bluuebunny/crossref_metadata_2025 huggingface dataset:
Multilayer Dielectric Periodic Antenna Structure in a Cascade View
Authors: Wnuk Marian
Published: April 2022

The spectral response of the periodic antenna structure placed in a dielectric homogeneous medium depends on the antenna geometry, the parameters of the medium, the angle of incidence, polarization, and the geometry of the excitation field. Increasing the number of antenna structure parameters can be achieved by introducing a multilayer dielectric medium with a certain number of metallized periodic surfaces located on flat boundaries between the dielectric layers. There are two complementary approaches to the analysis of such structures. In the first, the composite antenna system is analysed by constructing supermodes of the entire structure. In the second, the system is considered as a cascade assembly of flat discrete elements, i.e., the boundaries between two dielectrics, periodic metallized planes, and dielectric layers. The latter approach leads to the definition of the scattering, transmission, or impedance matrix of the entire structure by cascading the corresponding matrices associated with the individual discrete elements of the antenna structure. It is particularly useful in modelling dielectric multilayer antenna walls, where the stored data on one planar antenna element can be used many times in the analysis of various antenna systems with modified parameters of other discrete structure elements. Microstrip antennas combine field and peripheral problems and require the use of analytical methods of a high degree of complexity. Therefore, at present, there are no standard methods that can be used in engineering practice. This work is a step towards filling these gaps.
Curved Path Following Control for a Small Fixed-Wing UAV with Parameters Adaptation
Authors: Chen Yang , Li Nan , Zeng Wei , Wu Yongliang
Published: April 2022

This paper presents an approach to address the curved-path following problem of a fixed-wing UAV, which can reach uniform optimal path-following performance for different initial states and control processes. First, a proper guidance law is designed following a class of horizontal smooth paths with fixed control parameters. The stability of the relative nonlinear system is guaranteed by the Lyapunov stability theory. The influence of the control parameters on path-following performance has been analyzed. Second, the rules of the time-varying control parameters are designed separately. The rules of the time-varying P-like parameter are designed by analyzing the dynamic characteristics of the nonlinear system with different initial flight states. The rules of the time-varying D-like parameter are designed based on the fuzzy logic technique. The stability of the corresponding nonautonomous nonlinear system is also proved. The simulations are carried out in the Matlab/Simulink environment with an Aerosonde UAV model. The results are presented to illustrate the effectiveness and high path-following performances of the proposed control strategies.
Texture Modification of 3D-Printed Maltitol Candy by Changing Internal Design
Authors: Kim Ga-In , Boo Seong-Jae , Lim Jang-Wook , Chung Jin-Kyo , Park Min-Soo
Published: April 2022

The purpose of this study is to show more diverse texture modifications by changing the material of a food 3D-printed structure conducted only with soft materials (in this case, potatoes and chocolate) to a hard material (in this case, maltitol here). However, unlike previous 3D-printed food materials, sweetener materials such as sucrose and maltitol are sensitively caramelized at a high melting temperature. As such, there is no commercialized printing equipment. Therefore, a printing process experiment was conducted first in this case. To do this, a high-temperature syringe pump-based extrusion device was designed, and process tests according to the temperature and environment were conducted. An assessment of the internal structural changes according to the infill patterns and infill percentages was conducted based on the acquired process conditions. The texture strength increased as the infill percentage increased. Depending on the infill patterns, the texture strength increased in the order of the Hilbert curve, honeycomb, and rectilinear samples here. As a result, a change in the texture strength was determined through a change in the internal structure of a hard food material using 3D printing, which showed a wider range of change than in conventional soft food materials.
Mechanical and Fatigue Behavior of Cellular Structure Ti-6Al-4V Alloy Femoral Stems: A Finite Element Analysis
Authors: Al Zoubi Naser Fawzi , Tarlochan Faris , Mehboob Hassan
Published: April 2022

Repetitive loads acting on the hip joint fluctuate according to the type of activities produced by the human body. Repetitive loading is one of the factors that leads to fatigue failure of the implanted stems. The objective of this study is to develop lightweight femoral stems with cubic porous structures that will survive under fatigue loading. Cubic porous structures with different volumetric porosities were designed and subjected to compressive loading using finite element analysis (FEA) to measure the elastic moduli, yield strength, and ultimate tensile strength. These porous structures were employed to design femoral stems containing mechanical properties under compressive loading close to the intact bone. Several arrangements of radial geometrical porous functionally graded (FG) and homogenous Ti-6Al-4V porous femoral stems were designed and grouped under three average porosities of 30%, 50%, and 70% respectively. The designed stems were simulated inside the femoral bone with physiological loads demonstrating three walking speeds of 1, 3, and 5 km/h using ABAQUS. Stresses at the layers of the functionally graded stem were measured and compared with the yield strength of the relevant porous structure to check the possibility of yielding under the subjected load. The Soderberg approach is employed to compute the safety factor (Nf > 1.0) for each design under each loading condition. Several designs were shortlisted as potential candidates for orthopedic implants.
An Information-Theoretic Approach for Detecting Community Structure Based on Network Representation
Authors: Chen Yinan , Wang Chuanpeng , Li Dong
Published: April 2022

