bluuebunny/crossref_metadata_2025 huggingface dataset:
Highly Sensitive Uric Acid Detection Based on a Graphene Chemoresistor and Magnetic Beads
Authors: Zhang Wangyang , Zhao Xiaoqiang , Diao Lina , Li Hao , Tong Zhonghao , Gu Zhiqi , Miao Bin , Xu Zhan , Zhang Han , Wu Yue , Li Jiadong
Published: August 2021

In this study, we developed a low-cost, reusable, and highly sensitive analytical platform for the detection of the human metabolite uric acid (UA). This novel analysis platform combines the graphene chemoresistor detection technique with a magnetic bead (MB) system. The heterojunction (single-layer graphene and HfO2 thin-film material) of our graphene-based biosensor worked as a transducer to detect the pH change caused by the specific catalytic reaction between UA and uricase, and hence acquires a UA concentration. Immobilization of uricase on MBs can decouple the functionalization steps from the sensor surface, which allows the sensor to be reusable. Our microsensor platform exhibits a relatively lower detection limit (1 μM), high sensitivity (5.6 mV/decade), a linear range (from 1 μM to 1000 μM), and excellent linearity (R2 = 0.9945). In addition, interference assay and repeatability tests were conducted, and the result suggests that our method is highly stable and not affected by common interfering substances (glucose and urea). The integration of this high-performance and compact biosensor device can create a point-of-care diagnosis system with reduced cost, test time, and reagent volume.
Immunosensing Based on Optical Fiber Technology: Recent Advances
Authors: Soares Maria Simone , Vidal Miguel , Santos Nuno F. , Costa Florinda M. , Marques Carlos , Pereira Sónia O. , Leitão Cátia
Published: August 2021

The evolution of optical fiber technology has revolutionized a variety of fields, from optical transmission to environmental monitoring and biomedicine, given their unique properties and versatility. For biosensing purposes, the light guided in the fiber core is exposed to the surrounding media where the analytes of interest are detected by different techniques, according to the optical fiber configuration and biofunctionalization strategy employed. These configurations differ in manufacturing complexity, cost and overall performance. The biofunctionalization strategies can be carried out directly on bare fibers or on coated fibers. The former relies on interactions between the evanescent wave (EW) of the fiber and the analyte of interest, whereas the latter can comprise plasmonic methods such as surface plasmon resonance (SPR) and localized SPR (LSPR), both originating from the interaction between light and metal surface electrons. This review presents the basics of optical fiber immunosensors for a broad audience as well as the more recent research trends on the topic. Several optical fiber configurations used for biosensing applications are highlighted, namely uncladded, U-shape, D-shape, tapered, end-face reflected, fiber gratings and special optical fibers, alongside practical application examples. Furthermore, EW, SPR, LSPR and biofunctionalization strategies, as well as the most recent advances and applications of immunosensors, are also covered. Finally, the main challenges and an outlook over the future direction of the field is presented.
Changes in Sleep Patterns and Disorders in Children and Adolescents with Attention Deficit Hyperactivity Disorders and Autism Spectrum Disorders during the COVID-19 Lockdown
Authors: Bruni Oliviero , Breda Maria , Ferri Raffaele , Melegari Maria Grazia
Published: August 2021

Background. The COVID-19 lockdown determined important changes in the sleep of a large percentage of the world population. We assessed the modifications of reported sleep patterns and disturbances in Italian children and adolescents with autism spectrum disorders (ASD) or attention deficit hyperactivity disorders (ADHD), compared to control children, before and during the COVID-19 lockdown in Italy. Methods. Parents of 100 ASD, 236 ADHD patients, and 340 healthy children filled out an anonymous online survey and a modified version of the Sleep Disturbance Scale for Children (SDSC), advertised via social media, to evaluate sleep patterns and disturbances of their children before and during the lockdown. Results. Before the lockdown, bedtime and risetime were not different between the three groups. During the lockdown, ADHD children tended to have a later bedtime and risetime than ASD and controls, while ASD children tended to maintain similar bedtime and risetime. Overall, during the lockdown, a reduced sleep duration significantly differentiated clinical groups from controls. Anxiety at bedtime, difficulties in falling asleep, and daytime sleepiness increased in all groups during the lockdown. Hypnic jerks, rhythmic movement disorders, night awakenings, restless sleep, sleepwalking, and daytime sleepiness increased in ASD and ADHD patients, in particular. Conclusions. This is the first study comparing sleep habits and disorders in ASD and ADHD during the lockdown showing specific differences consistent with the core characteristics of two neurodevelopmental disorders.
Prognostic Factors in Neurorehabilitation of Stroke: A Comparison among Regression, Neural Network, and Cluster Analyses
Authors: Iosa Marco , Morone Giovanni , Antonucci Gabriella , Paolucci Stefano
Published: August 2021

There is a large body of literature reporting the prognostic factors for a positive outcome of neurorehabilitation performed in the subacute phase of stroke. Despite the recent development of algorithms based on neural networks or cluster analysis for the identification of these prognostic factors, the literature lacks a rigorous comparison among classical regression, neural network, and cluster analysis. Moreover, the three methods have rarely been tested on a sample independent from that in which prognostic factors have been identified. This study aims at providing this comparison on a wide sample of data (1522 patients) and testing the results on an independent sample (1000 patients) using 30 variables. The accuracy was similar among regression, neural network, and cluster analyses on the analyzed sample (76.6%, 74%, and 76.1%, respectively), but on the test sample, the accuracy of neural network decreased (70.1%). The three models agreed in identifying older age, severe impairment, unilateral spatial neglect, and total anterior circulation infarcts as important prognostic factors. The binary regression analysis also provided solid results in the test sample, especially in terms of specificity (81.8%). Cluster analysis also showed a high sensitivity in the test sample (82.6%) and allowed a meaningful easy-to-use classification tree to be obtained.
The Combined Use of SLAM Laser Scanning and TLS for the 3D Indoor Mapping
Authors: Keitaanniemi Aino , Virtanen Juho-Pekka , Rönnholm Petri , Kukko Antero , Rantanen Toni , Vaaja Matti
Published: August 2021

