bluuebunny/crossref_metadata_2025 huggingface dataset:
A Method to Probe the Interfaces in La2−xSrxCuO4-LaSrAlO4-La2−xSrxCuO4 Trilayer Junctions
Authors: Xu Xiaotao , He Xi , Bollinger Anthony T. , Han Myung-Geun , Zhu Yimei , Shi Xiaoyan , Božović Ivan
Published: February 2023

C-axis trilayer cuprate Josephson junctions are essential for basic science and digital circuit applications of high-temperature superconductors. We present a method for probing the interface perfection in La2−xSrxCuO4 (LSCO)-LaSrAlO4 (LSAO)-La2−xSrxCuO4 trilayer junctions. A series of LSCO-LSAO superlattices with atomically smooth surfaces and sharp interfaces were grown by the atomic-layer-by-layer molecular beam epitaxy (ALL-MBE) technique. We have systematically varied the thickness of LSCO and LSAO layers with monolayer precision. By studying the mutual inductance and electrical transport in these superlattices, we detect the non-superconducting (“dead”) layers at the interfaces and quantify their thicknesses. Our results indicate that two optimally doped LSCO monolayers just above and below the one monolayer LSAO barrier are no longer superconducting, rendering the actual barrier thickness of five monolayers. Next, we have shown that introducing a protective highly-overdoped LSCO layer reduces the thickness of dead layers by one or two monolayers.
A Novel Approach for Modeling the Non-Newtonian Behavior of Simple Liquids: Application to Liquid Water Viscosity from Low to High Shear Rates
Authors: Aitken Frédéric , Volino Ferdinand
Published: February 2023

The aim of this paper is to present a model for the rheological behavior of simple liquids as a function of the amplitude of the imposed shear stress or strain. The elastic mode theory is first generalized to take into account the fact that, during a flow experiment, mechanical energy is injected in a system initially at thermodynamic equilibrium. This generalized theory can be seen as a particular aspect of the general problem of perturbation by the measurement, associated with that of the coupling between fluctuation and dissipation. This generalization leads to a “finitary” character of the model. It is then combined with the inertial mode theory. The formalism thus obtained allows us to model the rheological behavior of liquids over a wide range of velocity gradients, including the intermediate narrow range corresponding to the Newtonian regime. As experimental tests, viscosity measurements with two kinds of moving rotor rheometers were performed. Only data obtained with liquid water at room temperature are presented and quantitatively analyzed here. It is also shown that liquid n-octane exhibits the same qualitative behaviors as those of liquid water. In the appendices, connection of this theory with quantum mechanics and turbulence phenomena are discussed, and the notion of viscous mass is introduced.
Secreted Protein Acidic and Rich in Cysteine (SPARC)—Mediated Exercise Effects: Illustrative Molecular Pathways against Various Diseases
Authors: Ghanemi Abdelaziz , Yoshioka Mayumi , St-Amand Jonny
Published: February 2023

The strong benefits of exercise, in addition to the development of both the therapeutic applications of physical activity and molecular biology tools, means that it has become very important to explore the underlying molecular patterns linking exercise and its induced phenotypic changes. Within this context, secreted protein acidic and rich in cysteine (SPARC) has been characterized as an exercise-induced protein that would mediate and induce some important effects of exercise. Herein, we suggest some underlying pathways to explain such SPARC-induced exercise-like effects. Such mechanistic mapping would not only allow us to understand the molecular processes of exercise and SPARC effects but would also highlight the potential to develop novel molecular therapies. These therapies would be based on mimicking the exercise benefits via either introducing SPARC or pharmacologically targeting the SPARC-related pathways to produce exercise-like effects. This is of a particular importance for those who do not have the ability to perform the required physical activity due to disabilities or diseases. The main objective of this work is to highlight selected potential therapeutic applications deriving from SPARC properties that have been reported in various publications.
Venous Thromboembolism in Severe Burns Patients with Intravascular Warming Catheter: A Retrospective Cohort Study
Authors: Reid Isabella , Bortz Hadley , Burrell Aidan , Gantner Dashiell , Rosenblum Samara , Cleland Heather
Published: February 2023

Background: Use of intravascular warming catheters following major burns has been shown to be effective to maintain normothermia, but their use may be associated with complications. The aim of this study was to determine what proportion of patients with an intravascular warming catheter developed a potentially catheter-related venous thromboembolism (VTE) and to identify contributing risk factors. Methods: This was a retrospective cohort study of patients admitted to the Victorian Adult Burns Service January 2013 to July 2018 with major burns (TBSA > 20%) who had an ICYTM intravascular warming catheter. Warming catheter insertion and other details were identified with a manual search of the patients’ medical records by a single author while incidence of VTE was determined by the coding department from a central database. Results: Forty patients had an intravascular warming catheter inserted during the study period. The number of patients in the catheter group that sustained a VTE was eight (20%), of which four (10%) could have been catheter-related due to the anatomical location. In the cases of the four potentially catheter-related VTE, other preventable VTE risk factors including suboptimal prophylactic anticoagulation (n = 2), prolonged catheter duration (n = 1) and prolonged haemoconcentration (n = 2) were identified. Conclusions: We found 20% of major burns patients with an intravascular warming device had significant VTE; however, only half of these may have been related to the catheter. A careful assessment for each patient that balances risks and benefits should be undertaken prior to using intravascular warming devices.
Optimized and Efficient Color Prediction Algorithms Using Mask R-CNN
Authors: Megalingam Rajesh Kannan , Tanmayi Balla , Sree Gadde Sakhita , Reddy Gunnam Monika , Krishna Inti Rohith Sri , Pai Sreejith S.
Published: February 2023