Community structure is a network characteristic where nodes can be naturally divided into densely connected groups. Community structures are ubiquitous in social, biological, and technological networks. Revealing community structure in the network helps in the understanding of the topological associations and interactions of elements in the network, as well as helping to mine their potential information. However, this has been proven to be a difficult challenge. On the one hand, this is because there is no unified definition of the quality of a community; on the other hand, due to the complexity of the network, it is impossible to traverse all the possibilities of community partitions to find the best one. Aiming at performing high-accuracy community detection, an information-theoretic approach AMI-NRL was proposed. The approach first constructs a community evolution process based on the representation of the target network, then finds the most stable community structure during the evolution using an average-mutual-information-based criterion. The experiments show that the approach can effectively detect community structures on real-world datasets and synthetic datasets.
Integrated Framework for Bus Timetabling and Scheduling in Multi-Line Operation Mode
Authors: Chen Shengmei , He Zhaocheng , Zhong Jiaming
Published: April 2022

Bus service is of great significance to urban residents. With the convergence of bus lines and the formation of bus hubs, a multi-line operation mode which can realize the centralized management of vehicles is applied to the daily bus service planning. To solve the bus service planning problem systematically in the multi-line operation mode, we propose an integrated framework for bus timetabling (TT) and vehicle scheduling (VS), which are the two fundamental processes of bus service planning. Firstly, the determination processes of TT and VS are correlated by constructing the multiple vehicles’ trip-link chains with departure time information to facilitate simultaneous optimization. Secondly, a multi-objective optimization model is constructed, which considers higher service quality and lower operating costs as objectives. Logic and operational rules are also considered as constraints to ensure the implementation of the solutions. Thirdly, we propose and implement a heuristic solution algorithm based on neighborhood search to achieve high-performance solutions. Finally, we validate the efficiency and effectiveness of our framework under the actual bus operation scenario in Chongqing, China. The Pareto frontier solutions are provided to bus operators as alternative operation schemes.
Research on the Evacuation Characteristics of Cruise Ship Passengers in Multi-Scenarios
Authors: Hu Min , Cai Wei
Published: April 2022

As a popular way of travelling on water, cruise tourism is welcomed by the public. The cruise ship, as a large water-borne city, can accommodate a large number of passengers, but simultaneously their safety should be ensured in the event of an emergency. This work studied the evacuation characteristics of passengers by analyzing evacuation processes in multiple scenarios on cruise ships. Four typical evacuation scenarios were established, and the initial parameters of passengers were defined by creating a passenger agent. Simulation experiments were carried out for these scenarios, and the results show that groups of passengers need more time to complete the evacuation than individual passengers. The number of passengers arriving at the embarkation area in one time period under the group evacuation scenario is less than that under the individual evacuation scenario. However, the peak period of arrival at the embarkation area under the group evacuation scenario lasts longer than that under the individual evacuation scenario. For passengers with slower walking speeds, they may complete the evacuation in a shorter time as long as their cabins are near the embarkation deck or in the suitable main vertical zones. This proves that the evacuation efficiency of passengers is affected by their initial positions, and evacuation time can be reduced by means of the allocation of cabins according to the movement characteristics of passengers.
Investigations into the Recognisability of Gear Damage Sizes in Vibration Signals and Calculation of Appropriate Digital Filter Limits
Authors: Beering Andreas , Krieger Karl-Ludwig
Published: April 2022

The present work investigates the size of gear damage required for significant recognisable change in the vibration signal and presents a method to determine digital filter limits in order to emphasise the vibration behaviour in the time domain. For this purpose, two gears are artificially damaged to four different degrees. The damage levels are determined by a tactile gear measurement and the gears are inserted into two intact gearboxes. Measurements at different speeds are used to generate a representative dataset. On the one hand, the recorded signals are examined via cross-correlation in the time domain. On the other hand, the occurring frequency components are examined using a windowed fast Fourier transformation. Based on the two observations, a statement is made about the recognisability of the damage levels of the two gears in the vibration signal. Furthermore, smoothed spectra are calculated via linear prediction coefficients (LPC) and an appropriate number of required coefficients is estimated via the Akaike information criterion. Subsequently, the calculated prediction coefficients are used as coefficients of an all-pole filter to calculate difference spectra. Based on the difference spectra, filter limits for a digital filter are derived to emphasise the damaged tooth meshing in the time domain.
Detection of Sleep Apnea from Electrocardiogram and Pulse Oximetry Signals Using Random Forest
Authors: Zhu Jianming , Zhou Aojie , Gong Qiong , Zhou Yu , Huang Junxiang , Chen Zhencheng
Published: April 2022