An efficient 3D survey of a complex indoor environment remains a challenging task, especially if the accuracy requirements for the geometric data are high for instance in building information modeling (BIM) or construction. The registration of non-overlapping terrestrial laser scanning (TLS) point clouds is laborious. We propose a novel indoor mapping strategy that uses a simultaneous localization and mapping (SLAM) laser scanner (LS) to support the building-scale registration of non-overlapping TLS point clouds in order to reconstruct comprehensive building floor/3D maps. This strategy improves efficiency since it allows georeferenced TLS data to only be collected from those parts of the building that require such accuracy. The rest of the building is measured with SLAM LS accuracy. Based on the results of the case study, the introduced method can locate non-overlapping TLS point clouds with an accuracy of 18–51 mm using target sphere comparison.
Intra-Tumor Heterogeneity Revealed by Mass Spectrometry Imaging Is Associated with the Prognosis of Breast Cancer
Authors: Gawin Marta , Kurczyk Agata , Niemiec Joanna , Stanek-Widera Agata , Grela-Wojewoda Aleksandra , Adamczyk Agnieszka , Biskup-Frużyńska Magdalena , Polańska Joanna , Widłak Piotr
Published: August 2021

Intra-tumor heterogeneity (ITH) results from the coexistence of genetically distinct cancer cell (sub)populations, their phenotypic plasticity, and the presence of heterotypic components of the tumor microenvironment (TME). Here we addressed the potential association between phenotypic ITH revealed by mass spectrometry imaging (MSI) and the prognosis of breast cancer. Tissue specimens resected from 59 patients treated radically due to the locally advanced HER2-positive invasive ductal carcinoma were included in the study. After the on-tissue trypsin digestion of cellular proteins, peptide maps of all cancer regions (about 380,000 spectra in total) were segmented by an unsupervised approach to reveal their intrinsic heterogeneity. A high degree of similarity between spectra was observed, which indicated the relative homogeneity of cancer regions. However, when the number and diversity of the detected clusters of spectra were analyzed, differences between patient groups were observed. It is noteworthy that a higher degree of heterogeneity was found in tumors from patients who remained disease-free during a 5-year follow-up (n = 38) compared to tumors from patients with progressive disease (distant metastases detected during the follow-up, n = 21). Interestingly, such differences were not observed between patients with a different status of regional lymph nodes, cancer grade, or expression of estrogen receptor at the time of the primary treatment. Subsequently, spectral components with different abundance in cancer regions were detected in patients with different outcomes, and their hypothetical identity was established by assignment to measured masses of tryptic peptides identified in corresponding tissue lysates. Such differentiating components were associated with proteins involved in immune regulation and hemostasis. Further, a positive correlation between the level of tumor-infiltrating lymphocytes and heterogeneity revealed by MSI was observed. We postulate that a higher heterogeneity of tumors with a better prognosis could reflect the presence of heterotypic components including infiltrating immune cells, that facilitated the response to treatment.
Free Periosteal Flaps with Scaffold: An Overlooked Armamentarium for Maxillary and Mandibular Reconstruction
Authors: Accorona Remo , Gazzini Luca , Grigolato Roberto , Fazio Enrico , Nitro Letizia , Abousiam Monir , Giorgetti Giovanni , Pignataro Lorenzo , Capaccio Pasquale , Calabrese Luca
Published: August 2021

Introduction: Head and neck bone reconstruction is a challenging surgical scenario. Although several strategies have been described in the literature, bone free flaps (BFFs) have become the preferred technique for large defects. Revascularized free periosteal flaps (FPFs) with support scaffold represents a possible alternative in compromised patient, BFF failure, or relapsing cancers as salvage treatment. However, only few clinical applications in head and neck are reported in literature. Purpose of the study was to systematically analyse the results of functional and oncologic maxillary and mandibular reconstruction with FPF with scaffold. Materials and Methods: A comprehensive review of the dedicated literature was performed according to the PRISMA guidelines searching on Scopus, PubMed/MEDLINE, Cochrane Library, Embase, Researchgate and Google Scholar databases using relevant keywords, phrases and medical subject headings (MeSH) terms. An excursus on the most valuable FPF’ harvesting sites was also carried out. Results: A total of 7 studies with 55 patients were included. Overall, the majority of the patients (n = 54, 98.1%) underwent an FPF reconstruction of the mandibular site. The most used technique was the radial forearm FPF with autologous frozen bone as scaffold (n = 40, 72.7%). The overall rate of complications was 43.7%. The success rate intended as scaffold integration resulted to be 74.5%. Conclusions: Maxillary and mandibular reconstruction with FPF and scaffold is a possible alternative in patient unfit for complex BFF reconstruction and it should be considered as a valid alternative in the sequential salvage surgery for locally advanced cancer. Moreover, it opens future scenarios in head and neck reconstructive surgery, as a promising tool that can be modelled to tailor complex 3D defects, with less morbidities to the donor site.
Familial Risks and Proportions Describing Population Landscape of Familial Cancer
Authors: Hemminki Kari , Sundquist Kristina , Sundquist Jan , Försti Asta , Hemminki Akseli , Li Xinjun
Published: August 2021

