bluuebunny/crossref_metadata_2025 huggingface dataset:
Too Close for Comfort? Isotopic Niche Segregation in New Zealand’s Odontocetes
Authors: Peters Katharina J. , Bury Sarah J. , Hinton Bethany , Betty Emma L. , Casano-Bally Déborah , Parra Guido J. , Stockin Karen A.
Published: August 2022

Species occurring in sympatry and relying on similar and limited resources may partition resource use to avoid overlap and interspecific competition. Aotearoa, New Zealand hosts an extraordinarily rich marine megafauna, including 50% of the world’s cetacean species. In this study, we used carbon and nitrogen stable isotopes as ecological tracers to investigate isotopic niche overlap between 21 odontocete (toothed whale) species inhabiting neritic, mesopelagic, and bathypelagic waters. Results showed a clear niche separation for the bathypelagic Gray’s beaked whales (Mesoplodon grayi) and sperm whales (Physeter macrocephalus), but high isotopic niche overlap and potential interspecific competition for neritic and mesopelagic species. For these species, competition could be reduced via temporal or finer-scale spatial segregation or differences in foraging behaviour. This study represents the first insights into the coexistence of odontocetes in a biodiverse hotspot. The data presented here provide a critical baseline to a system already ongoing ecosystem change via ocean warming and subsequent effects on prey abundance and distributions.
Integrative Phylogenetics: Tools for Palaeontologists to Explore the Tree of Life
Authors: López-Antoñanzas Raquel , Mitchell Jonathan , Simões Tiago R. , Condamine Fabien L. , Aguilée Robin , Peláez-Campomanes Pablo , Renaud Sabrina , Rolland Jonathan , Donoghue Philip C. J.
Published: August 2022

The modern era of analytical and quantitative palaeobiology has only just begun, integrating methods such as morphological and molecular phylogenetics and divergence time estimation, as well as phenotypic and molecular rates of evolution. Calibrating the tree of life to geological time is at the nexus of many disparate disciplines, from palaeontology to molecular systematics and from geochronology to comparative genomics. Creating an evolutionary time scale of the major events that shaped biodiversity is key to all of these fields and draws from each of them. Different methodological approaches and data employed in various disciplines have traditionally made collaborative research efforts difficult among these disciplines. However, the development of new methods is bridging the historical gap between fields, providing a holistic perspective on organismal evolutionary history, integrating all of the available evidence from living and fossil species. Because phylogenies with only extant taxa do not contain enough information to either calibrate the tree of life or fully infer macroevolutionary dynamics, phylogenies should preferably include both extant and extinct taxa, which can only be achieved through the inclusion of phenotypic data. This integrative phylogenetic approach provides ample and novel opportunities for evolutionary biologists to benefit from palaeontological data to help establish an evolutionary time scale and to test core macroevolutionary hypotheses about the drivers of biological diversification across various dimensions of organisms.
A Review of Suggested Mechanisms of MHC Odor Signaling
Authors: Milinski Manfred
Published: August 2022

Although an individual’s mix of MHC immune genes determines its resistance, finding MHC-dependent mate choice occurred by accident in inbred mice. Inbred mice prefer MHC dissimilar mates, even when the choice was restricted to urine. It took decades to find the info-chemicals, which have to be as polymorphic as the MHC. Microbiota were suggested repeatedly as the origin of the odor signal though germ-free mice maintained normal preference. Different versions of the ‘carrier hypothesis’ suggested MHC molecules carry volatiles after the bound peptide is released. Theory predicted an optimal individual MHC diversity to maximize resistance. The optimally complementary mate should be and is preferred as several studies show. Thus, the odor signal needs to transmit the exact information of the sender’s MHC alleles, as do MHC ligand peptides but not microbiota. The ‘MHC peptide hypothesis’ assumes that olfactory perception of the peptide ligand provides information about the MHC protein in a key-lock fashion. Olfactory neurons react only to the anchors of synthesized MHC peptides, which reflect the binding MHC molecule’s identity. Synthesized peptides supplemented to a male’s signal affect choice in the predicted way, however, not when anchors are mutated. Also, the human brain detects smelled synthesized self-peptides as such. After mate choice, the lottery of meiosis of randomly paired oocyte and sperm haplotypes would often produce MHC non-optimal offspring. In sticklebacks, eggs select MHC-compatible sperm, thus prefer the best combination close to the population optimum.
Cisplatin-Induced Kidney Toxicity: Potential Roles of Major NAD+-Dependent Enzymes and Plant-Derived Natural Products
Authors: Iskander Amany , Yan Liang-Jun
Published: August 2022

Cisplatin is an FDA approved anti-cancer drug that is widely used for the treatment of a variety of solid tumors. However, the severe adverse effects of cisplatin, particularly kidney toxicity, restrict its clinical and medication applications. The major mechanisms of cisplatin-induced renal toxicity involve oxidative stress, inflammation, and renal fibrosis, which are covered in this short review. In particular, we review the underlying mechanisms of cisplatin kidney injury in the context of NAD+-dependent redox enzymes including mitochondrial complex I, NAD kinase, CD38, sirtuins, poly-ADP ribosylase polymerase, and nicotinamide nucleotide transhydrogenase (NNT) and their potential contributing roles in the amelioration of cisplatin-induced kidney injury conferred by natural products derived from plants. We also cover general procedures used to create animal models of cisplatin-induced kidney injury involving mice and rats. We highlight the fact that more studies will be needed to dissect the role of each NAD+-dependent redox enzyme and its involvement in modulating cisplatin-induced kidney injury, in conjunction with intensive research in NAD+ redox biology and the protective effects of natural products against cisplatin-induced kidney injury.
Identification of Serum Ferritin-Specific Nanobodies and Development towards a Diagnostic Immunoassay
Authors: Hu Yaozhong , Lin Jing , Wang Yi , Wu Sihao , Wu Jing , Lv Huan , Ji Xuemeng , Muyldermans Serge , Zhang Yan , Wang Shuo
Published: August 2022