Sleep apnea (SA) is a common sleep disorder which could impair the human physiological system. Therefore, early diagnosis of SA is of great interest. The traditional method of diagnosing SA is an overnight polysomnography (PSG) evaluation. When PSG has limited availability, automatic SA screening with a fewer number of signals should be considered. The primary purpose of this study is to develop and evaluate a SA detection model based on electrocardiogram (ECG) and blood oxygen saturation (SpO2). We adopted a multimodal approach to fuse ECG and SpO2 signals at the feature level. Then, feature selection was conducted using the recursive feature elimination with cross-validation (RFECV) algorithm and random forest (RF) classifier used to discriminate between apnea and normal events. Experiments were conducted on the Apnea-ECG database. The introduced algorithm obtained an accuracy of 97.5%, a sensitivity of 95.9%, a specificity of 98.4% and an AUC of 0.992 in per-segment classification, and outperformed previous works. The results showed that ECG and SpO2 are complementary in detecting SA, and that the combination of ECG and SpO2 enhances the ability to diagnose SA. Therefore, the proposed method has the potential to be an alternative to conventional detection methods.
Reliability-Based Topology Optimization: An Extension of the SESO and SERA Methods for Three-Dimensional Structures
Authors: Simonetti Hélio Luiz , Almeida Valério Silva , de Assis das Neves Francisco , Del Duca Almeida Vírgil , de Oliveira Neto Luttgardes
Published: April 2022

This study takes an approach to reliability-based topology optimization (RBTO) for 3D structures by applying an expansion of smoothing evolutionary structural optimization (SESO) and sequential element rejection and admission (SERA) for three-dimensional optimization. In the search for the stable optimal solution, and a more reliable structure, we present a performance index with the ability to monitor the evolutionary optimization procedure and adopt the filtering scheme usually applied in solid isotropic material with penalization (SIMP). The limit state functions are the maximum displacement constraints imposed in the topology optimization procedure and a structure’s performance control; a comparative analysis of the deterministic topology optimization (DTO) with the RBTO models is also explored. The obtained results suggest the importance of using the RBTO concept in 3D structures as part of the design analysis process.
Audiovestibular Disorders after COVID-19 Vaccine: Is There an Association?
Authors: Pisani Davide , Gioacchini Federico Maria , Viola Pasquale , Scarpa Alfonso , Astorina Alessia , Re Massimo , Marcianò Gianmarco , Manti Francesco , Anzivino Roberta , Chiarella Giuseppe
Published: April 2022

The SARS-CoV-2 vaccination campaign is probably one of the most historic public hygiene measures in modern medicine. The drama of the pandemic has forced the scientific community to accelerate the development and commercialization of vaccines, thereby enhancing the phases of active surveillance. Among the adverse events following immunization (AEFI) reported, those of an audiovestibular interest, such as sudden sensorineural hearing loss (SSNHL), tinnitus, dizziness, and vertigo, constitute a very small percentage. There are many plausible etiological hypotheses, and scientific research needs to pay more attention to the correct collection of data, which up until now have often been inadequate and fragmented, on which to base future studies. SSNHL, new onset tinnitus, vertigo, and dizziness require a prompt evaluation, while the proposed treatment is the same as it is for events unrelated to vaccination. These are uncommon adverse events, and the risk rates for these diseases have not increased in conjunction with the COVID-19 vaccinations, therefore there is no justification of any hesitation towards the vaccination campaign.
Continuous-Stage Runge–Kutta Approximation to Differential Problems
Authors: Amodio Pierluigi , Brugnano Luigi , Iavernaro Felice
Published: April 2022

In recent years, the efficient numerical solution of Hamiltonian problems has led to the definition of a class of energy-conserving Runge–Kutta methods named Hamiltonian Boundary Value Methods (HBVMs). Such methods admit an interesting interpretation in terms of continuous-stage Runge–Kutta methods. In this review paper, we recall this aspect and extend it to higher-order differential problems.
A New Protocol to Treat Abdominal Subcutaneous Fat Combining Microwaves and Flat magnetic stimulation
Authors: Nisticò Steven Paul , Bonan Paolo , Coli Federica , Verdelli Alice , Fusco Irene , Gratteri Francesco , Sicilia Claudia , Cantisani Carmen , Pellacani Giovanni , Bennardo Luigi , Cannarozzo Giovanni
Published: April 2022

Background: A healthy lifestyle is not always able to improve the abdomen’s appearance, especially in those patients who have undergone sudden weight changes. Objective: We aimed at evaluating the efficacy of combined microwaves and flat magnetic stimulation (FMS) to treat abdominal localized adiposity and laxity. Methods: Twenty-five patients were subjected to two treatment sessions per month on the abdominal area with microwaves. FMS was also performed twice per week, with a minimum of two days between each session for two months. The technology uses three types of different protocols: massage, muscle definition (shaping), and muscular strengthening. Measurements, including body mass index (BMI) and waist, and abdominal ultrasound were performed at baseline and three months after the last treatment session. Blood examinations were performed, and a 5-Likert scale questionnaire was used to assess patient satisfaction. Results: At follow-up, three months after the last treatment, the mean waist circumference (WC) was significantly reduced, and skin laxity improved in all patients (p < 0.001). A significant improvement in abdominal muscle tissue thickness was also shown in all abdominal areas, and the thickness of the adipose tissue evaluated by ultrasound was reduced. Conclusions: This study proves that the combination of microwaves and FMS treatment is secure and efficient for treating abdominal subcutaneous fat and skin laxity.
Prediction of Glucose Concentration in Children with Type 1 Diabetes Using Neural Networks: An Edge Computing Application
Authors: D’Antoni Federico , Petrosino Lorenzo , Sgarro Fabiola , Pagano Antonio , Vollero Luca , Piemonte Vincenzo , Merone Mario
Published: April 2022