Background: Familial cancer can be defined through the occurrence of the same cancer in two or more family members. We describe a nationwide landscape of familial cancer, including its frequency and the risk that it conveys, by using the largest family database in the world with complete family structures and medically confirmed cancers. Patients/methods: We employed standardized incidence ratios (SIRs) to estimate familial risks for concordant cancer among first-degree relatives using the Swedish Cancer Registry from years 1958 through 2016. Results: Cancer risks in a 20–84 year old population conferred by affected parents or siblings were about two-fold compared to the risk for individuals with unaffected relatives. For small intestinal, testicular, thyroid and bone cancers and Hodgkin disease, risks were higher, five-to-eight-fold. Novel familial associations included adult bone, lip, pharyngeal, and connective tissue cancers. Familial cancers were found in 13.2% of families with cancer; for prostate cancer, the proportion was 26.4%. High-risk families accounted for 6.6% of all cancer families. Discussion/Conclusion: High-risk family history should be exceedingly considered for management, including targeted genetic testing. For the major proportion of familial clustering, where genetic testing may not be feasible, medical and behavioral intervention should be indicated for the patient and their family members, including screening recommendations and avoidance of carcinogenic exposure.
Glycerol Valorization over ZrO2-Supported Copper Nanoparticles Catalysts Prepared by Chemical Reduction Method
Authors: Garcés Juan , Arrué Ramón , Novoa Néstor , Peixoto Andreia F. , Chimentão Ricardo J.
Published: August 2021

Copper nanoparticles (NPs) and ZrO2-supported copper NPs (Cu NPs/ZrO2) were synthesized via a chemical reduction method applying different pH (4, 7 and 9) and evaluated in a glycerol dehydration reaction. Copper NPs were characterized with transmission electron microscopy (TEM) and UV–vis spectroscopy. Transmission electron microcopy (TEM) results revealed a homogeneous distribution of copper NPs. A hypsochromic shift was identified with UV–vis spectroscopy as the pH of the synthesis increased from pH = 4 to pH = 9. Zirconia-supported copper NPs catalysts were characterized using N2 physisorption, X-ray diffraction (XRD), TEM, X-ray photoelectron spectroscopy (XPS), temperature-programmed reduction (TPR), temperature-programmed desorption of ammonia (NH3-TPD) and N2O chemisorption. The presence of ZrO2 in the chemical reduction method confirmed the dispersion of the copper nanoparticles. X-ray diffraction indicated only the presence of tetragonal zirconia patterns in the catalysts. XPS identified the Cu/Zr surface atomic ratio of the catalysts. TPR patterns showed two main peaks for the Cu NPS/ZrO2 pH = 9 catalyst; the first peak between 125 and 180 °C (region I) was ascribed to more dispersed copper species, and the second one between 180 and 250 °C (region II) was assigned to bulk CuO. The catalysts prepared at pH = 4 and pH = 7 only revealed reduction at lower temperatures (region I). Copper dispersion was determined by N2O chemisorption. With NH3-TPD it was found that Cu NPs/ZrO2 pH = 9 exhibited the highest total quantity of acidic sites and the highest apparent kinetic constant, with a value of 0.004 min−1. The different pH applied to the synthesis media of the copper nanoparticles determined the resultant copper dispersion on the ZrO2 support, providing active domains for glycerol conversion.
Special Issue on “Green Catalysts: Application to Waste and Groundwater Treatment”
Authors: Dominguez Carmen M. , Santos Aurora
Published: August 2021

Water and soil pollution are among the most critical global problems due to population growth, industrial development, and associated resource consumption [...]
The Catalysis Effect of Na and Point Defect on NO Heterogeneous Adsorption on Carbon during High-Sodium Zhundong Coal Reburning: Structures, Interactions and Thermodynamic Characteristics
Authors: Kou Xuesen , Jin Jing , Wang Yongzhen , Li Yanhui , Hou Fengxiao
Published: August 2021

The reburning process in a furnace, a key way to reduce NOx emissions, is a heterogeneous reaction during coal combustion, in which the heterogeneous adsorption is dominant. Zhundong coal with a high content of alkali metal can enhance the reburning process. In this paper, the influence of sodium and a defect on NO heterogeneous adsorption was studied by the density functional theory, and the thermodynamic characteristic was also analyzed. The results indicate that the binding energy for NO adsorption on the pristine graphene surface (graphene-NO), Na-decorated pristine graphene surface (graphene-Na-NO), defect graphene surface (gsv-NO) and Na-decorated defect graphene (gsv-Na-NO) is −5.86, −137.12, −48.94 and −74.85 kJ/mol, respectively, and that the heterogeneous adsorption is an exothermic reaction. Furthermore, except for covalent bonds of C and N, C and O for gsv-NO, other interactions are a closed-shell one, based on the analysis of AIM, ELF and IGM. The area of electron localization for NO is graphene-Na-NO > gsv-Na-NO > gsv-NO > graphene-NO. The dispersion interaction is the main interaction force between NO and the pristine graphene surface. The δg index for the atom pairs about N–C and O–C on the pristine graphene surface is also the smallest. The density of spikes at graphene-Na-NO is bigger than that at gsv-Na-NO. Moreover, the thermodynamics characteristic showed that the reaction equilibrium constant of graphene-NO is less than those on the other surfaces under the same temperature. Thus, NO on the pristine graphene surface is the most difficult to adsorb, but the presence of sodium and a defect structure can promote its adsorption.
Biochar Nanoparticles over TiO2 Nanotube Arrays: A Green Co-Catalyst to Boost the Photocatalytic Degradation of Organic Pollutants
Authors: Pinna Marco , Binda Gilberto , Altomare Marco , Marelli Marcello , Dossi Carlo , Monticelli Damiano , Spanu Davide , Recchia Sandro
Published: August 2021