Color cognizant capability has a significant impact in service robots for object detection based on color, traffic signal interpretation for autonomous vehicles, etc. Conventional clustering algorithms such as K-means and mean shift can be used for predicting the dominant color of an image by mapping the pixels from RGB to HSV and clustering them based on HSV values, thereby picking the cluster with the most pixels as the dominant color of the image, but these approaches are not solely dedicated to the same outcome. This research’s goal is to introduce novel techniques for predicting the dominant color of objects in images, as well as pixel extraction concepts, which allow these algorithms to be more time and efficiency optimized. This investigation appraises propriety of integrating object detection and color prediction algorithms. We introduce a dominant color prediction color map model and two new algorithms: average windowing and pixel skip. To predict objects in an image prior to color prediction, we combined the Mask R-CNN framework with our proposed techniques. Verification of our approach is done by creating a benchmark dataset of 200 images and comparing color predicted by algorithms with actual color. The accuracy and runtime of existing techniques are compared with those of the proposed algorithms to prove the superiority of our algorithms. The viability of the proposed algorithms was demonstrated by scores of 95.4% accuracy and color prediction time of 9.2 s for the PXS algorithm and corresponding values of 93.6% and 6.5 s for the AVW algorithm.
Combined Use of Schizosaccharomyces pombe and a Lachancea thermotolerans Strain with a High Malic Acid Consumption Ability for Wine Production
Authors: Vicente Javier , Kelanne Niina , Navascués Eva , Calderón Fernando , Santos Antonio , Marquina Domingo , Yang Baoru , Benito Santiago
Published: February 2023

The development of new fermentative strategies exploiting the potential of different wine-related species is of great interest for new winemaking conditions and consumer preferences. One of the most promising non-conventional approaches to wine fermentation is the combined use of deacidifying and acidifying yeasts. Lachancea thermotolerans shows several other properties besides lactic acid production; among them, high malic acid consumption is of great interest in the production of red wines for avoiding undesirable refermentations once bottled. The combination of a L. thermotolerans strain that is able to consume malic acid with a Schizosaccharomyces pombe strain helps to ensure malic acid elimination during alcoholic fermentation while increasing the final acidity by lactic acid production. To properly assess the influence of this alternative strategy, we developed combined fermentations between specific strains of L. thermotolerans and S. pombe under sequential inoculation. Both species showed a great performance under the studied conditions, influencing not only the acidity but also the aromatic compound profiles of the resulting wines. The new proposed biotechnological strategy reduced the final concentrations of ethanol, malic acid and succinic acid, while it increased the concentrations of lactic acid and esters.
Genome-Wide Identification, Phylogenetic Analysis and Expression Pattern Profiling of the Aquaporin Family Genes in Leuciscus waleckii
Authors: Zhan Feifei , Liang Liqun , Wang Shuangyi , Liew Honjung , Chang Yumei , Zhang Limin
Published: February 2023

Aquaporin (Aqp) is a transmembrane-specific channel for small molecules that help in regulating homeostasis in fishes when adapting to changing environments, but its role in Amur ide’s response to alkaline stress is yet to be revealed. Therefore, the purpose of this study is to investigate the response of the Aqp gene exposed to alkaline water in Amur ide (Leuciscus waleckii) using a genome-transcriptional assay. Based on the results, we classified the Aqps of the L. waleckii (LwAqps) genome and analyzed its transcriptional expression profile and genetic evolution under carbonate alkalinity stress. A total of 18 Aqp genes were identified in four grades in L. waleckii. The highest Aqp gene expression was found in the gill and kidney of L. waleckii from the Wusuli River (WSL) in comparison to those in the Dali Lake (DL), whereas aqp3a, -3ap1, -7, and -9a expressions were found at intensively higher levels in the gill rather than in the kidneys and livers. The experiment of L. waleckii under alkalinity stress (carbonate alkalinity 50 mmol·L−1) and its recovery showed that the expressions of aqp0a, -3a, -3ap1, -7, -8aa, and -9a were upregulated in alkaline water and downregulated in freshwater. We identified 1460 single nucleotide polymorphism (SNP) markers in the Aqp genes. The average value of Fst of SNP markers in the CDS region was 0.177 ± 0.256, and the first 5% SNPs were identified at aqp3a and -11b. Residue Ser66 does not bring about an overall change in the three-dimensional structure of Aqp3a, but may change the penetration of solutes across the membrane. This indicates that Aqp genes are involved in the response of L. waleckii to alkaline stress, and aqp3a is one of the key genes involved in regulating L. waleckii’s adaptation to alkaline environments.
Modeling and Experimental Study on Drying Characteristics of Corn Particles with Hot Air in Downward Moving Bed
Authors: Wang Hairui , Zhang Shuangming , Fan Haodong , Zhang Man , Hu Nan , Yang Hairui
Published: February 2023