Background: Type 1 Diabetes Mellitus (T1D) is an autoimmune disease that can cause serious complications that can be avoided by preventing the glycemic levels from exceeding the physiological range. Straightforwardly, many data-driven models were developed to forecast future glycemic levels and to allow patients to avoid adverse events. Most models are tuned on data of adult patients, whereas the prediction of glycemic levels of pediatric patients has been rarely investigated, as they represent the most challenging T1D population. Methods: A Convolutional Neural Network (CNN) and a Long Short-Term Memory (LSTM) Recurrent Neural Network were optimized on glucose, insulin, and meal data of 10 virtual pediatric patients. The trained models were then implemented on two edge-computing boards to evaluate the feasibility of an edge system for glucose forecasting in terms of prediction accuracy and inference time. Results: The LSTM model achieved the best numeric and clinical accuracy when tested in the .tflite format, whereas the CNN achieved the best clinical accuracy in uint8. The inference time for each prediction was far under the limit represented by the sampling period. Conclusion: Both models effectively predict glucose in pediatric patients in terms of numerical and clinical accuracy. The edge implementation did not show a significant performance decrease, and the inference time was largely adequate for a real-time application.
Development and Operation of an Experimental System to Measure the Moments Generated in the Finger Joints
Authors: Chagnon Gregory , Achouri Khouloud , Connesson Nathanael , Gerbelot Julien , Courvoisier Aurelien
Published: April 2022

Little information is available on the forces that fingers can generate, and few devices exist to measure the forces they can create. The objective of this paper is to propose an experimental device to measure the moments generated by finger joints. The idea is to focus on a single joint and not on the effort generated by the whole finger. A system leaving only one joint free is developed to measure the maximum attainable moment in different joint positions between the extended and flexed finger. The device is tested on the proximal interphalangeal joints of the index fingers of thirty people for both hands. The results show a dispersion of results from one person to another but with similar trends in the evolution of the maximum achievable moment depending on the angle. Average values of the maximum moments attained by men and women for both hands are given for all angular positions of the joint. The results are analysed using principal component analysis. This analysis shows that four main modes represent more than 99% of the signal and allow the reconstruction of all the data for all the subjects. The four modes obtained can be used as a basis for the development of finger devices by hospital practitioners.
Recreating Tissue Structures Representative of Teratomas In Vitro Using a Combination of 3D Cell Culture Technology and Human Embryonic Stem Cells
Authors: Hidalgo Aguilar Alejandro , Smith Lucy , Owens Dominic , Quelch Rebecca , Przyborski Stefan
Published: April 2022

In vitro studies using human embryonic stem cells (hESCs) are a valuable method to study aspects of embryogenesis, avoiding ethical issues when using embryonic materials and species dissimilarities. The xenograft teratoma assay is often traditionally used to establish pluripotency in putative PSC populations, but also has additional applications, including the study of tissue differentiation. The stem cell field has long sought an alternative due to various well-established issues with the in vivo technique, including significant protocol variability and animal usage. We have established a two-step culture method which combines PSC-derived embryoid bodies (EBs) with porous scaffolds to enhance their viability, prolonging the time these structures can be maintained, and therefore, permitting more complex, mature differentiation. Here, we have utilised human embryonic stem cell-derived EBs, demonstrating the formation of tissue rudiments of increasing complexity over time and the ability to manipulate their differentiation through the application of exogenous morphogens to achieve specific lineages. Crucially, these EB-derived tissues are highly reminiscent of xenograft teratoma samples derived from the same cell line. We believe this in vitro approach represents a reproducible, animal-free alternative to the teratoma assay, which can be used to study human tissue development.
Dietary Supplementation of a New Probiotic Compound Improves the Growth Performance and Health of Broilers by Altering the Composition of Cecal Microflora
Authors: Qiu Kai , Wang Xiaocui , Zhang Haijun , Wang Jing , Qi Guanghai , Wu Shugeng
Published: April 2022

The current study aimed to investigate the effects of a new probiotic compound developed as a potential alternative to synthetic antibiotics for broilers. A total of 360 newly hatched Arbor Acres male chicks were randomly divided into three treatment groups. Each treatment consisted of six replicates with 20 birds in each replicate. The negative control group was fed the basal diet. The positive control group was fed the basal diet supplemented with a commercial antimicrobial, virginiamycin, at 30 mg/kg of basal feed. The compound probiotics group was fed a basal diet containing 4.5 × 106 CFU of Lactobacillus LP184 and 2.4 × 106 CFU of Yeast SC167 per gram of basal feed. The feeding trial lasted for 42 days. The results showed that the compound probiotics were a competent alternative to synthetic antibiotics for improving the growth performance and carcass traits of broilers. The compound probiotics enhanced the immune and antioxidant capacities of the broilers, while antibiotics lacked such merits. The positive effects of compound probiotics could be attributed to an improvement in the intestinal morphology and cecal microbial diversity of broilers, effects which are distinct from those of antibiotics. These findings revealed the differences between probiotics and antibiotics in terms of improving broilers’ performance and enriched the basic knowledge surrounding the intestinal microbial structure of broilers.
A Reappraisal of Polyploidy Events in Grasses (Poaceae) in a Rapidly Changing World
Authors: Cheng Acga , Mohd Hanafiah Noraikim , Harikrishna Jennifer Ann , Eem Lim Phaik , Baisakh Niranjan , Mispan Muhamad Shakirin
Published: April 2022