Biochar nanoparticles (BC NPs), produced by low temperature pyrolysis (350 °C) of microalgae (Nannochloropsis sp.) and nutshells, are proposed as low-cost and sustainable co-catalysts to promote the photocatalytic activity of TiO2 nanotube (NT) arrays towards the degradation of methylene blue (MB) used as an organic pollutant model molecule. BC NPs (size < 25 nm) were obtained by treating bulk BC (i.e., biomass after pyrolysis) by sonication–centrifugation cycles in a water solution. The filtered BC NPs dispersion was deposited by simple drop-casting on the TiO2 NT support. The BC loading was varied by performing multiple depositions. Photocatalytic experiments under UV light (365 nm) revealed that the decoration with BC NPs significantly improves the TiO2 photoactivity. Such enhancement is mainly influenced by the amount of BC deposited; upon optimizing the BC deposition conditions, the rate of photocatalytic degradation of MB increases approximately three times with respect to bare TiO2, almost irrespective of the nature of the raw material. The greater photocatalytic activity of BC-TiO2 can be attributed to the synergistic combination of reactant/product adsorption and catalytic degradation of the adsorbed organic pollutant, as well as an improved charge carrier separation and electron transfer.
PT-BI Co-Deposit Shell on AU Nanoparticle Core: High Performance and Long Durability for Formic Acid Oxidation
Authors: Kim Young Jun , Lee Hyein , Chung Hee-Suk , Sohn Youngku , Rhee Choong Kyun
Published: August 2021

This work presents the catalysts of Pt-Bi shells on Au nanoparticle cores and Pt overlayers on the Pt-Bi shells toward formic acid oxidation (FAO). Pt and Bi were co-deposited on Au nanoparticles (Au NP) via the irreversible adsorption method using a mixed precursor solution of Pt and Bi ions, and the amount of the co-deposits was controlled with the repetition of the deposition cycle. Rinsing of the co-adsorbed ionic layers of Pt and Bi with a H2SO4 solution selectively removed the Bi ions to leave Pt-rich and Bi-lean (<0.4 atomic %) co-deposits on Au NP (Pt-Bi/Au NP), conceptually similar to de-alloying. Additional Pt was deposited over Pt-Bi/Au NPs (Pt/Pt-Bi/Au NPs) to manipulate further the physicochemical properties of Pt-Bi/Au NPs. Transmission electron microscopy revealed the core–shell structures of Pt-Bi/Au NPs and Pt/Pt-Bi/Au NPs, whose shell thickness ranged from roughly four to six atomic layers. Moreover, the low crystallinity of the Pt-containing shells was confirmed with X-ray diffraction. Electrochemical studies showed that the surfaces of Pt-Bi/Au NPs were characterized by low hydrogen adsorption abilities, which increased after the deposition of additional Pt. Durability tests were carried out with 1000 voltammetric cycles between −0.26 and 0.4 V (versus Ag/AgCl) in a solution of 1.0 M HCOOH + 0.1 M H2SO4. The initial averaged FAO performance on Pt-Bi/Au NPs and Pt/Pt-Bi/Au NPs (0.11 ± 0.01 A/mg, normalized to the catalyst weight) was higher than that of a commercial Pt nanoparticle catalyst (Pt NP, 0.023 A/mg) by a factor of ~5, mainly due to enhancement of dehydrogenation and suppression of dehydration. The catalytic activity of Pt/Pt-Bi/Au NP (0.04 ± 0.01 A/mg) in the 1000th cycle was greater than that of Pt-Bi/Au NP (0.026 ± 0.003 A/mg) and that of Pt NP (0.006 A/mg). The reason for the higher durability was suggested to be the low mobility of surface Pt atoms on the investigated catalysts.
Pt-Based Intermetallic Nanocrystals in Cathode Catalysts for Proton Exchange Membrane Fuel Cells: From Precise Synthesis to Oxygen Reduction Reaction Strategy
Authors: Gao Peng , Pu Min , Chen Qingjun , Zhu Hong
Published: August 2021

Although oxygen reduction reaction (ORR) catalysts have been extensively investigated and developed, there is a lack of clarity on catalysts that can balance high performance and low cost. Pt-based intermetallic nanocrystals are of special interest in the commercialization of proton exchange membrane fuel cells (PEMFCs) due to their excellent ORR activity and stability. This review summarizes the wide range of applications of Pt-based intermetallic nanocrystals in cathode catalysts for PEMFCs and their unique advantages in the field of ORR. Firstly, we introduce the fundamental understanding of Pt-based intermetallic nanocrystals, and highlight the difficulties and countermeasures in their synthesis. Then, the progress of theoretical and experimental studies related to the ORR activity and stability of Pt-based intermetallic nanocrystals in recent years are reviewed, especially the integrated strategies for enhancing the stability of ORR. Finally, the challenges faced by Pt-based intermetallic nanocrystals are summarized and future research directions are proposed. In addition, numerous design ideas of Pt-based intermetallic nanocrystals as ORR catalysts are summarized, aiming to promote further development of commercialization of PEMFC catalysts while fully understanding Pt-based intermetallic nanocrystals.
Current Applications and Discoveries Related to the Membrane Components of Circulating Tumor Cells and Extracellular Vesicles
Authors: Cortés-Hernández Luis Enrique , Eslami-S Zahra , Costa-Silva Bruno , Alix-Panabières Catherine
Published: August 2021

