bluuebunny/crossref_metadata_2025 huggingface dataset:
Dynamic Scheduling Optimization of Production Workshops Based on Digital Twin
Authors: Ding Guozhi , Guo Shiyao , Wu Xiaohui
Published: October 2022

Production scheduling is the key to manufacturing process decision support, which directly affects the efficiency and competitiveness of enterprises. The production process of discrete workshops is complex and changeable, and it is usually difficult to make adjustments quickly and accurately in response to disturbance events. In this paper, a workshop production scheduling method based on digital twin is proposed and applied to the manufacturing workshop of an aerospace factory. Combined with the advantages of real-time virtual real interaction fusion of digital twin technology, the dynamic scheduling problem under fault disturbance factors is studied. A high-fidelity digital twin workshop is established to realize the mapping and interaction between the real production and the virtual factory. Based on the vibration data of machine tool spindle, a fault prediction method of learning vector quantization neural network is proposed. The dynamic scheduling strategy of workshop production based on digital twin is constructed and compared with the scheduling results without digital twin under fault disturbance. The results show that the scheduling method based on digital twin can effectively deal with disturbances and improve workshop productivity. This study can be used for the application of digital twin and production scheduling in practical factories.
IoT-Based Discomfort Monitoring and a Precise Point Positioning Technique System for Smart Wheelchairs
Authors: Muangmeesri Benchalak , Wisaeng Kittipol
Published: October 2022

The Internet is becoming increasingly important in our daily lives, allowing people to exchange and receive a wide variety of data. It can be utilized in a variety of ways for maximum benefit. For example, the concept of the Internet of Things (IoT) suggests that objects can be linked to the Internet. Based on this concept, in this paper, we describe the creation of modern smart-wheelchair accessories. These make the wheelchair simple to use, suitable for the elderly, and foldable. A health monitoring accessory is one of the critical functions. The Internet of Things is central to the concept of an electric-powered smart wheelchair. Residential communication networks connect electrical appliances and services, enable monitoring, and provide access from which to control various devices. The controls of a smart wheelchair comprise three essential components: a smart device that connects to the wheelchair, an Internet network, and a microcontroller. The results of our tests enable remote operation of the electric-powered wheelchair; command and control are excellent. Most significantly, our method provides consumers with an extra stage of security.
Stability and Damping in the Disks of Massive Galaxies
Authors: Marr John Herbert
Published: October 2022

After their initial formation, disk galaxies are observed to be rotationally stable over periods of >6 Gyr, implying that any large velocity disturbances of stars and gas clouds are damped rapidly on the timescale of their rotation. However, it is also known that despite this damping, there must be a degree of random local motion to stabilize the orbits against degenerate collapse. A mechanism for such damping is proposed by a combination of inter-stellar gravitational interactions, and interactions with the Oort clouds and exo-Oort objects associated with each star. These mechanisms may produce rapid damping of large perturbations within a time period that is short on the scale of observational look-back time, but long on the scale of the disk rotational period for stars with small perturbations. This mechanism may also account for the locally observed mean perturbations in the Milky Way of 8–15 km/s for younger stars and 20–30 km/s for older stars.
Factors Influencing the CO2 Corrosion Pattern of Oil–Water Mixed Transmission Pipeline during High Water Content Period
Authors: Yang Zhonghua , Shi Lihong , Zou Minghua , Wang Changquan
Published: October 2022

After the oil field enters the high water content period, the oil–water mixed fluid in the mixing system will gradually change into the water-in-oil mixed fluid, while the dissolved CO2 causes the pH value of the mixed fluid to decrease. There is also a certain amount of bacteria in the output fluid, with many factors leading to the intensification in the corrosion of the oil–water mixed system pipeline in the high water content period. To clarify its corrosion law, through the mixed transmission pipeline material, 20# carbon steel, in high water conditions under the action of different single factor dynamic corrosion rate experiments, along with the use of the SPSS method, were used to determine the corrosion of the main control factors. The results show that in the high water content period, the corrosion rate of the mixed pipeline 20# steel gradually increases with the increase in temperature pressure, CO2 partial pressure, SRB content, Ca2+ + Mg2+ content, and Cl− content. The corrosion rate with the CO2 partial pressure and SRB content changes show a strong multiplicative power relationship; with Ca2+ + Mg2+ content, Cl− content changes show a logarithmic relationship, the relationship degree R2 is above 0.98. Through SPSS data analysis software combined with experimental data for correlation degree analysis, it is concluded that the correlation magnitude relationship between each factor and corrosion rate is CO2 partial pressure > SRB content > Cl− content > Ca2+ + Mg2+ content > temperature pressure, which provides a theoretical basis for the corrosion protection of an oil gathering pipeline.
Enhancing Rainfall-Runoff Simulation via Meteorological Variables and a Deep-Conceptual Learning-Based Framework
Authors: Achite Mohammed , Mohammadi Babak , Jehanzaib Muhammad , Elshaboury Nehal , Pham Quoc Bao , Duan Zheng
Published: October 2022

