bluuebunny/crossref_metadata_2025 huggingface dataset:
Mobile Augmented Reality for Low-End Devices Based on Planar Surface Recognition and Optimized Vertex Data Rendering
Authors: Verykokou Styliani , Boutsi Argyro-Maria , Ioannidis Charalabos
Published: September 2021

Mobile Augmented Reality (MAR) is designed to keep pace with high-end mobile computing and their powerful sensors. This evolution excludes users with low-end devices and network constraints. This article presents ModAR, a hybrid Android prototype that expands the MAR experience to the aforementioned target group. It combines feature-based image matching and pose estimation with fast rendering of 3D textured models. Planar objects of the real environment are used as pattern images for overlaying users’ meshes or the app’s default ones. Since ModAR is based on the OpenCV C++ library at Android NDK and OpenGL ES 2.0 graphics API, there are no dependencies on additional software, operating system version or model-specific hardware. The developed 3D graphics engine implements optimized vertex-data rendering with a combination of data grouping, synchronization, sub-texture compression and instancing for limited CPU/GPU resources and a single-threaded approach. It achieves up to 3× speed-up compared to standard index rendering, and AR overlay of a 50 K vertices 3D model in less than 30 s. Several deployment scenarios on pose estimation demonstrate that the oriented FAST detector with an upper threshold of features per frame combined with the ORB descriptor yield best results in terms of robustness and efficiency, achieving a 90% reduction of image matching time compared to the time required by the AGAST detector and the BRISK descriptor, corresponding to pattern recognition accuracy of above 90% for a wide range of scale changes, regardless of any in-plane rotations and partial occlusions of the pattern.
Laser Assisted Size Reduction of Gold (Au) Particles onto a Titanium (Ti) Substrate Surface
Authors: Bialas Oktawian , Poloczek Tomasz , Lis Mateusz , Skowronek Adam , Górka Jacek , Adamiak Marcin
Published: September 2021

This paper aims to perform laser assisted size reduction to nanoparticles of gold (Au) sputtered layer on titanium (Ti) base material using an innovative method that could potentially be applied in novel blood contact and thromboresistive devices in the living body, such as ventricular assist devices (VADs). The enrichment of the surface layer of titanium with gold nanoparticles, due to its bioproperties, may contribute to the reduction of inflammatory reactions and infections occurring mainly in the first postoperative period causing implant failure. The possibility of obtaining superficial size reduction and/or bonding of nano gold particles with Ti micromachining by picosecond laser treatment was evaluated. The quantitative assessment of the particles has been made using SEM and are depicted on the histograms, whereby the appropriate number of particles determine the antibacterial properties and health safety. The initial analysis of micromachining process of the prepared material was focused on power-depth dependence by confocal microscopy. The evaluation of gold particles was conducted using scanning electron microscopy (SEM) using SE and QBSD detectors with energy dispersive spectroscopy (EDS) analysis. Attempts to reduce the deposited gold coating to the size of Au nanoparticles and to melt them into titanium matrix using a laser beam have been successfully completed. There seems to be no strict relationship between particle size distribution of gold onto Ti, probably due to too low energy to excite titanium enough, resulting from difference in Ti and Au melting point temperatures. However, the obtained results allow continuation of pilot studies for augmented research and material properties analysis in the future.
Rutile in Amphibolite Facies Metamorphic Rocks: A Rare Example from the East Qinling Orogen, China
Authors: Wang Changming , Rao Shicheng , Shi Kangxing , Bagas Leon , Chen Qi , Zhu Jiaxuan , Duan Hongyu , Liu Lijun
Published: September 2021

Rutile is an important ore mineral to meet the increasing demand of critical metal Ti in various sectors. Here we report a rare example of rutile deposits hosted within the Baishugang–Wujianfang amphibolite-facies metamorphic rocks in the East Qinling Orogen, central China. The rutiles are mostly located within or along the margins of biotite and show 94.6 to 99 wt% TiO2. Rutiles occur as chains, thin layers along the foliation, and dense clusters. The grains are coexisted with magnetite. Based on Zr-in-rutile thermometer the estimated crystallisation temperature is at 630 °C at 7.0 kba. Based on Cr/Nb ratio, the source of the rutile is correlated with Ti-bearing silicate minerals such as biotite from aluminous sedimentary protoliths. The rutile deposit formed during lower amphibolite-facies metamorphism, and is distinct from the eclogite- and granulite-related types elsewhere in the orogen. The LA-ICP-MS U–Pb analyses of rutiles from the deposit yield lower intercept 238U/206Pb ages of 386 ± 16 Ma at the Baishugang–Wujianfang district. These ages correspond to a Devonian arc–continent collisional event between the South and North Qinling domains in the East Qinling Orogen.
Homomorphic Encryption Based Privacy-Preservation for IoMT
Authors: Salim Mikail Mohammed , Kim Inyeung , Doniyor Umarov , Lee Changhoon , Park Jong Hyuk
Published: September 2021