In cancer, many analytes can be investigated through liquid biopsy. They play fundamental roles in the biological mechanisms underpinning the metastatic cascade and provide clinical information that can be monitored in real time during the natural course of cancer. Some of these analytes (circulating tumor cells and extracellular vesicles) share a key feature: the presence of a phospholipid membrane that includes proteins, lipids and possibly nucleic acids. Most cell-to-cell and cell-to-matrix interactions are modulated by the cell membrane composition. To understand cancer progression, it is essential to describe how proteins, lipids and nucleic acids in the membrane influence these interactions in cancer cells. Therefore, assessing such interactions and the phospholipid membrane composition in different liquid biopsy analytes might be important for future diagnostic and therapeutic strategies. In this review, we briefly describe some of the most important surface components of circulating tumor cells and extracellular vesicles as well as their interactions, putting an emphasis on how they are involved in the different steps of the metastatic cascade and how they can be exploited by the different liquid biopsy technologies.
Modeling Notch-Induced Tumor Cell Survival in the Drosophila Ovary Identifies Cellular and Transcriptional Response to Nuclear NICD Accumulation
Authors: Jevitt Allison , Huang Yi-Chun , Zhang Su-Mei , Chatterjee Deeptiman , Wang Xian-Feng , Xie Geng-Qiang , Deng Wu-Min
Published: August 2021

Notch is a conserved developmental signaling pathway that is dysregulated in many cancer types, most often through constitutive activation. Tumor cells with nuclear accumulation of the active Notch receptor, NICD, generally exhibit enhanced survival while patients experience poorer outcomes. To understand the impact of NICD accumulation during tumorigenesis, we developed a tumor model using the Drosophila ovarian follicular epithelium. Using this system we demonstrated that NICD accumulation contributed to larger tumor growth, reduced apoptosis, increased nuclear size, and fewer incidents of DNA damage without altering ploidy. Using bulk RNA sequencing we identified key genes involved in both a pre- and post- tumor response to NICD accumulation. Among these are genes involved in regulating double-strand break repair, chromosome organization, metabolism, like raptor, which we experimentally validated contributes to early Notch-induced tumor growth. Finally, using single-cell RNA sequencing we identified follicle cell-specific targets in NICD-overexpressing cells which contribute to DNA repair and negative regulation of apoptosis. This valuable tumor model for nuclear NICD accumulation in adult Drosophila follicle cells has allowed us to better understand the specific contribution of nuclear NICD accumulation to cell survival in tumorigenesis and tumor progression.
Thrombo-Inflammation: A Focus on NTPDase1/CD39
Authors: Morello Silvana , Caiazzo Elisabetta , Turiello Roberta , Cicala Carla
Published: August 2021

There is increasing evidence for a link between inflammation and thrombosis. Following tissue injury, vascular endothelium becomes activated, losing its antithrombotic properties whereas inflammatory mediators build up a prothrombotic environment. Platelets are the first elements to be activated following endothelial damage; they participate in physiological haemostasis, but also in inflammatory and thrombotic events occurring in an injured tissue. While physiological haemostasis develops rapidly to prevent excessive blood loss in the endothelium activated by inflammation, hypoxia or by altered blood flow, thrombosis develops slowly. Activated platelets release the content of their granules, including ATP and ADP released from their dense granules. Ectonucleoside triphosphate diphosphohydrolase-1 (NTPDase1)/CD39 dephosphorylates ATP to ADP and to AMP, which in turn, is hydrolysed to adenosine by ecto-5′-nucleotidase (CD73). NTPDase1/CD39 has emerged has an important molecule in the vasculature and on platelet surfaces; it limits thrombotic events and contributes to maintain the antithrombotic properties of endothelium. The aim of the present review is to provide an overview of platelets as cellular elements interfacing haemostasis and inflammation, with a particular focus on the emerging role of NTPDase1/CD39 in controlling both processes.
Immune Checkpoint Inhibitors in People Living with HIV/AIDS: Facts and Controversies
Authors: Castelli Valeria , Lombardi Andrea , Palomba Emanuele , Bozzi Giorgio , Ungaro Riccardo , Alagna Laura , Mangioni Davide , Muscatello Antonio , Bandera Alessandra , Gori Andrea
Published: August 2021

Immune checkpoint inhibitors (ICIs) are reshaping the landscape of cancer treatment, redefining the prognosis of several tumors. They act by restoring the cytotoxic activity of tumor-specific T lymphocytes that are in a condition of immune exhaustion. The same condition has been widely described in chronic HIV infection. In this review, we dissect the role of ICIs in people living with HIV/AIDS (PLWHIV). First, we provide an overview of the immunologic scenario. Second, we discuss the possible use of ICIs as adjuvant treatment of HIV to achieve elimination of the viral reservoir. Third, we examine the influence of HIV infection on ICI safety and effectiveness. Finally, we describe how the administration of ICIs impacts opportunistic infections.
Roles of the FGF-FGFR Signaling System in Cancer Development and Inflammation
Authors: Wiedlocha Antoni , Haugsten Ellen Margrethe , Zakrzewska Malgorzata
Published: August 2021