Accurate streamflow simulation is crucial for many applications, such as optimal reservoir operation and irrigation. Conceptual techniques employ physical ideas and are suitable for representing the physics of the hydrologic model, but they might fail in competition with their more advanced counterparts. In contrast, deep learning (DL) approaches provide a great computational capability for streamflow simulation, but they rely on data characteristics and the physics of the issue cannot be fully understood. To overcome these limitations, the current study provided a novel framework based on a combination of conceptual and DL techniques for enhancing the accuracy of streamflow simulation in a snow-covered basin. In this regard, the current study simulated daily streamflow in the Kalixälven river basin in northern Sweden by integrating a snow-based conceptual hydrological model (MISD) with a DL model. Daily precipitation, air temperature (average, minimum, and maximum), dew point temperature, evapotranspiration, relative humidity, sunshine duration, global solar radiation, and atmospheric pressure data were used as inputs for the DL model to examine the effect of each meteorological variable on the streamflow simulation. Results proved that adding meteorological variables to the conceptual hydrological model underframe of parallel settings can improve the accuracy of streamflow simulating by the DL model. The MISD model simulated streamflow had an MAE = 8.33 (cms), r = 0.88, and NSE = 0.77 for the validation phase. The proposed deep-conceptual learning-based framework also performed better than the standalone MISD model; the DL method had an MAE = 7.89 (cms), r = 0.90, and NSE = 0.80 for the validation phase when meteorological variables and MISD results were combined as inputs for the DL model. The integrated rainfall-runoff model proposed in this research is a new concept in rainfall-runoff modeling which can be used for accurate streamflow simulations.
First Results of the Application of a Citizen Science-Based Mobile Monitoring System to the Study of Household Heating Emissions
Authors: Diviacco Paolo , Iurcev Massimiliano , Carbajales Rodrigo José , Potleca Nikolas
Published: October 2022

This work aims at understanding whether a citizen science-based monitoring system could be adequate to detect the effects, in terms of air quality, of solid and liquid fuel combustion for household heating. Citizen science is known to be able to improve the coverage and resolution of measurements at a very low cost. On the other hand, it also has severe limitations. Since low-cost sensors are to be used, measurements are problematic in terms of precision and accuracy. In order to test these aspects, we developed a system named COCAL that supports all the phases of air quality monitoring, from data acquisition, georeferencing, transmission, and processing up to web mapping. In this work, we focus on particulate matter. To address the limitations of the citizen science approach, we carefully tested all the parts of the system and, in particular, the performances of the low-cost sensors. We highlighted that their precision is acceptable, while their accuracy is insufficient. Measurements taken within such a paradigm cannot be used, therefore, as reference values. They can be used, instead, as relative values, in order to identify and to map trends, anomalies and hotspots. We used COCAL extensively in the city of Trieste and were able to identify different behaviors in different areas of the city. In the city center, PM values increase constantly during the day. In the rural suburbs of the city, we observed that PM values are low during the day but increase very rapidly after 5 p.m. It is important to note that, in the city center, household heating is based almost completely on natural gas. In the rural areas, household heating is generally based on wood burning stoves or liquid and solid fuel. A possible explanation of the different behavior between the two areas can then be related to commuters living in the rural areas but working in the city center. When they return home in the evening, they switch on the heating systems triggering the release of large quantities of particulate matter. We were able to map peaks of particulate matter values and highlight that they are initially located within the village centers to later propagate to the areas around them. The possibility of mapping air quality with the coverage and resolution we were able to obtain within a citizen science approach is very encouraging. This can be very helpful in understanding the impact that liquid and solid fuel combustion can have on the environment and human health. In addition, we think that this opportunity can be very important considering the current geopolitical situation where a (hopefully only temporary) shift toward pollutant fuels is expected in the near future.
Laboratory Search for Fe IX Solar Diagnostic Lines Using an Electron Beam Ion Trap
Authors: Träbert Elmar , Beiersdorfer Peter , Brown Gregory V. , Hell Natalie , Lepson Jaan K. , Fairchild Alexander J. , Hahn Michael , Savin Daniel W.
Published: October 2022

The Fe IX spectrum features two lines in the extreme ultraviolet whose ratio has been rated among the best density diagnostics in the solar spectrum. One line is an E1-allowed intercombination transition at 244.909 Å, the other an E1-forbidden M2 transition at 241.739 Å. Employing a medium and a high resolution spectrometer at the Livermore EBIT-I electron beam ion trap, we have observed the line pair in the laboratory for the first time. Using a CHIANTI model computation, the observed line ratio yields a value of the electron density that is compatible with typical densities in our device.
On Entire Function Solutions to Fermat Delay-Differential Equations
Authors: Zhang Xue-Ying , Xu Ze-Kun , Lü Wei-Ran
Published: October 2022

This paper concerns the existence and precise expression form of entire solutions to a certain type of delay-differential equation. The significance of our results lie in that we generalize and supplement the related results obtained recently.
On the Method of Differential Invariants for Solving Higher Order Ordinary Differential Equations
Authors: Sinkala Winter , Kakuli Molahlehi Charles
Published: October 2022

There are many routines developed for solving ordinary differential Equations (ODEs) of different types. In the case of an nth-order ODE that admits an r-parameter Lie group (3≤r≤n), there is a powerful method of Lie symmetry analysis by which the ODE is reduced to an (n−r)th-order ODE plus r quadratures provided that the Lie algebra formed by the infinitesimal generators of the group is solvable. It would seem this method is not widely appreciated and/or used as it is not mentioned in many related articles centred around integration of higher order ODEs. In the interest of mainstreaming the method, we describe the method in detail and provide four illustrative examples. We use the case of a third-order ODE that admits a three-dimensional solvable Lie algebra to present the gist of the integration algorithm.
A Shortcut Method to Solve for a 1D Heat Conduction Model under Complicated Boundary Conditions
Authors: Wei Ting , Tao Yuezan , Ren Honglei , Lin Fei
Published: October 2022

