bluuebunny/crossref_metadata_2025 huggingface dataset:
Sphingosine kinase 1 regulates lysyl oxidase through STAT3 in hyperoxia-mediated neonatal lung injury
Authors: Ha Alison W , Bai Tao , Ebenezer David L , Sethi Tanvi , Sudhadevi Tara , Mangio Lizar Ace , Garzon Steven , Pryhuber Gloria S , Natarajan Viswanathan , Harijith Anantha
Published: April 2021

Introduction

Neonatal lung injury as a consequence of hyperoxia (HO) therapy and ventilator care contribute to the development of bronchopulmonary dysplasia (BPD). Increased expression and activity of lysyl oxidase (LOX), a key enzyme that cross-links collagen, was associated with increased sphingosine kinase 1 (SPHK1) in human BPD. We, therefore, examined closely the link between LOX and SPHK1 in BPD.

Method

The enzyme expression of SPHK1 and LOX were assessed in lung tissues of human BPD using immunohistochemistry and quantified (Halo). In vivo studies were based on Sphk1−/− and matched wild type (WT) neonatal mice exposed to HO while treated with PF543, an inhibitor of SPHK1. In vitro mechanistic studies used human lung microvascular endothelial cells (HLMVECs).

Results

Both SPHK1 and LOX expressions were increased in lungs of patients with BPD. Tracheal aspirates from patients with BPD had increased LOX, correlating with sphingosine-1-phosphate (S1P) levels. HO-induced increase of LOX in lungs were attenuated in both Sphk1−/− and PF543-treated WT mice, accompanied by reduced collagen staining (sirius red). PF543 reduced LOX activity in both bronchoalveolar lavage fluid and supernatant of HLMVECs following HO. In silico analysis revealed STAT3 as a potential transcriptional regulator of LOX. In HLMVECs, following HO, ChIP assay confirmed increased STAT3 binding to LOX promoter. SPHK1 inhibition reduced phosphorylation of STAT3. Antibody to S1P and siRNA against SPNS2, S1P receptor 1 (S1P1) and STAT3 reduced LOX expression.

Conclusion

HO-induced SPHK1/S1P signalling axis plays a critical role in transcriptional regulation of LOX expression via SPNS2, S1P1 and STAT3 in lung endothelium.
Study on cut-off characteristics of sub-nanosecond silicon carbide PiN switch
Authors: Wu Zhaoyang , Lu Wei , Bao Xiangyang , Meng Fanbao , Yang Zhoubing , Sun Qian , Zhao Fangzhou , Wang Yutian
Published: April 2021

In this paper, a simulation model of [Formula: see text] type PiN high voltage pulse open switch is established. The switch operates in “punch through” mode, with a 4 kA/cm2 cut-off current density and sub-nanosecond cut-off speed. The cut-off process of switch can be divided into three stages, that is, non-equilibrium carriers extraction stage, majority carriers drift stage and charging stage of junction capacitance by change of internal electric field and carrier concentration. Keeping injection current and cut-off current as 20 A and 40 A, the switch cut-off speed and “pedestal” voltage are reciprocally determined. Thus, optimizing the doping concentration and thickness of [Formula: see text] layer is a valid solution for the actual system design.
Realizing high-efficiency low frequency sound absorption of underwater meta-structures by acoustic siphon effect
Authors: Wang Li Bo , Ma Cheng Zhi , Wu Jiu Hui , Liu Chong Rui
Published: April 2021

The underwater acoustic siphon effect is proposed in this work, which aims to reveal the basic physical mechanism of high-efficiency sound absorption in meta-structures composed of multiple detuned units. Furthermore, the influence of the area ratio on the underwater acoustic siphon effect is then investigated by finite element simulation (FES) and theoretical calculation. On this basis, a meta-structure with the maximum absorption coefficient of almost 100% and average absorption coefficient of 80% at 600–1400 Hz is achieved. The underwater acoustic siphon effect could provide a better understanding of high-efficiency sound absorption and offer a new perspective in controlling underwater noises.
TipTap: Approximate Mining of Frequent
k
-Subgraph Patterns in Evolving Graphs
Authors: Nasir Muhammad Anis Uddin , Aslay Cigdem , Morales Gianmarco De Francisci , Riondato Matteo
Published: April 2021

“Perhaps he could dance first and think afterwards, if it isn’t too much to ask him.”

S. Beckett,
Waiting for Godot

Given a labeled graph, the collection of
k
-vertex induced connected subgraph patterns that appear in the graph more frequently than a user-specified minimum threshold provides a compact summary of the characteristics of the graph, and finds applications ranging from biology to network science. However, finding these patterns is challenging, even more so for dynamic graphs that evolve over time, due to the streaming nature of the input and the exponential time complexity of the problem.

We study this task in both incremental and fully-dynamic streaming settings, where arbitrary edges can be added or removed from the graph. We present
TipTap
, a suite of algorithms to compute high-quality approximations of the frequent
k
-vertex subgraphs w.r.t. a given threshold, at any time (i.e., point of the stream), with high probability. In contrast to existing state-of-the-art solutions that require iterating over the entire set of subgraphs in the vicinity of the updated edge,
TipTap
operates by efficiently maintaining a uniform sample of connected
k
-vertex subgraphs, thanks to an optimized neighborhood-exploration procedure. We provide a theoretical analysis of the proposed algorithms in terms of their unbiasedness and of the sample size needed to obtain a desired approximation quality. Our analysis relies on sample-complexity bounds that use Vapnik–Chervonenkis dimension, a key concept from statistical learning theory, which allows us to derive a sufficient sample size that is independent from the size of the graph. The results of our empirical evaluation demonstrates that
TipTap
returns high-quality results more efficiently and accurately than existing baselines.
Analysis of High-Frequency Behavior of AlGaN/GaN HEMTs and MIS-HEMTs under UV Illumination
Authors: Chen Kun-Ming , Lin Chuang-Ju , Nagarajan Venkatesan , Chang Edward Yi , Lin Chao-Wen , Huang Guo-Wei
Published: April 2021