With regard to drying fresh grain prior to storage, the drying tower with a downward moving bed with hot air is often used, which always has high energy consumption during operation. To optimize the operation, according to the actual operating parameters of a corn drying tower with hot air, a heat balance model was established, and the heat transfer between the hot air and corn flow in a downward moving bed was analyzed. Since the downward moving time is short, the heat absorbed by corn significantly depends on the heat transfer coefficient, mainly the convective heat transfer, between the hot air and corn surface. To determine the convective heat transfer coefficient, a hot air drying experimental system for corn grains was established, and the effects of hot air temperature and wind speed on the central temperature and moisture content of corn grains were analyzed. Utilizing the heat balance model, the convective heat transfer coefficients between corn particles and hot air were calculated. The total convective heat transfer coefficients are in the range of 39.4–53.8 W/m2 · K. With an average value of 46.7 W/m2 · K, drying energy efficiencies in different drying zones in the drying tower were calculated, and the accuracy of the model was verified by the operation data. Due to the high inlet temperature of hot air, the maximum energy efficiency of the first zone is 60.15%, whereas when the temperature of hot air in the second drying tower is 140 °C, the energy efficiency is only 41.97%. Therefore, under the premise of ensuring the drying rate, the temperature of hot air of the second zone should be appropriately reduced to improve the whole drying energy efficiency.
Experimental and Numerical Investigation of the Aerodynamic Ventilation Drag of Heavy-Duty Vehicle Wheels
Authors: Peiró Frasquet Carlos , Stoll Daniel , Kuthada Timo , Wagner Andreas
Published: February 2023

Due to current EU regulations, constant-speed testing on test tracks is used for aerodynamic certification of heavy-duty vehicles (HDV). However, the aerodynamic development of HDVs is performed using wind tunnels and computational fluid dynamics (CFD). Both techniques commonly neglect the rotational aerodynamic losses of the wheels—the so-called ventilation drag—that are present when driving on the road. This is due to the fact that there is no full-scale wind tunnel for this type of vehicle with a suitable belt system for the simulation of the wheel rotation. Furthermore, the ventilation drag of HDV wheels has been neglected in CFD due to their almost completely closed rim design. These constraints lead to an underprediction of the aerodynamic forces in comparison to the results under on-road conditions when performing constant-speed tests. In order to investigate the ventilation drag of HDV wheels, measurements were carried out on a 1:4.5 scale generic tractor-trailer model in the Model Scale Wind Tunnel of the University of Stuttgart. The measured aerodynamic forces as well as the measured flow field data provide the basis for the definition and validation of a procedure for analyzing the ventilation drag in CFD. Accordingly, the ventilation drag of a full scale HDV was investigated in CFD. The results show that the tire treading and rim geometry have a significant influence on ventilation drag that contributes to the total aerodynamic drag of the HDV. The present work shows that the ventilation drag has a relevant impact on the total aerodynamic drag of HDVs and should therefore not be neglected. The presented CFD approach thus allows to assess the aerodynamic drag under real on-road conditions in an early stage of the vehicle development.
On Caputo Fractional Derivatives and Caputo–Fabrizio Integral Operators via (s, m)-Convex Functions
Authors: Nosheen Ammara , Tariq Maria , Khan Khuram Ali , Shah Nehad Ali , Chung Jae Dong
Published: February 2023

This paper contains a variety of new integral inequalities for (s,m)-convex functions using Caputo fractional derivatives and Caputo–Fabrizio integral operators. Various generalizations of Hermite–Hadamard-type inequalities containing Caputo–Fabrizio integral operators are derived for those functions whose derivatives are (s,m)-convex. Inequalities involving the digamma function and special means are deduced as applications.
Severe Periodontitis Increases the Risk of Oral Frailty: A Six-Year Follow-Up Study from Kashiwa Cohort Study
Authors: Nishimoto Misa , Tanaka Tomoki , Hirano Hirohiko , Watanabe Yutaka , Ohara Yuki , Shirobe Maki , Iijima Katsuya
Published: February 2023

Oral frailty, overlapping a decline in multi-faceted oral functions and often seen in older adults, increases risks of adverse health outcomes, thereby necessitating earlier measures. Tooth loss, a major element of oral frailty, is mainly caused by periodontal disease and is an irreversible event. Therefore, this study aimed to clarify whether advanced periodontal disease increases the risks of “new-onset” oral frailty through a longitudinal analysis based on the 2012 baseline survey of the Kashiwa cohort and the follow-up assessments conducted in 2013, 2014, 2016, and 2018. The participants were disability-free, non-orally frail older adults living in Kashiwa City. Of the 1234 participants (72.2 ± 5.1 years old; 50.8% men) analyzed in this study, oral frailty occurred in 23.1% within the six-year period. The group with Community Periodontal Index (CPI) ≥ 3 at baseline had no significant difference in the risk of oral frailty compared with CPI ≤ 2; however, CPI4 at baseline was related to the increased risk of oral frailty compared with CPI ≤ 3 (an adjusted hazard ratio (95% confidence interval): 1.42 (1.12–1.81). Conclusively, severe periodontitis (CPI4) might be associated with new-onset oral frailty, suggesting that prevention of periodontal disease could contribute to oral frailty prevention.
Prospects of Hogweed (Heracleum sphondylium L.) as a New Horticultural Crop for Food and Non-Food Uses: A Review
Authors: Matarrese Eleonora , Renna Massimiliano
Published: February 2023

