2021

Skin cancers are the most common malignancies in the world. Among the most frequent skin cancer entities, squamous cell carcinoma (SCC) ranks second (~20%) after basal cell carcinoma (~77%). In early stages, a complete surgical removal of the affected tissue is carried out as standard therapy. To treat advanced and metastatic cancers, targeted therapies with small molecule inhibitors are gaining increasing attention. Small molecules are a heterogeneous group of protein regulators, which are produced by chemical synthesis or fermentation. The majority of them belong to the group of receptor tyrosine kinase inhibitors (RTKIs), which specifically bind to certain RTKs and directly influence the respective signaling pathway. Knowledge of characteristic molecular alterations in certain cancer entities, such as SCC, can help identify tumor-specific substances for targeted therapies. Most frequently, altered genes in SCC include TP53, NOTCH, EGFR, and CCND1. For example, the gene CCND1, which codes for cyclin D1 protein, is upregulated in nearly half of SCC cases and promotes proliferation of affected cells. A treatment with the small molecule 5′-nitroindirubin-monoxime (INO) leads to inhibition of cyclin D1 and thus inhibition of proliferation. As a component of Danggui Longhui Wan, a traditional Chinese medicine, indirubins are used to treat chronic diseases and have been shown to inhibit inflammatory reactions. Indirubins are pharmacologically relevant small molecules with proapoptotic and antiproliferative activity. In this review, we discuss the current literature on indirubin-based small molecules in cancer treatment. A special focus is on the molecular biology of squamous cell carcinomas, their alterations, and how these are rendered susceptible to indirubin-based small molecule inhibitors. The potential molecular mechanisms of the efficacy of indirubins in killing SCC cells will be discussed as well.
Cold Atmospheric Plasma Increases Temozolomide Sensitivity of Three-Dimensional Glioblastoma Spheroids via Oxidative Stress-Mediated DNA Damage
Authors: Shaw Priyanka , Kumar Naresh , Privat-Maldonado Angela , Smits Evelien , Bogaerts Annemie
Published: April 2021

Glioblastoma multiforme (GBM) is the most frequent and aggressive primary malignant brain tumor in adults. Current standard radiotherapy and adjuvant chemotherapy with the alkylating agent temozolomide (TMZ) yield poor clinical outcome. This is due to the stem-like properties of tumor cells and genetic abnormalities in GBM, which contribute to resistance to TMZ and progression. In this study, we used cold atmospheric plasma (CAP) to enhance the sensitivity to TMZ through inhibition of antioxidant signaling (linked to TMZ resistance). We demonstrate that CAP indeed enhances the cytotoxicity of TMZ by targeting the antioxidant specific glutathione (GSH)/glutathione peroxidase 4 (GPX4) signaling. We optimized the threshold concentration of TMZ on five different GBM cell lines (U251, LN18, LN229, U87-MG and T98G). We combined TMZ with CAP and tested it on both TMZ-sensitive (U251, LN18 and LN229) and TMZ-resistant (U87-MG and T98G) cell lines using two-dimensional cell cultures. Subsequently, we used a three-dimensional spheroid model for the U251 (TMZ-sensitive) and U87-MG and T98G (TMZ-resistant) cells. The sensitivity of TMZ was enhanced, i.e., higher cytotoxicity and spheroid shrinkage was obtained when TMZ and CAP were administered together. We attribute the anticancer properties to the release of intracellular reactive oxygen species, through inhibiting the GSH/GPX4 antioxidant machinery, which can lead to DNA damage. Overall, our findings suggest that the combination of CAP with TMZ is a promising combination therapy to enhance the efficacy of TMZ towards the treatment of GBM spheroids.
Therapeutic Application of Monoclonal Antibodies in Pancreatic Cancer: Advances, Challenges and Future Opportunities
Authors: Arias-Pinilla Gustavo A. , Modjtahedi Helmout
Published: April 2021

Pancreatic cancer remains as one of the most aggressive cancer types. In the absence of reliable biomarkers for its early detection and more effective therapeutic interventions, pancreatic cancer is projected to become the second leading cause of cancer death in the Western world in the next decade. Therefore, it is essential to discover novel therapeutic targets and to develop more effective and pancreatic cancer-specific therapeutic agents. To date, 45 monoclonal antibodies (mAbs) have been approved for the treatment of patients with a wide range of cancers; however, none has yet been approved for pancreatic cancer. In this comprehensive review, we discuss the FDA approved anticancer mAb-based drugs, the results of preclinical studies and clinical trials with mAbs in pancreatic cancer and the factors contributing to the poor response to antibody therapy (e.g. tumour heterogeneity, desmoplastic stroma). MAb technology is an excellent tool for studying the complex biology of pancreatic cancer, to discover novel therapeutic targets and to develop various forms of antibody-based therapeutic agents and companion diagnostic tests for the selection of patients who are more likely to benefit from such therapy. These should result in the approval and routine use of antibody-based agents for the treatment of pancreatic cancer patients in the future.
The rs599839 A>G Variant Disentangles Cardiovascular Risk and Hepatocellular Carcinoma in NAFLD Patients
Authors: Meroni Marica , Longo Miriam , Paolini Erika , Alisi Anna , Miele Luca , De Caro Emilia Rita , Pisano Giuseppina , Maggioni Marco , Soardo Giorgio , Valenti Luca Vittorio , Fracanzani Anna Ludovica , Dongiovanni Paola
Published: April 2021

