bluuebunny/crossref_metadata_2025 huggingface dataset:
Experimental Measurement and Numerical Validation of the Flow Ripple in Internal Gear Pumps
Authors: Ferrari Alessandro , Fresia Paola , Rundo Massimo , Vento Oscar , Pizzo Pietro
Published: December 2022

The flow ripple in an internal gear pump was measured by means of a new instantaneous high-pressure flowmeter. The flowmeter consists of two pressure sensors mounted on a piece of the straight steel pump delivery line, and a variable-diameter orifice was installed along such a line, downstream of the flowmeter, to generate a variable load. Three distinct configurations of the high-pressure flowmeter, characterized by a different distance between the pressure transducers, were analyzed. Furthermore, a comprehensive fluid dynamic 3D model of the pump and of its high-pressure delivery line was developed and validated in terms of both the delivery pressure and the flow ripple for different pump working conditions. For the three examined configurations of the flowmeter, the measured flowrate time histories matched the corresponding numerical distributions at the various operating points. Finally, the validated 3D model was applied to predict the incomplete filling working of the interteeth chambers, and the obtained numerical pressure time histories along the delivery line were used, as input data, to assess the reliability of the flowmeter algorithm even in these severe operating conditions.
A Novel Six-Phase V-Shaped Flux-Switching Permanent Magnet Generator for Wind Power Generation
Authors: Seangwong Pattasad , Chamchuen Supanat , Fernando Nuwantha , Siritaratiwat Apirat , Khunkitti Pirat
Published: December 2022

Flux-switching permanent magnet (FSPM) machines have attracted wide attention in many rotating applications that require high-power density. In this research, we propose for the first time a novel six-phase FSPM generator with a stator featuring a V-shaped flux-focusing magnet arrangement. The design is targeted for low-speed wind power generation. To achieve the design objectives as a wind generator, the highly comprehensive structural parameters, including the number of rotor poles, split ratio, and rotor pole width, are designed and optimized using 2D finite-element analysis. From findings, the optimal stator/rotor pole combination is discovered to be 12/19 for the considered power and speed requirements. When compared to the initial structure, the optimized structure of the V-shaped FSPM generator is found to produce a significant improvement in EMF, cogging torque, electromagnetic torque, power, and efficiency. The power-generating performance of the proposed FSPM generator is found to be outstanding when compared to the radial-flux PM generators described in the literature. Therefore, the proposed V-shaped FSPM generator is capable of being used for low-speed wind power generation. The machine configuration adjustment approach presented in this work can also be utilized for the design of permanent magnet wind generators.
A Study on The Electromagnetic Multi-Step Transmission Characteristics of Interior Permanent Magnet Synchronous Motors
Authors: Lee Chung-Hui , Shin Hui-Seong , Noh Hong-Rae , Kim Ki-Chan
Published: December 2022

In this paper, electromagnetic multi-step transmissions are introduced as a method for increasing the torque and efficiency of electric vehicle driving motors. Motors using permanent magnets have a limited ability in increasing the speed as the back electromotive force increases as the speed increases. The electric vehicle driving motor performs field-weakening controls to increase the speed after the rated point. Field-weakening control increases the rotor’s speed by weakening the magnetic flux of the field. At this time, the output is constant as the speed increases. Motors have voltage limits, which also affect the maximum speed of the motor. In order to improve these constraints, there is a case study of electromagnetic shifting phenomena. Examples of the research include the wye-delta method and the method of changing the number of equivalent serial turns. As in the case of previous studies, the problem of increasing back electromotive forces as the speed increases is solved. In this paper, we propose a method to increase the maximum speed by changing the number of parallel paths. In order to lower the back electromotive force at high speeds, the number of parallel paths of the stator windings changed via the thyristor. As the number of stator parallel paths increases, the back electromotive force decreases. When the back electromotive force is lowered, the torque that can be output is reduced, but the maximum speed can increase as the voltage is also lowered. Before shifting, the number of parallel paths is set to two to satisfy high torque at low speeds. After shifting, the maximum speed can be increased to 4 with the number of parallel paths, which can broaden the operating range of the motor. In addition, the resistance of the stator windings is reduced by increasing the number of parallel paths in the high-speed region. The loss that accounts for the largest proportion of the electromagnetic loss of the motor is copper loss, and by reducing it, the efficiency increased. As a result, it increases the operating area and simultaneously increases the high-efficiency area. In order to analyze the electromagnetic characteristic, a finite-element-method-based simulation was used.
Memory Effect: How the Initial Structure of Nanoparticles Affects the Performance of De-Alloyed PtCu Electrocatalysts?
Authors: Pavlets Angelina S. , Alekseenko Anastasia A. , Pankov Ilya V. , Belenov Sergey V. , Guterman Vladimir E.
Published: December 2022

An important feature of this research is the investigation of the de-alloyed catalysts based on the nanoparticles with a simple structure (alloy) and a complex structure (gradient). The resulting samples exhibit the 2–4 times higher mass activity in the ORR compared with the commercial Pt/C. The novelty of this study is due to the application of the express-electrochemical experiment to register the trend of changes in the ORR activity caused by rearranging the structure of bimetallic nanoparticles. The state-of-the-art protocol makes it possible to establish the dependence of properties of the de-alloyed catalysts on the nanoparticles’ structure obtained at the stage of the material’s synthesis. The study shows the possibility of determining the rate of the ongoing reorganization of bimetallic nanoparticles with different architectures. The PtCu/C electrocatalysts for proton-exchange membrane fuel cells presented in this work are commercially promising in terms of both the high functional characteristics and the production by facile one-pot methods.
Review of Energy Deposition for High-Speed Flow Control
Authors: Knight Doyle , Kianvashrad Nadia
Published: December 2022