Heracleum sphondylium L., commonly known as hogweed, common hogweed, or cow parsnip, is an herbaceous plant of the Apiaceae family native to Europe and Asia. This wild edible plant is common in grasslands, herb-rich meadows, hedges, wooded areas, roadsides, and railway embankments and in both waste and cultivated grounds. This review presents both the characteristics and ethnobotany, as well as the findings, technical advances, and potential of hogweed research with the goal of improving and disseminating knowledge regarding the value and potential of this wild edible plant. Current knowledge suggests that H. sphondylium L. shows good potential as a new cash crop, being an interesting food ingredient and also a source of compounds with biological activities. Therefore, hogweed may be proposed as a new horticultural crop, although several aspects of cultivation must be examined before full domestication.
Vitamin D and the Thyroid: A Critical Review of the Current Evidence
Authors: Babić Leko Mirjana , Jureško Iva , Rozić Iva , Pleić Nikolina , Gunjača Ivana , Zemunik Tatijana
Published: February 2023

Vitamin D is necessary for the normal functioning of many organs, including the thyroid gland. It is, therefore, not surprising that vitamin D deficiency is considered a risk factor for the development of many thyroid disorders, including autoimmune thyroid diseases and thyroid cancer. However, the interaction between vitamin D and thyroid function is still not fully understood. This review discusses studies involving human subjects that (1) compared vitamin D status (primarily determined by serum calcidiol (25-hydroxyvitamin D [25(OH)D]) levels) with thyroid function assessed by thyroid stimulating hormone (TSH), thyroid hormones, and anti-thyroid antibody levels; and (2) evaluated the effect of vitamin D supplementation on thyroid function. Due to the many inconsistencies in the results between the studies, it is still difficult to draw a definite conclusion on how vitamin D status affects thyroid function. Studies in healthy participants observed either a negative correlation or no association between TSH and 25(OH)D levels, while the results for thyroid hormones showed high variability. Many studies have observed a negative association between anti-thyroid antibodies and 25(OH)D levels, but equally many studies have failed to observe such an association. Regarding the studies that examined the effect of vitamin D supplementation on thyroid function, almost all observed a decrease in anti-thyroid antibody levels after vitamin D supplementation. Factors that could contribute to the high variability between the studies are the use of different assays for the measurement of serum 25(OH)D levels and the confounding effects of sex, age, body-mass index, dietary habits, smoking, and the time of year when the samples were collected. In conclusion, additional studies with larger numbers of participants are needed to fully understand the effect of vitamin D on thyroid function.
Human-Centric Lighting: Rare-Earth-Free Photoluminescent Materials for Correlated Color Temperature Tunable White LEDs
Authors: Menéndez-Velázquez Amador , García-Delgado Ana Belén , Morales Dolores
Published: February 2023

Artificial lighting is ubiquitous in modern society, with detrimental effects on sleep and health. The reason for this is that light is responsible not only for vision but also for non-visual functions, such as the regulation of the circadian system. To avoid circadian disruption, artificial lighting should be dynamic, changing throughout the day in a manner comparable to natural light in terms of both light intensity and associated color temperature. This is one of the main goals of human-centric lighting. Regarding the type of materials, the majority of white light-emitting diodes (WLEDs) make use of rare-earth photoluminescent materials; therefore, WLED development is at serious risk due to the explosive growth in demand for these materials and a monopoly on sources of supply. Photoluminescent organic compounds are a considerable and promising alternative. In this article, we present several WLEDs that were manufactured using a blue LED chip as the excitation source and two photoluminescent organic dyes (Coumarin 6 and Nile Red) embedded in flexible layers, which function as spectral converters in a multilayer remote phosphor arrangement. The correlated color temperature (CCT) values range from 2975 K to 6261 K, while light quality is preserved with chromatic reproduction index (CRI) values superior to 80. Our findings illustrate for the first time the enormous potential of organic materials for supporting human-centric lighting.
Carcinoid Syndrome: Preclinical Models and Future Therapeutic Strategies
Authors: Vitale Giovanni , Carra Silvia , Alessi Ylenia , Campolo Federica , Pandozzi Carla , Zanata Isabella , Colao Annamaria , Faggiano Antongiulio ,   on behalf of the NIKE Group
Published: February 2023

Carcinoid syndrome represents a debilitating paraneoplastic disease, caused by the secretion of several substances, occurring in about 10–40% of patients with well-differentiated neuroendocrine tumors (NETs). The main signs and symptoms associated with carcinoid syndrome are flushing, diarrhea, hypotension, tachycardia, bronchoconstriction, venous telangiectasia, dyspnea and fibrotic complications (mesenteric and retroperitoneal fibrosis, and carcinoid heart disease). Although there are several drugs available for the treatment of carcinoid syndrome, the lack of therapeutic response, poor tolerance or resistance to drugs are often reported. Preclinical models are indispensable tools for investigating the pathogenesis, mechanisms for tumor progression and new therapeutic approaches for cancer. This paper provides a state-of-the-art overview of in vitro and in vivo models in NETs with carcinoid syndrome, highlighting the future developments and therapeutic approaches in this field.
The Plant Derived 3-3′-Diindolylmethane (DIM) Behaves as CB2 Receptor Agonist in Prostate Cancer Cellular Models
Authors: Tucci Paolo , Brown Iain , Bewick Guy S. , Pertwee Roger G. , Marini Pietro
Published: February 2023