Background and Aims: Dyslipidemia and cardiovascular diseases (CVD) are comorbidities of nonalcoholic fatty liver disease (NAFLD), which ranges from steatosis to hepatocellular carcinoma (HCC). The rs599839 A>G variant, in the CELSR2-PSRC1-SORT1 gene cluster, has been associated CVD, but its impact on metabolic traits and on the severity liver damage in NAFLD has not been investigated yet. Methods: We evaluated the effect of the rs599839 variant in 1426 NAFLD patients (Overall cohort) of whom 131 had HCC (NAFLD-HCC), in 500,000 individuals from the UK Biobank Cohort (UKBBC), and in 366 HCC samples from The Cancer Genome Atlas (TCGA). Hepatic PSRC1, SORT1 and CELSR2 expressions were evaluated by RNAseq (n = 125). Results: The rs599839 variant was associated with reduced circulating LDL, carotid intima-media thickness, carotid plaques and hypertension (p < 0.05) in NAFLD patients and with protection against dyslipidemia in UKBBC. The minor G allele was associated with higher risk of HCC, independently of fibrosis severity (odds ratio (OR): 5.62; 95% c.i. 1.77–17.84, p = 0.003), poor prognosis and advanced tumor stage (p < 0.05) in the overall cohort. Hepatic PSRC1, SORT1 and CELSR2 expressions were increased in NAFLD patients carrying the rs599839 variant (p < 0.0001). SORT1 mRNA levels negatively correlated with circulating lipids and with those of genes involved in lipoprotein turnover (p < 0.0001). Conversely, PSRC1 expression was positively related to that of genes implicated in cell proliferation (p < 0.0001). In TCGA, PSRC1 over-expression promoted more aggressive HCC development (p < 0.05). Conclusions: In sum, the rs599839 A>G variant is associated with protection against dyslipidemia and CVD in NAFLD patients, but as one it might promote HCC development by modulating SORT1 and PSRC1 expressions which impact on lipid metabolism and cell proliferation, respectively.
An Enhanced Histopathology Analysis: An AI-Based System for Multiclass Grading of Oral Squamous Cell Carcinoma and Segmenting of Epithelial and Stromal Tissue
Authors: Musulin Jelena , Štifanić Daniel , Zulijani Ana , Ćabov Tomislav , Dekanić Andrea , Car Zlatan
Published: April 2021

Oral squamous cell carcinoma is most frequent histological neoplasm of head and neck cancers, and although it is localized in a region that is accessible to see and can be detected very early, this usually does not occur. The standard procedure for the diagnosis of oral cancer is based on histopathological examination, however, the main problem in this kind of procedure is tumor heterogeneity where a subjective component of the examination could directly impact patient-specific treatment intervention. For this reason, artificial intelligence (AI) algorithms are widely used as computational aid in the diagnosis for classification and segmentation of tumors, in order to reduce inter- and intra-observer variability. In this research, a two-stage AI-based system for automatic multiclass grading (the first stage) and segmentation of the epithelial and stromal tissue (the second stage) from oral histopathological images is proposed in order to assist the clinician in oral squamous cell carcinoma diagnosis. The integration of Xception and SWT resulted in the highest classification value of 0.963 (σ = 0.042) AUCmacro and 0.966 (σ = 0.027) AUCmicro while using DeepLabv3+ along with Xception_65 as backbone and data preprocessing, semantic segmentation prediction resulted in 0.878 (σ = 0.027) mIOU and 0.955 (σ = 0.014) F1 score. Obtained results reveal that the proposed AI-based system has great potential in the diagnosis of OSCC.
Computational Catalysis—Trends and Outlook
Authors: Turner Christoffer Heath
Published: April 2021

Computational catalysis has been one of the most dynamic research fields over the last decade, and it now represents a critical tool for the analysis of chemical mechanisms and active sites [...]
Neurodegeneration Induced by Anti-IgLON5 Antibodies Studied in Induced Pluripotent Stem Cell-Derived Human Neurons
Authors: Ryding Matias , Gamre Mattias , Nissen Mette S. , Nilsson Anna C. , Okarmus Justyna , Poulsen Anne A. E. , Meyer Morten , Blaabjerg Morten
Published: April 2021

Anti-IgLON5 disease is a progressive neurological disorder associated with autoantibodies against a neuronal cell adhesion molecule, IgLON5. In human postmortem brain tissue, the neurodegeneration and accumulation of hyperphosphorylated tau (p-tau) are found. Whether IgLON5 antibodies induce neurodegeneration or neurodegeneration provokes an immune response causing inflammation and antibody formation remains to be elucidated. We investigated the effects of anti-IgLON5 antibodies on human neurons. Human neural stem cells were differentiated for 14–48 days and exposed from Days 9 to 14 (short-term) or Days 13 to 48 (long-term) to either (i) IgG from a patient with confirmed anti-IgLON5 antibodies or (ii) IgG from healthy controls. The electrical activity of neurons was quantified using multielectrode array assays. Cultures were immunostained for β-tubulin III and p-tau and counterstained with 4′,6-Diamidine-2′-phenylindole dihydrochloride (DAPI). To study the impact on synapses, cultures were also immunostained for the synaptic proteins postsynaptic density protein 95 (PSD95) and synaptophysin. A lactate dehydrogenase release assay and nuclei morphology analysis were used to assess cell viability. Cultures exposed to anti-IgLON5 antibodies showed reduced neuronal spike rate and synaptic protein content, and the proportion of neurons with degenerative appearance including p-tau (T205)-positive neurons was higher when compared to cultures exposed to control IgG. In addition, cell death was increased in cultures exposed to anti-IgLON5 IgG for 21 days. In conclusion, pathological anti-IgLON5 antibodies induce neurodegenerative changes and cell death in human neurons. This supports the hypothesis that autoantibodies may induce the neurodegenerative changes found in patients with anti-IgLON5-mediated disease. Furthermore, this study highlights the potential use of stem cell-based in vitro models for investigations of antibody-mediated diseases. As anti-IgLON5 disease is heterogeneous, more studies with different IgLON5 antibody samples tested on human neurons are needed.