Serum ferritin (SF) is an iron-rich protein tightly connected with iron homeostasis, and the variations are frequently observed in diseased states, including iron-deficiency anemia, inflammation, liver disease, and tumors, which renders SF level an indicator of potential malignancies in clinical practice. Nanobodies (Nbs) have been widely explored and developed into theranostic reagents. Surprisingly, no reports stated the identification of anti-SF Nbs, nor the potential of such Nbs as a diagnostic tool. In this study, we generated SF-specific Nbs and provided novel clinical diagnostic approaches to develop an immunoassay. An immune library was constructed after immunizing an alpaca with SF, and five Nbs specifically targeting human SF were retrieved. The obtained Nbs exhibited robust properties including high stability, affinity, and specificity. Then, an ELISA-based test using a heterologous Nb-pair was developed. The calibration curve demonstrated a linear range of SF between 9.0 to 1100 ng/mL, and a limit of detection (LOD) of 1.01 ng/mL. The detecting recovery and coefficient variation (CV) were determined by spiking different concentrations of SF into the serum sample, to verify the successful application of our selected Nbs for SF monitoring. In general, this study generated SF-specific Nbs and demonstrated their potential as diagnostic immunoassay tools.
Development of Systemic Autoimmune Diseases in Healthy Subjects Persistently Positive for Antiphospholipid Antibodies: Long-Term Follow-Up Study
Authors: Ceccarelli Fulvia , Natalucci Francesco , Olivieri Giulio , Pirone Carmelo , Picciariello Licia , Orefice Valeria , Truglia Simona , Spinelli Francesca Romana , Alessandri Cristiano , Chistolini Antonio , Conti Fabrizio
Published: August 2022

We longitudinally followed a single-center cohort of anti-phospholipid (aPL) positive healthy subjects to evaluate the evolution to systemic autoimmune diseases (sAD) and to describe clinical and serological associated features. Since 2010, we have consecutively screened healthy subjects who were positive, in at least two consecutive determinations, for one or more aPL [anti-Cardiolipin (aCL) IgM/IgG, anti-Beta2Glycoprotein I (aB2GPI) IgM/IgG, Lupus Anticoagulant (LA)]. All subjects were evaluated every six months, or in accordance with the patient’s clinical course, in order to record the development of clinical and laboratory features suggestive for sAD. Ninety-five subjects [M/F 20/75, median age at first determination 46 years, Interquartile Range (IQR) 19] were enrolled. Thirty-three subjects (34.7%) were positive for only one aPL [15 (15.8%) for aCL, 15 (15.8%) for LA, and 5 (5.3%) for aB2GPI]; 37 (38.9%) had double positivity [32 (33.6%) for aCL and aB2GPI; 5 (5.3%) for aCL and LA], 23 (24.2%) had triple positivity. We prospectively followed up our cohort for a median period of 72 months (IQR 84). During a total follow-up of 7692 person-months, we found an absolute risk for sAD development equal to 1.8%. Specifically, 14 (14.7%) patients developed a sAD: in four patients (4.2%), after developing a thrombotic event, an antiphospholipid syndrome was diagnosed, 7 (7.4%) patients developed an Undifferentiated Connective Tissue Disease after a median period of 76 months (IQR 75.5), and lastly, three (3.1%) patients could be classified as affected by Systemic Lupus Erythematosus according to the ACR/EULAR 2019 criteria. The presence of triple positivity status resulted in being significantly associated with the progression to sAD (p-value = 0.03). In conclusion, we observed the development of sAD in almost 15% of aPL positive subjects. Triple positivity was significantly associated with this progression, suggesting a possible role as biomarker for this condition. Thus, our results could suggest the need for periodic follow-up for such patients to assess early diagnosis and treatment.
Design of Biocompatible Chitosan/Polyaniline/Laponite Hydrogel with Photothermal Conversion Capability
Authors: Zhang Liying , He Gao , Yu Yang , Zhang Yu , Li Xiang , Wang Shige
Published: August 2022

In recent years, multifunctional hydrogels have received a great deal of attention because they are biocompatible and can mimic the extracellular matrix. Herein, we prepared hydrogels of biocompatible cross-linked networks with photothermal properties. In this study, a chitosan/polyaniline/laponite (COL) hydrogel with photothermal conversion capability was designed. Polyaniline was firstly grafted onto chitosan and its solution was mixed with oxidized dextran, which was then cross-linked into a hydrogel via a Schiff base reaction. Furthermore, an aluminosilicate clay material, laponite (LAP), was incorporated into the hydrogel. The swelling ratio of the COL hydrogel in various solutions was greater than 580%, and it showed good degradation ability (the mass–loss ratio was over 45% after 28 days). This composite hydrogel was demonstrated to have good photothermal conversion properties and biocompatibility at both the cell (cell viability was over 97%) and animal levels. The COL hydrogel showed a photothermal conversion efficiency of 23.7% under the irradiation of a near-infrared laser. Coupled with the osteogenic differentiation-inducing potential of LAP, the COL hydrogel has the potential to kill tumors via hyperthermia or serve as scaffolds for bone tissue regeneration.
Therapeutic Strategies in Huntington’s Disease: From Genetic Defect to Gene Therapy
Authors: Jurcau Anamaria , Jurcau Maria Carolina
Published: August 2022