Healthcare applications store private user data on cloud servers and perform computation operations that support several patient diagnoses. Growing cyber-attacks on hospital systems result in user data being held at ransom. Furthermore, mathematical operations on data stored in the Cloud are exposed to untrusted external entities that sell private data for financial gain. In this paper, we propose a privacy-preserving scheme using homomorphic encryption to secure medical plaintext data from being accessed by attackers. Secret sharing distributes computations to several virtual nodes on the edge and masks all arithmetic operations, preventing untrusted cloud servers from learning the tasks performed on the encrypted patient data. Virtual edge nodes benefit from cloud computing resources to accomplish computing-intensive mathematical functions and reduce latency in device–edge node data transmission. A comparative analysis with existing studies demonstrates that homomorphically encrypted data stored at the edge preserves data privacy and integrity. Furthermore, secret sharing-based multi-node computation using virtual nodes ensures data confidentiality from untrusted cloud networks.
Hepatoprotective Effects of Extract of Helicteres hirsuta Lour. on Liver Fibrosis Induced by Carbon Tetrachloride in Rats
Authors: Thang Hoang Dac , Hien Truong Thi Thu , Viet Duc Ngo , Anh Hoang Le Tuan , Do Thi Thao , Vinh Le Ba , Young Yang Seo , Dan Gao , Tuan Anh Le
Published: September 2021

Helicteres hirsuta Lour. is a traditional Vietnamese medicine for treating chronic liver diseases such as cirrhosis and liver cancer. Many in vitro and in vivo experiments have demonstrated that the extracts and isolated compounds from H. hirsuta have diverse pharmacological activities, including antioxidant, anti-inflammatory, and anti-cancer effects. However, the hepatoprotective effects have not been reported until now. Therefore, the methanolic and ethanolic extracts of the aerial part of the H. hirsuta L. (HHM and HHE-1/1) were examined on liver fibrosis induced by carbon tetrachloride (CCl4) in rats for the first time. The results revealed that all the livers of the model group had stage F4 cirrhosis; the group that received silymarin, and HHM and HHE-1/1 had milder liver damage cirrhosis stage F1-F2 which implies that the methanolic and ethanolic extracts of H. hirsute have a definite advantage in the development of food or oral medications for hepatoprotective activity.
A Novel Slicing Strategy to Print Overhangs without Support Material
Authors: Wüthrich Michael , Gubser Maurus , Elspass Wilfried J. , Jaeger Christian
Published: September 2021

Fused deposition modeling (FDM) 3D printers commonly need support material to print overhangs. A previously developed 4-axis printing process based on an orthogonal kinematic, an additional rotational axis around the z-axis and a 45° tilted nozzle can print overhangs up to 100° without support material. With this approach, the layers are in a conical shape and no longer parallel to the printing plane; therefore, a new slicer strategy is necessary to generate the paths. This paper describes a slicing algorithm compatible with this 4-axis printing kinematics. The presented slicing strategy is a combination of a geometrical transformation with a conventional slicing software and has three basic steps: Transformation of the geometry in the .STL file, path generation with a conventional slicer and back transformation of the G-code. A comparison of conventionally manufactured parts and parts produced with the new process shows the feasibility and initial results in terms of surface quality and dimensional accuracy.
Recent Advances on Machine Learning Applications in Machining Processes
Authors: Aggogeri Francesco , Pellegrini Nicola , Tagliani Franco Luis
Published: September 2021

This study aims to present an overall review of the recent research status regarding Machine Learning (ML) applications in machining processes. In the current industrial systems, processes require the capacity to adapt to manufacturing conditions continuously, guaranteeing high performance in terms of production quality and equipment availability. Artificial Intelligence (AI) offers new opportunities to develop and integrate innovative solutions in conventional machine tools to reduce undesirable effects during operational activities. In particular, the significant increase of the computational capacity may permit the application of complex algorithms to big data volumes in a short time, expanding the potentialities of ML techniques. ML applications are present in several contexts of machining processes, from roughness quality prediction to tool condition monitoring. This review focuses on recent applications and implications, classifying the main problems that may be solved using ML related to the machining quality, energy consumption and conditional monitoring. Finally, a discussion on the advantages and limits of ML algorithms is summarized for future investigations.
Discrete Semantics-Guided Asymmetric Hashing for Large-Scale Multimedia Retrieval
Authors: Long Jun , Sun Longzhi , Hua Liujie , Yang Zhan
Published: September 2021

Cross-modal hashing technology is a key technology for real-time retrieval of large-scale multimedia data in real-world applications. Although the existing cross-modal hashing methods have achieved impressive accomplishment, there are still some limitations: (1) some cross-modal hashing methods do not make full consider the rich semantic information and noise information in labels, resulting in a large semantic gap, and (2) some cross-modal hashing methods adopt the relaxation-based or discrete cyclic coordinate descent algorithm to solve the discrete constraint problem, resulting in a large quantization error or time consumption. Therefore, in order to solve these limitations, in this paper, we propose a novel method, named Discrete Semantics-Guided Asymmetric Hashing (DSAH). Specifically, our proposed DSAH leverages both label information and similarity matrix to enhance the semantic information of the learned hash codes, and the ℓ2,1 norm is used to increase the sparsity of matrix to solve the problem of the inevitable noise and subjective factors in labels. Meanwhile, an asymmetric hash learning scheme is proposed to efficiently perform hash learning. In addition, a discrete optimization algorithm is proposed to fast solve the hash code directly and discretely. During the optimization process, the hash code learning and the hash function learning interact, i.e., the learned hash codes can guide the learning process of the hash function and the hash function can also guide the hash code generation simultaneously. Extensive experiments performed on two benchmark datasets highlight the superiority of DSAH over several state-of-the-art methods.
Improving the Discriminability of Haptic Icons: The Haptic Tuning Fork
Authors: Raya Laura , Boga Sara A. , Garcia-Lorenzo Marcos , Bayona Sofia
Published: September 2021