For multi-cellular organisms to organize tissues, their cells must communicate with each other [...]
Hypoblast Formation in Bovine Embryos Does Not Depend on NANOG
Authors: Springer Claudia , Zakhartchenko Valeri , Wolf Eckhard , Simmet Kilian
Published: August 2021

The role of the pluripotency factor NANOG during the second embryonic lineage differentiation has been studied extensively in mouse, although species-specific differences exist. To elucidate the role of NANOG in an alternative model organism, we knocked out NANOG in fibroblast cells and produced bovine NANOG-knockout (KO) embryos via somatic cell nuclear transfer (SCNT). At day 8, NANOG-KO blastocysts showed a decreased total cell number when compared to controls from SCNT (NT Ctrl). The pluripotency factors OCT4 and SOX2 as well as the hypoblast (HB) marker GATA6 were co-expressed in all cells of the inner cell mass (ICM) and, in contrast to mouse Nanog-KO, expression of the late HB marker SOX17 was still present. We blocked the MEK-pathway with a MEK 1/2 inhibitor, and control embryos showed an increase in NANOG positive cells, but SOX17 expressing HB precursor cells were still present. NANOG-KO together with MEK-inhibition was lethal before blastocyst stage, similarly to findings in mouse. Supplementation of exogenous FGF4 to NANOG-KO embryos did not change SOX17 expression in the ICM, unlike mouse Nanog-KO embryos, where missing SOX17 expression was completely rescued by FGF4. We conclude that NANOG mediated FGF/MEK signaling is not required for HB formation in the bovine embryo and that another—so far unknown—pathway regulates HB differentiation.
CEBPD Potentiates the Macrophage Inflammatory Response but CEBPD Knock-Out Macrophages Fail to Identify CEBPD-Dependent Pro-Inflammatory Transcriptional Programs
Authors: Spek C. Arnold , Aberson Hella L. , Butler Joe M. , de Vos Alex F. , Duitman JanWillem
Published: August 2021

CCAAT/enhancer-binding protein delta (C/EBPδ) is a member of the C/EBP family of transcription factors. According to the current paradigm, C/EBPδ potentiates cytokine production and modulates macrophage function thereby enhancing the inflammatory response. Remarkably, however, C/EBPδ deficiency does not consistently lead to a reduction in Lipopolysaccharide (LPS)-induced cytokine production by macrophages. Here, we address this apparent discrepancy and show that the effect of C/EBPδ on cytokine production and macrophage function depends on both the macrophage subtype and the LPS concentration used. Using CRISPR-Cas generated macrophages in which the transactivation domain of C/EBPδ was deleted from the endogenous locus (ΔTAD macrophages), we next show that the context-dependent role of C/EBPδ in macrophage biology relies on compensatory transcriptional activity in the absence of C/EBPδ. We extend these findings by revealing a large discrepancy between transcriptional programs in C/EBPδ knock-out and C/EBPδ transactivation dead (ΔTAD) macrophages implying that compensatory mechanisms do not specifically modify C/EBPδ-dependent inflammatory responses but affect overall macrophage biology. Overall, these data imply that knock-out approaches are not suited for identifying the genuine transcriptional program regulated by C/EBPδ, and we suggest that this phenomenon applies for transcription factor families in general.
Beyond Activation: Characterizing Microglial Functional Phenotypes
Authors: Lier Julia , Streit Wolfgang J. , Bechmann Ingo
Published: August 2021

Classically, the following three morphological states of microglia have been defined: ramified, amoeboid and phagocytic. While ramified cells were long regarded as “resting”, amoeboid and phagocytic microglia were viewed as “activated”. In aged human brains, a fourth, morphologically novel state has been described, i.e., dystrophic microglia, which are thought to be senescent cells. Since microglia are not replenished by blood-borne mononuclear cells under physiological circumstances, they seem to have an “expiration date” limiting their capacity to phagocytose and support neurons. Identifying factors that drive microglial aging may thus be helpful to delay the onset of neurodegenerative diseases, such as Alzheimer’s disease (AD). Recent progress in single-cell deep sequencing methods allowed for more refined differentiation and revealed regional-, age- and sex-dependent differences of the microglial population, and a growing number of studies demonstrate various expression profiles defining microglial subpopulations. Given the heterogeneity of pathologic states in the central nervous system, the need for accurately describing microglial morphology and expression patterns becomes increasingly important. Here, we review commonly used microglial markers and their fluctuations in expression in health and disease, with a focus on IBA1 low/negative microglia, which can be found in individuals with liver disease.
Protective Role of Recombinant Human Thrombomodulin in Diabetes Mellitus
Authors: Okano Yuko , Takeshita Atsuro , Yasuma Taro , Toda Masaaki , Nishihama Kota , Fridman D’Alessandro Valeria , Inoue Chisa , D’Alessandro-Gabazza Corina N. , Kobayashi Tetsu , Yano Yutaka , Gabazza Esteban C.
Published: August 2021