The function of boundary temperature variation with time, f(t) is generally defined according to measured data. For f(t), which has a complicated expression, a corresponding one-dimensional heat conduction model was constructed under the first type of boundary conditions (Dirichlet conditions) in a semi-infinite domain. By taking advantage of the Fourier transform properties, a theoretical solution was given for the model, under the condition that f(t) does not directly participate in the transformation process. The solution consists of the product of erfc(t) and f(0) and the convolution of erfc(t) and the derivative of f(t). The piecewise linear interpolation equation of f(t), based on the measured data of temperature, was substituted into the theoretical solution, thus quickly solving the model and deriving a corresponding analytical solution. Based on the analytical solution under the linear decay function boundary condition, the inflection point method and curve fitting method for calculating the thermal diffusivity were introduced and exemplified, and the variation laws of the appearance moment of the inflection point were discussed. The obtained results show that the values of thermal diffusivity calculated by the two methods are basically consistent, and that the inflection point values rise with the increasing values of the initial temperature variation of the boundary, the decrease in boundary temperature velocity, and the distance from the boundary, respectively.
Proving, Refuting, Improving—Looking for a Theorem
Authors: Boričić Branislav
Published: October 2022

Exploring the proofs and refutations of an abstract statement, conjecture with the aim to give a formal syntactic treatment of its proving–refuting process, we introduce the notion of extrapolation of a possibly unprovable statement having the form if A, then B, and propose a procedure that should result in the new statement if A′, then B′, which is similar to the starting one, but provable. We think that this procedure, based on the extrapolation method, can be considered a basic methodological tool applicable to prove–refute–improve any conjecture. This new notion, extrapolation, presents a dual counterpart of the well-known interpolation introduced in traditional logic sixty-five years ago.
Fekete-Szegö Inequalities for Some Certain Subclass of Analytic Functions Defined with Ruscheweyh Derivative Operator
Authors: Orhan Halit , Cotîrlă Luminiţa-Ioana
Published: October 2022

In our present investigation, we introduce and study some new subclasses of analytic functions associated with Ruscheweyh differential operator Dr. We obtain a Fekete–Szegö inequality for certain normalized analytic function defined on the open unit disk for which Drl′(z)ϑzDrl′(z)Drl(z)1−ϑ≺ez (0≤ϑ≤1) lies in a starlike region with respect to 1 and symmetric with respect to the real axis. As a special case of this result, the Fekete–Szegö inequality for a class of functions defined through Poisson distribution series is obtained.
An Improved Elephant Herding Optimization for Energy-Saving Assembly Job Shop Scheduling Problem with Transportation Times
Authors: Jiang Tianhua , Liu Lu , Zhu Huiqi , Li Yaping
Published: October 2022

The energy-saving scheduling problem (ESSP) has gained increasing attention of researchers in the manufacturing field. However, there is a lack of studies on ESSPs in the assembly job shop environment. In contrast with traditional scheduling problems, the assembly job shop scheduling problem (AJSP) adds the additional consideration of hierarchical precedence constraints between different jobs of each final product. This paper focuses on developing a methodology for an energy-saving assembly job shop scheduling problem with job transportation times. Firstly, a mathematical model is constructed with the objective of minimizing total energy consumption. Secondly, an improved elephant herding optimization (IEHO) is proposed by considering the problem’s characteristics. Finally, thirty-two different instances are designed to verify the performance of the proposed algorithm. Computational results and statistical data demonstrate that the IEHO has advantages over other algorithms in terms of the solving accuracy for the considered problem.
Applications and Advantages of Atomic Layer Deposition for Lithium-Ion Batteries Cathodes: Review
Authors: Koshtyal Yury , Olkhovskii Denis , Rumyantsev Aleksander , Maximov Maxim
Published: October 2022

Nowadays, lithium-ion batteries (LIBs) are one of the most convenient, reliable, and promising power sources for portable electronics, power tools, hybrid and electric vehicles. The characteristics of the positive electrode (cathode active material, CAM) significantly contribute to the battery’s functional properties. Applying various functional coatings is one of the productive ways to improve the work characteristics of lithium-ion batteries. Nowadays, there are many methods for depositing thin films on a material’s surface; among them, one of the most promising is atomic layer deposition (ALD). ALD allows for the formation of thin and uniform coatings on surfaces with complex geometric forms, including porous structures. This review is devoted to applying the ALD method in obtaining thin functional coatings for cathode materials and includes an overview of more than 100 publications. The most thoroughly investigated surface modifications are lithium cobalt oxide (LCO), lithium manganese spinel (LMO), lithium nickel-cobalt-manganese oxides (NCM), lithium-nickel-manganese spinel (LNMO), and lithium-manganese rich (LMR) cathode materials. The most studied processes of deposition are aluminum oxide (Al2O3), titanium dioxide (TiO2) and zirconium dioxide (ZrO2) films. The primary purposes of such studies are to find the synthesis parameters of films, to find the optimal coating thickness (e.g., ~1–2 nm for Al2O3, ~1 nm for ZrO2, <1 nm for TiO2, etc.), and to reveal the effect of the coating on the electrochemical parameters of batteries. The review summarizes synthesis conditions, investigation results of deposited films on CAMs and positive electrodes and some functional effects observed due to films obtained by ALD on cathodes.
DC Bus Voltage Stabilization and SOC Management Using Optimal Tuning of Controllers for Supercapacitor Based PV Hybrid Energy Storage System
Authors: Pattnaik Saswati , Kumar Mano Ranjan , Mishra Sunil Kumar , Gautam Shivam Prakash , Appasani Bhargav , Ustun Taha Selim
Published: October 2022