Technological advances enable the capture and management of complex data sets that need to be correctly understood. Visualisation techniques can help in complex data analysis and exploration, but sometimes the visual channel is not enough, or it is not always available. Some authors propose using the haptic channel to reinforce or substitute the visual sense, but the limited human haptic short-term memory still poses a challenge. We present the haptic tuning fork, a reference signal displayed before the haptic information for increasing the discriminability of haptic icons. With this reference, the user does not depend only on short-term memory. We have decided to evaluate the usefulness of the haptic tuning fork in impedance kinesthetic devices as these are the most common. Furthermore, since the renderable signal ranges are device-dependent, we introduce a methodology to select a discriminable set of signals called the haptic scale. Both the haptic tuning fork and the haptic scale proved their usefulness in the performed experiments regarding haptic stimuli varying in frequency.
Comparison of Optimal Control Designs for a 5 MW Wind Turbine
Authors: Reddy Yiza-srikanth , Hur Sung-ho
Published: September 2021

Optimal controllers, namely Model Predictive Control (MPC), H∞ Control (H∞), and Linear Quadratic Gaussian control (LQG), are designed for a 5 MW horizontal-axis variable-speed wind turbine. The control design models required as part of the optimal control design are obtained by using a high fidelity aeroelastic model (i.e., DNV Bladed). The optimal controllers are eventually designed in three operating modes: below-rated, just below-rated, and above rated-wind speeds, based on linearized control design models. The linearized models are reduced by using a model reduction technique to facilitate the design of optimal controllers. The controllers are analyzed not only in the time domain but also in the frequency domain and on the torque/speed plane. Simulation results demonstrated that optimal controllers perform better than the standard proportional-integral-derivative (PID) controller, particularly for removing oscillation due to the drive-train mode without incorporating a drive-train damper.
Optimization of Storage Medium for Hematological Reference Samples in External Quality Assessment
Authors: Vo Ngoc Nguyen , Tran Huu Tam , Truong Quan Thuy , Nguyen Thuy Huong
Published: September 2021

Hematological reference samples for external quality assessment (EQA) in hematology are essential for many laboratories in Vietnam, however, the prices are high along with short storing time. This study attempted to establish an optimal formula for the manufacture of hematological reference samples for hematological EQA programs. Human red blood cells (RBCs) were mixed with goose RBCs (pseudo-leucocytes) and goat RBCs (pseudo-platelets) as alternatives for white blood cells (WBCs) and platelets (PLTs), respectively, in different formulas of storage media. The optimal formula was obtained using response surface methodology–central composite design (RSM-CCD). Three main factors affecting the concentrations of RBCs were determined by Plackett–Burmann matrix. The optimal concentrations determined by RSM-CCD were 46% serum, 0.44 g/L neomycin sulfate, and 2.5% glycerol. The model predicted that the maximum number of human RBCs was 4.1 × 1012 cells/L, pseudo-leucocytes was 6.4 × 109 cells/L, and pseudo-platelets was 188 × 109 cells/L. The practical concentrations of RBCs, pseudo-leucocytes, and pseudo-platelets were 4.21 × 1012 cells/L, 6.4 × 109 cells/L, and 187 × 109 cells/L, respectively, which showed 98.93% similarity with theoretical data. This result could be a premise for further study to improve manufacturing of hematological reference samples for hematology EQA programs.
A Compact Sequentially Rotated Circularly Polarized Dielectric Resonator Antenna Array
Authors: Qasaymeh Yazeed , Almuhaisen Abdullah , Alghamdi Ali S.
Published: September 2021

In this study, a compact 2 × 2 circularly polarized (CP) sequentially rotated (SR) dielectric resonator antenna (DRA) array operating in the IEEE 802.11a band is presented. To acquire the CP radiation, an elliptical slot (ES) was introduced to couple a rectangular dielectric resonator (RDR). The ES generates two resonant frequencies corresponding to the dominant even and odd modes. The SR feeder is made of four quarter-wavelength microstrip transformers to reduce the input impedance of the elements and, consequently, maximize the power transferred to each element. Experimental and simulation verifications were conducted on a 54 × 50 × 0.813 mm3 prototype to evaluate the performance of the proposed antenna array, which achieved a VSWR < −10 dB bandwidth of 1 GHz (5.1–6.05 GHz) and axial ratio (AR) < 3 dB of 0.95 GHz (5.1–5.85 GHz). The agreement between the simulated and measured results confirmed the validity of the proposed design.
Particle Shape Impact on the Radiative Forcing Efficiency Estimated from Single Levitated (NH4)2SO4 Particles
Authors: Gutierrez Antonio Valenzuela
Published: September 2021

Levitation of single trapped particles enables the exploration of fundamental physicochemical aerosol properties never previously achieved. Experimental measurements showed that (NH4)2SO4’s particle shape deviated from sphericity during the crystallization process. Despite that, salt aerosols are assumed to be spheres even in low relative humidity (RH) in most climate models. In the analysis performed here, Mie and T-Matrix codes were operated to simulate crucial parameters needed to estimate the radiative forcing efficiency: extinction efficiency, asymmetry parameter and backscattering fraction. The incorporation of non-spherical effects in (NH4)2SO4 particles can cause a difference of up to 46% radiative forcing efficiency compared to the assumption of sphericity in the 0.3–0.6 µm particle radius range.
Integral Characterizations for Uniform Stability with Growth Rates in Banach Spaces
Authors: Boruga (Toma) Rovana , Megan Mihail , Toth Daniela Maria-Magdalena
Published: September 2021