Despite the identification of an expanded CAG repeat on exon 1 of the huntingtin gene located on chromosome 1 as the genetic defect causing Huntington’s disease almost 30 years ago, currently approved therapies provide only limited symptomatic relief and do not influence the age of onset or disease progression rate. Research has identified various intricate pathogenic cascades which lead to neuronal degeneration, but therapies interfering with these mechanisms have been marked by many failures and remain to be validated. Exciting new opportunities are opened by the emerging techniques which target the mutant protein DNA and RNA, allowing for “gene editing”. Although some issues relating to “off-target” effects or immune-mediated side effects need to be solved, these strategies, combined with stem cell therapies and more traditional approaches targeting specific pathogenic cascades, such as excitotoxicity and bioavailability of neurotrophic factors, could lead to significant improvement of the outcomes of treated Huntington’s disease patients.
Xylitol Fluoride Varnish: In Vitro Effect Analysis on Enamel by Atomic Force Microscopy
Authors: Saveanu Catalina Iulia , Dragos Oana , Anistoroaei Daniela , Bobu Livia Ionela , Saveanu Alexandra Ecaterina , Armencia Adina , Solomon Sorina Mihaela , Tanculescu Oana
Published: August 2022

(1) Background: Numerous studies have shown the beneficial role of fluoride in the primary prevention of dental caries. The aim of the present study was to put into evidence the change in the enamel structure immediately after the application of a fluoride varnish. (2) Methods: A xylitol–fluoride varnish was evaluated. The enamel specimens (n = 10) were analyzed by atomic force microscopy on enamel surface and treatment with fluoride varnish applied. The dimensional topographic analysis was performed by 2D and 3D analysis software. Statistical analysis was performed using SPSS Version 26.00 (IBM, Armonk, NY, USA). A one-sample statistics test was used to identify significant differences (p < 0.05). (3) Results: Surface roughness (Ra) measurements ranged from Ra = 0.039 μm (±0.048), to Ra = 0.049 μm (±0.031), respectively (p < 0.05), with an increase in the surface roughness passing from the intact enamel to the enamel exposed to fluoride varnish. When comparing Ra values of the nonfluorinated enamel and fluorinated enamel, significant differences (p < 0.05) were found, suggesting that the varnish had a protective effect on the enamel surface. (4) Conclusions: Xylitol–fluoride varnish, even in one single short-time application, is effective in reducing the surface roughness of enamel structure exposed to abrasion, thus increasing resistance to dental caries.
Modeling Aversion Resistant Alcohol Intake in Indiana Alcohol-Preferring (P) Rats
Authors: Katner Simon N. , Sentir Alena M. , Steagall Kevin B. , Ding Zheng-Ming , Wetherill Leah , Hopf Frederic W. , Engleman Eric A.
Published: August 2022

With the substantial social and medical burden of addiction, there is considerable interest in understanding risk factors that increase the development of addiction. A key feature of alcohol use disorder (AUD) is compulsive alcohol (EtOH) drinking, where EtOH drinking becomes “inflexible” after chronic intake, and animals, such as humans with AUD, continue drinking despite aversive consequences. Further, since there is a heritable component to AUD risk, some work has focused on genetically-selected, EtOH-preferring rodents, which could help uncover critical mechanisms driving pathological intake. In this regard, aversion-resistant drinking (ARD) takes >1 month to develop in outbred Wistar rats (and perhaps Sardinian-P EtOH-preferring rats). However, ARD has received limited study in Indiana P-rats, which were selected for high EtOH preference and exhibit factors that could parallel human AUD (including front-loading and impulsivity). Here, we show that P-rats rapidly developed compulsion-like responses for EtOH; 0.4 g/L quinine in EtOH significantly reduced female and male intake on the first day of exposure but had no effect after one week of EtOH drinking (15% EtOH, 24 h free-choice paradigm). Further, after 4–5 weeks of EtOH drinking, males but not females showed resistance to even higher quinine (0.5 g/L). Thus, P-rats rapidly developed ARD for EtOH, but only males developed even stronger ARD with further intake. Finally, rats strongly reduced intake of quinine-adulterated water after 1 or 5 weeks of EtOH drinking, suggesting no changes in basic quinine sensitivity. Thus, modeling ARD in P-rats may provide insight into mechanisms underlying genetic predispositions for compulsive drinking and lead to new treatments for AUDs.
Hospital-Treated Infections and Increased Risk of Two EBV-Related Malignancies: A Nested Case-Control Study
Authors: Yang Yanping , Yin Li , Liu Qianwei , Sun Jiangwei , Adami Hans-Olov , Ye Weimin , Zhang Zhe , Fang Fang
Published: August 2022