3-3′-Diindolylmethane (DIM) is a biologically active dimer derived from the endogenous conversion of indole-3-carbinol (I3C), a naturally occurring glucosinolate found in many cruciferous vegetables (i.e., Brassicaceae). DIM was the first pure androgen receptor antagonist isolated from the Brassicaceae family and has been recently investigated for its potential pharmacological use in prostate cancer prevention and treatment. Interestingly, there is evidence that DIM can also interact with cannabinoid receptors. In this context, by considering the well-known involvement of the endocannabinoid system in prostate cancer, we have pharmacologically characterized the properties of DIM on both CB1 and CB2 cannabinoid receptors in two human prostate cancer cell lines: PC3 (androgen-independent/androgen receptor negative) and LNCaP (androgen-dependent). In the PC3 cell line, DIM was able to activate CB2 receptors and potentially associated apoptotic pathways. On the other hand, although DIM was also able to activate CB2 receptors in the LNCaP cell line, no apoptotic effects were observed. Our evidence confirms that DIM is a CB2 receptor ligand and, moreover, it has a potential anti-proliferative effect on androgen-independent/androgen receptor-negative prostate cancer cells.
Glucose 6-P Dehydrogenase Overexpression Improves Aging-Induced Endothelial Dysfunction in Aorta from Mice: Role of Arginase II
Authors: Serna Eva , Mauricio Maria D , San-Miguel Teresa , Guerra-Ojeda Sol , Verdú David , Valls Alicia , Arc-Chagnaud Coralie , De la Rosa Adrián , Viña José
Published: February 2023

The increase of vascular arginase activity during aging causes endothelial dysfunction. This enzyme competes with the endothelial nitric oxide synthase (eNOS) for L-arginine substrate. Our hypothesis is that glucose 6-P dehydrogenase (G6PD) overexpression could improve the endothelial function modulating the arginase pathway in aorta from mice. For this study, three groups of male mice were used: young wild type (WT) (6–9 months), old WT (21–22 months) and old G6PD-Tg (21–22 months) mice. Vascular reactivity results showed a reduced acetylcholine-dependent relaxation in the old WT but not old G6PD-Tg group. Endothelial dysfunction was reverted by nor-NOHA, an arginase inhibitor. Mice overexpressing G6PD underexpressed arginase II and also displayed a lower activity of this enzyme. Moreover, histological analyses demonstrated that age causes a thickness of aortic walls, but this did not occur in G6PD-Tg mice. We conclude that the overexpressing G6PD mouse is a model to improve vascular health via the arginase pathway.
Altered Mesenchymal Stem Cells Mechanotransduction from Oxidized Collagen: Morphological and Biophysical Observations
Authors: Komsa-Penkova Regina , Yordanova Adelina , Tonchev Pencho , Kyurkchiev Stanimir , Todinova Svetla , Strijkova Velichka , Iliev Mario , Dimitrov Borislav , Altankov George
Published: February 2023

Extracellular matrix (ECM) provides various mechanical cues that are able to affect the self-renewal and differentiation of mesenchymal stem cells (MSC). Little is known, however, how these cues work in a pathological environment, such as acute oxidative stress. To better understand the behavior of human adipose tissue-derived MSC (ADMSC) in such conditions, we provide morphological and quantitative evidence for significantly altered early steps of mechanotransduction when adhering to oxidized collagen (Col-Oxi). These affect both focal adhesion (FA) formation and YAP/TAZ signaling events. Representative morphological images show that ADMSCs spread better within 2 h of adhesion on native collagen (Col), while they tended to round up on Col-Oxi. It also correlates with the lesser development of the actin cytoskeleton and FA formation, confirmed quantitatively by morphometric analysis using ImageJ. As shown by immunofluorescence analysis, oxidation also affected the ratio of cytosolic-to-nuclear YAP/TAZ activity, concentrating in the nucleus for Col while remaining in the cytosol for Col-Oxi, suggesting abrogated signal transduction. Comparative Atomic Force Microscopy (AFM) studies show that native collagen forms relatively coarse aggregates, much thinner with Col-Oxi, possibly reflecting its altered ability to aggregate. On the other hand, the corresponding Young’s moduli were only slightly changed, so viscoelastic properties cannot explain the observed biological differences. However, the roughness of the protein layer decreased dramatically, from RRMS equal to 27.95 ± 5.1 nm for Col to 5.51 ± 0.8 nm for Col-Oxi (p < 0.05), which dictates our conclusion that it is the most altered parameter in oxidation. Thus, it appears to be a predominantly topographic response that affects the mechanotransduction of ADMSCs by oxidized collagen.
High-Efficiency CRISPR/Cas9-Mediated Correction of a Homozygous Mutation in Achromatopsia-Patient-Derived iPSCs
Authors: Siles Laura , Gaudó Paula , Pomares Esther
Published: February 2023