The global initiative of decarbonization has led to the popularity of renewable energy sources, especially solar photovoltaic (PV) cells and energy storage systems. However, standalone battery-based energy storage systems are inefficient in terms of the shelf and cycle life, reliability, and overall performance, especially in instantaneous variations in solar irradiance and load. In order to overcome this, a combination of a supercapacitor and battery-based hybrid energy storage system (HESS) is considered as an emerging and viable solution. The present work proposes an optimally tuned tilt-integral (TI) controller to develop an efficient power management strategy (PMS) to enhance the overall system performance. The controller parameters are tuned by optimization of the time-domain design specifications using a gradient-free simplex search technique. The robustness of the proposed TI controller is demonstrated in comparison to PI and fractional-order PI (FOPI) controllers. Furthermore, extensive experimentation was carried out to analyze the effectiveness of the proposed approach for DC bus voltage stabilization and state-of-charge (SOC) management under varying operating conditions such as solar irradiance, load, temperature, and SOC consumption by battery.
A Comprehensive Study of Degradation Characteristics and Mechanisms of Commercial Li(NiMnCo)O2 EV Batteries under Vehicle-To-Grid (V2G) Services
Authors: Wei Yifan , Yao Yuan , Pang Kang , Xu Chaojie , Han Xuebing , Lu Languang , Li Yalun , Qin Yudi , Zheng Yuejiu , Wang Hewu , Ouyang Minggao
Published: October 2022

Lithium-ion batteries on electric vehicles have been increasingly deployed for the enhancement of grid reliability and integration of renewable energy, while users are concerned about extra battery degradation caused by vehicle-to-grid (V2G) operations. This paper details a multi-year cycling study of commercial 24 Ah pouch batteries with Li(NiMnCo)O2 (NCM) cathode, varying the average state of charge (SOC), depth of discharge (DOD), and charging rate by 33 groups of experiment matrix. Based on the reduced freedom voltage parameter reconstruction (RF-VPR), a more efficient non-intrusive diagnosis is combined with incremental capacity (IC) analysis to evaluate the aging mechanisms including loss of lithium-ion inventory and loss of active material on the cathode and anode. By analyzing the evolution of indicator parameters and the cumulative degradation function (CDF) of the battery capacity, a non-linear degradation model with calendar and cyclic aging is established to evaluate the battery aging cost under different unmanaged charging (V0G) and V2G scenarios. The result shows that, although the extra energy throughput would cause cyclic degradation, discharging from SOC 90 to 65% by V2G will surprisingly alleviate the battery decaying by 0.95% compared to the EV charged within 90–100% SOC, due to the improvement of calendar life. By optimal charging strategies, the connection to the smart grid can potentially extend the EV battery life beyond the scenarios without V2G.
Development and Validation of a Subject-Specific Coupled Model for Foot and Sports Shoe Complex: A Pilot Computational Study
Authors: Song Yang , Cen Xuanzhen , Zhang Yan , Bíró István , Ji Yulei , Gu Yaodong
Published: October 2022

Nowadays, footwear serves an essential role in improving athletic performance and decreasing the risk of unexpected injuries in sports games. Finite element (FE) modeling is a powerful tool to reveal the biomechanical interactions between foot and footwear, and establishing a coupled foot-shoe model is the prerequisite. The purpose of this pilot study was to develop and validate a 3D FE coupled model of the foot and sports shoe complex during balanced standing. All major foot and shoe structures were constructed based on the participant’s medical CT images, and 3D gait analysis was conducted to define the loading and boundary conditions. Sensitivity analysis was applied to determine the optimum material property for shoe sole. Both the plantar and shoe sole areas were further divided into four regions for model validation, and the Bland–Altman method was used for consistency analysis between methods. The simulated peak plantar and sole pressure distribution showed good consistency with experimental pressure data, and the prediction errors were all less than 10% during balanced standing with only two exceptions (medial and lateral forefoot regions). Meanwhile, the Bland–Altman analysis demonstrated a good agreement between the two approaches. The sensitivity analysis suggested that shoe sole with Young’s modulus of 2.739 MPa presented the greatest consistency with the measured data in our scenario. The established model could be used for investing the complex biomechanical interactions between the foot and sports shoe and optimizing footwear design, after it has been fully validated in the subsequent works under different conditions.
The Role of Machine Learning and Design of Experiments in the Advancement of Biomaterial and Tissue Engineering Research
Authors: Al-Kharusi Ghayadah , Dunne Nicholas J. , Little Suzanne , Levingstone Tanya J.
Published: October 2022