Diabetes mellitus is a global threat to human health. The ultimate cause of diabetes mellitus is insufficient insulin production and secretion associated with reduced pancreatic β-cell mass. Apoptosis is an important and well-recognized mechanism of the progressive loss of functional β-cells. However, there are currently no available antiapoptotic drugs for diabetes mellitus. This study evaluated whether recombinant human thrombomodulin can inhibit β-cell apoptosis and improve glucose intolerance in a diabetes mouse model. A streptozotocin-induced diabetes mouse model was prepared and treated with thrombomodulin or saline three times per week for eight weeks. The glucose tolerance and apoptosis of β-cells were evaluated. Diabetic mice treated with recombinant human thrombomodulin showed significantly improved glucose tolerance, increased insulin secretion, decreased pancreatic islet areas of apoptotic β-cells, and enhanced proportion of regulatory T cells and tolerogenic dendritic cells in the spleen compared to counterpart diseased mice treated with saline. Non-diabetic mice showed no changes. This study shows that recombinant human thrombomodulin, a drug currently used to treat patients with coagulopathy in Japan, ameliorates glucose intolerance by protecting pancreatic islet β-cells from apoptosis and modulating the immune response in diabetic mice. This observation points to recombinant human thrombomodulin as a promising antiapoptotic drug for diabetes mellitus.
MNase Digestion Protection Patterns of the Linker DNA in Chromatosomes
Authors: Shen Chang-Hui , Allan James
Published: August 2021

The compact nucleosomal structure limits DNA accessibility and regulates DNA-dependent cellular activities. Linker histones bind to nucleosomes and compact nucleosomal arrays into a higher-order chromatin structure. Recent developments in high throughput technologies and structural computational studies provide nucleosome positioning at a high resolution and contribute to the information of linker histone location within a chromatosome. However, the precise linker histone location within the chromatin fibre remains unclear. Using monomer extension, we mapped core particle and chromatosomal positions over a core histone-reconstituted, 1.5 kb stretch of DNA from the chicken adult β-globin gene, after titration with linker histones and linker histone globular domains. Our results show that, although linker histone globular domains and linker histones display a wide variation in their binding affinity for different positioned nucleosomes, they do not alter nucleosome positions or generate new nucleosome positions. Furthermore, the extra ~20 bp of DNA protected in a chromatosome is usually symmetrically distributed at each end of the core particle, suggesting linker histones or linker histone globular domains are located close to the nucleosomal dyad axis.
Pro-Angiogenic and Osteogenic Effects of Adipose Tissue-Derived Pericytes Synergistically Enhanced by Nel-like Protein-1
Authors: An Hyun-Ju , Ko Kyung Rae , Baek Minjung , Jeong Yoonhui , Lee Hyeon Hae , Kim Hyungkyung , Kim Do Kyung , Lee So-Young , Lee Soonchul
Published: August 2021

An important objective of vascularized tissue regeneration is to develop agents for osteonecrosis. We aimed to identify the pro-angiogenic and osteogenic efficacy of adipose tissue-derived (AD) pericytes combined with Nel-like protein-1 (NELL-1) to investigate the therapeutic effects on osteonecrosis. Tube formation and cell migration were assessed to determine the pro-angiogenic efficacy. Vessel formation was evaluated in vivo using the chorioallantoic membrane assay. A mouse model with a 2.5 mm necrotic bone fragment in the femoral shaft was used as a substitute for osteonecrosis in humans. Bone formation was assessed radiographically (plain radiographs, three-dimensional images, and quantitative analyses), and histomorphometric analyses were performed. To identify factors related to the effects of NELL-1, analysis using microarrays, qRT-PCR, and Western blotting was performed. The results for pro-angiogenic efficacy evaluation identified synergistic effects of pericytes and NELL-1 on tube formation, cell migration, and vessel formation. For osteogenic efficacy analysis, the mouse model for osteonecrosis was treated in combination with pericytes and NELL-1, and the results showed maximum bone formation using radiographic images and quantitative analyses, compared with other treatment groups and showed robust bone and vessel formation using histomorphometric analysis. We identified an association between FGF2 and the effects of NELL-1 using array-based analysis. Thus, combinatorial therapy using AD pericytes and NELL-1 may have potential as a novel treatment for osteonecrosis.
Annexin A1 as a Regulator of Immune Response in Cancer
Authors: Araújo Thaise Gonçalves , Mota Sara Teixeira Soares , Ferreira Helen Soares Valença , Ribeiro Matheus Alves , Goulart Luiz Ricardo , Vecchi Lara
Published: August 2021

Annexin A1 is a 37 kDa phospholipid-binding protein that is expressed in many tissues and cell types, including leukocytes, lymphocytes and epithelial cells. Although Annexin A1 has been extensively studied for its anti-inflammatory activity, it has been shown that, in the cancer context, its activity switches from anti-inflammatory to pro-inflammatory. Remarkably, Annexin A1 shows pro-invasive and pro-tumoral properties in several cancers either by eliciting autocrine signaling in cancer cells or by inducing a favorable tumor microenvironment. Indeed, the signaling of the N-terminal peptide of AnxA1 has been described to promote the switching of macrophages to the pro-tumoral M2 phenotype. Moreover, AnxA1 has been described to prevent the induction of antigen-specific cytotoxic T cell response and to play an essential role in the induction of regulatory T lymphocytes. In this way, Annexin A1 inhibits the anti-tumor immunity and supports the formation of an immunosuppressed tumor microenvironment that promotes tumor growth and metastasis. For these reasons, in this review we aim to describe the role of Annexin A1 in the establishment of the tumor microenvironment, focusing on the immunosuppressive and immunomodulatory activities of Annexin A1 and on its interaction with the epidermal growth factor receptor.
Plectin in Cancer: From Biomarker to Therapeutic Target
Authors: Perez Samantha M. , Brinton Lindsey T. , Kelly Kimberly A.
Published: August 2021