Achromatopsia is an autosomal recessive disorder, in which cone photoreceptors undergo progressive degeneration, causing color blindness and poor visual acuity, among other significant eye affectations. It belongs to a group of inherited retinal dystrophies that currently have no treatment. Although functional improvements have been reported in several ongoing gene therapy studies, more efforts and research should be carried out to enhance their clinical application. In recent years, genome editing has arisen as one of the most promising tools for personalized medicine. In this study, we aimed to correct a homozygous PDE6C pathogenic variant in hiPSCs derived from a patient affected by achromatopsia through CRISPR/Cas9 and TALENs technologies. Here, we demonstrate high efficiency in gene editing by CRISPR/Cas9 but not with TALENs approximation. Despite a few of the edited clones displaying heterozygous on-target defects, the proportion of corrected clones with a potentially restored wild-type PDE6C protein was more than half of the total clones analyzed. In addition, none of them presented off-target aberrations. These results significantly contribute to advances in single-nucleotide gene editing and the development of future strategies for the treatment of achromatopsia.
Ferroptosis and Senescence: A Systematic Review
Authors: Coradduzza Donatella , Congiargiu Antonella , Chen Zhichao , Zinellu Angelo , Carru Ciriaco , Medici Serenella
Published: February 2023

Senescence is a cellular aging process in all multicellular organisms. It is characterized by a decay in cellular functions and proliferation, resulting in increased cellular damage and death. This condition plays an essential role in the aging process and significantly contributes to the development of age-related complications. On the other hand, ferroptosis is a systemic cell death pathway characterized by excessive iron accumulation followed by the generation of reactive oxygen species (ROS). Oxidative stress is a common trigger of this condition and may be induced by various factors such as toxins, drugs, and inflammation. Ferroptosis is linked to numerous disorders, including cardiovascular disease, neurodegeneration, and cancer. Senescence is believed to contribute to the decay in tissue and organ functions occurring with aging. It has also been linked to the development of age-related pathologies, such as cardiovascular diseases, diabetes, and cancer. In particular, senescent cells have been shown to produce inflammatory cytokines and other pro-inflammatory molecules that can contribute to these conditions. In turn, ferroptosis has been linked to the development of various health disorders, including neurodegeneration, cardiovascular disease, and cancer. Ferroptosis is known to play a role in the development of these pathologies by promoting the death of damaged or diseased cells and contributing to the inflammation often associated. Both senescence and ferroptosis are complex pathways that are still not fully understood. Further research is needed to thoroughly investigate the role of these processes in aging and disease, and to identify potential interventions to target such processes in order to prevent or treat age-related conditions. This systematic review aims to assess the potential mechanisms underlying the link connecting senescence, ferroptosis, aging, and disease, and whether they can be exploited to block or limit the decay of the physiological functions in elderly people for a healthy longevity.
Tri-Lineage Differentiation Potential of Osteosarcoma Cell Lines and Human Bone Marrow Stromal Cells from Different Anatomical Locations
Authors: Smith Hannah L. , Gray Juliet C. , Beers Stephen A. , Kanczler Janos M.
Published: February 2023

The bone cancer osteosarcoma, found mainly in adolescents, routinely forms around the growth plate/metaphysis of long bones. Bone marrow composition changes with age, shifting from a more hematopoietic to an adipocyte-rich tissue. This conversion occurs in the metaphysis during adolescence, implicating a link between bone marrow conversion and osteosarcoma initiation. To assess this, the tri-lineage differentiation potential of human bone marrow stromal cells (HBMSCs) isolated from the femoral diaphysis/metaphysis (FD) and epiphysis (FE) was characterized and compared to two osteosarcoma cell lines, Saos-2 and MG63. Compared to FE-cells, FD-cells showed an increase in tri-lineage differentiation. Additionally, differences were found between the Saos-2 cells exhibiting higher levels of osteogenic differentiation, lower adipogenic differentiation, and a more developed chondrogenic phenotype than MG63, with the Saos-2 being more comparable to FD-derived HBMSCs. The differences found between the FD and FE derived cells are consistent with the FD region containing more hematopoietic tissue compared to the FE. This may be related to the similarities between FD-derived cells and Saos-2 cells during osteogenic and chondrogenic differentiation. These studies reveal distinct differences in the tri-lineage differentiations of ‘hematopoietic’ and ‘adipocyte rich’ bone marrow, which correlate with specific characteristics of the two osteosarcoma cell lines.
The Dilemma of HSV-1 Oncolytic Virus Delivery: The Method Choice and Hurdles
Authors: Tang Guijin , Wang Dawei , Zhao Xiangqian , Feng Zhihua , Chen Qi , Shen Yangkun
Published: February 2023

Oncolytic viruses (OVs) have emerged as effective gene therapy and immunotherapy drugs. As an important gene delivery platform, the integration of exogenous genes into OVs has become a novel path for the advancement of OV therapy, while the herpes simplex virus type 1 (HSV-1) is the most commonly used. However, the current mode of administration of HSV-1 oncolytic virus is mainly based on the tumor in situ injection, which limits the application of such OV drugs to a certain extent. Intravenous administration offers a solution to the systemic distribution of OV drugs but is ambiguous in terms of efficacy and safety. The main reason is the synergistic role of innate and adaptive immunity of the immune system in the response against the HSV-1 oncolytic virus, which is rapidly cleared by the body’s immune system before it reaches the tumor, a process that is accompanied by side effects. This article reviews different administration methods of HSV-1 oncolytic virus in the process of tumor treatment, especially the research progress in intravenous administration. It also discusses immune constraints and solutions of intravenous administration with the intent to provide new insights into HSV-1 delivery for OV therapy.
Impact of Prenatal Exposure to Maternal Diabetes and High-Fat Diet on Postnatal Myocardial Ketone Body Metabolism in Rats
Authors: Ayyappan Prathapan , Larsen Tricia D. , Gandy Tyler C. T. , Louwagie Eli J. , Baack Michelle L.
Published: February 2023