The aim of this paper is to present some integral characterizations for the concept of uniform stability with growth rates in Banach spaces. In this sense, we prove necessary and sufficient conditions (of Barbashin and Datko type) for an evolution operator to be uniform h- stable. As particular cases of this notion, we obtain four characterizations for uniform exponential stability and two characterizations for uniform polynomial stability.
Mellin Transform of Logarithm and Quotient Function with Reducible Quartic Polynomial in Terms of the Lerch Function
Authors: Reynolds Robert , Stauffer Allan
Published: September 2021

A class of definite integrals involving a quotient function with a reducible polynomial, logarithm and nested logarithm functions are derived with a possible connection to contact problems for a wedge. The derivations are expressed in terms of the Lerch function. Special cases are also derived in terms fundamental constants. The majority of the results in this work are new.
Modeling Dengue Immune Responses Mediated by Antibodies: A Qualitative Study
Authors: Sebayang Afrina Andriani , Fahlena Hilda , Anam Vizda , Knopoff Damián , Stollenwerk Nico , Aguiar Maíra , Soewono Edy
Published: September 2021

Dengue fever is a viral mosquito-borne infection and a major international public health concern. With 2.5 billion people at risk of acquiring the infection around the world, disease severity is influenced by the immunological status of the individual, seronegative or seropositive, prior to natural infection. Caused by four antigenically related but distinct serotypes, DENV-1 to DENV-4, infection by one serotype confers life-long immunity to that serotype and a period of temporary cross-immunity (TCI) to other serotypes. The clinical response on exposure to a second serotype is complex with the so-called antibody-dependent enhancement (ADE) process, a disease augmentation phenomenon when pre-existing antibodies to previous dengue infection do not neutralize but rather enhance the new infection, used to explain the etiology of severe disease. In this paper, we present a minimalistic mathematical model framework developed to describe qualitatively the dengue immunological response mediated by antibodies. Three models are analyzed and compared: (i) primary dengue infection, (ii) secondary dengue infection with the same (homologous) dengue virus and (iii) secondary dengue infection with a different (heterologous) dengue virus. We explore the features of viral replication, antibody production and infection clearance over time. The model is developed based on body cells and free virus interactions resulting in infected cells activating antibody production. Our mathematical results are qualitatively similar to the ones described in the empiric immunology literature, providing insights into the immunopathogenesis of severe disease. Results presented here are of use for future research directions to evaluate the impact of dengue vaccines.
Common Metabolites in Two Different Hypertensive Mouse Models: A Serum and Urine Metabolome Study
Authors: Baranwal Gaurav , Pilla Rachel , Goodlett Bethany L. , Coleman Aja K. , Arenaz Cristina M. , Jayaraman Arul , Rutkowski Joseph M. , Alaniz Robert C. , Mitchell Brett M.
Published: September 2021

Recent metabolomics studies have identified a wide array of microbial metabolites and metabolite pathways that are significantly altered in hypertension. However, whether these metabolites play an active role in pathogenesis of hypertension or are altered because of this has yet to be determined. In the current study, we hypothesized that metabolite changes common between hypertension models may unify hypertension’s pathophysiology with respect to metabolites. We utilized two common mouse models of experimental hypertension: L-arginine methyl ester hydrochloride (L-NAME)/high-salt-diet-induced hypertension (LSHTN) and angiotensin II induced hypertension (AHTN). To identify common metabolites that were altered across both models, we performed untargeted global metabolomics analysis in serum and urine and the resulting data were analyzed using MetaboAnalyst software and compared to control mice. A total of 41 serum metabolites were identified as being significantly altered in any hypertensive model compared to the controls. Of these compounds, 14 were commonly changed in both hypertensive groups, with 4 significantly increased and 10 significantly decreased. In the urine, six metabolites were significantly altered in any hypertensive group with respect to the control; however, none of them were common between the hypertensive groups. These findings demonstrate that a modest, but potentially important, number of serum metabolites are commonly altered between experimental hypertension models. Further studies of the newly identified metabolites from this untargeted metabolomics analysis may lead to a greater understanding of the association between gut dysbiosis and hypertension.
The Surprising Story of Fusicoccin: A Wilt-Inducing Phytotoxin, a Tool in Plant Physiology and a 14-3-3-Targeted Drug
Authors: Marra Mauro , Camoni Lorenzo , Visconti Sabina , Fiorillo Anna , Evidente Antonio
Published: September 2021

Fusicoccin is the α glucoside of a carbotricyclic diterpene, produced by the fungus Phomopsis amygdali (previously classified as Fusicoccum amygdali), the causal agent of almond and peach canker disease. A great interest in this molecule started when it was discovered that it brought about an irreversible stomata opening of higher plants, thereby inducing the wilting of their leaves. Since then, several studies were carried out to elucidate its biological activity, biosynthesis, structure, structure-activity relationships and mode of action. After sixty years of research and more than 1800 published articles, FC is still the most studied phytotoxin and one of the few whose mechanism of action has been elucidated in detail. The ability of FC to stimulate several fundamental plant processes depends on its ability to activate the plasma membrane H+-ATPase, induced by eliciting the association of 14-3-3 proteins, a class of regulatory molecules widespread in eukaryotes. This discovery renewed interest in FC and prompted more recent studies aimed to ascertain the ability of the toxin to influence the interaction between 14-3-3 proteins and their numerous client proteins in animals, involved in the regulation of basic cellular processes and in the etiology of different diseases, including cancer. This review covers the different aspects of FC research partially treated in different previous reviews, starting from its discovery in 1964, with the aim to outline the extraordinary pathway which led this very uncommon diterpenoid to evolve from a phytotoxin into a tool in plant physiology and eventually into a 14-3-3-targeted drug.
The Underappreciated Role of Epithelial Mesenchymal Transition in Chronic Obstructive Pulmonary Disease and Its Strong Link to Lung Cancer
Authors: Mahmood Malik Quasir , Shukla Shakti D. , Ward Chris , Walters Eugene Haydn
Published: September 2021