Energy deposition for flow and flight control has received significant interest in the past several decades due to its potential application to high-speed flow and flight control. This paper reviews recent progress and recommends future research.
Effect of Acute Judo Training on Countermovement Jump Performance and Perceived Fatigue among Collegiate Athletes
Authors: Chang Chien-Chun , Chen Tzu-Yi , Wu Chia-Luan , Ho Pi-Yen , Chiang Chieh-Ying
Published: December 2022

This study focused on the effect of acute Judo training on countermovement jump (CMJ) performance and perceived fatigue among a group of highly trained collegiate judo athletes. Twenty male judo athletes participated in this study (age: 20.65 ± 1.22 years, weight: 84.17 ± 28.45 kg). Participants were assessed for CMJperformance changes before, immediately after (0 h), 12 h after, and 24 h after judo training (JT) using unloaded CMJ(CMJunloaded) and loaded CMJ(CMJloaded). All the jumps were performed on a force plate, and the force–time curves were collected for further analysis. Respondents’ perceptions were evaluated using the modified rating of perceived exertion (mRPE) before, after (0 h), 12 h, and 24 h after JT. CMJparameters were analyzed at four measured points using a one-way repeated analysis of variance. Effect sizes (ES) and percentage changes before versus 24 h after JT were calculated for comparison. Associations between the CMJparameters and mRPE were analyzed using the Pearson product–moment correlation. The ratio of flight time to contact time significantly decreased, whereas the eccentric duration, concentric duration, and total duration significantly increased (p < 0.05) in both CMJs 24 h after JT. Compared with CMJunloaded, CMJloaded had a significantly lower (p < 0.05) flight time, jump height, peak velocity, and peak power. The mRPE and CMJloaded peak velocity showed moderate- to high-level negative correlation results both 0 and 24 h after training (r = −0.543, p < 0.05; r = −0.479, p < 0.05). In this study, we only observed the effect of fatigue on the neuromuscular (NM) system 24 h after JT. CMJloaded height may help to better determine fatigue state compared with CMJunloaded. According to the results, the neuromuscular effects of fatigue were not observed until 24 h after a single high-intensity training. Therefore, when arranging high-intensity special training or strength and conditioning training, one should reduce the volume of training appropriately to avoid fatigue accumulation and reduce the risk of sports injuries.
Hepatoprotective Activity of Lignin-Derived Polyphenols Dereplicated Using High-Resolution Mass Spectrometry, In Vivo Experiments, and Deep Learning
Authors: Orlov Alexey , Semenov Savva , Rukhovich Gleb , Sarycheva Anastasia , Kovaleva Oxana , Semenov Alexander , Ermakova Elena , Gubareva Ekaterina , Bugrova Anna E. , Kononikhin Alexey , Fedoros Elena I. , Nikolaev Evgeny , Zherebker Alexander
Published: December 2022

Chronic liver diseases affect more than 1 billion people worldwide and represent one of the main public health issues. Nonalcoholic fatty liver disease (NAFLD) accounts for the majority of mortal cases, while there is no currently approved therapeutics for its treatment. One of the prospective approaches to NAFLD therapy is to use a mixture of natural compounds. They showed effectiveness in alleviating NAFLD-related conditions including steatosis, fibrosis, etc. However, understanding the mechanism of action of such mixtures is important for their rational application. In this work, we propose a new dereplication workflow for deciphering the mechanism of action of the lignin-derived natural compound mixture. The workflow combines the analysis of molecular components with high-resolution mass spectrometry, selective chemical tagging and deuterium labeling, liver tissue penetration examination, assessment of biological activity in vitro, and computational chemistry tools used to generate putative structural candidates. Molecular docking was used to propose the potential mechanism of action of these structures, which was assessed by a proteomic experiment.
Characterization of Antibodies against Receptor Activity-Modifying Protein 1 (RAMP1): A Cautionary Tale
Authors: Hendrikse Erica R. , Rees Tayla A. , Tasma Zoe , Garelja Michael L. , Siow Andrew , Harris Paul W. R. , Pawlak John B. , Caron Kathleen M. , Blakeney Elizabeth S. , Russo Andrew F. , Sowers Levi P. , Lutz Thomas A. , Le Foll Christelle , Walker Christopher S. , Hay Debbie L.
Published: December 2022

Calcitonin gene-related peptide (CGRP) is a key component of migraine pathophysiology, yielding effective migraine therapeutics. CGRP receptors contain a core accessory protein subunit: receptor activity-modifying protein 1 (RAMP1). Understanding of RAMP1 expression is incomplete, partly due to the challenges in identifying specific and validated antibody tools. We profiled antibodies for immunodetection of RAMP1 using Western blotting, immunocytochemistry and immunohistochemistry, including using RAMP1 knockout mouse tissue. Most antibodies could detect RAMP1 in Western blotting and immunocytochemistry using transfected cells. Two antibodies (844, ab256575) could detect a RAMP1-like band in Western blots of rodent brain but not RAMP1 knockout mice. However, cross-reactivity with other proteins was evident for all antibodies. This cross-reactivity prevented clear conclusions about RAMP1 anatomical localization, as each antibody detected a distinct pattern of immunoreactivity in rodent brain. We cannot confidently attribute immunoreactivity produced by RAMP1 antibodies (including 844) to the presence of RAMP1 protein in immunohistochemical applications in brain tissue. RAMP1 expression in brain and other tissues therefore needs to be revisited using RAMP1 antibodies that have been comprehensively validated using multiple strategies to establish multiple lines of convincing evidence. As RAMP1 is important for other GPCR/ligand pairings, our results have broader significance beyond the CGRP field.
Muscle Regeneration in Holothurians without the Upregulation of Muscle Genes
Authors: Nizhnichenko Vladimir A. , Boyko Alexey V. , Ginanova Talia T. , Dolmatov Igor Yu.
Published: December 2022