Infants exposed to diabetic pregnancy are at higher risk of cardiomyopathy at birth and early onset cardiovascular disease (CVD) as adults. Using a rat model, we showed how fetal exposure to maternal diabetes causes cardiac disease through fuel-mediated mitochondrial dysfunction, and that a maternal high-fat diet (HFD) exaggerates the risk. Diabetic pregnancy increases circulating maternal ketones which can have a cardioprotective effect, but whether diabetes-mediated complex I dysfunction impairs myocardial metabolism of ketones postnatally remains unknown. The objective of this study was to determine whether neonatal rat cardiomyocytes (NRCM) from diabetes- and HFD-exposed offspring oxidize ketones as an alternative fuel source. To test our hypothesis, we developed a novel ketone stress test (KST) using extracellular flux analyses to compare real-time ß-hydroxybutyrate (βHOB) metabolism in NRCM. We also compared myocardial expression of genes responsible for ketone and lipid metabolism. NRCM had a dose-dependent increase in respiration with increasing concentrations of βHOB, demonstrating that both control and combination exposed NRCM can metabolize ketones postnatally. Ketone treatment also enhanced the glycolytic capacity of combination exposed NRCM with a dose-dependent increase in the glucose-mediated proton efflux rate (PER) from CO2 (aerobic glycolysis) alongside a decreased reliance on PER from lactate (anaerobic glycolysis). Expression of genes responsible for ketone body metabolism was higher in combination exposed males. Findings demonstrate that myocardial ketone body metabolism is preserved and improves fuel flexibility in NRCM from diabetes- and HFD-exposed offspring, which suggests that ketones might serve a protective role in neonatal cardiomyopathy due to maternal diabetes.
Wolfram Syndrome 1: A Pediatrician’s and Pediatric Endocrinologist’s Perspective
Authors: Serbis Anastasios , Rallis Dimitrios , Giapros Vasileios , Galli-Tsinopoulou Assimina , Siomou Ekaterini
Published: February 2023

Wolfram syndrome 1 (WS1) is a rare autosomal recessive neurodegenerative disease caused by mutations in WFS1 and WFS2 genes that produce wolframin, a protein involved in endoplasmic reticulum calcium homeostasis and cellular apoptosis. Its main clinical features are diabetes insipidus (DI), early-onset non-autoimmune insulin-dependent diabetes mellitus (DM), gradual loss of vision due to optic atrophy (OA) and deafness (D), hence the acronym DIDMOAD. Several other features from different systems have been reported such as urinary tract, neurological, and psychiatric abnormalities. In addition, endocrine disorders that can appear during childhood and adolescence include primary gonadal atrophy and hypergonadotropic hypogonadism in males and menstrual cycle abnormalities in females. Further, anterior pituitary dysfunction with deficient GH and/or ACTH production have been described. Despite the lack of specific treatment for the disease and its poor life expectancy, early diagnosis and supportive care is important for timely identifying and adequately managing its progressive symptoms. The current narrative review focuses on the pathophysiology and the clinical features of the disease, with a special emphasis on its endocrine abnormalities that appear during childhood and adolescence. Further, therapeutic interventions that have been proven to be effective in the management of WS1 endocrine complications are discussed.
Comparative Pre-Clinical Analysis of CD20-Specific CAR T Cells Encompassing 1F5-, Leu16-, and 2F2-Based Antigen-Recognition Moieties
Authors: Belovezhets Tatyana , Kulemzin Sergey , Volkova Olga , Najakshin Alexander , Taranin Alexander , Gorchakov Andrey
Published: February 2023

Over the past decade, CAR T cell therapy for patients with B cell malignancies has evolved from an experimental technique to a clinically feasible option. To date, four CAR T cell products specific for a B cell surface marker, CD19, have been approved by the FDA. Despite the spectacular rates of complete remission in r/r ALL and NHL patients, a significant proportion of patients still relapse, frequently with the CD19 low/negative tumor phenotype. To address this issue, additional B cell surface molecules such as CD20 were proposed as targets for CAR T cells. Here, we performed a side-by-side comparison of the activity of CD20-specific CAR T cells based on the antigen-recognition modules derived from the murine antibodies, 1F5 and Leu16, and from the human antibody, 2F2. Whereas CD20-specific CAR T cells differed from CD19-specific CAR T cells in terms of subpopulation composition and cytokine secretion, they displayed similar in vitro and in vivo potency.
The Relationship between Iron and LRRK2 in a 6-OHDA-Induced Parkinson’s Disease Model
Authors: Jia Ruru , Liu Yanling , Shuai Ke , Zhou Cheng , Chen Lei , Zhu Li , Wu Xiao-Mei
Published: February 2023