The high-frequency characteristics of AlGaN/GaN high-electron-mobility transistors (HEMTs) and metal-insulator-semiconductor HEMTs (MIS-HEMTs) are investigated under ultraviolet (UV) radiation with 365 nm wavelength. When HEMTs and MIS-HEMTs are illuminated with an UV source, their drain currents increase apparently owing to the generated photocurrent. Nevertheless, they show different high-frequency response to the UV light. For HEMTs, the peak cutoff frequency (fT) and maximum oscillation frequency (fmax) of illuminated devices are 20% and 10% higher than those in dark condition, respectively, owing to the increased transconductance. For MIS-HEMTs, however, their high-frequency performances are degraded when transistors are subject to light exposure. The degradations of peak fT and fmax are around 3.7% and 18%, respectively. The small-signal model parameters relevant to the high-frequency characteristics were extracted to explain these phenomena. Additional trapped charges in the SiN gate dielectric induced by UV light would be responsible for the degraded high-frequency parameters in illuminated MIS-HEMTs. These experimental results are important for designing a suitable GaN-based HEMT for optoelectronic applications.
Mechanosensitive myosin II but not cofilin primarily contributes to cyclic cell stretch-induced selective disassembly of actin stress fibers
Authors: Huang Wenjing , Matsui Tsubasa S. , Saito Takumi , Kuragano Masahiro , Takahashi Masayuki , Kawahara Tomohiro , Sato Masaaki , Deguchi Shinji
Published: April 2021

Cells adapt to applied cyclic stretch (CS) to circumvent chronic activation of proinflammatory signaling. Currently, the molecular mechanism of the selective disassembly of actin stress fibers (SFs) in the stretch direction, which occurs at the early stage of the cellular response to CS, remains controversial. Here, we suggest that the mechanosensitive behavior of myosin II, a major cross-linker of SFs, primarily contributes to the directional disassembly of the actomyosin complex SFs in bovine vascular smooth muscle cells and human U2OS osteosarcoma cells. First, we identified that CS with a shortening phase that exceeds in speed the inherent contractile rate of individual SFs leads to the disassembly. To understand the biological basis, we investigated the effect of expressing myosin regulatory light-chain mutants and found that SFs with less actomyosin activities disassemble more promptly upon CS. We consequently created a minimal mathematical model that recapitulates the salient features of the direction-selective and threshold-triggered disassembly of SFs to show that disassembly or, more specifically, unbundling of the actomyosin bundle SFs is enhanced with sufficiently fast cell shortening. We further demonstrated that similar disassembly of SFs is inducible in the presence of an active LIM-kinase-1 mutant that deactivates cofilin, suggesting that cofilin is dispensable as opposed to a previously proposed mechanism.
NH2-terminal deletion of specific phosphorylation sites on PHOX2B disrupts the formation of enteric neurons in vivo
Authors: Chang David F. , Gilliam Elizabeth A. , Nucho Laura-Marie A. , Garcia Jazmin , Shevchenko Yevheniya , Zuber Samuel M. , Squillaro Anthony I. , Maselli Kathryn M. , Huang Sha , Spence Jason R. , Grikscheit Tracy C.
Published: April 2021

A mutation that affects only 17–20 NH2-terminal amino acids in the paired-like homeobox 2 b ( PHOX2B) gene hinders the subsequent in vivo establishment of intestinal neuronal cells, but not the in vitro differentiation of these cells.
Prolonged Diuretic and Renoprotective Effects of a Xanthone Obtained from Garcinia achachairu Rusby in Normotensive and Hypertensive Rats
Authors: Bolda Mariano Luísa Nathália , Boeing Thaise , Cechinel Filho Valdir , Niero Rivaldo , Gasparotto Junior Arquimedes , Mota da Silva Luisa , de Souza Priscila
Published: April 2021

The previous study showed that 1,5,8-trihydroxy-4′,5′-dimethyl-2H-pyrano(2,3 : 3,2)-4-(3-methylbut-2-enyl) xanthone (TDP) obtained from Garcinia achachairu Rusby (Clusiaceae) branches induces acute diuresis in normotensive (NTR) and spontaneously hypertensive rats (SHR) after 8 h of the experiment. In complementarity, the present study evaluated the prolonged diuretic and renoprotective effects of TDP in both NTR and SHR. The animals received, once a day, oral treatment with TDP (0.1 mg/kg), hydrochlorothiazide (10 mg/kg), or vehicle (VEH; 10 mL/kg). At the end of 7 days, the urine, blood, and kidney samples were collected for biochemical and histological analyzes. The urinary volume of both NTR and SHR after 7 days of treatment with the TDP was significantly increased, associated with augmented urinary electrolyte excretion levels. The treatments did not modify the urinary pH values nor the parameters analyzed in plasma (Na+, K+, Cl−, and Ca2+). Concerning the renal analyzes, when compared with the VEH-treated NTR group, while the activity of the enzymes catalase (CAT) and N-acetyl-β-D-glucosaminidase (NAG), as well as nitrite levels, were increased, the generation of lipid hydroperoxides and the activity of the enzyme myeloperoxidase (MPO) were unaltered. On the other hand, the activities of superoxide dismutase (SOD) and glutathione S-transferase (GST) and the levels of reduced glutathione (GSH) in kidney homogenates of the SHR group were decreased. However, TDP augmented the levels of GSH and GST activities and reduced the levels of nitrite and the activities of CAT and MPO, when compared with VEH-treated only SHR. Besides, the treatment with TDP alleviated the morphological changes of the renal corpuscle region of SHR. Together, these results revealed the prolonged diuretic effect of TDP and their renal protective effect by improving the antioxidative capacity.
Protection of Iron-Induced Oxidative Damage in Neuroblastoma (SH-SY5Y) Cells by Combination of 1-(N-Acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one and Green Tea Extract
Authors: Chansiw Nittaya , Kulprachakarn Kanokwan , Paradee Narisara , Prommaban Adchara , Srichairatanakool Somdet
Published: April 2021