The holothurian Eupentacta fraudatrix is capable of fully restoring its muscles after transverse dissection. Although the regeneration of these structures is well studied at the cellular level, the molecular basis of the process remains poorly understood. To identify genes that may be involved in the regulation of muscle regeneration, the transcriptome of the longitudinal muscle band of E. fraudatrix has been sequenced at different time periods post-injury. An analysis of the map of biological processes and pathways has shown that most genes associated with myogenesis decrease their expression during the regeneration. The only exception is the genes united by the GO term “heart valve development”. This may indicate the antiquity of mechanisms of mesodermal structure transformation, which was co-opted into various morphogeneses in deuterostomes. Two groups of genes that play a key role in the regeneration have been analyzed: transcription factors and matrix metalloproteinases. A total of six transcription factor genes (Ef-HOX5, Ef-ZEB2, Ef-RARB, Ef-RUNX1, Ef-SOX17, and Ef-ZNF318) and seven matrix metalloproteinase genes (Ef-MMP11, Ef-MMP13, Ef-MMP13-1, Ef-MMP16-2, Ef-MMP16-3, Ef-MMP24, and Ef-MMP24-1) showing differential expression during myogenesis have been revealed. The identified genes are assumed to be involved in the muscle regeneration in holothurians.
Dysregulation in Multiple Transcriptomic Endometrial Pathways Is Associated with Recurrent Implantation Failure and Recurrent Early Pregnancy Loss
Authors: Liaqat Ali Khan Norhayati , Nafee Tamer , Shao Tingting , Hart Amber Rose , Elliott Sarah , Ola Bolarinde , Heath Paul Roy , Fazeli Alireza
Published: December 2022

Overlapping disease aetiologies associated with multiple altered biological processes have been identified that change the endometrial function leading to recurrent implantation failure (RIF) and recurrent early pregnancy loss (REPL). We aimed to provide a detailed insight into the nature of the biological malfunction and related pathways of differentially expressed genes in RIF and REPL. Endometrial biopsies were obtained from 9 women experiencing RIF, REPL and control groups. Affymetrix microarray analysis was performed to measure the gene expression level of the endometrial biopsies. Unsupervised clustering of endometrial samples shows scattered distribution of gene expression between the RIF, REPL and control groups. 2556 and 1174 genes (p value < 0.05, Fold change > 1.2) were significantly altered in the endometria of RIF and REPL patients’ group, respectively compared to the control group. Downregulation in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of the differentially expressed genes (DEGs) in RIF and REPL including ribosome and oxidative phosphorylation pathways. Gene Ontology (GO) analysis revealed ribosomes and mitochondria inner membrane as the most significantly downregulated cellular component (CC) affected in RIF and REPL. Determination of the dysregulated genes and related biological pathways in RIF and REPL will be key in understanding their molecular pathology and of major importance in addressing diagnosis, prognosis, and treatment issues
The Impact of Nicotine along with Oral Contraceptive Exposure on Brain Fatty Acid Metabolism in Female Rats
Authors: Patel Shahil H. , Timón-Gómez Alba , Pradhyumnan Hari , Mankaliye Berk , Dave Kunjan R. , Perez-Pinzon Miguel A. , Raval Ami P.
Published: December 2022

Smoking-derived nicotine (N) and oral contraceptive (OC) synergistically exacerbate ischemic brain damage in females, and the underlying mechanisms remain elusive. In a previous study, we showed that N + OC exposure altered brain glucose metabolism in females. Since lipid metabolism complements glycolysis, the current study aims to examine the metabolic fingerprint of fatty acids in the brain of female rats exposed to N+/−OC. Adolescent and adult Sprague–Dawley female rats were randomly (n = 8 per group) exposed to either saline or N (4.5 mg/kg) +/−OC (combined OC or placebo delivered via oral gavage) for 16–21 days. Following exposure, brain tissue was harvested for unbiased metabolomic analysis (performed by Metabolon Inc., Morrisville, NC, USA) and the metabolomic profile changes were complemented with Western blot analysis of key enzymes in the lipid pathway. Metabolomic data showed significant accumulation of fatty acids and phosphatidylcholine (PC) metabolites in the brain. Adolescent, more so than adult females, exposed to N + OC showed significant increases in carnitine-conjugated fatty acid metabolites compared to saline control animals. These changes in fatty acyl carnitines were accompanied by an increase in a subset of free fatty acids, suggesting elevated fatty acid β-oxidation in the mitochondria to meet energy demand. In support, β-hydroxybutyrate was significantly lower in N + OC exposure groups in adolescent animals, implying a complete shunting of acetyl CoA for energy production via the TCA cycle. The reported changes in fatty acids and PC metabolism due to N + OC could inhibit post-translational palmitoylation of membrane proteins and synaptic vesicle formation, respectively, thus exacerbating ischemic brain damage in female rats.
Engineered Bacteriorhodopsin Film with Oriented Patterns for the Improvement of the Photoelectric Response
Authors: Wu Mian , Lin Feng , Song Yu
Published: December 2022