The pathogenesis of Parkinson’s disease (PD) is very complex and still needs further exploration. Leucine-rich repeat kinase 2 (LRRK2) is associated with familial PD in mutant forms and sporadic PD in the wild-type form. Abnormal iron accumulation is found in the substantia nigra of PD patients, but its exact effects are not very clear. Here, we show that iron dextran exacerbates the neurological deficit and loss of dopaminergic neurons in 6-OHDA lesioned rats. 6-OHDA and ferric ammonium citrate (FAC) significantly increase the activity of LRRK2 as reflected by the phosphorylation of LRRK2, at S935 and S1292 sites. 6-OHDA-induced LRRK2 phosphorylation is attenuated by the iron chelator deferoxamine, especially at the S1292 site. 6-OHDA and FAC markedly induce the expression of pro-apoptotic molecules and the production of ROS by activating LRRK2. Furthermore, G2019S-LRRK2 with high kinase activity showed the strongest absorptive capacity for ferrous iron and the highest intracellular iron content among WT-LRRK2, G2019S-LRRK2, and kinase-inactive D2017A-LRRK2 groups. Taken together, our results demonstrate that iron promotes the activation of LRRK2, and active LRRK2 accelerates ferrous iron uptake, suggesting that there exists an interplay between iron and LRRK2 in dopaminergic neurons, providing a new perspective to uncover the underlying mechanisms of PD occurrence.
Whole-Genome Duplication and Genome Instability in Cancer Cells: Double the Trouble
Authors: Lau Tsz Yin , Poon Randy Y.C.
Published: February 2023

Whole-genome duplication (WGD) is one of the most common genomic abnormalities in cancers. WGD can provide a source of redundant genes to buffer the deleterious effect of somatic alterations and facilitate clonal evolution in cancer cells. The extra DNA and centrosome burden after WGD is associated with an elevation of genome instability. Causes of genome instability are multifaceted and occur throughout the cell cycle. Among these are DNA damage caused by the abortive mitosis that initially triggers tetraploidization, replication stress and DNA damage associated with an enlarged genome, and chromosomal instability during the subsequent mitosis in the presence of extra centrosomes and altered spindle morphology. Here, we chronicle the events after WGD, from tetraploidization instigated by abortive mitosis including mitotic slippage and cytokinesis failure to the replication of the tetraploid genome, and finally, to the mitosis in the presence of supernumerary centrosomes. A recurring theme is the ability of some cancer cells to overcome the obstacles in place for preventing WGD. The underlying mechanisms range from the attenuation of the p53-dependent G1 checkpoint to enabling pseudobipolar spindle formation via the clustering of supernumerary centrosomes. These survival tactics and the resulting genome instability confer a subset of polyploid cancer cells proliferative advantage over their diploid counterparts and the development of therapeutic resistance.
Mitochondria-Targeted Antioxidants, an Innovative Class of Antioxidant Compounds for Neurodegenerative Diseases: Perspectives and Limitations
Authors: Fields Matteo , Marcuzzi Annalisa , Gonelli Arianna , Celeghini Claudio , Maximova Natalia , Rimondi Erika
Published: February 2023

Neurodegenerative diseases comprise a wide spectrum of pathologies characterized by progressive loss of neuronal functions and structures. Despite having different genetic backgrounds and etiology, in recent years, many studies have highlighted a point of convergence in the mechanisms leading to neurodegeneration: mitochondrial dysfunction and oxidative stress have been observed in different pathologies, and their detrimental effects on neurons contribute to the exacerbation of the pathological phenotype at various degrees. In this context, increasing relevance has been acquired by antioxidant therapies, with the purpose of restoring mitochondrial functions in order to revert the neuronal damage. However, conventional antioxidants were not able to specifically accumulate in diseased mitochondria, often eliciting harmful effects on the whole body. In the last decades, novel, precise, mitochondria-targeted antioxidant (MTA) compounds have been developed and studied, both in vitro and in vivo, to address the need to counter the oxidative stress in mitochondria and restore the energy supply and membrane potentials in neurons. In this review, we focus on the activity and therapeutic perspectives of MitoQ, SkQ1, MitoVitE and MitoTEMPO, the most studied compounds belonging to the class of MTA conjugated to lipophilic cations, in order to reach the mitochondrial compartment.
Differential Expression of MED12-Associated Coding RNA Transcripts in Uterine Leiomyomas
Authors: Chuang Tsai-Der , Gao Jianjun , Quintanilla Derek , McSwiggin Hayden , Boos Drake , Yan Wei , Khorram Omid
Published: February 2023

Recent studies have demonstrated that somatic MED12 mutations in exon 2 occur at a frequency of up to 80% and have a functional role in leiomyoma pathogenesis. The objective of this study was to elucidate the expression profile of coding RNA transcripts in leiomyomas, with and without these mutations, and their paired myometrium. Next-generation RNA sequencing (NGS) was used to systematically profile the differentially expressed RNA transcripts from paired leiomyomas (n = 19). The differential analysis indicated there are 394 genes differentially and aberrantly expressed only in the mutated tumors. These genes were predominantly involved in the regulation of extracellular constituents. Of the differentially expressed genes that overlapped in the two comparison groups, the magnitude of change in gene expression was greater for many genes in tumors bearing MED12 mutations. Although the myometrium did not express MED12 mutations, there were marked differences in the transcriptome landscape of the myometrium from mutated and non-mutated specimens, with genes regulating the response to oxygen-containing compounds being most altered. In conclusion, MED12 mutations have profound effects on the expression of genes pivotal to leiomyoma pathogenesis in the tumor and the myometrium which could alter tumor characteristics and growth potential.