Iron is a crucial trace element and essential for many cellular processes; however, excessive iron accumulation can induce oxidative stress and cell damage. Neurodegenerative disorders, such as Alzheimer’s disease and Parkinson’s disease, have been associated with altered iron homoeostasis causing altered iron distribution and accumulation in brain tissue. This study aims to investigate the protective effect of 1-(N-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one (CM1) in combination with green tea extract (GTE) on iron-induced oxidative stress in neuroblastoma (SH-SY5Y) cells. Cells were cultured in medium with or without ferric chloride loading. Their viability and mitochondrial activity were assessed using MTT and JC-1 staining methods. Levels of the cellular labile iron pool (LIP), reactive oxygen species (ROS), and lipid-peroxidation products were determined using calcein acetoxymethyl ester, 2′,7′-dichlorohydrofluorescein diacetate, and TBARS-based assays, respectively. The viability of iron-loaded cells was found to be significantly increased after treatment with CM1 (10 µM) for 24 h. CM1 co-treatment with GTE resulted in a greater protective effect than their monotherapy. Combination of CM1 and GTE also reduced mitochondrial disruption and LIP content and ROS and TBARS production. In conclusion, the combination of CM1 and GTE exhibits protection against iron-induced oxidative stress in neuroblastoma cells.
An Improved Vehicle Detection Algorithm Based on Multi-Intermediate State Machine
Authors: Xiao Baosen , Xia Jingbo , Li Xiaolu , Gao Qinquan
Published: April 2021

The vehicle detection algorithm is an important part of the intelligent transportation system. The accuracy of the algorithm will determine whether accurate vehicle information can be obtained. The system contains several functional modules, including signal amplification, wireless communication, A/D converter, and sensor set/reset functions. To detect all the intersection vehicles, a number of magnetoresistive sensors are connected to the computer system through the wireless communication module, and then, the detected vehicle information will be transferred back to the master host computer. In this paper, two common vehicle detection algorithms, fixed threshold algorithm and adaptive threshold algorithm, were analyzed in the vehicle detection system with magnetoresistive sensors, simultaneously. Finally, an improved multi-intermediate state machine algorithm for vehicle detection was proposed. Using the intermediate state, this algorithm cannot only detect when the vehicle enters the detection area but also decide whether the vehicle leaves the sensor node or not. In this way, it improves the detection accuracy.
A 90-Day Oral Toxicity of Hydroethanolic Root Extract of Carissa spinarum in Wistar Rats
Authors: Dossou-Yovo Komlan M. , Diallo Aboudoulatif , Lawson-Evi Povi , Kantati Yendubé T. , Darré Tchin , Bakoma Batomayena , Eklu-Gadégbéku Kwashie
Published: April 2021

Background. Herbal medication is a worldwide and ancient practice, mostly in developing countries, where a large part of the population is involved in this practice. Hence, studies must be conducted to evaluate their safety and efficiency to avoid or prevent toxicological risks due to their usage. In Togo, Carissa spinarum is a medicinal plant belonging to Apocynaceae family, used as an aphrodisiac or to heal some ailments including malaria, sickle cell anemia, hypertension, pain, and asthma. Notwithstanding its several ethnomedicinal benefits, just a few toxicological data associated with its chronic use are available. Objective. Therefore, this study aims to assess the toxicity of an ethanolic root extract of Carissa spinarum in Wistar rats. Methods. The 90-day oral toxicity process following OECD TG 408 guidelines is used. Male Wistar rats received Carissa spinarum root hydroethanolic extract at 500 and 1000 mg/kg for 90 days by oral gavage. Body weight changes, hematological and blood biochemical parameters, organ weight changes, malondialdehyde as a lipoperoxidation marker expressed according to tissue proteins, and histopathology of vital organs were assessed. Results. No signs of toxicity or mortality were observed during the 90 days experiment. Hematological parameters have not shown any treatment-related abnormalities. According to biochemical parameters, an increase in the chloride ion level was observed at 1000 mg/kg

p
<
0.01

. There was no significant difference between the treated groups and the control group concerning the malondialdehyde concentration, body weight, and organ relative weight. No changes in necropsy and histopathology of vital organs associated with extract treatment were observed. Conclusion. The results indicated that an ethanolic root extract of Carissa spinarum does not cause adverse effects, which can lead to Wistar rats’ death after 90-day oral administration at 500 and 1000 mg.
The Influence Study on Environmental Regulation and Green Total Factor Productivity of China’s Manufacturing Industry
Authors: Li Ying , Li Siyu
Published: April 2021