Background: To assess the association of hospital-treated infections with the subsequent risk of two Epstein-Barr virus (EBV)-related malignancies, namely Hodgkin’s lymphoma (HL) and nasopharyngeal carcinoma (NPC). Methods: We performed a nested case-control study based on several national registers in Sweden. Cases were individuals newly diagnosed with HL or NPC during 1994–2016 in Sweden, according to the Swedish Cancer Register. For each case, we randomly selected five controls individually matched to the case on sex and year of birth from the general Swedish population. Hospital-treated infections (i.e., infections requiring either inpatient or outpatient hospital care) were identified from the Swedish Patient Register. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of HL and NPC, in relation to hospital-treated infections, after adjustment for age, sex, calendar period, educational achievement, and region of residence. Results: The study included a total of 890 cases of HL and 306 cases of NPC. A hospital-treated infection three years ago or earlier was associated with a higher risk of HL (OR = 1.49, 95%CI: 1.26–1.75) as well as NPC (OR = 1.36; 95%CI: 1.01–1.83). The positive association was noted for both bacterial and viral infections and primarily for respiratory and skin infections. A monotonous dose-response relationship was found between a number of hospital-treated infections and the risk of HL (p = 0.02) but less compelling for NPC (p = 0.06). Using a 5-year lag time rendered similar results (OR = 1.43, 95%CI: 1.21–1.70 for HL; OR = 1.43, 95%CI: 1.05–1.95 for NPC). Conclusions: These findings suggest that infections requiring hospital treatment might contribute to the carcinogenesis of malignancies potentially related to EBV.
Pathogenic Roles of RNA-Binding Proteins in Sarcomas
Authors: Hai Yu , Kawachi Asuka , He Xiaodong , Yoshimi Akihide
Published: August 2022

RNA-binding proteins (RBPs) are proteins that physically and functionally bind to RNA to regulate the RNA metabolism such as alternative splicing, polyadenylation, transport, maintenance of stability, localization, and translation. There is accumulating evidence that dysregulated RBPs play an essential role in the pathogenesis of malignant tumors including a variety of types of sarcomas. On the other hand, prognosis of patients with sarcoma, especially with sarcoma in advanced stages, is very poor, and almost no effective standard treatment has been established for most of types of sarcomas so far, highlighting the urgent need for identifying novel therapeutic targets based on the deep understanding of pathogenesis. Therefore, defining the network of interactions between RBPs and disease-related RNA targets will contribute to a better understanding of sarcomagenesis and identification of a novel therapeutic target for sarcomas.
How Gut Microbiota Are Shaped by Pattern Recognition Receptors in Colitis and Colorectal Cancer
Authors: Qing Furong , Xie Tao , Xie Lu , Guo Tianfu , Liu Zhiping
Published: August 2022

Disorders of gut microbiota have been closely linked to the occurrence of various intestinal diseases including colitis and colorectal cancer (CRC). Specifically, the production of beneficial bacteria and intestinal metabolites may slow the development of some intestinal diseases. Recently, it has been proposed that pattern recognition receptors (PRRs) not only recognize pathogens and initiate inflammatory signal transduction to induce immune responses but also influence the composition of intestinal microorganisms. However, the mechanisms through which PRRs regulate gut microbiota in the setting of colitis and CRC have rarely been systematically reviewed. Therefore, in this paper, we summarize recent advances in our understanding of how PRRs shape gut microbiota and how this influences the development of colitis and CRC.
Chemokine Receptor Expression on T Cells Is Modulated by CAFs and Chemokines Affect the Spatial Distribution of T Cells in Pancreatic Tumors
Authors: Gorchs Laia , Oosthoek Marlies , Yucel-Lindberg Tülay , Moro Carlos Fernández , Kaipe Helen
Published: August 2022

The accumulation of T cells is associated with a better prognosis in pancreatic cancer. However, the immunosuppressive tumor microenvironment, largely composed by cancer-associated fibroblasts (CAFs), can prevent T cells from reaching the tumor nests. We examined how human CAFs modulated chemokine receptors known to be associated with T cell trafficking, CXCR3 and CCR5, and T cell exclusion, CXCR4. CAFs decreased the expression of CXCR3 and CCR5 but increased CXCR4 expression in both 2D and 3D cultures, affecting the migratory capacity of T cells towards CXCL10. An immunohistochemistry analysis showed that very few T cells were found in the tumor nests. Within the stroma, CD8+ T cells were localized more distantly from the malignant cells whereas CD4+ T cells were more equally distributed. Tumor tissues with a high production of chemokines were associated with less T cell infiltration when the whole tissue was analyzed. However, when the spatial localization of CD8+ T cells within the tissue was taken into account, levels of CXCR3 ligands and the CCR5 ligand CCL8 showed a positive association with a high relative T cell infiltration in tumor-rich areas. Thus, CXCR3 ligands could mediate T cell trafficking but CAFs could prevent T cells from reaching the malignant cells.
The Challenging Management of Craniopharyngiomas in Adults: Time for a Reappraisal?
Authors: Cuny Thomas , Buchfelder Michael , Dufour Henry , Grossman Ashley , Gatta-Cherifi Blandine , Jouanneau Emmanuel , Raverot Gerald , Vasiljevic Alexandre , Castinetti Frederic
Published: August 2022

Craniopharyngiomas (CPs) are rare tumors of the skull base, developing near the pituitary gland and hypothalamus and responsible for severe hormonal deficiencies and an overall increase in mortality rate. While surgery and radiotherapy represent the recommended first-line therapies for CPs, a new paradigm for treatment is currently emerging, as a consequence of accumulated knowledge concerning the molecular mechanisms involved in tumor growth, paving the way for anticipated use of targeted therapies. Significant clinical and basic research conducted in the field of CPs will undoubtedly constitute a real step forward for a better understanding of the behavior of these tumors and prevent associated complications. In this review, our aim is to summarize the multiple steps in the management of CPs in adults and emphasize the most recent studies that will contribute to advancing the diagnostic and therapeutic algorithms.
Explorative Sonophotocatalytic Study of C-H Arylation Reaction of Pyrazoles Utilizing a Novel Sonophotoreactor for Green and Sustainable Organic Synthesis
Authors: Saleh Tamer S. , Al-Bogami Abdullah S. , Narasimharao Katabathini , Khan Ziya A. , Amenabar Iban , Mokhtar Mohamed
Published: August 2022