The World Health Organisation reported COPD to be the third leading cause of death globally in 2019, and in 2020, the most common cause of cancer death was lung cancer; when these linked conditions are added together they come near the top of the leading causes of mortality. The cell-biological program termed epithelial-to-mesenchymal transition (EMT) plays an important role in organ development, fibrosis and cancer progression. Over the past decade there has emerged a substantial literature that also links EMT specifically to the pathophysiology of chronic obstructive pulmonary disease (COPD) as primarily an airway fibrosis disease; COPD is a recognised strong independent risk factor for the development of lung cancer, over and above the risks associated with smoking. In this review, our primary focus is to highlight these linkages and alert both the COPD and lung cancer fields to these complex interactions. We emphasise the need for inter-disciplinary attention and research focused on the likely crucial roles of EMT (and potential for its inhibition) with recognition of its strategic place mechanistically in both COPD and lung cancer. As part of this we discuss the future potential directions for novel therapeutic opportunities, including evidence-based strategic repurposing of currently used familiar/approved medications.
A Novel Competitive Binding Screening Assay Reveals Sennoside B as a Potent Natural Product Inhibitor of TNF-α
Authors: Peng Lei , Durai Prasannavenkatesh , Park Keunwan , Pyo Jeong Joo , Choi Yongsoo
Published: September 2021

Natural products (NPs) have played a significant role in drug discovery for diverse diseases, and numerous attempts have been made to discover promising NP inhibitors of tumor necrosis factor α (TNF-α), a major therapeutic target in autoimmune diseases. However, NP inhibitors of TNF-α, which have the potential to be developed as new drugs, have not been reported for over a decade. To facilitate the search for new promising inhibitors of TNF-α, we developed an efficient competitive binding screening assay based on analytical size exclusion chromatography coupled with liquid chromatography-tandem mass spectrometry. Application of this screening method to the NP library led to the discovery of a potent inhibitor of TNF-α, sennoside B, with an IC50 value of 0.32 µM in TNF-α induced HeLa cell toxicity assays. Surprisingly, the potency of sennoside B was 5.7-fold higher than that of the synthetic TNF-α inhibitor SPD304. Molecular docking was performed to determine the binding mode of sennoside B to TNF-α. In conclusion, we successfully developed a novel competition binding screening method to discover small molecule TNF-α inhibitors and identified the natural compound sennoside B as having exceptional potency.
Ladostigil Attenuates Induced Oxidative Stress in Human Neuroblast-like SH-SY5Y Cells
Authors: Zohar Keren , Lezmi Elyad , Eliyahu Tsiona , Linial Michal
Published: September 2021

A hallmark of the aging brain is the robust inflammation mediated by microglial activation. Pathophysiology of common neurodegenerative diseases involves oxidative stress and neuroinflammation. Chronic treatment of aging rats by ladostigil, a compound with antioxidant and anti-inflammatory function, prevented microglial activation and learning deficits. In this study, we further investigate the effect of ladostigil on undifferentiated SH-SY5Y cells. We show that SH-SY5Y cells exposed to acute (by H2O2) or chronic oxidative stress (by Sin1, 3-morpholinosydnonimine) induced apoptotic cell death. However, in the presence of ladostigil, the decline in cell viability and the increase of oxidative levels were partially reversed. RNA-seq analysis showed that prolonged oxidation by Sin1 resulted in a simultaneous reduction of the expression level of endoplasmic reticulum (ER) genes that participate in proteostasis. By comparing the differential gene expression profile of Sin1 treated cells to cells incubated with ladostigil before being exposed to Sin1, we observed an over-expression of Clk1 (Cdc2-like kinase 1) which was implicated in psychophysiological stress in mice and Alzheimer’s disease. Ladostigil also suppressed the expression of Ccpg1 (Cell cycle progression 1) and Synj1 (Synaptojanin 1) that are involved in ER-autophagy and endocytic pathways. We postulate that ladostigil alleviated cell damage induced by oxidation. Therefore, under conditions of chronic stress that are observed in the aging brain, ladostigil may block oxidative stress processes and consequently reduce neurotoxicity.
Enisamium Inhibits SARS-CoV-2 RNA Synthesis
Authors: Elli Stefano , Bojkova Denisa , Bechtel Marco , Vial Thomas , Boltz David , Muzzio Miguel , Peng Xinjian , Sala Federico , Cosentino Cesare , Goy Andrew , Guerrini Marco , Müller Lutz , Cinatl Jindrich , Margitich Victor , te Velthuis Aartjan J. W.
Published: September 2021