Around 80% of megaflora species became extinct at the Cretaceous–Paleogene (K–Pg) boundary. Subsequent polyploidy events drove the survival of thousands of plant species and played a significant historical role in the development of the most successful modern cereal crops. However, current and rapid global temperature change poses an urgent threat to food crops worldwide, including the world’s big three cereals: rice, wheat, and maize, which are members of the grass family, Poaceae. Some minor cereals from the same family (such as teff) have grown in popularity in recent years, but there are important knowledge gaps regarding the similarities and differences between major and minor crops, including how polyploidy affects their biological processes under natural and (a)biotic stress conditions and thus the potential to harness polyploidization attributes for improving crop climate resilience. This review focuses on the impact of polyploidy events on the Poaceae family, which includes the world’s most important food sources, and discusses the past, present, and future of polyploidy research for major and minor crops. The increasing accessibility to genomes of grasses and their wild progenitors together with new tools and interdisciplinary research on polyploidy can support crop improvement for global food security in the face of climate change.
Histopathology of Corn Plants Infected by Endophytic Fungi
Authors: Terna Tersoo P. , Mohamed Nor Nik Mohd Izham , Zakaria Latiffah
Published: April 2022

Endophytic fungi inhabiting plant tissues show extensive functional diversity, ranging from mutualism to pathogenicity. The present study evaluated the histological responses of corn plants to colonization by three species of endophytic fungi isolated from corn. Corn seedlings were inoculated with 1 × 106 conidia per mL spore suspensions of endophytic Fusarium verticillioides, Fusarium sacchari, and Penicillium citrinum and observed for 14 days for the emergence of disease symptoms. Histological examination of diseased root, stem, and leaf tissues was conducted using light and transmission electron microscopy. The results indicated that the mean diameters of root phloem, stem vascular bundles, and leaf vascular bundles, of corn plants infected with endophytic P. citrinum (18.91 µm, 146.96 µm, and 107.86 µm, respectively), F. verticillioides (18.75 µm, 85.45 µm, and 118.24 µm, respectively), and F. sacchari (24.15 µm root phloem, and 98.90 µm stem vascular bundle diameters), were significantly lower than the root phloem (33.68 µm), stem vascular bundle (186.77 µm), and leaf vascular bundle (155.88 µm) of the uninfected corn plants (p ≤ 0.05). Endophytic F. verticillioides was the most virulent, resulting in severe degradation and the eventual collapse of infected plant tissues. The study showed that endophytic fungi recovered from corn plants are capable of initiating significant disease responses in infected corn tissues.
Lyso-IP: Uncovering Pathogenic Mechanisms of Lysosomal Dysfunction
Authors: Chen Chase , Sidransky Ellen , Chen Yu
Published: April 2022

Lysosomes are ubiquitous membrane-bound organelles found in all eukaryotic cells. Outside of their well-known degradative function, lysosomes are integral in maintaining cellular homeostasis. Growing evidence has shown that lysosomal dysfunction plays an important role not only in the rare group of lysosomal storage diseases but also in a host of others, including common neurodegenerative disorders, such as Alzheimer disease and Parkinson disease. New technological advances have significantly increased our ability to rapidly isolate lysosomes from cells in recent years. The development of the Lyso-IP approach and similar methods now allow for lysosomal purification within ten minutes. Multiple studies using the Lyso-IP approach have revealed novel insights into the pathogenic mechanisms of lysosomal disorders, including Niemann-Pick type C disease, showing the immense potential for this technique. Future applications of rapid lysosomal isolation techniques are likely to greatly enhance our understanding of lysosomal dysfunction in rare and common neurodegeneration causes.
The Impact of Pancreatic Exocrine Diseases on the β-Cell and Glucose Metabolism—A Review with Currently Available Evidence
Authors: Ciochina Marina , Balaban Daniel Vasile , Manucu George , Jinga Mariana , Gheorghe Cristian
Published: April 2022

Pancreatic exocrine and endocrine dysfunctions often come together in the course of pancreatic diseases as interdependent manifestations of the same organ. However, the mechanisms underlying the bidirectional connection of the exocrine and endocrine pancreas are not fully understood. In this review, we aimed to synthetize the current knowledge regarding the effects of several exocrine pancreatic pathologies on the homeostasis of β-cells, with a special interest in the predisposition toward diabetes mellitus (DM). We focused on the following pancreatic exocrine diseases: chronic pancreatitis, acute pancreatitis, cystic fibrosis, pancreatic cancer, pancreatic resections, and autoimmune pancreatitis. We discuss the pathophysiologic mechanisms behind the impact on β-cell function and evolution into DM, as well as the associated risk factors in progression to DM, and we describe the most relevant and statistically significant findings in the literature. An early and correct diagnosis of DM in the setting of pancreatic exocrine disorders is of paramount importance for anticipating the disease’s course and its therapeutical needs.
Biology of the Extracellular Proteasome
Authors: Ben-Nissan Gili , Katzir Naama , Füzesi-Levi Maria Gabriella , Sharon Michal
Published: April 2022