The development of a mild, general, and green method for the C-H arylation of pyrazoles with relatively unreactive aryl halides is an ongoing challenge in organic synthesis. We describe herein a novel sonophotoreactor based on an ultrasonic cleaning bath and blue LED light (visible light) that induce copper-catalyzed monoarylation for pharmacologically relevant pyrazoles. The hybrid effect of ultrasonic irradiation and blue LED is discussed to interpret the observed synergistic action. A broad array of pyrazoles coupled with iodobenzene avoids expensive palladium metal or salts, and certain designed substrates were attained. Only comparatively inexpensive copper(I)iodide and 1,10-phenanthroline were used all together as the catalyst. The presented technique is a greener way to create C-H arylation of pyrazoles. It significantly reduces the amount of energy needed.
Differentiation of Human Induced Pluripotent Stem Cells from Patients with Severe COPD into Functional Airway Epithelium
Authors: Ahmed Engi , Fieldes Mathieu , Bourguignon Chloé , Mianné Joffrey , Petit Aurélie , Jory Myriam , Cazevieille Chantal , Boukhaddaoui Hassan , Garnett James P. , Hirtz Christophe , Massiera Gladys , Vachier Isabelle , Assou Said , Bourdin Arnaud , De Vos John
Published: August 2022

Background: Chronic Obstructive Pulmonary Disease (COPD), a major cause of mortality and disability, is a complex disease with heterogeneous and ill-understood biological mechanisms. Human induced pluripotent stem cells (hiPSCs) are a promising tool to model human disease, including the impact of genetic susceptibility. Methods: We developed a simple and reliable method for reprogramming peripheral blood mononuclear cells into hiPSCs and to differentiate them into air–liquid interface bronchial epithelium within 45 days. Importantly, this method does not involve any cell sorting step. We reprogrammed blood cells from one healthy control and three patients with very severe COPD. Results: The mean cell purity at the definitive endoderm and ventral anterior foregut endoderm (vAFE) stages was >80%, assessed by quantifying C-X-C Motif Chemokine Receptor 4/SRY-Box Transcription Factor 17 (CXCR4/SOX17) and NK2 Homeobox 1 (NKX2.1) expression, respectively. vAFE cells from all four hiPSC lines differentiated into bronchial epithelium in air–liquid interface conditions, with large zones covered by beating ciliated, basal, goblets, club cells and neuroendocrine cells, as found in vivo. The hiPSC-derived airway epithelium (iALI) from patients with very severe COPD and from the healthy control were undistinguishable. Conclusions: iALI bronchial epithelium is ready for better understanding lung disease pathogenesis and accelerating drug discovery.
Regulation of APD and Force by the Na+/Ca2+ Exchanger in Human-Induced Pluripotent Stem Cell-Derived Engineered Heart Tissue
Authors: Ismaili Djemail , Gurr Katrin , Horváth András , Yuan Lei , Lemoine Marc D. , Schulz Carl , Sani Jascha , Petersen Johannes , Reichenspurner Hermann , Kirchhof Paulus , Jespersen Thomas , Eschenhagen Thomas , Hansen Arne , Koivumäki Jussi T. , Christ Torsten
Published: August 2022

The physiological importance of NCX in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) is not well characterized but may depend on the relative strength of the current, compared to adult cardiomyocytes, and on the exact spatial arrangement of proteins involved in Ca2+ extrusion. Here, we determined NCX currents and its contribution to action potential and force in hiPSC-CMs cultured in engineered heart tissue (EHT). The results were compared with data from rat and human left ventricular tissue. The NCX currents in hiPSC-CMs were larger than in ventricular cardiomyocytes isolated from human left ventricles (1.3 ± 0.2 pA/pF and 3.2 ± 0.2 pA/pF for human ventricle and EHT, respectively, p < 0.05). SEA0400 (10 µM) markedly shortened the APD90 in EHT (by 26.6 ± 5%, p < 0.05) and, to a lesser extent, in rat ventricular tissue (by 10.7 ± 1.6%, p < 0.05). Shortening in human left ventricular preparations was small and not different from time-matched controls (TMCs; p > 0.05). Force was increased by the NCX block in rat ventricle (by 31 ± 5.4%, p < 0.05) and EHT (by 20.8 ± 3.9%, p < 0.05), but not in human left ventricular preparations. In conclusion, hiPSC-CMs possess NCX currents not smaller than human left ventricular tissue. Robust NCX block-induced APD shortening and inotropy makes EHT an attractive pharmacological model.
Peroxisome Proliferator-Activated Receptors and the Hallmarks of Cancer
Authors: Wagner Nicole , Wagner Kay-Dietrich
Published: August 2022