Pandemic SARS-CoV-2 causes a mild to severe respiratory disease called coronavirus disease 2019 (COVID-19). While control of the SARS-CoV-2 spread partly depends on vaccine-induced or naturally acquired protective herd immunity, antiviral strategies are still needed to manage COVID-19. Enisamium is an inhibitor of influenza A and B viruses in cell culture and clinically approved in countries of the Commonwealth of Independent States. In vitro, enisamium acts through metabolite VR17-04 and inhibits the activity of the influenza A virus RNA polymerase. Here we show that enisamium can inhibit coronavirus infections in NHBE and Caco-2 cells, and the activity of the SARS-CoV-2 RNA polymerase in vitro. Docking and molecular dynamics simulations provide insight into the mechanism of action and indicate that enisamium metabolite VR17-04 prevents GTP and UTP incorporation. Overall, these results suggest that enisamium is an inhibitor of SARS-CoV-2 RNA synthesis in vitro.
Assessment of Bulbar Function in Adult Patients with 5q-SMA Type 2 and 3 under Treatment with Nusinersen
Authors: Brakemeier Svenja , Stolte Benjamin , Thimm Andreas , Kizina Kathrin , Totzeck Andreas , Munoz-Rosales Juan , Kleinschnitz Christoph , Hagenacker Tim
Published: September 2021

The antisense oligonucleotide nusinersen has been shown to improve trunk and limb motor function in patients with spinal muscular atrophy (SMA). Bulbar dysfunction, which is regularly present in SMA, is not captured by standard motor scores, and validated measurement instruments to assess it have not yet been established. Data on whether and how bulbar function changes under gene-based therapies in adult SMA patients are also unavailable. Here, we present data on the course of bulbar dysfunction assessed prospectively before nusinersen treatment initiation and 6 and 14 months later in 23 adult SMA patients using the Sydney Swallow Questionnaire (SSQ) and the bulbar subscore of the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R). While no improvement in bulbar scores was observed under treatment with nusinersen, the absence of a decline still implies a therapeutic effect of nusinersen on bulbar dysfunction. The results of this study aim to contribute to a standardized assessment of bulbar function in adult SMA patients, which may show therapeutic effects of gene-based therapies that are not evident from standard motor scores.
Developing a Digital Solution for Remote Assessment in Multiple Sclerosis: From Concept to Software as a Medical Device
Authors: van der Walt Anneke , Butzkueven Helmut , Shin Robert K. , Midaglia Luciana , Capezzuto Luca , Lindemann Michael , Davies Geraint , Butler Lesley M. , Costantino Cristina , Montalban Xavier
Published: September 2021

There is increasing interest in the development and deployment of digital solutions to improve patient care and facilitate monitoring in medical practice, e.g., by remote observation of disease symptoms in the patients’ home environment. Digital health solutions today range from non-regulated wellness applications and research-grade exploratory instruments to regulated software as a medical device (SaMD). This paper discusses the considerations and complexities in developing innovative, effective, and validated SaMD for multiple sclerosis (MS). The development of SaMD requires a formalised approach (design control), inclusive of technical verification and analytical validation to ensure reliability. SaMD must be clinically evaluated, characterised for benefit and risk, and must conform to regulatory requirements associated with device classification. Cybersecurity and data privacy are also critical. Careful consideration of patient and provider needs throughout the design and testing process help developers overcome challenges of adoption in medical practice. Here, we explore the development pathway for SaMD in MS, leveraging experiences from the development of Floodlight™ MS, a continually evolving bundled solution of SaMD for remote functional assessment of MS. The development process will be charted while reflecting on common challenges in the digital space, with a view to providing insights for future developers.
Brain Abnormalities in Individuals with a Desire for a Healthy Limb Amputation: Somatosensory, Motoric or Both? A Task-Based fMRI Verdict
Authors: Gandola Martina , Zapparoli Laura , Saetta Gianluca , Reverberi Carlo , Salvato Gerardo , Squarza Silvia Amaryllis Claudia , Invernizzi Paola , Sberna Maurizio , Brugger Peter , Bottini Gabriella , Paulesu Eraldo
Published: September 2021

Body integrity dysphoria (BID), a long-lasting desire for the amputation of physically healthy limbs, is associated with reduced fMRI resting-state functional connectivity of somatosensory cortices. Here, we used fMRI to evaluate whether these findings could be replicated and expanded using a task-based paradigm. We measured brain activations during somatosensory stimulation and motor tasks for each of the four limbs in ten individuals with a life-long desire for the amputation of the left leg and fourteen controls. For the left leg, BID individuals had reduced brain activation in the right superior parietal lobule for somatosensory stimulation and in the right paracentral lobule for the motor task, areas where we previously found reduced resting-state functional connectivity. In addition, for somatosensory stimulation only, we found a robust reduction in activation of somatosensory areas SII bilaterally, mostly regardless of the stimulated body part. Areas SII were regions of convergent activations for signals from all four limbs in controls to a significantly greater extent than in subjects with BID. We conclude that BID is associated with altered integration of somatosensory and, to a lesser extent, motor signals, involving limb-specific cortical maps and brain regions where the first integration of body-related signals is achieved through convergence.
Changes in Affective Behavior and Oxidative Stress after Binge Alcohol in Male and Female Rats
Authors: Cortez Ibanelo , Brocardo Patricia S. , Leasure J. Leigh
Published: September 2021