Proteasomes are traditionally considered intracellular complexes that play a critical role in maintaining proteostasis by degrading short-lived regulatory proteins and removing damaged proteins. Remarkably, in addition to these well-studied intracellular roles, accumulating data indicate that proteasomes are also present in extracellular body fluids. Not much is known about the origin, biological role, mode(s) of regulation or mechanisms of extracellular transport of these complexes. Nevertheless, emerging evidence indicates that the presence of proteasomes in the extracellular milieu is not a random phenomenon, but rather a regulated, coordinated physiological process. In this review, we provide an overview of the current understanding of extracellular proteasomes. To this end, we examine 143 proteomic datasets, leading us to the realization that 20S proteasome subunits are present in at least 25 different body fluids. Our analysis also indicates that while 19S subunits exist in some of those fluids, the dominant proteasome activator in these compartments is the PA28α/β complex. We also elaborate on the positive correlations that have been identified in plasma and extracellular vesicles, between 20S proteasome and activity levels to disease severity and treatment efficacy, suggesting the involvement of this understudied complex in pathophysiology. In addition, we address the considerations and practical experimental methods that should be taken when investigating extracellular proteasomes. Overall, we hope this review will stimulate new opportunities for investigation and thoughtful discussions on this exciting topic that will contribute to the maturation of the field.
In Silico Design Strategies for the Production of Target Chemical Compounds Using Iterative Single-Level Linear Programming Problems
Authors: Shirai Tomokazu , Kondo Akihiko
Published: April 2022

The optimization of metabolic reaction modifications for the production of target compounds is a complex computational problem whose execution time increases exponentially with the number of metabolic reactions. Therefore, practical technologies are needed to identify reaction deletion combinations to minimize computing times and promote the production of target compounds by modifying intracellular metabolism. In this paper, a practical metabolic design technology named AERITH is proposed for high-throughput target compound production. This method can optimize the production of compounds of interest while maximizing cell growth. With this approach, an appropriate combination of metabolic reaction deletions can be identified by solving a simple linear programming problem. Using a standard CPU, the computation time could be as low as 1 min per compound, and the system can even handle large metabolic models. AERITH was implemented in MATLAB and is freely available for non-profit use.
O-GlcNAcylation and Regulation of Galectin-3 in Extraembryonic Endoderm Differentiation
Authors: Gatie Mohamed I. , Spice Danielle M. , Garha Amritpal , McTague Adam , Ahmer Mariam , Timoshenko Alexander V. , Kelly Gregory M.
Published: April 2022

The regulation of proteins through the addition and removal of O-linked β-N-acetylglucosamine (O-GlcNAc) plays a role in many signaling events, specifically in stem cell pluripotency and the regulation of differentiation. However, these post-translational modifications have not been explored in extraembryonic endoderm (XEN) differentiation. Of the plethora of proteins regulated through O-GlcNAc, we explored galectin-3 as a candidate protein known to have various intracellular and extracellular functions. Based on other studies, we predicted a reduction in global O-GlcNAcylation levels and a distinct galectin expression profile in XEN cells relative to embryonic stem (ES) cells. By conducting dot blot analysis, XEN cells had decreased levels of global O-GlcNAc than ES cells, which reflected a disbalance in the expression of genes encoding O-GlcNAc cycle enzymes. Immunoassays (Western blot and ELISA) revealed that although XEN cells (low O-GlcNAc) had lower concentrations of both intracellular and extracellular galectin-3 than ES cells (high O-GlcNAc), the relative secretion of galectin-3 was significantly increased by XEN cells. Inducing ES cells toward XEN in the presence of an O-GlcNAcase inhibitor was not sufficient to inhibit XEN differentiation. However, global O-GlcNAcylation was found to decrease in differentiated cells and the extracellular localization of galectin-3 accompanies these changes. Inhibiting global O-GlcNAcylation status does not, however, impact pluripotency and the ability of ES cells to differentiate to the XEN lineage.
The Potential Important Role of Mitochondrial Rieske Iron–Sulfur Protein as a Novel Therapeutic Target for Pulmonary Hypertension in Chronic Obstructive Pulmonary Disease
Authors: Truong Lillian , Zheng Yun-Min , Wang Yong-Xiao
Published: April 2022

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide, which is often due to pulmonary hypertension (PH). The underlying molecular mechanisms are poorly understood, and current medications are neither specific nor always effective. In this review, we highlight the recent findings on the roles of altered mitochondrial bioenergetics in PH in COPD. We also discuss the central role of mitochondrial reactive oxygen species (ROS) generation mediated by Rieske iron–sulfur protein (RISP) and review the contributions of RISP-dependent DNA damage and NF-κB-associated inflammatory signaling. Finally, the potential importance of mitochondrial RISP and its associated molecules as novel therapeutic targets for PH in COPD are meticulously discussed.
Fatty Hepatocytes Induce Skeletal Muscle Atrophy In Vitro: A New 3D Platform to Study the Protective Effect of Albumin in Non-Alcoholic Fatty Liver
Authors: De Chiara Francesco , Ferret-Miñana Ainhoa , Fernández-Costa Juan M. , Senni Alice , Jalan Rajiv , Ramón-Azcón Javier
Published: April 2022