The cytolinker and scaffolding protein, plectin, has emerged as a potent driver of malignant hallmarks in many human cancers due to its involvement in various cellular activities contributing to tumorigenesis, including cancer cell proliferation, adhesion, migration, invasion, and signal transduction. Evidence shows that beyond plectin’s diverse protein interactome, its cancer-specific mislocalization to the cell surface enables its function as a potent oncoprotein. As such, therapeutic targeting of plectin, its protein interactors, and, in particular, cancer-specific plectin (CSP) presents an attractive opportunity to impede carcinogenesis directly. Here, we report on plectin’s differential gene and protein expression in cancer, explore its mutational profile, and discuss the current understanding of plectin’s and CSP’s biological function in cancer. Moreover, we review the landscape of plectin as a prognostic marker, diagnostic biomarker, and target for imaging and therapeutic modalities. We highlight how, beyond their respective biological importance, plectin’s common overexpression in cancer and CSP’s cancer-specific bioavailability underscore their potential as high-value druggable targets. We discuss how recent evidence of the potent anti-cancer effects of CSP therapeutic targeting opens the door for cell-surface mislocalized proteins as novel therapeutic targets.
Hypothyroidism Intensifies Both Canonic and the De Novo Pathway of Peroxisomal Biogenesis in Rat Brown Adipocytes in a Time-Dependent Manner
Authors: Aleksic Marija , Golic Igor , Kalezic Andjelika , Jankovic Aleksandra , Korac Bato , Korac Aleksandra
Published: August 2021

Despite peroxisomes being important partners of mitochondria by carrying out fatty acid oxidation in brown adipocytes, no clear evidence concerning peroxisome origin and way(s) of biogenesis exists. Herein we used methimazole-induced hypothyroidism for 7, 15, and 21 days to study peroxisomal remodeling and origin in rat brown adipocytes. We found that peroxisomes originated via both canonic, and de novo pathways. Each pathway operates in euthyroid control and over the course of hypothyroidism, in a time-dependent manner. Hypothyroidism increased the peroxisomal number by 1.8-, 3.6- and 5.8-fold on days 7, 15, and 21. Peroxisomal presence, their distribution, and their degree of maturation were heterogeneous in brown adipocytes in a Harlequin-like manner, reflecting differences in their origin. The canonic pathway, through numerous dumbbell-like and “pearls on strings” structures, supported by high levels of Pex11β and Drp1, prevailed on day 7. The de novo pathway of peroxisomal biogenesis started on day 15 and became dominant by day 21. The transition of peroxisomal biogenesis from canonic to the de novo pathway was driven by increased levels of Pex19, PMP70, Pex5S, and Pex26 and characterized by numerous tubular structures. Furthermore, specific peroxisomal origin from mitochondria, regardless of thyroid status, indicates their mutual regulation in rat brown adipocytes.
HCV-Induced Immunometabolic Crosstalk in a Triple-Cell Co-Culture Model Capable of Simulating Systemic Iron Homeostasis
Authors: Foka Pelagia , Dimitriadis Alexios , Karamichali Eirini , Kochlios Emmanouil , Eliadis Petros , Valiakou Vaia , Koskinas John , Mamalaki Avgi , Georgopoulou Urania
Published: August 2021

Iron is crucial to the regulation of the host innate immune system and the outcome of many infections. Hepatitis C virus (HCV), one of the major viral human pathogens that depends on iron to complete its life cycle, is highly skilled in evading the immune system. This study presents the construction and validation of a physiologically relevant triple-cell co-culture model that was used to investigate the input of iron in HCV infection and the interplay between HCV, iron, and determinants of host innate immunity. We recorded the expression patterns of key proteins of iron homeostasis involved in iron import, export and storage and examined their relation to the iron regulatory hormone hepcidin in hepatocytes, enterocytes and macrophages in the presence and absence of HCV. We then assessed the transcriptional profiles of pro-inflammatory cytokines Interleukin-6 (IL-6) and interleukin-15 (IL-15) and anti-inflammatory interleukin-10 (IL-10) under normal or iron-depleted conditions and determined how these were affected by infection. Our data suggest the presence of a link between iron homeostasis and innate immunity unfolding among liver, intestine, and macrophages, which could participate in the deregulation of innate immune responses observed in early HCV infection. Coupled with iron-assisted enhanced viral propagation, such a mechanism may be important for the establishment of viral persistence and the ensuing chronic liver disease.
Housekeeping Genes for Parkinson’s Disease in Humans and Mice
Authors: Alieva Anelya Kh. , Filatova Elena V. , Rudenok Margarita M. , Slominsky Petr A. , Shadrina Maria I.
Published: August 2021

A critical aspect of real-time PCR is the presence of housekeeping genes (HKGs) as an internal control for the normalization of expression data for genes of interest. It is necessary to select correct HKGs in the investigation of various pathologies. Thereby, we analyzed the stability of expression of the HKGs in Parkinson’s disease (PD). The work was carried out in the peripheral blood of patients with PD and in the brain tissues and peripheral blood of mice with MPTP-induced PD. As a result, Aars was the most stably expressed HKG in the mouse brain as a whole. However, different genes were more stably expressed in different parts of the brain. Polr2f was the most stably expressed in the cortex, Psmd6 was the most stably expressed in the cerebellum, and Psmd7 was the most stably expressed in the striatum and substantia nigra. HKGs were different in similar tissues of the studied organisms. Polr2f was the most stably expressed HKG in the peripheral blood of mice, whereas PSMD6 was the most stably expressed gene in humans. Thus, there is no universal HKG both for different brain tissues of one organism and for similar tissues of different organisms. Furthermore, the identified most stably expressed HKGs can be considered as such only under conditions in PD.