Green development is the theme of the current era. Environmental regulation is an essential means to achieve environmental benefits and improve the total green factor productivity of manufacturing facing a series of problems brought by the development model of “high investment, high pollution, and high consumption.” Appropriate environmental regulations need to be implemented to achieve economic and environmental harvest. Based on the panel data of 25 manufacturing industries from 2003 to 2016 in China, this thesis constructs a comprehensive indicator of environmental regulation and calculates the green total factor productivity, and its decomposition applied SBM directional distance function and Malmquist–Luenberger productivity index. Besides, this thesis conducts an empirical analysis of environmental regulation’s effect on green productivity in China. The main conclusions showed that the green total factor productivity of China’s manufacturing industry maintains an upward trend on the whole, and the growth of GTFP mainly depends on technological progress rather than the improvement of technical efficiency. The great differences have significant industrial heterogeneity characteristics of GTFP. A single threshold in the whole manufacturing industry, environmental regulation, and GTFP of industries are shown to be “U shape,” and the left of the inflection point is not significant. Environmental regulations and GTFP of moderation and slightly pollution industries are “U shape,” and there is no nonlinear relationship between environmental regulation intensity and GTFP in light pollution industries. Therefore, the government’s optimal environmental regulation intensity should be implemented according to the industry’s heterogeneity to prevent the phenomenon of “ineffective regulation;” it is necessary to pay attention to both technological innovation and technical efficiency.
Towards Activity Recognition through Multidimensional Mobile Data Fusion with a Smartphone and Deep Learning
Authors: Cao Junkuo , Lin Mingcai , Wang Han , Fang Jiacheng , Xu Yueshen
Published: April 2021

The field of activity recognition has evolved relatively early and has attracted countless researchers. With the continuous development of science and technology, people’s research on human activity recognition is also deepening and becoming richer. Nowadays, whether it is medicine, education, sports, or smart home, various fields have developed a strong interest in activity recognition, and a series of research results have also been put into people’s real production and life. Nowadays, smart phones have become quite popular, and the technology is becoming more and more mature, and various sensors have emerged at the historic moment, so the related research on activity recognition based on mobile phone sensors has its necessity and possibility. This article will use an Android smartphone to collect the data of six basic behaviors of human, which are walking, running, standing, sitting, going upstairs, and going downstairs, through its acceleration sensor, and use the classic model of deep learning CNN (convolutional neural network) to fuse those multidimensional mobile data, using TensorFlow for model training and test evaluation. The generated model is finally transplanted to an Android phone to complete the mobile-end activity recognition system.
Robust Frame Duplication Detection for Degraded Videos
Authors: Han Qi , Chen Hao , Yu Liyang , Li Qiong
Published: April 2021

To detect frame duplication in degraded videos, we proposed a coarse-to-fine approach based on locality-sensitive hashing and image registration. The proposed method consists of a coarse matching stage and a duplication verification step. In the coarse matching stage, visually similar frame sequences are preclustered by locality-sensitive hashing and considered as potential duplication candidates. These candidates are further checked by a duplication verification step. Being different from the existing methods, our duplication verification does not rely on a fixed distance (or correlation) threshold to judge whether two frames are identical. We resorted to image registration, which is intrinsically a global optimal matching process, to determine whether two frames coincide with each other. We integrated the stability information into the registration objective function to make the registration process more robust for degraded videos. To test the performance of the proposed method, we created a dataset, which consists of

3

subsets of different kinds of degradation and 117 forged videos in total. The experimental results show that our method outperforms state-of-the-art methods for most cases in our dataset and exhibits outstanding robustness under different conditions. Thanks to the coarse-to-fine strategy, the running time of the proposed method is also quite competitive.
Mixture Ratio Design Optimization of Coal Gangue‐Based Geopolymer Concrete Based on Modified Gravitational Search Algorithm
Authors: Zhang Daming , Sun Fangjin , Liu Tiantian , Xu Zhonghao
Published: April 2021

A green concrete, new type of coal gangue‐based geopolymer concrete, was prepared. Coal gangue geopolymer concrete contains many mineral admixtures and alkaline activators; the concrete mixture ratio design has always been a complex problem. The framework of the mix design optimization by the proposed method is established in this work. The paper aims to minimize the economic cost under the premise of ensuring the strength and workability of coal gangue‐based geopolymer concrete. Gravitational search algorithm (GSA) has the advantages of faster convergence speed and stronger exploitation performance compared with the traditional optimization algorithms. However, GSA tends to premature convergence and local optimum, with weak search ability. Therefore, chaotic map is introduced in the work here. Gravitational search algorithm was modified based on Chebyshev map in chaotic theory, and the modified equations were derived. The modified algorithm was verified by the calculation of typical functions. And results from traditional GSA and GSA modified by another chaotic mapping, logistic mapping, were compared and the characteristics of different GSA were analyzed and concluded. After that, the mix design of geopolymer concrete based on coal gangue with different strength grades was optimized with the modified GSA. Through analysis of the optimization results, cost variation of different strength grade coal gangue‐based geopolymer concrete was revealed. Costs declined significantly; the higher the grades within a certain strength range, the more saved. Therefore, it can be inferred that the modified gravity search method provides a reliable tool for the optimization of mixture ratio of similar geopolymer concrete.
COVID-19 Infection Negative in Nasopharyngeal Swabs but Suspected in Computed Tomography and Confirmed in Bronchoalveolar Lavage Material
Authors: Chrzan Robert , Popiela Tadeusz , Małecki Maciej , Skupień Jan , Bryll Amira , Grochowska Anna
Published: April 2021

We present a case of a patient with clinical symptoms of pneumonia, negative in several polymerase chain reaction COVID-19 tests from nasopharyngeal swabs but suspected in computed tomography and finally confirmed in bronchoalveolar lavage material.
Critical Height of Unfilled Zone in Underlying Gob Piles
Authors: Yi Xiaoyong , Zhu Weibing , Ning Shan , Wang Laolao , Luo Zeqiang
Published: April 2021