The liver neutralizes endogenous and exogenous toxins and metabolites, being metabolically interconnected with many organs. Numerous clinical and experimental studies show a strong association between Non-alcoholic fatty liver disease (NAFLD) and loss of skeletal muscle mass known as sarcopenia. Liver transplantation solves the hepatic-related insufficiencies, but it is unable to revert sarcopenia. Knowing the mechanism(s) by which different organs communicate with each other is crucial to improve the drug development that still relies on the two-dimensional models. However, those models fail to mimic the pathological features of the disease. Here, both liver and skeletal muscle cells were encapsulated in gelatin methacryloyl and carboxymethylcellulose to recreate the disease’s phenotype in vitro. The 3D hepatocytes were challenged with non-esterified fatty acids (NEFAs) inducing features of Non-alcoholic fatty liver (NAFL) such as lipid accumulation, metabolic activity impairment and apoptosis. The 3D skeletal muscle tissues incubated with supernatant from fatty hepatocytes displayed loss of maturation and atrophy. This study demonstrates the connection between the liver and the skeletal muscle in NAFL, narrowing down the players for potential treatments. The tool herein presented was employed as a customizable 3D in vitro platform to assess the protective effect of albumin on both hepatocytes and myotubes.
Recent Advances in Biocatalysis for Drug Synthesis
Authors: Kinner Alina , Nerke Philipp , Siedentop Regine , Steinmetz Till , Classen Thomas , Rosenthal Katrin , Nett Markus , Pietruszka Jörg , Lütz Stephan
Published: April 2022

Biocatalysis is constantly providing novel options for the synthesis of active pharmaceutical ingredients (APIs). In addition to drug development and manufacturing, biocatalysis also plays a role in drug discovery and can support many active ingredient syntheses at an early stage to build up entire scaffolds in a targeted and preparative manner. Recent progress in recruiting new enzymes by genome mining and screening or adapting their substrate, as well as product scope, by protein engineering has made biocatalysts a competitive tool applied in academic and industrial spheres. This is especially true for the advances in the field of nonribosomal peptide synthesis and enzyme cascades that are expanding the capabilities for the discovery and synthesis of new bioactive compounds via biotransformation. Here we highlight some of the most recent developments to add to the portfolio of biocatalysis with special relevance for the synthesis and late-stage functionalization of APIs, in order to bypass pure chemical processes.
Arsenic Activates the ER Stress-Associated Unfolded Protein Response via the Activating Transcription Factor 6 in Human Bronchial Epithelial Cells
Authors: Wadgaonkar Priya , Bi Zhuoyue , Wan Junmei , Fu Yao , Zhang Qian , Almutairy Bandar , Zhang Wenxuan , Qiu Yiran , Thakur Chitra , Hüttemann Maik , Chen Fei
Published: April 2022

Arsenic is a well-known human carcinogen associated with a number of cancers, including lung cancers. We have previously shown that long-term exposure to an environmentally relevant concentration of inorganic arsenic (As3+) leads to the malignant transformation of the BEAS2B cells, and some of the transformed cells show cancer stem-like features (CSCs) with a significant upregulation of glycolysis and downregulation of mitochondrial oxidative phosphorylation. In the present report, we investigate the short-term effect of As3+ on the endoplasmic reticulum (ER) stress response—the “unfolded protein response (UPR)” and metabolism in human bronchial epithelial cell line BEAS-2B cells. Treatment of the cells with inorganic As3+ upregulated both glycolysis and mitochondrial respiration. Analysis of ER UPR signaling pathway using a real-time human UPR array revealed that As3+ induced a significant up-regulation of some UPR genes, including ATF6, CEBPB, MAPK10, Hsp70, and UBE2G2. Additional tests confirmed that the induction of ATF6, ATF6B and UBE2G2 mRNAs and/or proteins by As3+ is dose dependent. Chromosome immunoprecipitation and global sequencing indicated a critical role of Nrf2 in mediating As3+-induced expression of these UPR genes. In summary, our data suggest that As3+ is able to regulate the ER stress response, possibly through activating the ATF6 signaling.
Predictive Response to Immunotherapy Score: A Useful Tool for Identifying Eligible Patients for Allergen Immunotherapy
Authors: Mormile Ilaria , Granata Francescopaolo , Detoraki Aikaterini , Pacella Daniela , Della Casa Francesca , De Rosa Felicia , Romano Antonio , de Paulis Amato , Rossi Francesca Wanda
Published: April 2022