The use of photosensitive proteins has become a competitive solar energy solution, owing to its pollution-free nature, high conversion efficiency, and good biocompatibility. Bacteriorhodopsin (bR) is an important light-sensitive protein that is widely used in the fabrication of photoelectronic devices. However, research on the optimization and comparison of the immobilization techniques is lacking. In this study, in order to obtain bR films with a high energy conversion efficiency, three immobilization techniques, namely dropcasting, electrophoretic sedimentation, and Langmuir–Blodgett deposition, were used to fabricate films, and their topographical and photoelectrical characteristics were compared. All three immobilization techniques can transfer bR molecules to substrates, forming functional photosensitive bR films. The absorption of the bR films at 568 nm reached the highest value of 0.3 under the EPS technique. The peak photocurrent for the EPS technique reached 5.03 nA. In addition, the EPS technique has the highest efficiency factor of 13.46, indicating that it can generate the highest value of photocurrent under the same light conditions, owing to the improved orientation, and no significant decrease in the peak photocurrent was observed after three weeks, which indicates the stability of the photoelectric response. These results indicate that the EPS technique has a great potential for the photoelectrical device fabrication and solar-energy conversion.
Nicotinamide n-Oxide Attenuates HSV-1-Induced Microglial Inflammation through Sirtuin-1/NF-κB Signaling
Authors: Song Xiaowei , Cao Wenyan , Wang Zexu , Li Feng , Xiao Ji , Zeng Qiongzhen , Wang Yuan , Li Shan , Ye Cuifang , Wang Yifei , Zheng Kai
Published: December 2022

HSV-1 is a typical neurotropic virus that infects the brain and causes keratitis, cold sores, and occasionally, acute herpes simplex encephalitis (HSE). The large amount of proinflammatory cytokines induced by HSV-1 infection is an important cause of neurotoxicity in the central nervous system (CNS). Microglia, as resident macrophages in CNS, are the first line of defense against neurotropic virus infection. Inhibiting the excessive production of inflammatory cytokines in overactivated microglia is a crucial strategy for the treatment of HSE. In the present study, we investigated the effect of nicotinamide n-oxide (NAMO), a metabolite mainly produced by gut microbe, on HSV-1-induced microglial inflammation and HSE. We found that NAMO significantly inhibits the production of cytokines induced by HSV-1 infection of microglia, such as IL-1β, IL-6, and TNF-α. In addition, NAMO promotes the transition of microglia from the pro-inflammatory M1 type to the anti-inflammatory M2 type. More detailed studies revealed that NAMO enhances the expression of Sirtuin-1 and its deacetylase enzymatic activity, which in turn deacetylates the p65 subunit to inhibit NF-κB signaling, resulting in reduced inflammatory response and ameliorated HSE pathology. Therefore, Sirtuin-1/NF-κB axis may be promising therapeutic targets against HSV-1 infection-related diseases including HSE.
iPSC-Derived Macrophages: The Differentiation Protocol Affects Cell Immune Characteristics and Differentiation Trajectories
Authors: Klepikova Anna , Nenasheva Tatiana , Sheveleva Olga , Protasova Elena , Antonov Daniil , Gainullina Anastasiia , Chikina Evgeniia , Sakovnich Olga , Gerasimova Tatiana , Nikitina Irina , Shevalie Dmitry , Lyadova Irina
Published: December 2022

The generation of human macrophages from induced pluripotent stem cells (iMacs) is a rapidly developing approach used to create disease models, screen drugs, study macrophage–pathogen interactions and develop macrophage-based cell therapy. To generate iMacs, different types of protocols have been suggested, all thought to result in the generation of similar iMac populations. However, direct comparison of iMacs generated using different protocols has not been performed. We have compared the productivity, the differentiation trajectories and the characteristics of iMacs generated using two widely used protocols: one based on the formation of embryoid bodies and the induction of myeloid differentiation by only two cytokines, interleukin-3 and macrophage colony-stimulating factor, and the other utilizing multiple exogenous factors for iMac generation. We report inter-protocol differences in the following: (i) protocol productivity; (ii) dynamic changes in the expression of genes related to inflammation and lipid homeostasis following iMac differentiation and (iii) the transcriptomic profiles of terminally differentiated iMacs, including the expression of genes involved in inflammatory response, antigen presentation and lipid homeostasis. The results document the dependence of fine iMac characteristics on the type of differentiation protocol, which is important for further development of the field, including the development of iMac-based cell therapy.
PLEKHM2 Loss of Function Impairs the Activity of iPSC-Derived Neurons via Regulation of Autophagic Flux
Authors: Ben-Zvi Hadas , Rabinski Tatiana , Ofir Rivka , Cohen Smadar , Vatine Gad D.
Published: December 2022