Peroxisome proliferator-activated receptors (PPARs) function as nuclear transcription factors upon the binding of physiological or pharmacological ligands and heterodimerization with retinoic X receptors. Physiological ligands include fatty acids and fatty-acid-derived compounds with low specificity for the different PPAR subtypes (alpha, beta/delta, and gamma). For each of the PPAR subtypes, specific pharmacological agonists and antagonists, as well as pan-agonists, are available. In agreement with their natural ligands, PPARs are mainly focused on as targets for the treatment of metabolic syndrome and its associated complications. Nevertheless, many publications are available that implicate PPARs in malignancies. In several instances, they are controversial for very similar models. Thus, to better predict the potential use of PPAR modulators for personalized medicine in therapies against malignancies, it seems necessary and timely to review the three PPARs in relation to the didactic concept of cancer hallmark capabilities. We previously described the functions of PPAR beta/delta with respect to the cancer hallmarks and reviewed the implications of all PPARs in angiogenesis. Thus, the current review updates our knowledge on PPAR beta and the hallmarks of cancer and extends the concept to PPAR alpha and PPAR gamma.
A Comprehensive Transcriptomic Analysis of Arsenic-Induced Bladder Carcinogenesis
Authors: Shukla Vaibhav , Chandrasekaran Balaji , Tyagi Ashish , Navin Ajit Kumar , Saran Uttara , Adam Rosalyn M. , Damodaran Chendil
Published: August 2022

Arsenic (sodium arsenite: NaAsO2) is a potent carcinogen and a known risk factor for the onset of bladder carcinogenesis. The molecular mechanisms that govern arsenic-induced bladder carcinogenesis remain unclear. We used a physiological concentration of NaAsO2 (250 nM: 33 µg/L) for the malignant transformation of normal bladder epithelial cells (TRT-HU1), exposed for over 12 months. The increased proliferation and colony-forming abilities of arsenic-exposed cells were seen after arsenic exposure from 4 months onwards. Differential gene expression (DEG) analysis revealed that a total of 1558 and 1943 (padj < 0.05) genes were deregulated in 6-month and 12-month arsenic-exposed TRT-HU1 cells. The gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that cell proliferation and survival pathways, such as the MAPK, PI3K/AKT, and Hippo signaling pathways, were significantly altered. Pathway analysis revealed that the enrichment of stem cell activators such as ALDH1A1, HNF1b, MAL, NR1H4, and CDH1 (p < 0.001) was significantly induced during the transformation compared to respective vehicle controls. Further, these results were validated by qPCR analysis, which corroborated the transcriptomic analysis. Overall, the results suggested that stem cell activators may play a significant role in facilitating the arsenic-exposed cells to gain a survival advantage, enabling the healthy epithelial cells to reprogram into a cancer stem cell phenotype, leading to malignant transformation.
The Exocyst Is Required for CD36 Fatty Acid Translocase Trafficking and Free Fatty Acid Uptake in Skeletal Muscle Cells
Authors: Nakamura Nicole K. , Tokunaga Darcy S. , Ha Herena Y. , Polgar Noemi
Published: August 2022

In obesity, chronic membrane-localization of CD36 free fatty acid (FFA) translocase, but not other FFA transporters, enhances FFA uptake and intracellular lipid accumulation. This ectopic lipid accumulation promotes insulin resistance by inhibiting insulin-induced GLUT4 glucose transporter trafficking and glucose uptake. GLUT4 and CD36 cell surface delivery is triggered by insulin- and contraction-induced signaling, which share conserved downstream effectors. While we have gathered detailed knowledge on GLUT4 trafficking, the mechanisms regulating CD36 membrane delivery and subsequent FFA uptake in skeletal muscle are not fully understood. The exocyst trafficking complex facilitates the docking of membrane-bound vesicles, a process underlying the controlled surface delivery of fuel transporters. The exocyst regulates insulin-induced glucose uptake via GLUT4 membrane trafficking in adipocytes and skeletal muscle cells and plays a role in lipid uptake in adipocytes. Based on the high degree of conservation of the GLUT4 and CD36 trafficking mechanisms in adipose and skeletal muscle tissue, we hypothesized that the exocyst also contributes to lipid uptake in skeletal muscle and acts through the targeted plasma membrane delivery of CD36 in response to insulin and contraction. Here, we show that the exocyst complex is necessary for insulin- and contraction-induced CD36 membrane trafficking and FFA uptake in muscle cells.
Immunoregulation via Cell Density and Quorum Sensing-like Mechanisms: An Underexplored Emerging Field with Potential Translational Implications
Authors: Naoun Adrian A. , Raphael Itay , Forsthuber Thomas G.
Published: August 2022

Quorum sensing (QS) was historically described as a mechanism by which bacteria detect and optimize their population density via gene regulation based on dynamic environmental cues. Recently, it was proposed that QS or similar mechanisms may have broader applications across different species and cell types. Indeed, emerging evidence shows that the mammalian immune system can also elicit coordinated responses on a population level to regulate cell density and function, thus suggesting that QS-like mechanisms may also be a beneficial trait of the immune system. In this review, we explore and discuss potential QS-like mechanisms deployed by the immune system to coordinate cellular-level responses, such as T cell responses mediated via the common gamma chain (γc) receptor cytokines and the aryl hydrocarbon receptors (AhRs). We present evidence regarding a novel role of QS as a multifunctional mechanism coordinating CD4+ and CD8+ T cell behavior during steady state and in response to infection, inflammatory diseases, and cancer. Successful clinical therapies such as adoptive cell transfer for cancer treatment may be re-evaluated to harness the effects of the QS mechanism(s) and enhance treatment responsiveness. Moreover, we discuss how signaling threshold perturbations through QS-like mediators may result in disturbances of the complex crosstalk between immune cell populations, undesired T cell responses, and induction of autoimmune pathology. Finally, we discuss the potential therapeutic role of modulating immune-system-related QS as a promising avenue to treat human diseases.
Duplication and Segregation of Centrosomes during Cell Division
Authors: Prigent Claude , Uzbekov Rustem
Published: August 2022