Optimisation of tissue engineering (TE) processes requires models that can identify relationships between the parameters to be optimised and predict structural and performance outcomes from both physical and chemical processes. Currently, Design of Experiments (DoE) methods are commonly used for optimisation purposes in addition to playing an important role in statistical quality control and systematic randomisation for experiment planning. DoE is only used for the analysis and optimisation of quantitative data (i.e., number-based, countable or measurable), while it lacks the suitability for imaging and high dimensional data analysis. Machine learning (ML) offers considerable potential for data analysis, providing a greater flexibility in terms of data that can be used for optimisation and predictions. Its application within the fields of biomaterials and TE has recently been explored. This review presents the different types of DoE methodologies and the appropriate methods that have been used in TE applications. Next, ML algorithms that are widely used for optimisation and predictions are introduced and their advantages and disadvantages are presented. The use of different ML algorithms for TE applications is reviewed, with a particular focus on their use in optimising 3D bioprinting processes for tissue-engineered construct fabrication. Finally, the review discusses the future perspectives and presents the possibility of integrating DoE and ML in one system that would provide opportunities for researchers to achieve greater improvements in the TE field.
Insights into Environmental Drivers on the Reproductive Cycle of Diopatra neapolitana (Polychaeta: Onuphidae)
Authors: Escobar-Ortega Daniel , Couceiro Lucía , Muíño Ramón , No Edgar , Fernández Nuria
Published: October 2022

The reproductive cycle of Diopatra neapolitana was studied over two years in Redondela (NW Spain), considering both the monthly evolution of the percentage of individuals with oocytes and the variation of the mean oocyte size. Moreover, since three other species of Diopatra have recently been documented in regions geographically close to NW Spain, we first confirmed the identity of this species by carrying out a morphological identification of a representative number of the specimens collected. Our data showed a discontinuous reproductive season, with a period of proliferation and maturation of oocytes from January to September and asynchronous spawning events between July and October. Then, a resting period in the months of November and December was observed. We also explored the influence of some relevant environmental factors (namely, water temperature, photoperiod, salinity, primary production and upwelling index) on the observed reproductive cycle. The results suggest that water temperature is one of the most important drivers of the reproductive cycle for this species. Particularly, in Ría de Vigo, the reproductive cycle seems to be influenced by upwelling events of deep cold water that occur frequently between March and September, and that could act as a spawning-inducing switch.
Effectiveness of a Group-Based Rehabilitation Program Combining Education with Multimodal Exercises in the Treatment of Patients with Nonspecific Chronic Low Back Pain: A Retrospective Uncontrolled Study
Authors: Martins Cristiano , Sayegh Souheil , Faundez Antonio , Fourchet François , Bothorel Hugo
Published: October 2022

Currently, there is no consensus on the best rehabilitation program to perform for nonspecific chronic low back pain (NSCLBP). However, multimodal exercises, education, and group-based sessions seem to be beneficial. We, therefore, launched such a treatment program and aimed to evaluate its effectiveness in improving patient health status. We retrospectively analyzed the records of 23 NSCLB patients who followed the MyBack program at La Tour hospital from 2020 to 2022 (25 sessions, 8 weeks). Patients were evaluated before and after intervention using pain on a visual analog scale (pVAS), Roland–Morris Disability Questionnaire (RMDQ), Pain Catastrophizing Scale (PCS), Tampa Scale of Kinesiophobia (TSK), and the EuroQol-5D-3L (EQ-5D-3L). Responder rates were calculated using minimal clinically important differences. Patients reported a significant reduction (p < 0.05) in the pVAS (5.3 ± 1.2 vs. 3.1 ± 1.6), RMDQ (8.8 ± 3.3 vs. 4.0 ± 3.7), PCS (24.5 ± 9.4 vs. 11.7 ± 7.9) and TSK (41.5 ± 9.2 vs. 32.7 ± 7.0). The EQ-5D-3L also statistically improved (score: 0.59 ± 0.14 vs. 0.73 ± 0.07; and VAS: 54.8 ± 16.8 vs. 67.0 ± 15.2). The responder rates were 78% for the pVAS and PCS, 74% for the RMDQ and TSK, and only 26% for the EQ-5D-3L. The MyBack program combining education with multimodal group exercises led to satisfactory clinical, functional, and psychosocial outcomes.
Dual Targeting of Soluble Oligomeric and Aggregated Transthyretin with a Monoclonal Antibody Ameliorates Experimental Neuropathy
Authors: Fassler Michael , Tshori Sagi , Barac Yaron , Bowles Dawn E. , Benaim Clara , George Jacob
Published: October 2022