Pleckstrin Homology And RUN Domain Containing M2 (PLEKHM2) [delAG] mutation causes dilated cardiomyopathy with left ventricular non-compaction (DCM-LVNC), resulting in a premature death of PLEKHM2[delAG] individuals due to heart failure. PLEKHM2 is a factor involved in autophagy, a master regulator of cellular homeostasis, decomposing pathogens, proteins and other cellular components. Autophagy is mainly carried out by the lysosome, containing degradation enzymes, and by the autophagosome, which engulfs substances marked for decomposition. PLEKHM2 promotes lysosomal movement toward the cell periphery. Autophagic dysregulation is associated with neurodegenerative diseases’ pathogenesis. Thus, modulation of autophagy holds considerable potential as a therapeutic target for such disorders. We hypothesized that PLEKHM2 is involved in neuronal development and function, and that mutated PLEKHM2 (PLEKHM2[delAG]) neurons will present impaired functions. Here, we studied PLEKHM2-related abnormalities in induced pluripotent stem cell (iPSC)-derived motor neurons (iMNs) as a neuronal model. PLEKHM2[delAG] iMN cultures had healthy control-like differentiation potential but exhibited reduced autophagic activity. Electrophysiological measurements revealed that PLEKHM2[delAG] iMN cultures displayed delayed functional maturation and more frequent and unsynchronized activity. This was associated with increased size and a more perinuclear lysosome cellular distribution. Thus, our results suggest that PLEKHM2 is involved in the functional development of neurons through the regulation of autophagic flux.
Efficient and Reusable Sorbents Based on Nanostructured BN Coatings for Water Treatment from Antibiotics
Authors: Kotyakova Kristina Yu. , Antipina Liubov Yu. , Sorokin Pavel B. , Shtansky Dmitry V.
Published: December 2022

Increasing contamination of wastewater with antibiotics used in agriculture, animal husbandry, and medicine is a serious problem for all living things. To address this important issue, we have developed an efficient platform based on a high specific surface area hexagonal boron nitride (BN) coating formed by numerous nanopetals and nanoneedles. The maximum sorption capacity of 1 × 1 cm2 BN coatings is 502.78 µg/g (tetracycline, TET), 315.75 µg/g (ciprofloxacin, CIP), 400.17 µg/g (amoxicillin, AMOX), and 269.7 µg/g (amphotericin B, AMP), which exceeds the sorption capacity of many known materials. Unlike nanoparticles, BN-coated Si wafers are easy to place in and remove from antibiotic-contaminated aqueous solutions, and are easy to clean. When reusing the adsorbents, 100% efficiency was observed at the same time intervals as in the first cleaning cycle: 7 days (TET) and 14 days (CIP, AMOX, AMP) at 10 µg/mL, 14 days (TET, CIP, and AMOX) and 28 days (AMP) at 50 µg/mL, and 14 days (TET) and 28 days (CIP, AMOX and AMP) at 100 µg/mL. The results obtained showed that TET and CIP are best adsorbed on the surface of BN, so TET was chosen as an example for further theoretical modeling of the sorption process. It was found that adsorption is the main mechanism, and this process is spontaneous and endothermic. This highlights the importance of a high specific surface area for the efficient removal of antibiotics from aqueous solutions.
Regulating Th17/Treg Balance Contributes to the Therapeutic Effect of Ziyuglycoside I on Collagen-Induced Arthritis
Authors: Wang Manman , Su Tiantian , Sun Hanfei , Cheng Huijuan , Jiang Chunru , Guo Paipai , Zhu Zhenduo , Fang Ruhong , He Feng , Ge Mingli , Guan Qiuyun , Wei Wei , Wang Qingtong
Published: December 2022

To investigate the therapeutic effect and primary pharmacological mechanism of Ziyuglycoside I (Ziyu I) on collagen-induced arthritis (CIA) mice. CIA mice were treated with 5, 10, or 20 mg/kg of Ziyu I or 2 mg/kg of methotrexate (MTX), and clinical manifestations, as well as pathological changes, were observed. T cell viability and subset type were determined, and serum levels of transforming growth factor-beta (TGF-β) and interleukin-17 (IL-17) were detected. The mRNA expression of retinoid-related orphan receptor-γt (RORγt) and transcription factor forkhead box protein 3 (Foxp3) in mouse spleen lymphocytes was ascertained by the real-time reverse transcriptase-polymerase chain reaction (RT-qPCR). Molecular docking was used to detect whether there was a molecular interaction between Ziyu I and protein kinase B (Akt). The activation of mechanistic target of rapamycin (mTOR) in T cells was verified by Western blotting or immunofluorescence. Ziyu I treatment effectively alleviated arthritis symptoms of CIA mice, including body weight, global score, arthritis index, and a number of swollen joints. Similarly, pathological changes of joints and spleens in arthritic mice were improved. The thymic index, T cell activity, and RORγt production of Ziyu I-treated mice were significantly reduced. Notably, through molecular docking, western blotting, and immunofluorescence data analysis, it was found that Ziyu I could interact directly with Akt to reduce downstream mTOR activation and inhibit helper T cell 17 (Th17) differentiation, thereby regulating Th17/regulatory T cell (Treg) balance and improving arthritis symptoms. Ziyu I effectively improves arthritic symptoms in CIA mice by inhibiting mTOR activation, thereby affecting Th17 differentiation and regulating Th17/Treg balance.
Identification of Transcriptional Networks Involved in De Novo Organ Formation in Tomato Hypocotyl Explants
Authors: Larriba Eduardo , Nicolás-Albujer Míriam , Sánchez-García Ana Belén , Pérez-Pérez José Manuel
Published: December 2022

Some of the hormone crosstalk and transcription factors (TFs) involved in wound-induced organ regeneration have been extensively studied in the model plant Arabidopsis thaliana. In previous work, we established Solanum lycopersicum “Micro-Tom” explants without the addition of exogenous hormones as a model to investigate wound-induced de novo organ formation. The current working model indicates that cell reprogramming and founder cell activation requires spatial and temporal regulation of auxin-to-cytokinin (CK) gradients in the apical and basal regions of the hypocotyl combined with extensive metabolic reprogramming of some cells in the apical region. In this work, we extended our transcriptomic analysis to identify some of the gene regulatory networks involved in wound-induced organ regeneration in tomato. Our results highlight a functional conservation of key TF modules whose function is conserved during de novo organ formation in plants, which will serve as a valuable resource for future studies.
Varicocele, Functional Foods and Nutraceuticals: From Mechanisms of Action in Animal Models to Therapeutic Application
Authors: Marini Herbert Ryan , Micali Antonio , Puzzolo Domenico , Minutoli Letteria , Antonuccio Pietro
Published: December 2022