During its division the cell must ensure the equal distribution of its genetic material in the two newly created cells, but it must also distribute organelles such as the Golgi apparatus, the mitochondria and the centrosome. DNA, the carrier of heredity, located in the nucleus of the cell, has made it possible to define the main principles that regulate the progression of the cell cycle. The cell cycle, which includes interphase and mitosis, is essentially a nuclear cycle, or a DNA cycle, since the interphase stages names (G1, S, G2) phases are based on processes that occur exclusively with DNA. However, centrosome duplication and segregation are two equally important events for the two new cells that must inherit a single centrosome. The centrosome, long considered the center of the cell, is made up of two small cylinders, the centrioles, made up of microtubules modified to acquire a very high stability. It is the main nucleation center of microtubules in the cell. Apart from a few exceptions, each cell in G1 phase has only one centrosome, consisting in of two centrioles and pericentriolar materials (PCM), which must be duplicated before the cell divides so that the two new cells formed inherit a single centrosome. The centriole is also the origin of the primary cilia, motile cilia and flagella of some cells.
Investigation of Radiotracer Metabolic Stability In Vitro with CYP-Overexpressing Hepatoma Cell Lines
Authors: Lemm Sandy , Köhler Susanne , Wodtke Robert , Jung Friedrich , Küpper Jan-Heiner , Pietzsch Jens , Laube Markus
Published: August 2022

The characterization of novel radiotracers toward their metabolic stability is an essential part of their development. While in vitro methods such as liver microsome assays or ex vivo blood or tissue samples provide information on overall stability, little or no information is obtained on cytochrome P450 (CYP) enzyme and isoform-specific contribution to the metabolic fate of individual radiotracers. Herein, we investigated recently established CYP-overexpressing hepatoblastoma cell lines (HepG2) for their suitability to study the metabolic stability of radiotracers in general and to gain insight into CYP isoform specificity. Wildtype HepG2 and CYP1A2-, CYP2C19-, and CYP3A4-overexpressing HepG2 cells were incubated with radiotracers, and metabolic turnover was analyzed. The optimized protocol, covering cell seeding in 96-well plates and analysis of supernatant by radio thin-layer-chromatography for higher throughput, was transferred to the evaluation of three 18F-labeled celecoxib-derived cyclooxygenase-2 inhibitors (coxibs). These investigations revealed time-dependent degradation of the intact radiotracers, as well as CYP isoform- and substrate-specific differences in their metabolic profiles. HepG2 CYP2C19 proved to be the cell line showing the highest metabolic turnover for each radiotracer studied here. Comparison with human and murine liver microsome assays showed good agreement with the human metabolite profile obtained by the HepG2 cell lines. Therefore, CYP-overexpressing HepG2 cells provide a good complement for assessing the metabolic stability of radiotracers and allow the analysis of the CYP isoform-specific contribution to the overall radiotracer metabolism.
Burden of Childhood Malnutrition: A Roadmap of Global and European Policies Promoting Healthy Nutrition for Infants and Young Children
Authors: Sotiraki Marianthi , Malliou Aggeliki , Tachirai Ntaniela , Kellari Nikoletta , Grammatikopoulou Maria G. , Sergentanis Theodoros N. , Vassilakou Tonia
Published: August 2022

Childhood malnutrition is a global epidemic with significant public health ramifications. The alarming increase in childhood obesity rates, in conjunction with the COVID-19 pandemic, pose major challenges. The present review aims to critically discuss policies and action plans promoting healthy nutrition among infants and children, globally. Since the Convention on the Rights of the Child in 1989 and the joint consortium held by the World Health Organization (WHO) and the United Nations Children’s Fund (UNICEF) that led to the “Ten Steps to Successful Breastfeeding”, several policymakers and scientific societies have produced relevant reports. Today, the WHO and UNICEF remain the key players on the field, elaborating the guidelines shaped by international expert teams over time, but we still have a long way to go before assuring the health of our children.
Resilience: Conceptualization and Keys to Its Promotion in Educational Centers
Authors: Moll Riquelme Isaac , Bagur Pons Sara , Rosselló Ramon Maria Rosa
Published: August 2022

This article conceptualizes resilience, a capacity present in all people that can be activated to face and overcome adversity. Based on a systematic review of the literature, the different lines by which research on this subject has been developed to the present moment, when it is interpreted from neuroscience, are identified. From the first descriptions of risk and protective factors, the concept has moved through the consideration of resilience as a process that can be carried out by anyone and not as an intrinsic characteristic of exceptional people, to the study of the will to not let oneself be discouraged and the personal commitment to overcome. Next, the keys to promote this capacity in educational centers are analyzed. There are two main focuses of intervention: the relationship that the teacher can establish with students and the pedagogical strategies and resources that can be used. From the purpose of the integral formation of people and in an inclusive framework, educational centers have the challenge and responsibility to promote resilient processes in all students, especially in those who experience more barriers to learning and participation due to personal circumstances and adversities. In this way, educational centers are encouraged to be protective environments where all students feel safe and can empower themselves and unfold their potential. The review has been conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol, and the bibliographic search has been performed in the Dialnet Plus, Web of Science (WoS) and Scopus databases.
The Nutraceuticals as Modern Key to Achieve Erythrocyte Oxidative Stress Fighting in Osteoarthritis
Authors: Mariano Alessia , Bigioni Irene , Misiti Francesco , Fattorini Luigi , Scotto d’Abusco Anna , Rodio Angelo
Published: August 2022