To address problems associated with mining above gob piles in the Chinese midwest mining area, a mechanic model for a coal pillar was established based on the displacement variation method. Additionally, the effect of critical unfilled zone height in the underlying gob (UZHUG) on the coal pillar was investigated through a 3DEC numerical simulation; fieldwork was conducted with a borehole televiewer to measure the UZHUG in the Yuanbaowan Coal Mine. The results indicated that the shear stress value and distribution layout in the coal pillar were affected by the UZHUG. The larger the UZHUG, the greater the shear stress and the wider the distribution scope, moving from two sides to the middle zone. Moreover, the larger the UZHUG, the smaller the maximum bearing capacity of the coal pillar, and subsequently, the greater the horizontal deformation of the coal pillar and roof convergence. The critical UZHUG is 2 m considering coal pillar deformation and stress transfer characteristics. Field measurements have confirmed that the UZHUG of 2 m ensured safe mining in the No. 6 coal seam. However, a second round of filling is needed when achieving a UZHUG of 4.4 m. This study serves as a reference for safe mining above gob piles.
Metal Contents of Lake Fish in Area Close to Disposal of Industrial Waste
Authors: Utomo Suyud Warno , Rahmadina Frisca , Wispriyono Bambang , Kusnoputranto Haryoto , Asyary Al
Published: April 2021

This research was conducted to analyze the content of Fe, Cu, Cd, Cr, and Pb in several species of fish taken from three lakes that are close to the disposal of industrial waste in Indonesia. The fish samples were taken from three lakes, namely, Muara Angke, Weda, and Morowali. The samples from Morowali were analyzed in April 2019, those from Weda from November to December 2019, and those from Muara Angke in June 2018. All the samples were then analyzed at the Chemistry Laboratory of the Department of Chemistry, Faculty of Mathematics and Natural Science, University of Indonesia, and the Integrated Laboratory of IPB. The main results showed that all types of fish from Morowali and Weda were no longer safe to consume because they contained Fe, Cu, Cd, and Cr exceeding the threshold of metal contamination. Meanwhile, all types of fish from Muara Angke, except for ayam-ayam, are still safe for consumption. The results of this study can be a source of information regarding metal content in fish and fish feed for safe consumption. Given the high consumption rate of fish and the hazards of heavy metals on humans’ health, such research must be furthered.
Paracontact Metric

κ
,
μ

-Manifold Satisfying the Miao-Tam Equation
Authors: Li Dehe , Yin Jiabin
Published: April 2021

In this paper, we classified the paracontact metric

κ
,
μ

-manifold satisfying the Miao-Tam critical equation with

κ
>
−
1

. We proved that it is locally isometric to the product of a flat

n
+
1

-dimensional manifold and an

n

-dimensional manifold of negative constant curvature

−
4

.
Walking Characteristics of Dual-Arm Inspection Robot with Flexible-Cable
Authors: Wei Yongle , Zhang Jiashun , Fang Lijin
Published: April 2021

The overhead transmission line has a catenary shape, which has great influence on the dynamic characteristics of an inspection robot walking along the line and may even cause the walking-wheel to fall from the line. Compared with other similar inspection robots, the unique structure of the dual-arm inspection robot with flexible-cable is introduced. Taking the dual-arm inspection robot with flexible-cable walking along the uphill section of the line as an example, the force states of the robot when it works at acceleration, uniform speed, deceleration, and stopping were studied in detail. The corresponding force balance equations were established, and the walking-wheel torques in each working state were solved. The working states of the robot walking along the catenary shape line were simulated using ADAMS software. Simulation results show that the walking process of the robot is stable, the walking-wheels have good contact with the line, and the forces of two walking-wheels are almost balanced, which enables the robot to have good adaptability and climbing ability for the line. The prototype test that the robot walked along the line was carried out. The results of the simulation and prototype test are consistent with the theoretical analysis, so the rationality of robot structure design is verified. In the future, the navigation control and stability of the robot walking along the line will be researched, so that the robot can complete the patrol task in the real environment.
Solvability for a New Class of Moore-Gibson-Thompson Equation with Viscoelastic Memory, Source Terms, and Integral Condition
Authors: Boulaaras Salah Mahmoud , Choucha Abdelbaki , Ouchenane Djamel , Alharbi Asma , Abdalla Mohamed , Cherif Bahri Belkacem
Published: April 2021

This paper deals with the existence and uniqueness of solutions of a new class of Moore-Gibson-Thompson equation with respect to the nonlocal mixed boundary value problem, source term, and nonnegative memory kernel. Galerkin’s method was the main used tool for proving our result. This work is a generalization of recent homogenous work.
A Protective Strategy to Counteract the Oxidative Stress Induced by Simulated Microgravity on H9C2 Cardiomyocytes
Authors: Guarnieri Simone , Morabito Caterina , Bevere Michele , Lanuti Paola , Mariggiò Maria A.
Published: April 2021