Binge alcohol consumption and alcohol use disorders (AUD) are prevalent, and there is comorbidity with depression and anxiety. Potential underlying mechanisms include neurophysiological, genetic, and metabolic changes resulting from alcohol exposure. Mood and anxiety disorders are more common among women, but whether females are more susceptible to binge-induced oxidative stress and co-occurring anxiety and depression-like behaviors remains unknown. Here, we used a repeated, weekly binge alcohol paradigm in male and female rats to investigate sex differences in despair and anxiety-like behaviors and brain oxidative stress parameters. A single binge alcohol exposure significantly elevated glutathione (GSH) levels in prefrontal cortex (PFC) of both male and female animals. This was accompanied by increased lipid peroxidation in PFC of both sexes. Repeated (once weekly) binge exposure induced changes in anxiety- and depression-like behaviors in both males and females and increased GSH level in the PFC without detectable oxidative damage. Our findings suggest that repeated binge alcohol exposure influences affect regardless of sex and in the absence of membrane damage.
3D Tree Reconstruction in Support of Urban Microclimate Simulation: A Comprehensive Literature Review
Authors: Xu Han , Wang Cynthia Changxin , Shen Xuesong , Zlatanova Sisi
Published: September 2021

The negative climate change induced by rapid urbanization has become a global environmental issue. Numerous studies have been devoted to microclimate regulation functions performed by urban vegetation. Digital city information modeling provides a powerful tool for various simulations and data analytics for the sustainable development of urban areas. However, the method reconstructing urban trees is still in its early stage compared to the relatively mature building modeling. Most prior studies on tree reconstruction focused on retrieving geometric features, while other factors related to urban microclimate simulation were rarely addressed. This paper presents a comprehensive literature review and in-depth analysis covering two distinct research directions in relation to urban microclimate simulation. The first one is set on the identification of key factors related to trees’ impact on urban microclimate. The second one is dedicated to approaches for three-dimensional (3D) tree reconstruction. Based on the findings, the paper identifies information including trees’ geometric, physiological characteristics and relation to the surroundings required for 3D tree reconstruction in the context of urban microclimate simulation, and further assesses the potential of the 3D tree reconstruction approaches to accommodate these pieces of information. An appropriate 3D tree reconstruction approach, which allows for the supply of the required information for urban microclimate simulation, is recommended.
Effect of Vitamin D Supplements on Relapse of Digestive Tract Cancer with Tumor Stromal Immune Response: A Secondary Analysis of the AMATERASU Randomized Clinical Trial
Authors: Akutsu Taisuke , Kanno Kazuki , Okada Shinya , Ohdaira Hironori , Suzuki Yutaka , Urashima Mitsuyoshi
Published: September 2021

The aim was to examine whether vitamin D supplementation (2000 IU/day) reduces the risk of relapse in a subgroup of patients with digestive tract cancer, showing a sufficient immune response in tumor stroma by conducting secondary subgroup analyses of the AMATERASU randomized, double-blind, placebo-controlled trial (UMIN000001977). A total of 372 patients were divided into two subgroups stratified by the median density of immune cells infiltrating in tumor stroma into higher and lower halves. In the higher-half subgroup of CD56+ cells, the relapse ratio was significantly lower in the vitamin D group (7.4%) than in the placebo group (20.5%) (subdistribution hazard ratio (SHR), 0.35; 95% confidence interval (CI), 0.15–0.82), but it was equivalent (25.2% vs. 22.7%) in the lower-half subgroup of CD56+ cells (SHR, 1.21; 95% CI, 0.68–2.19) with a significant interaction (Pinteraction = 0.02). Although there were no significant differences, the risk of relapse was lower in the vitamin D group than in the placebo group in the higher half of CD45RO+ memory T cells (8.9% vs. 19.2%), and of CD8+ cytotoxic T cells (11.3% vs. 22.5%). In patients with digestive tract cancer, vitamin D supplementation was hypothesized to reduce the risk of relapse in the subgroup of patients who already have an adequate infiltration of immune cells in their tumor stroma.
Feasibility and Short-Term Outcomes of Three-Dimensional Hand-Sewn Esophago-Jejunal Anastomosis in Completely Laparoscopic Total Gastrectomy for Cancer
Authors: Charalabopoulos Alexandros , Davakis Spyridon , Paraskeva Panorea , Machairas Nikolaos , Kapelouzou Alkistis , Kordzadeh Ali , Sakarellos Panagiotis , Vailas Michail , Baili Efstratia , Bakoyiannis Christos , Felekouras Evangelos
Published: September 2021

Laparoscopic total gastrectomy is on the rise. One of the most technically demanding steps of the approach is the construction of esophago-jejunal anastomosis. Several laparoscopic anastomotic techniques have been described, like linear stapler side-to-side or circular stapler end-to-side anastomosis; limited data exist regarding hand-sewn esophago-jejunal anastomosis. The study took place between January 2018 and June 2021. Patients enrolled in this study were adults with proximal gastric or esophago-gastric junction Siewert type III tumors that underwent 3D-assisted laparoscopic total gastrectomy. A hand-sewn esophago-jejunal anastomosis was performed in all cases laparoscopically. Forty consecutive cases were performed during the study period. Median anastomotic suturing time was 55 min, with intra-operative methylene blue leak test being negative in all cases. Median operating time was 240 min, and there were no conversions to open. The anastomotic leak rate and postoperative stricture rate were zero. The 30- and 90-day mortality rates were zero. Laparoscopic manual esophago-jejunal anastomosis utilizing a 3D platform in total gastrectomy for cancer can be performed with excellent outcomes regarding anastomotic leak and stricture rate. This anastomotic approach, although technically challenging, is safe and reproducible, with prominent results that can be disseminated in the surgical community.
Comparison of the Clinical Features and Outcomes of Gallbladder Neuroendocrine Carcinoma with Those of Adenocarcinoma: A Propensity Score-Matched Analysis
Authors: Do Min-Young , Jang Sung-Ill , Kang Hua-Pyong , Kim Eui-Joo , Lee Kyong-Joo , Park Go-Eun , Lee Su-Jee , Lee Dong-Ki , Woo Sang-Myung , Cho Jae-Hee
Published: September 2021