ATTR amyloidosis comprises a spectrum of multiple clinical presentations, including, predominantly, neuropathy and cardiomyopathy. The common triggering pathogenic protein is misfolded transthyretin, a carrier protein that destabilizes misfolds and assembles into mature amyloid fibrils. The current management of ATTR amyloidosis includes the use of agents that stabilize TTR or attenuate its liver inducible production. Herein, we tested the hypothesis that a monoclonal antibody targeting the soluble oligomeric as well as the aggregated TTR would influence experimental neuropathy. We have shown that Ab-A, our previously described humanized IgG monoclonal antibody, dose-dependently ameliorates the toxicity to neurons triggered by misfolded TTR oligomers. Furthermore, the antibody that exhibits wide misTTR epitope recognition that includes the oligomeric and aggregated forms of the protein dose-dependently enhances the uptake of misfolded TTR to microglia, the resident predominant cells of the innate immune system within the CNS. These in vitro mechanistic properties of the antibody were corroborated by experimental in vivo data showing that the antibody rapidly clears human TTR amyloid extracts infiltrated to the sciatic nerves of rats. Thus, the monoclonal antibody targeting soluble and aggregated TTR is effective in experimental neuropathy, likely due its ability to act as a neuroprotective agent, as well its misTTR-mediated clearance via microglia.
The Role of Long Noncoding RNAs on Male Infertility: A Systematic Review and In Silico Analysis
Authors: Kyrgiafini Maria-Anna , Sarafidou Theologia , Mamuris Zissis
Published: October 2022

Male infertility is a complex disorder affecting many couples worldwide. Long noncoding RNAs (lncRNAs) regulate important cellular processes; however, a comprehensive understanding of their role in male infertility is limited. This systematic review investigates the differential expressions of lncRNAs in male infertility or variations in lncRNA regions associated with it. The PRISMA guidelines were used to search Pubmed and Web of Science (1 June 2022). Inclusion criteria were human participants, patients diagnosed with male infertility, and English language speakers. We also performed an in silico analysis investigating lncRNAs that are reported in many subtypes of male infertility. A total of 625 articles were found, and after the screening and eligibility stages, 20 studies were included in the final sample. Many lncRNAs are deregulated in male infertility, and interactions between lncRNAs and miRNAs play an important role. However, there is a knowledge gap regarding the impact of variants found in lncRNA regions. Furthermore, eight lncRNAs were identified as differentially expressed in many subtypes of male infertility. After in silico analysis, gene ontology (GO) and KEGG enrichment analysis of the genes targeted by them revealed their association with bladder and prostate cancer. However, pathways involved in general in tumorigenesis and cancer development of all types, such as p53 pathways, apoptosis, and cell death, were also enriched, indicating a link between cancer and male infertility. This evidence, however, is preliminary. Future research is needed to explore the exact mechanism of action of the identified lncRNAs and investigate the association between male infertility and cancer.
Quantifying Coexistence Concentrations in Multi-Component Phase-Separating Systems Using Analytical HPLC
Authors: Bremer Anne , Posey Ammon E. , Borgia Madeleine B. , Borcherds Wade M. , Farag Mina , Pappu Rohit V. , Mittag Tanja
Published: October 2022

Over the last decade, evidence has accumulated to suggest that numerous instances of cellular compartmentalization can be explained by the phenomenon of phase separation. This is a process by which a macromolecular solution separates spontaneously into dense and dilute coexisting phases. Semi-quantitative, in vitro approaches for measuring phase boundaries have proven very useful in determining some key features of biomolecular condensates, but these methods often lack the precision necessary for generating quantitative models. Therefore, there is a clear need for techniques that allow quantitation of coexisting dilute and dense phase concentrations of phase-separating biomolecules, especially in systems with more than one type of macromolecule. Here, we report the design and deployment of analytical High-Performance Liquid Chromatography (HPLC) for in vitro separation and quantification of distinct biomolecules that allows us to measure dilute and dense phase concentrations needed to reconstruct coexistence curves in multicomponent mixtures. This approach is label-free, detects lower amounts of material than is accessible with classic UV-spectrophotometers, is applicable to a broad range of macromolecules of interest, is a semi-high-throughput technique, and if needed, the macromolecules can be recovered for further use. The approach promises to provide quantitative insights into the balance of homotypic and heterotypic interactions in multicomponent phase-separating systems.
Prognostic Impacts of LL-37 in Relation to Lipid Profiles of Patients with Myocardial Infarction: A Prospective Cohort Study
Authors: Chen Runzhen , Zhao Hanjun , Zhou Jinying , Wang Ying , Li Jiannan , Zhao Xiaoxiao , Li Nan , Liu Chen , Zhou Peng , Chen Yi , Song Li , Yan Hongbing
Published: October 2022