Varicocele is one of the main causes of infertility in men, thus representing an important clinical problem worldwide. Inflammation contributes mainly to its pathogenesis, even if the exact pathophysiological mechanisms that correlate varicocele and infertility are still unknown. In addition, oxidative stress, apoptosis, hypoxia, and scrotal hyperthermia seem to play important roles. So far, the treatment of varicocele and the care of the fertility-associated problems still represent an area of interest for researchers, although many advances have occurred over the past few years. Recent experimental animal studies, as well as the current epidemiological evidence in humans, demonstrated that many functional foods of natural origin and nutraceuticals that are particularly abundant in the Mediterranean diet showed anti-inflammatory effects in varicocele. The aim of the present narrative review is to mainly evaluate recent experimental animal studies regarding the molecular mechanisms of varicocele and the state of the art about possible therapeutic approaches. As the current literature demonstrates convincing associations between diet, food components and fertility, the rational intake of nutraceuticals, which are particularly abundant in foods typical of plant-based eating patterns, may be a reliable therapeutic supportive care against varicocele and, consequently, could be very useful in the cure of fertility-associated problems in patients.
Exploring Saduria entomon (Crustacea Isopoda) as a New Source for Chitin and Chitosan Isolation
Authors: Rodriguez-Veiga Isabel , Acosta Niuris , Aranaz Inmaculada , Dobrzycka-Krahel Aldona
Published: December 2022

Chitin and chitosan demand is growing very fast due to interest from industries such as pharmaceutical, cosmetic, agricultural and others. New sources for chitin and chitosan isolation are being extensively searched to fulfil this demand. In this paper, Saduria entomon a Baltic benthic crustacean, is evaluated as a source for chitin and chitosan isolation. Chitin and chitosan yield from S. entomon were 14.8 and 8.2%, respectively, in a similar range to other sources. Samples were characterized in terms of physicochemical properties (acetylation degree, molecular weight, thermal stability, and crystallinity) and two biological properties, antimicrobial activity and antioxidant activity were evaluated. Chitosan S. entomon exhibited antimicrobial activity against S. aureus but not against E. coli. An antioxidant activity of 20.98 TROLOX µmol equivalent/g polymer was detected for the chitosan sample. These properties are very promising for the use of this organism as a source for chitin and chitosan isolation in the biomedical field.
A General Signal Pathway to Regulate Multiple Detoxification Genes Drives the Evolution of Helicoverpa armigera Adaptation to Xenobiotics
Authors: Zhang Lei , Lv Shenglan , Li Mingjian , Gu Meng , Gao Xiwu
Published: December 2022

The study of insect adaptation to the defensive metabolites of host plants and various kinds of insecticides in order to acquire resistance is a hot topic in the pest-control field, but the mechanism is still unclear. In our study, we found that a general signal pathway exists in H. armigera which can regulate multiple P450s, GSTs and UGTs genes to help insects decrease their susceptibility to xenobiotics. Knockdown of HaNrf2 and HaAhR expression could significantly increase the toxicity of xenobiotics to H. armigera, and simultaneously decrease the gene expression of P450s, GSTs and UGTs which are related to the xenobiotic metabolism and synthesis of insect hormone pathways. Then, we used EMSA and dual luciferase assay to verify that a crosstalk exists between AhR and Nrf2 to regulate multiple P450s, GSTs and UGTs genes to mediate H. armigera susceptibility to plant allelochemicals and insecticides. The detoxification genes’ expression network which can be regulated by Nrf2 and AhR is still unknown, and there were also no reports about the crosstalk between AhR and Nrf2 that exist in insects and can regulate multiple detoxification genes’ expression. Our results provide a new general signaling pathway to reveal the adaptive mechanism of insects to xenobiotics and provides further insight into designing effective pest-management strategies to avoid the overuse of insecticides.
Oral Therapy for the Treatment of Transthyretin-Related Amyloid Cardiomyopathy
Authors: Nuvolone Mario , Girelli Maria , Merlini Giampaolo
Published: December 2022

The care of systemic amyloidosis has improved dramatically due to improved awareness, accurate diagnostic tools, the development of powerful prognostic and companion biomarkers, and a continuous flow of innovative drugs, which translated into the blooming of phase 2/3 interventional studies for light chain (AL) and transthyretin (ATTR) amyloidosis. The unprecedented availability of effective drugs ignited great interest across various medical specialties, particularly among cardiologists who are now recognizing cardiac amyloidosis at an extraordinary pace. In all amyloidosis referral centers, we are observing a substantial increase in the prevalence of wild-type transthyretin (ATTRwt) cardiomyopathy, which is now becoming the most common form of cardiac amyloidosis. This review focuses on the oral drugs that have been recently introduced for the treatment of ATTR cardiac amyloidosis, for their ease of use in the clinic. They include both old repurposed drugs or fit-for-purpose designed compounds which bind and stabilize the TTR tetramer, thus reducing the formation of new amyloid fibrils, such as tafamidis, diflunisal, and acoramidis, as well as fibril disruptors which have the potential to promote the clearance of amyloid deposits, such as doxycycline. The development of novel therapies is based on the advances in the understanding of the molecular events underlying amyloid cardiomyopathy.
Cognate RNA-Binding Modes by the Alternative-Splicing Regulator MBNL1 Inferred from Molecular Dynamics
Authors: González Àlex L. , Fernández-Remacha Daniel , Borrell José Ignacio , Teixidó Jordi , Estrada-Tejedor Roger
Published: December 2022