Microgravity affects human cardiovascular function inducing heart rhythm disturbances and even cardiac atrophy. The mechanisms triggered by microgravity and the search for protection strategies are difficult to be investigated in vivo. This study is aimed at investigating the effects induced by simulated microgravity on a cardiomyocyte‐like phenotype. The Random Positioning Machine (RPM), set in a CO2 incubator, was used to simulate microgravity, and H9C2 cell line was used as the cardiomyocyte‐like model. H9C2 cells were exposed to simulated microgravity up to 96 h, showing a slower cell proliferation rate and lower metabolic activity in comparison to cell grown at earth gravity. In exposed cells, these effects were accompanied by increased levels of intracellular reactive oxygen species (ROS), cytosolic Ca2+, and mitochondrial superoxide anion. Protein carbonyls, markers of protein oxidation, were significantly increased after the first 48 h of exposition in the RPM. In these conditions, the presence of an antioxidant, the N‐acetylcysteine (NAC), counteracted the effects induced by the simulated microgravity. In conclusion, these data suggest that simulated microgravity triggers a concomitant increase of intracellular ROS and Ca2+ levels and affects cell metabolic activity which in turn could be responsible for the slower proliferative rate. Nevertheless, the very low number of detectable dead cells and, more interestingly, the protective effect of NA, demonstrate that simulated microgravity does not have “an irreversible toxic effect” but, affecting the oxidative balance, results in a transient slowdown of proliferation.
Bone Marrow Mesenchymal Stromal Cells Can Render Multiple Myeloma Cells Resistant to Cytotoxic Machinery of CAR T Cells through Inhibition of Apoptosis
Authors: Holthof Lisa C. , van der Schans Jort J. , Katsarou Afroditi , Poels Renée , Gelderloos Anne T. , Drent Esther , van Hal-van Veen Susan E. , Li Fengzhi , Zweegman Sonja , van de Donk Niels W.C.J. , Themeli Maria , Groen Richard W.J. , Mutis Tuna
Published: April 2021

Purpose:

The microenvironment of multiple myeloma (MM) can critically impair therapy outcome, including immunotherapies. In this context, we have earlier demonstrated that bone marrow mesenchymal stromal cells (BMMSC) protect MM cells against the lytic machinery of MM-reactive cytotoxic T cells (CTL) and daratumumab-redirected natural killer (NK) cells through the upregulation of antiapoptotic proteins Survivin and Mcl-1 in MM cells. Here, we investigated the significance of this mode of immune escape on T cells engineered to express chimeric antigen receptors (CAR T cells).

Experimental Design:

We tested the cytolytic ability of a panel of 10 BCMA-, CD38-, and CD138-specific CAR T cells with different affinities against a model MM cell line and against patient-derived MM cells in the presence versus absence of BMMSCs.

Results:

Although BMMSCs hardly protected MM cells from lysis by high-affinity, strongly lytic BCMA- and CD38-CAR T cells, they significantly protected against lower affinity, moderately lytic BCMA-, CD38-, and CD138-specific CAR T cells in a cell–cell contact-dependent manner. Overall, there was a remarkable inverse correlation between the protective ability of BMMSCs and the lytic activity of all CAR T cells, which was dependent on CAR affinity and type of costimulation. Furthermore, BMMSC-mediated resistance against CAR T cells was effectively modulated by FL118, an inhibitor of antiapoptotic proteins Survivin, Mcl-1, and XIAP.

Conclusions:

These results extend our findings on the negative impact of the microenvironment against immunotherapies and suggest that outcome of CAR T cell or conventional CTL therapies could benefit from inhibition of antiapoptotic proteins upregulated in MM cells through BMMSC interactions.
Lutetium-177-PSMA-617 in Low-Volume Hormone-Sensitive Metastatic Prostate Cancer: A Prospective Pilot Study
Authors: Privé Bastiaan M. , Peters Steffie M.B. , Muselaers Constantijn H.J. , van Oort Inge M. , Janssen Marcel J.R. , Sedelaar J.P. Michiel , Konijnenberg Mark W. , Zámecnik Patrik , Uijen Maike J.M. , Schilham Melline G.M. , Eek Annemarie , Scheenen Tom W.J. , Verzijlbergen J. Fred , Gerritsen Winald R. , Mehra Niven , Kerkmeijer Linda G.W. , Smeenk Robert J. , Somford Diederik M. , van Basten Jean-Paul A. , Heskamp Sandra , Barentsz Jelle O. , Gotthardt Martin , Witjes J. Alfred , Nagarajah James
Published: April 2021

Purpose:

[177Lu]Lu-PSMA-617 radioligand therapy (177Lu-PSMA) is a novel treatment for metastatic castration-resistant prostate cancer (mCRPC), which could also be applied to patients with metastatic hormone-sensitive prostate cancer (mHSPC) with PSMA expression. In this prospective study (NCT03828838), we analyzed toxicity, radiation doses, and treatment effect of 177Lu-PSMA in pateints with low-volume mHSPC.

Patients and Methods:

Ten progressive patients with mHSPC following local treatment, with a maximum of ten metastatic lesions on [68Ga]Ga-PSMA-11 PET/diagnostic-CT imaging (PSMA-PET) and serum PSA doubling time <6 months received two cycles of 177Lu-PSMA. Whole-body single-photon emission CT/CT (SPECT/CT) and blood dosimetry was performed to calculate doses to the tumors and organs at risk (OAR). Adverse events (AE), laboratory values (monitoring response and toxicity), and quality of life were monitored until week 24 after cycle 2, the end of study (EOS). All patients underwent PSMA-PET at screening, 8 weeks after cycle 1, 12 weeks after cycle 2, and at EOS.

Results:

All patients received two cycles of 177Lu-PSMA without complications. No treatment-related grade III–IV adverse events were observed. According to dosimetry, none of the OAR reached threshold doses for radiation-related toxicity. Moreover, all target lesions received a higher radiation dose than the OAR. All 10 patients showed altered PSA kinetics, postponed androgen deprivation therapy, and maintained good quality of life. Half of the patients showed a PSA response of more than 50%. One patient had a complete response on PSMA-PET imaging until EOS and two others had only minimal residual disease.