Osteoarthritis (OA), the most common joint disease, shows an increasing prevalence in the aging population in industrialized countries. OA is characterized by low-grade chronic inflammation, which causes degeneration of all joint tissues, such as articular cartilage, subchondral bone, and synovial membrane, leading to pain and loss of functionality. Erythrocytes, the most abundant blood cells, have as their primary function oxygen transport, which induces reactive oxygen species (ROS) production. For this reason, the erythrocytes have several mechanisms to counteract ROS injuries, which cause damage to lipids and proteins of the cell membrane. Oxidative stress and inflammation are highly correlated and are both causes of joint disorders. In the synovial fluid and blood of osteoarthritis patients, erythrocyte antioxidant enzyme expression is decreased. To date, OA is a non-curable disease, treated mainly with non-steroidal anti-inflammatory drugs and corticosteroids for a prolonged period of time, which cause several side effects; thus, the search for natural remedies with anti-inflammatory and antioxidant activities is always ongoing. In this review, we analyze several manuscripts describing the effect of traditional remedies, such as Harpagophytum procumbens, Curcumin longa, and Boswellia serrata extracts, in the treatments of OA for their anti-inflammatory, analgesic, and antioxidant activity. The effects of such remedies have been studied both in in vitro and in vivo models, considering both joint cells and erythrocytes.
Performance and Simulation Study of Aged Asphalt Regenerated from Waste Engine Oil
Authors: Zhang Fan , Li Haibin , Zou Xiaolong , Cui Canyang , Shi Yaping , Wang Hongwei , Yang Fayong
Published: August 2022

In order to reuse waste resources (waste engine oil and waste asphalt mixture), the regeneration process of waste oil on aged asphalt is systematically explained. The BA was treated by aging test, and the basic mechanical properties, molecular dynamics simulation, and infrared spectrum test were carried out on this basis. The results showed that the WEO can restore the physical properties of the aged asphalt, and the recommended amount of WEO is 3%. The density of the asphalt model corresponds to the actual situation of the asphalt. The aged asphalt components are more aggregated. After the WEO was added, the components of asphalt aggregation were reduced and the diffusion ability was improved. Finally, infrared spectroscopy tests were conducted on asphalt specimens, and the results showed that the process of rejuvenated asphalt was dominated by physical reactions. Consequentially, the results of this study build a bridge between the performance and simulation of aged asphalt rejuvenated by WEO. Consequentially, the results of this research promote the recycling of WEO and waste asphalt pavement materials, ultimately advocating the sustainability of pavement construction.
Exploring the Effect of Pt Addition on the Fracture Behavior of CrN Coatings by Finite Element Simulation
Authors: Sun Haifeng , Zhang Weilun , Feng Yongjun , Hu Suying , Tian Hua , Xie Zhiwen
Published: August 2022

Previous research confirmed that Pt addition induced a prominent refinement effect of CrN coating, resulting in an enhanced conductivity and corrosion resistance. In this work, a detailed finite element simulation and scratch test were employed to calculate and characterize the fracture failure behaviors (stress distribution, crack damage process, critical coating load, and coating–substrate adhesion energy) of CrN coatings with different Pt contents. Simulation results showed that the synergistic action of dynamic scratch load and extrusion load induced the fracture of the coatings. S11 and S22 caused transverse cracks in the CrN coating, S11 caused longitudinal cracks in the CrN-Pt coating and CrN-3Pt coatings, S22 led to the inclined propagation of cracks in these coatings, and S11 and S22 jointly induced the separation of the coating from the substrate. The doping Pt element in the CrN coating will make the coating easier to fracture and reduce the adhesion strength between the coating and substrate. Scratch test results revealed that adding Pt into the CrN coating will make this coating easier to fracture and cause more serious damage; the simulation results are in good accordance with the scratch test characterizations. The current founding provided a comprehensive understanding for the fracture damage mechanism of Pt-doped nitride coatings.
Effective Coating System Should Be Applied to Concrete with Recycled Waste Materials
Authors: Wang Junjie
Published: August 2022

With global concerns over increasing CO2 emissions, many countries have set up different strategies to achieve net zero CO2 emissions [...]
Influence of Interlayer Materials on the Mechanical Properties and Thermal Stability of a CrAlN Coating on a Tungsten Carbide Substrate
Authors: Kim Hoe-Kun , Kim Sung-Min , Lee Sang-Yul
Published: August 2022

CrAlN coatings have earned significant attention for use in cutting tool coating applications due to their excellent properties such as high hardness and superb oxidation resistance. It is well known that the interlayer between the coating and the substrate can influence the mechanical properties of the coatings. In this work, three interlayers—CrN, CrZrN, and CrN/CrZrSiN—were synthesized between a CrAlN coating and a tungsten carbide substrate to improve the mechanical properties and thermal stability of the CrAlN coating. All the CrAlN coatings with their respective interlayers showed high hardness values in the range of 34.5 to 35.1 GPa, and they were not significantly affected by the interlayer type. However, wear and scratch tests showed that the CrAlN coatings with CrN and CrN/CrZrSiN interlayers exhibited an improved friction coefficient of 0.33 and adhesion strength (Lc2) of 69 N compared to the CrAlN coating with the CrZrN interlayer. These improved wear properties were attributed to the H/E ratio of the interlayer between the coating and the substrate, in that the CrN and CrZrSiN interlayers effectively induced a smooth transition of the coating stress under a loading condition. During the thermal stability tests, the hardness of the CrAlN coating with the CrN/CrZrSiN interlayer was maintained up to 1000 °C due to the excellent oxidation resistance of the CrZrSiN layer, which contained an amorphous SixNy phase.