bluuebunny/crossref_metadata_2025 huggingface dataset:
Lactoferrin as Antiviral Treatment in COVID-19 Management: Preliminary Evidence
Authors: Campione Elena , Lanna Caterina , Cosio Terenzio , Rosa Luigi , Conte Maria Pia , Iacovelli Federico , Romeo Alice , Falconi Mattia , Del Vecchio Claudia , Franchin Elisa , Lia Maria Stella , Minieri Marilena , Chiaramonte Carlo , Ciotti Marco , Nuccetelli Marzia , Terrinoni Alessandro , Iannuzzi Ilaria , Coppeta Luca , Magrini Andrea , Bernardini Sergio , Sabatini Stefano , Rosapepe Felice , Bartoletti Pier Luigi , Moricca Nicola , Di Lorenzo Andrea , Andreoni Massimo , Sarmati Loredana , Miani Alessandro , Piscitelli Prisco , Squillaci Ettore , Valenti Piera , Bianchi Luca
Published: October 2021

Lactoferrin (Lf), a multifunctional cationic glycoprotein synthesized by exocrine glands and neutrophils, possesses an in vitro antiviral activity against SARS-CoV-2. Thus, we conducted an in vivo preliminary study to investigate the antiviral effect of oral and intranasal liposomal bovine Lf (bLf) in asymptomatic and mild-to-moderate COVID-19 patients. From April 2020 to June 2020, a total of 92 mild-to-moderate (67/92) and asymptomatic (25/92) COVID-19 patients were recruited and divided into three groups. Thirty-two patients (14 hospitalized and 18 in home-based isolation) received only oral and intranasal liposomal bLf; 32 hospitalized patients were treated only with standard of care (SOC) treatment; and 28, in home-based isolation, did not take any medication. Furthermore, 32 COVID-19 negative, untreated, healthy subjects were added for ancillary analysis. Liposomal bLf-treated COVID-19 patients obtained an earlier and significant (p < 0.0001) SARS-CoV-2 RNA negative conversion compared to the SOC-treated and untreated COVID-19 patients (14.25 vs. 27.13 vs. 32.61 days, respectively). Liposomal bLf-treated COVID-19 patients showed fast clinical symptoms recovery compared to the SOC-treated COVID-19 patients. In bLf-treated patients, a significant decrease in serum ferritin, IL-6, and D-dimers levels was observed. No adverse events were reported. These observations led us to speculate a potential role of bLf in the management of mild-to-moderate and asymptomatic COVID-19 patients.
Gender and Socioeconomic Inequality in the Prescription of Direct Oral Anticoagulants in Patients with Non-Valvular Atrial Fibrillation in Primary Care in Catalonia (Fantas-TIC Study)
Authors: Dalmau Llorca Mª Rosa , Aguilar Martín Carina , Carrasco-Querol Noèlia , Hernández Rojas Zojaina , Forcadell Drago Emma , Rodríguez Cumplido Dolores , Castro Blanco Elisabet , Pepió Vilaubí Josep Mª , Gonçalves Alessandra Queiroga , Fernández-Sáez José
Published: October 2021

Background: Evidence points to unequal access to direct oral anticoagulant (DOAC) therapy, to the detriment of the most socioeconomically disadvantaged patients in different geographic areas; however, few studies have focused on people with atrial fibrillation. This study aimed to assess gender-based and socioeconomic differences in the prescriptions of anticoagulants in people with non-valvular atrial fibrillation who attended Primary Care. Method: A cross-sectional study with real-world data from patients treated in Primary Care in Catalonia (Spain). Data were obtained from the SIDIAP database, covering 287 Primary Care centers in 2018. Results were presented as descriptive statistics and odds ratios estimated by multivariable logistic regression. Results: A total of 60,978 patients on anticoagulants for non-valvular atrial fibrillation were identified: 41,430 (68%) were taking vitamin K antagonists and 19,548 (32%), DOACs. Women had higher odds of treatment with DOAC (adjusted odds ratio [ORadj] 1.12), while lower DOAC prescription rates affected patients from Primary Care centers located in high-deprivation urban centers (ORadj 0.58) and rural areas (ORadj 0.34). Conclusions: DOAC prescription patterns differ by population. Women are more likely to receive it than men, while people living in rural areas and deprived urban areas are less likely to receive this therapy. Following clinical management guidelines could help to minimize the inequality.
Developing a Dynamic Model for Assessing Green Infrastructure Investments in Urban Areas
Authors: Barrios-Crespo Esther , Torres-Ortega Saúl , Díaz-Simal Pedro
Published: October 2021

In recent decades, cities have been experiencing accelerated population growth, associated with an increase in the scales of production and consumption. This fact, combined with deficient management of resources and waste, has led to the loss of biological diversity, compromising the generation of ecosystem services, with disastrous consequences for human health and well-being, but also for the economic system. In the field of civil engineering, the predominance of artificialisation and impermeabilization of cities (called “grey engineering”) is being questioned to be replaced or complemented with new types of infrastructures that represent a transformative change to achieving more sustainable cities. Through system dynamics applied to the economic modelling of the city of Santander (Spain), the aim of this study is to analyse the profitability of investment in ecosystem restoration and in both green and blue infrastructure, and of the implementation of environmental policies based on the relationships of affection established in the model, which represent the interactions between the main actors in urban dynamics. As a main conclusion, it is found that investing in green infrastructures and ecosystem restoration, and environmental policies is highly profitable: EUR 1 spent can produce up to EUR 100 as a benefit.
Development of a Digital Case Management Tool for Community Based Inclusive Development Program
Authors: Marella Manjula , Koolmees Donna , Vongvilay Chandalin , Frank Bernard , Pryor Wesley , Smith Fleur
Published: October 2021