Conclusions:

177Lu-PSMA appeared to be a feasible and safe treatment modality in patients with low-volume mHSPC.
Phase I/Ib Clinical Trial of Sabatolimab, an Anti–TIM-3 Antibody, Alone and in Combination with Spartalizumab, an Anti–PD-1 Antibody, in Advanced Solid Tumors
Authors: Curigliano Giuseppe , Gelderblom Hans , Mach Nicolas , Doi Toshihiko , Tai David , Forde Patrick M. , Sarantopoulos John , Bedard Philippe L. , Lin Chia-Chi , Hodi F. Stephen , Wilgenhof Sofie , Santoro Armando , Sabatos-Peyton Catherine A. , Longmire Tyler A. , Xyrafas Alexandros , Sun Haiying , Gutzwiller Sabine , Manenti Luigi , Naing Aung
Published: April 2021

Purpose:

Sabatolimab (MBG453) and spartalizumab are mAbs that bind T-cell immunoglobulin domain and mucin domain-3 (TIM-3) and programmed death-1 (PD-1), respectively. This phase I/II study evaluated the safety and efficacy of sabatolimab, with or without spartalizumab, in patients with advanced solid tumors.

Patients and Methods:

Primary objectives of the phase I/Ib part were to characterize the safety and estimate recommended phase II dose (RP2D) for future studies. Dose escalation was guided by a Bayesian (hierarchical) logistic regression model. Sabatolimab was administered intravenously, 20 to 1,200 mg, every 2 or 4 weeks (Q2W or Q4W). Spartalizumab was administered intravenously, 80 to 400 mg, Q2W or Q4W.

Results:

Enrolled patients (n = 219) had a range of cancers, most commonly ovarian (17%) and colorectal cancer (7%); patients received sabatolimab (n = 133) or sabatolimab plus spartalizumab (n = 86). The MTD was not reached. The most common adverse event suspected to be treatment-related was fatigue (9%, sabatolimab; 15%, combination). No responses were seen with sabatolimab. Five patients receiving combination treatment had partial responses (6%; lasting 12–27 months) in colorectal cancer (n = 2), non–small cell lung cancer (NSCLC), malignant perianal melanoma, and SCLC. Of the five, two patients had elevated expression of immune markers in baseline biopsies; another three had >10% TIM-3–positive staining, including one patient with NSCLC who received prior PD-1 therapy.

Conclusions:

Sabatolimab plus spartalizumab was well tolerated and showed preliminary signs of antitumor activity. The RP2D for sabatolimab was selected as 800 mg Q4W (alternatively Q3W or Q2W schedules, based on modeling), with or without 400 mg spartalizumab Q4W.
Selective Modulation of a Pan-Essential Protein as a Therapeutic Strategy in Cancer
Authors: Malone Clare F. , Dharia Neekesh V. , Kugener Guillaume , Forman Alexandra B. , Rothberg Michael V. , Abdusamad Mai , Gonzalez Alfredo , Kuljanin Miljan , Robichaud Amanda L. , Conway Amy Saur , Dempster Joshua M. , Paolella Brenton R. , Dumont Nancy , Hovestadt Volker , Mancias Joseph D. , Younger Scott T. , Root David E. , Golub Todd R. , Vazquez Francisca , Stegmaier Kimberly
Published: April 2021

Cancer dependency maps, which use CRISPR/Cas9 depletion screens to profile the landscape of genetic dependencies in hundreds of cancer cell lines, have identified context-specific dependencies that could be therapeutically exploited. An ideal therapy is both lethal and precise, but these depletion screens cannot readily distinguish between gene effects that are cytostatic or cytotoxic. Here, we use a diverse panel of functional genomic screening assays to identify NXT1 as a selective and rapidly lethal in vivo relevant genetic dependency in MYCN-amplified neuroblastoma. NXT1 heterodimerizes with NXF1, and together they form the principal mRNA nuclear export machinery. We describe a previously unrecognized mechanism of synthetic lethality between NXT1 and its paralog NXT2: their common essential binding partner NXF1 is lost only in the absence of both. We propose a potential therapeutic strategy for tumor-selective elimination of a protein that, if targeted directly, is expected to cause widespread toxicity.

Significance:

We provide a framework for identifying new therapeutic targets from functional genomic screens. We nominate NXT1 as a selective lethal target in neuroblastoma and propose a therapeutic approach where the essential protein NXF1 can be selectively eliminated in tumor cells by exploiting the NXT1–NXT2 paralog relationship.

See related commentary by Wang and Abdel-Wahab, p. 2129.

This article is highlighted in the In This Issue feature, p. 2113
Bulky Condyloma Acuminata following Ustekinumab Treatment for Plaque Psoriasis: A Case Report
Authors: Burlando Martina , Molle Mattia Fabio , Cozzani Emanuele , Parodi Aurora
Published: April 2021

Ustekinumab is a fully human monoclonal antibody targeting the pro-inflammatory cytokines interleukin (IL)-12 and IL-23 approved for the treatment of psoriasis and psoriatic arthritis. We report a case of a patient treated for chronic plaque psoriasis with ustekinumab who developed bulky condyloma acuminata shortly after initiating the treatment. Although ustekinumab has already been described in literature associated with other forms of human papilloma virus skin infections, this is the first case to our knowledge in which ustekinumab is associated with genital warts.
A Stronger Effect of Body Mass Index and Waist Circumference on the Prevalence of Uncontrolled Hypertension among Caucasian Men than Women
Authors: Chudek Anna , Owczarek Aleksander Jerzy , Ficek Joanna , Olszanecka-Glinianowicz Magdalena , Wieczorowska-Tobis Katarzyna , Walencka Zofia , Almgren-Rachtan Agnieszka , Chudek Jerzy
Published: April 2021