The muscleblind-like protein family (MBNL) plays a prominent role in the regulation of alternative splicing. Consequently, the loss of MBNL function resulting from sequestration by RNA hairpins triggers the development of a neuromuscular disease called myotonic dystrophy (DM). Despite the sequence and structural similarities between the four zinc-finger domains that form MBNL1, recent studies have revealed that the four binding domains have differentiated splicing activity. The dynamic behaviors of MBNL1 ZnFs were simulated using conventional molecular dynamics (cMD) and steered molecular dynamics (sMD) simulations of a structural model of MBNL1 protein to provide insights into the binding selectivity of the four zinc-finger (ZnF) domains toward the GpC steps in YGCY RNA sequence. In accordance with previous studies, our results suggest that both global and local residue fluctuations on each domain have great impacts on triggering alternative splicing, indicating that local motions in RNA-binding domains could modulate their affinity and specificity. In addition, all four ZnF domains provide a distinct RNA-binding environment in terms of structural sampling and mobility that may be involved in the differentiated MBNL1 splicing events reported in the literature.
Neuroprotection of Kaji-Ichigoside F1 via the BDNF/Akt/mTOR Signaling Pathways against NMDA-Induced Neurotoxicity
Authors: Chen Faju , Wang Li , Jin Fengli , Li Liangqun , Wang Tao , Gao Ming , Li Lilang , Wang Yu , Lou Zhongsheng , Yang Juan , Li Qiji , Yang Xiaosheng
Published: December 2022

Kaji-ichigoside F1 (KF1), a natural oleanane-type triterpenoid saponin, is the main active constituent from Rosa roxburghii. In the southwest regions of China, particularly in Guizhou Province, this plant was used as a Miao ethnic medicine to prevent and treat dyspepsia, dysentery, hypoimmunity, and neurasthenia. In the present study, the neuroprotective effect of KF1 was evaluated against N-methyl-D-aspartate (NMDA)-induced neurotoxicity in vivo and in vitro. An NMDA-induced PC12 cell neurotoxicity assay showed that KF1 effectively improved cellular viability, inhibited the release of lactate dehydrogenase (LDH), and reduced cell apoptosis. Furthermore, KF1-treated NMDA-induced excitotoxicity mice displayed a remarkable capacity for improving spatial learning memory in the Y-maze and Morris water maze tests. In addition, KF1 increased the levels of the neurotransmitters 5-hydroxytryptamine, dopamine, and monoamine oxidase and reduced the calcium ion concentration in the hippocampus of mice. Hematoxylin and eosin and Nissl staining indicated that KF1 effectively reduced the impairment of neurons. Furthermore, Western blot assays showed that KF1 decreased NMDAR1 expression. In contrast, the NMDAR2B (NR2B), glutamate receptor (AMPA), TrkB, protein kinase B (AKT), mammalian target of rapamycin (mTOR), PSD95, and synapsin 1 were upregulated in NMDA-induced PC12 cells and an animal model. These results suggest that KF1 has a remarkable protective effect against NMDA-induced neurotoxicity, which is directly related to the regulation of the NMDA receptor and the activation of the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR) and BDNF/AKT/mTOR signaling pathways.
The Plant Fatty Acyl Reductases
Authors: Zhang Xuanhao , Liu Yi , Ayaz Asma , Zhao Huayan , Lü Shiyou
Published: December 2022

Fatty acyl reductase (FAR) is a crucial enzyme that catalyzes the NADPH-dependent reduction of fatty acyl-CoA or acyl-ACP substrates to primary fatty alcohols, which in turn acts as intermediate metabolites or metabolic end products to participate in the formation of plant extracellular lipid protective barriers (e.g., cuticular wax, sporopollenin, suberin, and taproot wax). FARs are widely present across plant evolution processes and play conserved roles during lipid synthesis. In this review, we provide a comprehensive view of FAR family enzymes, including phylogenetic analysis, conserved structural domains, substrate specificity, subcellular localization, tissue-specific expression patterns, their varied functions in lipid biosynthesis, and the regulation mechanism of FAR activity. Finally, we pose several questions to be addressed, such as the roles of FARs in tryphine, the interactions between transcription factors (TFs) and FARs in various environments, and the identification of post-transcriptional, translational, and post-translational regulators.
PARP Inhibitor Inhibits the Vasculogenic Mimicry through a NF-κB-PTX3 Axis Signaling in Breast Cancer Cells
Authors: Chivot Justine , Ferrand Nathalie , Fert Aude , Van Dreden Patrick , Morichon Romain , Sabbah Michèle
Published: December 2022

Poly (ADP-ribose) polymerase inhibitors (PARPi) are targeted therapies that inhibit PARP proteins which are involved in a variety of cell functions. PARPi may act as modulators of angiogenesis; however, the relationship between PARPi and the vasculogenic mimicry (VM) in breast cancer remains unclear. To determine whether PARPi regulate the vascular channel formation, we assessed whether the treatment with olaparib, talazoparib and veliparib inhibits the vascular channel formation by breast cancer cell lines. Here, we found that PARPi act as potent inhibitors of the VM formation in triple negative breast cancer cells, independently of the BRCA status. Mechanistically, we find that PARPi trigger and inhibit the NF-κB signaling, leading to the inhibition of the VM. We further show that PARPi decrease the expression of the angiogenic factor PTX3. Moreover, PTX3 rescued the PARPi-inhibited VM inhibition. In conclusion, our results indicate that PARPi, by targeting the VM, may provide a new therapeutic approach for triple negative breast cancer.
A Fucosylated Lactose-Presenting Tetravalent Glycocluster Acting as a Mutual Ligand of Pseudomonas aeruginosa Lectins A (PA-IL) and B (PA-IIL)—Synthesis and Interaction Studies
Authors: Csávás Magdolna , Kalmár László , Szőke Petronella , Farkas László Bence , Bécsi Bálint , Kónya Zoltán , Kerékgyártó János , Borbás Anikó , Erdődi Ferenc , Kövér Katalin E.
Published: December 2022