Background. In vivo studies show that LL-37 inhibits the progression of atherosclerosis and predicts a lower risk of recurrent ischemia in patients with acute myocardial infarction (AMI), which could be mediated by the modulation of lipid metabolism. The current study aimed to investigate the effects of various lipid contents on the prognostic impacts of LL-37 in patients with AMI. Methods. A total of 1567 consecutive AMI patients were prospectively recruited from March 2017 to January 2020. Patients were firstly stratified into two groups by the median level of LL-37 and then stratified by levels of various lipid contents and proprotein convertase subtilisin/kexin type 9 (PCSK9). Cox regression with multiple adjustments was performed to analyze associations between LL-37, lipid profiles, PCSK9, and various outcomes. The primary outcome was major adverse cardiovascular event (MACE), a composite of all-cause death, recurrent MI, and ischemic stroke. Results. During a median follow-up of 786 (726–1107) days, a total of 252 MACEs occurred. A high level of LL-37 was associated with lower risk of MACE in patients with elevated lipoprotein(a) (≥300 mg/L, hazard ratio (HR): 0.49, 95% confidence interval (CI): 0.29–0.86, p = 0.012) or PCSK9 levels above the median (≥47.4 ng/mL, HR: 0.57, 95% CI: 0.39–0.82, p < 0.001), which was not observed for those without elevated lp(a) (<300 mg/L, HR: 0.96, 95% CI: 0.70–1.31, p = 0.781, pinteraction = 0.035) or PCSK9 (<47.4 ng/mL, HR: 1.02, 95% CI: 0.68–1.54, p = 0.905, pinteraction = 0.032). Conclusions. For patients with AMI, a high level of LL-37 was associated with lower ischemic risk among patients with elevated lp(a) and PCSK9.
Effects of One-Year Tofacitinib Therapy on Lipids and Adipokines in Association with Vascular Pathophysiology in Rheumatoid Arthritis
Authors: Czókolyová Monika , Hamar Attila , Pusztai Anita , Tajti Gábor , Végh Edit , Pethő Zsófia , Bodnár Nóra , Horváth Ágnes , Soós Boglárka , Szamosi Szilvia , Szentpéteri Anita , Seres Ildikó , Harangi Mariann , Paragh György , Kerekes György , Bodoki Levente , Domján Andrea , Hodosi Katalin , Seres Tamás , Panyi György , Szekanecz Zoltán , Szűcs Gabriella
Published: October 2022

Background: Cardiovascular (CV) morbidity, mortality and metabolic syndrome are associated with rheumatoid arthritis (RA). A recent trial has suggested increased risk of major CV events (MACE) upon the Janus kinase (JAK) inhibitor tofacitinib compared with anti-tumor necrosis factor α (TNF-α) therapy. In our study, we evaluated lipids and other metabolic markers in relation to vascular function and clinical markers in RA patients undergoing one-year tofacitinib therapy. Patients and methods: Thirty RA patients treated with either 5 mg or 10 mg bid tofacitinib were included in a 12-month follow-up study. Various lipids, paraoxonase (PON1), myeloperoxidase (MPO), thrombospondin-1 (TSP-1) and adipokine levels, such as adiponectin, leptin, resistin, adipsin and chemerin were determined. In order to assess flow-mediated vasodilation (FMD), common carotid intima-media thickness (IMT) and arterial pulse-wave velocity (PWV) ultrasonography were performed. Assessments were carried out at baseline, and 6 and 12 months after initiating treatment. Results: One-year tofacitinib therapy significantly increased TC, HDL, LDL, APOA, APOB, leptin, adipsin and TSP-1, while significantly decreasing Lp(a), chemerin, PON1 and MPO levels. TG, lipid indices (TC/HDL and LDL/HDL), adiponectin and resistin showed no significant changes. Numerous associations were found between lipids, adipokines, clinical markers and IMT, FMD and PWV (p < 0.05). Regression analysis suggested, among others, association of BMI with CRP and PWV (p < 0.05). Adipokines variably correlated with age, BMI, CRP, CCP, FMD, IMT and PWV, while MPO, PON1 and TSP-1 variably correlated with age, disease duration, BMI, RF and PWV (p < 0.05). Conclusions: JAK inhibition by tofacitinib exerts balanced effects on lipids and other metabolic markers in RA. Various correlations may exist between metabolic, clinical parameters and vascular pathophysiology during tofacitinib treatment. Complex assessment of lipids, metabolic factors together with clinical parameters and vascular pathophysiology may be utilized in clinical practice to determine and monitor the CV status of patients in relation with clinical response to JAK inhibition.
6-(Methylsulfonyl) Hexyl Isothiocyanate: A Chemopreventive Agent Inducing Autophagy in Leukemia Cell Lines
Authors: Cocchi Veronica , Jávega Beatriz , Gasperini Sofia , O’Connor José-Enrique , Lenzi Monia , Hrelia Patrizia
Published: October 2022

Autophagy is a fundamental catabolic process of cellular survival. The role of autophagy in cancer is highly complex: in the early stages of neoplastic transformation, it can act as a tumor suppressor avoiding the accumulation of proteins, damaged organelles, and reactive oxygen species (ROS), while during the advanced stages of cancer, autophagy is exploited by cancer cells to survive under starvation. 6-(Methylsulfonyl) hexyl isothiocyanate (6-MITC) is the most interesting compound in the Wasabia Japonica rizhome. Recently, we proved its ability to induce cytotoxic, cytostatic, and cell differentiation effects on leukemic cell lines and its antimutagenic activity on TK6 cells. In the current study, to further define its chemopreventive profile, Jurkat and HL-60 cells were treated with 6-MITC for 24 h. The modulation of the autophagic process and the involvement of ROS levels as a possible trigger mechanisms were analyzed by flow cytometry. We found that 6-MITC induced autophagy in Jurkat and HL-60 cells at the highest concentration tested and increased ROS intracellular levels in a dose-dependent manner. Our results implement available data to support 6-MITC as an attractive potential chemopreventive agent.
Functional Tuning of Intrinsically Disordered Regions in Human Proteins by Composition Bias
Authors: Kastano Kristina , Mier Pablo , Dosztányi Zsuzsanna , Promponas Vasilis J. , Andrade-Navarro Miguel A.
Published: October 2022