Neuroendocrine neoplasms (NENs) of the gallbladder (GB) are extremely rare. We aimed to compare the clinical features, disease progression, management, and prognosis of patients with GB-NENs with those of patients with GB-adenocarcinomas (ADCs). A total of 21 patients with GB-NENs and 206 patients with GB-ADCs, treated at three tertiary medical centers between January 2010 and December 2020, were enrolled. Of the 21 patients with GB-NENs, 20 were diagnosed with poorly differentiated small-cell neuroendocrine carcinomas (NECs), and 1 patient had large-cell NEC. All patients presented with advanced stages of cancer with extensive local extension and/or distant metastasis and non-specific symptoms. Tumor-node-metastasis stage IIIB and IV (A/B) tumors were found in 6 and 15 (1/14) patients, respectively. Nine patients with GB-NEC who underwent surgical resection had a significantly better progression-free survival (PFS) than those who did not undergo surgery. After a propensity score matching with a 1:1 ratio using the American Joint Committee on Cancer stage, age, sex, and operation status, 19 pairs of patients were included. Compared with stage-matched patients with GB-ADC, patients with GB-NEC had similar overall survival and PFS. However, as GB-NEC is rarely diagnosed early, further studies investigating methods for the early diagnosis and improvement in the survival of patients with GB-NEC are needed.
Tumour-Derived Cell Lines and Their Potential for Therapy Prediction in Patients with Metastatic Colorectal Cancer
Authors: Wagner Sandra , Beger Nicola T. , Matschos Stephanie , Szymanski Antonia , Przybylla Randy , Bürtin Florian , Prall Friedrich , Linnebacher Michael , Mullins Christina S.
Published: September 2021

The prognosis of metastatic colorectal cancer (CRC) remains poor. Patients and physicians are in need of individual therapies and precise response predictions. We investigated the predictive capacity of primary tumour material for treatment response of metastases. Mutational landscapes of primary tumours and corresponding metastases of 10 CRC patients were compared. Cell line characteristics and chemosensitivity were investigated pairwise for primary and metastatic tumours of four patients. PDX models of one patient were treated in vivo for proof of concept. Driver mutations did not differ between primaries and metastases, while the latter accumulated additional mutations. In vitro chemosensitivity testing revealed no differences for responses to 5-FU and oxaliplatin between primary and metastatic cell lines. However, irinotecan response differed significantly: the majority of metastases-derived cell lines was less sensitive to irinotecan than their matching primary counterpart. Therapy recommendations based on these findings were compared to clinical treatment response and mostly in line with the predicted outcome. Therefore, primary tumour cell models seem to be a good tool for drug response testing and conclusion drawing for later metastases. With further data from tumour-derived cell models, such predictions could improve clinical treatment decisions, both recommending likely effective therapeutic options while excluding ineffective treatments.
Reproducibility of mRNA-Based Testing of ESR1, PGR, ERBB2, and MKI67 Expression in Invasive Breast Cancer—A Europe-Wide External Quality Assessment
Authors: Erber Ramona , Hartmann Arndt , Fasching Peter Andreas , Ruebner Matthias , Stöhr Robert , Beckmann Matthias Wilhelm , Zentgraf Miriam , Popp Verena , Weidler Jodi , Simon Iris , Becker Steffi , Huebner Hanna , Fischer Josephine , Guerini Rocco Elena , Viale Giuseppe , Cayre Anne , Penault-Llorca Frederique , Caniego Casas Tamara , Pérez-Miés Belén , Palacios José , Jank Paul , Denkert Carsten , Khoury Lina , Mairinger Thomas , Ferrazzi Fulvia
Published: September 2021

Estrogen receptor (ER), progesterone receptor (PgR), Ki-67, and HER2 immunohistochemistry (IHC) together with HER2 in situ hybridization (ISH) are utilized to classify invasive breast cancer (IBC) into predictive molecular subtypes. As IHC evaluation may be hampered by analytical errors, gene expression assays could offer a reliable alternative. In this first Europe-wide external quality assessment (EQA) study, we investigated performance of mRNA-based Xpert® Breast Cancer STRAT4 (CE-IVD) in five European laboratories. The cohort comprised ten pre-therapy IBC core biopsies diagnosed in the coordinating center (CC). STRAT4 binary (positive or negative) mRNA results of each marker (ESR1, PGR, ERBB2, MKI67) were compared with the gold standard IHC/ISH performed by the CC. Sensitivity, specificity, and accuracy of ESR1 and ERBB2 mRNA were 100% for all samples. In contrast, PGR expression was falsely negative for one case by two sites and MKI67 falsely negative for two cases (respectively by four and one sites). These cases had STRAT4 expression values close to assay cut-offs and immunohistochemically presented heterogeneous low positive PgR and heterogeneous Ki-67. Our EQA shows that STRAT4 mRNA assay may be a reproducible method to evaluate ER, PgR, HER2, and Ki-67 status. However, cases with expression values close to assay cut-offs should be carefully reviewed.