The Gram-negative bacterium Pseudomonas aeruginosa is an important opportunistic human pathogen associated with cystic fibrosis. P. aeruginosa produces two soluble lectins, the d-galactose-specific lectin PA-IL (LecA) and the l-fucose-specific lectin PA-IIL (LecB), among other virulence factors. These lectins play an important role in the adhesion to host cells and biofilm formation. Moreover, PA-IL is cytotoxic to respiratory cells in the primary culture. Therefore, these lectins are promising therapeutic targets. Specifically, carbohydrate-based compounds could inhibit their activity. In the present work, a 3-O-fucosyl lactose-containing tetravalent glycocluster was synthesized and utilized as a mutual ligand of galactophilic and fucophilic lectins. Pentaerythritol equipped with azido ethylene glycol-linkers was chosen as a multivalent scaffold and the glycocluster was constructed by coupling the scaffold with propargyl 3-O-fucosyl lactoside using an azide-alkyne 1,3-dipolar cycloaddition reaction. The interactions between the glycocluster and PA-IL or PA-IIL were investigated by isothermal titration microcalorimetry and saturation transfer difference NMR spectroscopy. These results may assist in the development of efficient anti-adhesion therapy for the treatment of a P. aeruginosa infection.
Usnic Acid-Mediated Exchange of Protons for Divalent Metal Cations across Lipid Membranes: Relevance to Mitochondrial Uncoupling
Authors: Rokitskaya Tatyana I. , Arutyunyan Alexander M. , Khailova Ljudmila S. , Kataeva Alisa D. , Firsov Alexander M. , Kotova Elena A. , Antonenko Yuri N.
Published: December 2022

Usnic acid (UA), a unique lichen metabolite, is a protonophoric uncoupler of oxidative phosphorylation, widely known as a weight-loss dietary supplement. In contrast to conventional proton-shuttling mitochondrial uncouplers, UA was found to carry protons across lipid membranes via the induction of an electrogenic proton exchange for calcium or magnesium cations. Here, we evaluated the ability of various divalent metal cations to stimulate a proton transport through both planar and vesicular bilayer lipid membranes by measuring the transmembrane electrical current and fluorescence-detected pH gradient dissipation in pyranine-loaded liposomes, respectively. Thus, we obtained the following selectivity series of calcium, magnesium, zinc, manganese and copper cations: Zn2+ > Mn2+ > Mg2+ > Ca2+ >> Cu2+. Remarkably, Cu2+ appeared to suppress the UA-mediated proton transport in both lipid membrane systems. The data on the divalent metal cation/proton exchange were supported by circular dichroism spectroscopy of UA in the presence of the corresponding cations.
Effect of Novel AKT Inhibitor Vevorisertib as Single Agent and in Combination with Sorafenib on Hepatocellular Carcinoma in a Cirrhotic Rat Model
Authors: Kurma Keerthi , Zeybek Kuyucu Ayca , Roth Gaël S. , Sturm Nathalie , Mercey-Ressejac Marion , Abbadessa Giovanni , Yu Yi , Lerat Herve , Marche Patrice N. , Decaens Thomas , Macek Jilkova Zuzana
Published: December 2022

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. The AKT pathway is often activated in HCC cases, and a longer exposure to tyrosine kinase inhibitors such as sorafenib may lead to over-activation of the AKT pathway, leading to HCC resistance. Here, we studied the efficacy of a new generation of allosteric AKT inhibitor, vevorisertib, alone or in combination with sorafenib. To identify specific adverse effects related to the background of cirrhosis, we used a diethylnitrosamine (DEN)-induced cirrhotic rat model. Vevorisertib was tested in vitro on Hep3B, HepG2, HuH7 and PLC/PRF cell lines. Rats were treated weekly with intra-peritoneal injections of DEN for 14 weeks to obtain cirrhosis with fully developed HCC. After that, rats were randomized into four groups (n = 7/group): control, sorafenib, vevorisertib and the combination of vevorisertib + sorafenib, and treated for 6 weeks. Tumor progression was followed by MRI. We demonstrated that the vevorisertib is a highly potent treatment, blocking the phosphorylation of AKT. The tumor progression in the rat liver was significantly reduced by treatment with vevorisertib + sorafenib (49.4%) compared to the control group (158.8%, p < 0.0001). Tumor size, tumor number and tumor cell proliferation were significantly reduced in both the vevorisertib group and vevorisertib + sorafenib groups compared to the control group. Sirius red staining showed an improvement in liver fibrosis by vevorisertib and the combination treatment. Moreover, vevorisertib + sorafenib treatment was associated with a normalization in the liver vasculature. Altogether, vevorisertib as a single agent and its combination with sorafenib exerted a strong suppression of tumor progression and improved liver fibrosis. Thus, results provide a rationale for testing vevorisertib in clinical settings and confirm the importance of targeting AKT in HCC.