A specific predictive tool of allergen immunotherapy (AIT) outcome has not been identified yet. This study aims to evaluate the efficacy of a disease score referred to as Predictive Response to Immunotherapy Score (PRIS) to predict the response to AIT and identify eligible patients. A total of 110 patients diagnosed with allergic rhinitis with or without concomitant asthma were enrolled in this study. Before beginning sublingual immunotherapy (SLIT), patients were evaluated by analyzing clinical and laboratory parameters. A specific rating was assigned to each parameter to be combined in a total score named PRIS. At baseline (T0) and follow-up [after 12 (T12) and 24 months (T24) of SLIT], a Visual Analogue Scale (VAS) was used to calculate a mean symptom score (MSS). Finally, the percentage variation between the MSS at T0 and at T12 [ΔMSS-12(%)] and T24 [ΔMSS-24 (%)] was measured. We observed a significant improvement of symptoms at T12 and T24 compared to T0 in all groups undergoing SLIT. PRIS was effective in predicting ΔMSS-24 (%) in patients treated with single-allergen SLIT. In addition, PRIS was effective in predicting ΔMSS-24 (%) in both patients with only rhinitis and with concomitant asthma. PRIS assessment can represent a useful tool to individuate potential responders before SLIT prescription.
Current Clinical Trials in Traumatic Brain Injury
Authors: Ahmed Zubair
Published: April 2022

Traumatic brain injury (TBI) is one of the leading causes of morbidity, disability and mortality across all age groups globally. Currently, only palliative treatments exist, but these are suboptimal and do little to combat the progressive damage to the brain that occurs after a TBI. However, multiple experimental treatments are currently available that target the primary and secondary biochemical and cellular changes that occur after a TBI. Some of these drugs have progressed to clinical trials and are currently being evaluated for their therapeutic benefits in TBI patients. The aim of this study was to identify which drugs are currently being evaluated in clinical trials for TBI. A search of ClinicalTrials.gov was performed on 3 December 2021 and all clinical trials that mentioned “TBI” OR “traumatic brain injury” AND “drug” were searched, revealing 362 registered trials. Of the trials, 46 were excluded due to the drug not being mentioned, leaving 138 that were completed and 116 that were withdrawn. Although the studies included 267,298 TBI patients, the average number of patients per study was 865 with a range of 5–200,000. Of the completed studies, 125 different drugs were tested in TBI patients but only 7 drugs were used in more than three studies, including amantadine, botulinum toxin A and tranexamic acid (TXA). However, previous clinical studies using these seven drugs showed variable results. The current study concludes that clinical trials in TBI have to be carefully conducted so as to reduce variability across studies, since the severity of TBI and timing of therapeutic interventions were key aspects of trial success.
Connectivity in Large-Scale Resting-State Brain Networks Is Related to Motor Learning: A High-Density EEG Study
Authors: Titone Simon , Samogin Jessica , Peigneux Philippe , Swinnen Stephan , Mantini Dante , Albouy Genevieve
Published: April 2022

Previous research has shown that resting-state functional connectivity (rsFC) between different brain regions (seeds) is related to motor learning and motor memory consolidation. Using high-density electroencephalography (hdEEG), we addressed this question from a brain network perspective. Specifically, we examined frequency-dependent functional connectivity in resting-state networks from twenty-nine young healthy participants before and after they were trained on a motor sequence learning task. Consolidation was assessed with an overnight retest on the motor task. Our results showed training-related decreases in gamma-band connectivity within the motor network, and between the motor and functionally distinct resting-state networks including the attentional network. Brain-behavior correlation analyses revealed that baseline beta, delta, and theta rsFC were related to subsequent motor learning and memory consolidation such that lower connectivity within the motor network and between the motor and several distinct resting-state networks was correlated with better learning and overnight consolidation. Lastly, training-related increases in beta-band connectivity between the motor and the visual networks were related to greater consolidation. Altogether, our results indicate that connectivity in large-scale resting-state brain networks is related to—and modulated by—motor learning and memory consolidation processes. These finding corroborate previous seed-based connectivity research and provide evidence that frequency-dependent functional connectivity in resting-state networks is critically linked to motor learning and memory consolidation.
Statistical Nonparametric fMRI Maps in the Analysis of Response Inhibition in Abstinent Individuals with History of Alcohol Use Disorder
Authors: Pandey Ashwini Kumar , Ardekani Babak Assai , Byrne Kelly Nicole-Helen , Kamarajan Chella , Zhang Jian , Pandey Gayathri , Meyers Jacquelyn Leigh , Kinreich Sivan , Chorlian David Balin , Kuang Weipeng , Stimus Arthur T. , Porjesz Bernice
Published: April 2022

Inhibitory impairments may persist after abstinence in individuals with alcohol use disorder (AUD). Using traditional statistical parametric mapping (SPM) fMRI analysis, which requires data to satisfy parametric assumptions often difficult to satisfy in biophysical system as brain, studies have reported equivocal findings on brain areas responsible for response inhibition, and activation abnormalities during inhibition found in AUD persist after abstinence. Research is warranted using newer analysis approaches. fMRI scans were acquired during a Go/NoGo task from 30 abstinent male AUD and 30 healthy control participants with the objectives being (1) to characterize neuronal substrates associated with response inhibition using a rigorous nonparametric permutation-based fMRI analysis and (2) to determine whether these regions were differentially activated between abstinent AUD and control participants. A blood oxygen level dependent contrast analysis showed significant activation in several right cortical regions and deactivation in some left cortical regions during successful inhibition. The largest source of variance in activation level was due to group differences. The findings provide evidence of cortical substrates employed during response inhibition. The largest variance was explained by lower activation in inhibition as well as ventral attentional cortical networks in abstinent individuals with AUD, which were not found to be associated with length of abstinence, age, or impulsiveness.