Intrinsically disordered regions (IDRs) in protein sequences are flexible, have low structural constraints and as a result have faster rates of evolution. This lack of evolutionary conservation greatly limits the use of sequence homology for the classification and functional assessment of IDRs, as opposed to globular domains. The study of IDRs requires other properties for their classification and functional prediction. While composition bias is not a necessary property of IDRs, compositionally biased regions (CBRs) have been noted as frequent part of IDRs. We hypothesized that to characterize IDRs, it could be helpful to study their overlap with particular types of CBRs. Here, we evaluate this overlap in the human proteome. A total of 2/3 of residues in IDRs overlap CBRs. Considering CBRs enriched in one type of amino acid, we can distinguish CBRs that tend to be fully included within long IDRs (R, H, N, D, P, G), from those that partially overlap shorter IDRs (S, E, K, T), and others that tend to overlap IDR terminals (Q, A). CBRs overlap more often IDRs in nuclear proteins and in proteins involved in liquid-liquid phase separation (LLPS). Study of protein interaction networks reveals the enrichment of CBRs in IDRs by tandem repetition of short linear motifs (rich in S or P), and the existence of E-rich polar regions that could support specific protein interactions with non-specific interactions. Our results open ways to pin down the function of IDRs from their partial compositional biases.
Combination of Antimalarial and CNS Drugs with Antineoplastic Agents in MCF-7 Breast and HT-29 Colon Cancer Cells: Biosafety Evaluation and Mechanism of Action
Authors: Duarte Diana , Nunes Mariana , Ricardo Sara , Vale Nuno
Published: October 2022

Drug combination and drug repurposing are two strategies that allow to find novel oncological therapies, in a faster and more economical process. In our previous studies, we developed a novel model of drug combination using antineoplastic and different repurposed drugs. We demonstrated the combinations of doxorubicin (DOX) + artesunate, DOX + chloroquine, paclitaxel (PTX) + fluoxetine, PTX + fluphenazine, and PTX + benztropine induce significant cytotoxicity in Michigan Cancer Foundation-7 (MCF-7) breast cancer cells. Furthermore, it was found that 5-FU + thioridazine and 5-fluorouracil (5-FU) + sertraline can synergistically induce a reduction in the viability of human colorectal adenocarcinoma cell line (HT-29). In this study, we aim to (1) evaluate the biosafety profile of these drug combinations for non-tumoral cells and (2) determine their mechanism of action in cancer cells. To do so, human fetal lung fibroblast cells (MRC-5) fibroblast cells were incubated for 48 h with all drugs, alone and in combination in concentrations of 0.25, 0.5, 1, 2, and 4 times their half-maximal inhibitory concentration (IC50). Cell morphology and viability were evaluated. Next, we designed and constructed a cell microarray to perform immunohistochemistry studies for the evaluation of palmitoyl-protein thioesterase 1 (PPT1), Ki67, cleaved-poly (ADP-ribose) polymerase (cleaved-PARP), multidrug resistance-associated protein 2 (MRP2), P-glycoprotein (P-gp), and nuclear factor-kappa-B (NF-kB) p65 expression. We demonstrate that these combinations are cytotoxic for cancer cells and safe for non-tumoral cells at lower concentrations. Furthermore, it is also demonstrated that PPT1 may have an important role in the mechanism of action of these combinations, as demonstrated by their ability to decrease PPT1 expression. These results support the use of antimalarial and central nervous system (CNS) drugs in combination regimens with chemotherapeutic agents; nevertheless, additional studies are recommended to further explore their complete mechanisms of action.
Gene Delivery of Manf to Beta-Cells of the Pancreatic Islets Protects NOD Mice from Type 1 Diabetes Development
Authors: Singh Kailash , Bricard Orian , Haughton Jeason , Björkqvist Mikaela , Thorstensson Moa , Luo Zhengkang , Mascali Loriana , Pasciuto Emanuela , Mathieu Chantal , Dooley James , Liston Adrian
Published: October 2022

In type 1 diabetes, dysfunctional glucose regulation occurs due to the death of insulin-producing beta-cells in the pancreatic islets. Initiation of this process is caused by the inheritance of an adaptive immune system that is predisposed to responding to beta-cell antigens, most notably to insulin itself, coupled with unknown environmental insults priming the autoimmune reaction. While autoimmunity is a primary driver in beta-cell death, there is growing evidence that cellular stress participates in the loss of beta-cells. In the beta-cell fragility model, partial loss of islet mass requires compensatory upregulation of insulin production in the remaining islets, driving a cellular stress capable of triggering apoptosis in the remaining cells. The Glis3-Manf axis has been identified as being pivotal to the relative fragility or robustness of stressed islets, potentially operating in both type 1 and type 2 diabetes. Here, we have used an AAV-based gene delivery system to enhance the expression of the anti-apoptotic protein Manf in the beta-cells of NOD mice. Gene delivery substantially lowered the rate of diabetes development in treated mice. Manf-treated mice demonstrated minimal insulitis and superior preservation of insulin production. Our results demonstrating the therapeutic potential of Manf delivery to enhance beta-cell robustness and avert clinical diabetes.
Editorial of Special Issue “Hyaluronic Acid in Human Medicine”
Authors: Suchánek Jakub
Published: October 2022

Hyaluronic acid (HA) is an acidic, non-sulfated glycosaminoglycan that is intensively studied as a biodegradable and biocompatible material for scaffolding, regenerative medicine, and clinical applications [...]