Background: Gender-related differences in fat distribution may affect blood pressure (BP) control in hypertensive subjects. The aim of the study was to assess how body mass (BM), BMI, and waist circumference (WC) influence the effectiveness of antihypertension therapy in hypertensive men and women in daily clinical practice. Patients and Methods: The observational study involved 12,289 adult hypertensive Caucasians (6,163 women) declaring regular use of antihypertensive drugs. BP control was scored based on the mean values of 2 attended office BP measurements. WC thresholds for visceral obesity were adopted from definitions of the International Diabetes Federation (≥94/80 cm for men/women) and National Cholesterol Education Program Adult Treatment Panel III (≥102/88 cm for men/women). Stepwise backward multivariable logistic regression was used to analyse correlates of the effectiveness of hypertension therapy. Results: The predictive value of BMI ≥30 (for uncontrolled hypertension) was stronger than that of visceral obesity, regardless of the criteria used. In men, BP control rapidly deteriorated with BMI (odds ratio [OR] up to 8.58 [95% CI: 5.74–12.83]) and WC (OR up to 5.09 [3.84–6.74]), while in women, the association was more flattened (OR up to 3.63 [2.78–4.74] and 1.93 [1.59–2.35], respectively). However, the highest risk of uncontrolled BP occurred in women with BM ≥110 kg (OR = 10.47 [5.05–21.71]) and men with BM ≥125 kg (OR = 9.66 [5.86–15.94]). Conclusions: (1) Obesity and visceral obesity limit the effectiveness of antihypertension therapy more in men than in women. (2) This phenomenon should be taken into account in the prescription of adequate doses of antihypertensive drugs.
Gene Transfer Therapy for Neurodevelopmental Disorders
Authors: Ozlu Can , Bailey Rachel M. , Sinnett Sarah , Goodspeed Kimberly D.
Published: April 2021

Neurodevelopmental disorders (NDDs) include a broad spectrum of disorders that disrupt normal brain development. Though some NDDs are caused by acquired insults (i.e., toxic or infectious encephalopathy) or may be cryptogenic, many NDDs are caused by variants in a single gene or groups of genes that disrupt neuronal development or function. In this review, we will focus on those NDDs with a genetic etiology. The exact mechanism, timing, and progression of the molecular pathology are seldom well known; however, the abnormalities in development typically manifest in similar patterns such as delays or regression in motor function, social skills, and language or cognitive abilities. Severity of impairment can vary widely. At present, only symptomatic treatments are available to manage seizures and behavioral problems commonly seen in NDDs. In recent years, there has been a rapid expansion of research into gene therapy using adeno-associated viruses (AAVs). Using AAVs as vectors to replace the non- or dysfunctional gene in vivo is a relatively simple model which has created an unprecedented opportunity for the future of NDD treatment. Advances in this field are of paramount importance as NDDs lead to a massive lifelong burden of disease on the affected individuals and families. In this article, we review the unique advantages and challenges of AAV gene therapies. We then look at potential applications of gene therapy for 3 of the more common NDDs (Rett syndrome, fragile X syndrome, and Angelman syndrome), as well as 2 less common NDDs (SLC13A5 deficiency disorder and SLC6A1-related disorder). We will review the available natural history of each disease and current state of preclinical studies including a discussion on the application of AAV gene therapies for each disease.
Asporin Expression on Stromal Cells and/or Cancer Cells Might Be A Useful Prognostic Marker in Patients with Diffuse-Type Gastric Cancer
Authors: Yashiro Masakazu , Hasegawa Tsuyoshi , Yamamoto Yurie , Tsujio Gen , Nishimura Sadaaki , Sera Tomohiro , Sugimoto Atsushi , Kushiyama Shuhei , Kasashima Hiroaki , Fukuoka Tatsunari , Sakurai Katsunobu , Toyokawa Takahiro , Kubo Naoshi , Ohira Masaichi
Published: April 2021

Background: Asporin (ASPN), a member of the proteoglycan family, has been shown to have a close correlation with cancer progression. It is not known whether ASPN is an oncogenic driver or a tumor suppressor in human gastric cancer. We sought herein to determine the relationship between ASPN expression and clinicopathological features of gastric cancer. Patients and Methods: A total of 296 gastric cancer patients (diffuse type, n = 144; intestinal type, n = 152) were enrolled. The ASPN expression level in each case was analyzed by immunohistochemistry. Results: ASPN was mainly found on stromal cells, especially on fibroblasts in tumor stroma, i.e., cancer-associated fibroblasts. The ASPN expression on either cancer cells or stromal cells was significantly high in macroscopic scirrhous-type tumors (p < 0.001) and histologically abundant stroma-type tumors (p < 0.001). Interestingly, a Kaplan-Meier survival curve of the 144 cases of diffuse-type gastric cancer revealed a significantly poorer prognosis in patients with ASPN-positive expression (p = 0.043; log rank) compared to those with ASPN-negative expression, but the prognoses were not significantly different in these subgroups of the 152 cases of intestinal-type gastric cancer. A multivariate analysis with respect to overall survival showed that ASPN expression on stromal cells and/or cancer cells was significantly correlated with overall survival in patients with diffuse-type gastric cancer (p = 0.041). Conclusion: In gastric cancer, ASPN was expressed mainly on stromal cells and partially on cancer cells. ASPN expression on stromal cells and/or cancer cells might be a useful prognostic marker in patients with diffuse-type gastric cancer.