Disability inclusive development practices require reliable data to identify people with disabilities, their barriers to participation and support needs. Although several tools are available for measuring different components of disability, it is often difficult for program teams in low resource settings, including lay community workers of community based inclusive development (CBID) programs, to collect and analyze data for program monitoring and evaluation. This paper presents the development of a digital CBID Modular Tool with automated data analysis to support routine case management processes and monitoring of a CBID program in Laos PDR. The tool was developed in different phases involving stakeholder consultations, auditing of existing tools, content development for the different modules for disability assessment and support needs, software development and testing. The tool was developed in a participatory process including people with disabilities. The tool measures needs and support requirements of people with disabilities in health, functioning, economic, education and caregiver support domains, and enables intervention planning. The content included is both context specific and universal as derived from the widely used validated tools. This unique digital CBID Modular Tool can support data collection by lay community workers and support reliable data collection to measure disability inclusion in a development program.
Policymakers’ Research Capacities, Engagement, and Use of Research in Public Health Policymaking
Authors: Loncarevic Natasa , Andersen Pernille Tanggaard , Leppin Anja , Bertram Maja
Published: October 2021

The use of research in public health policymaking is one of the prerequisites for successfully implemented health policies which have better population health as an outcome. This policy process is influenced by the actors involved under the policy umbrella, with inter-related contextual factors and specific structural and institutional circumstances. Our study investigates how policymakers’ research capacities influence the use of research in the health policy process and identify areas where capacity-building interventions give the most meaning and impact. Furthermore, we investigate policymakers’ research engagement and use this to inform public health policy in the public sector in Denmark. We collect and report data using Seeking, Engaging with, and Evaluation Research (SEER) methodology. Policymakers are reported to have research capacity, but it is questionable how those competences have actually been used in policymaking. Decision-makers were often not aware or did not know about the existing organizational tools and systems for research engagement and use and two third of respondents had not been part of any research activities or had any collaboration with researchers. Overall, research use in public health policymaking and evaluation was limited. As a conclusion, we propose that capacity-building interventions for increasing research use and collaboration in EIPM should be context-oriented, measurable, and sustainable in developing individual and organizational competences.
Multiparameter Evaluation of the Platelet-Inhibitory Effects of Tyrosine Kinase Inhibitors Used for Cancer Treatment
Authors: Tullemans Bibian , Veninga Alicia , Fernandez Delia , Aarts Maureen , Eble Johannes , van der Meijden Paola , Heemskerk Johan , Kuijpers Marijke
Published: October 2021

Current antiplatelet drugs for the treatment of arterial thrombosis often coincide with increased bleeding risk. Several tyrosine kinase inhibitors (TKIs) for cancer treatment inhibit platelet function, with minor reported bleeding symptoms. The aim of this study was to compare the antiplatelet properties of eight TKIs to explore their possible repurposing as antiplatelet drugs. Samples of whole blood, platelet-rich plasma (PRP), or isolated platelets from healthy donors were treated with TKI or the vehicle. Measurements of platelet aggregation, activation, intracellular calcium mobilization, and whole-blood thrombus formation under flow were performed. Dasatinib and sunitinib dose-dependently reduced collagen-induced aggregation in PRP and washed platelets; pazopanib, cabozantinib, and vatalanib inhibited this response in washed platelets only; and fostamatinib, axitinib, and lapatinib showed no/limited effects. Fostamatinib reduced thrombus formation by approximately 50% on collagen and other substrates. Pazopanib, sunitinib, dasatinib, axitinib, and vatalanib mildly reduced thrombus formation on collagen by 10–50%. Intracellular calcium responses in isolated platelets were inhibited by dasatinib (>90%), fostamatinib (57%), sunitinib (77%), and pazopanib (82%). Upon glycoprotein-VI receptor stimulation, fostamatinib, cabozantinib, and vatalanib decreased highly activated platelet populations by approximately 15%, while increasing resting populations by 39%. In conclusion, the TKIs with the highest affinities for platelet-expressed molecular targets most strongly inhibited platelet functions. Dasatinib, fostamatinib, sunitinib, and pazopanib interfered in early collagen receptor-induced molecular-signaling compared with cabozantinib and vatalanib. Fostamatinib, sunitinib, pazopanib, and vatalanib may be promising for future evaluation as antiplatelet drugs.
Bio-Based Rigid Polyurethane Foam Composites Reinforced with Bleached Curauá Fiber
Authors: Członka Sylwia , Fischer Kerche Eduardo , Motta Neves Roberta , Strąkowska Anna , Strzelec Krzysztof
Published: October 2021

This study aims to evaluate the influence of using a bleached Curauá fiber (CF) as filler in a novel rigid polyurethane foam (RPUF) composite. The influence of 0.1, 0.5 and 1 wt.% of the reinforcements on the processing characteristics, cellular structure, mechanical, dynamic-mechanical, thermal, and flame behaviors were assessed and discussed for RPUF freely expanded. The results showed that the use of 0.5 wt.% of CF resulted in RPUF with smoother cell structure with low differences on the processing times and viscosity for the filled pre-polyol. These morphological features were responsible for the gains in mechanical properties, in both parallel and perpendicular rise directions, and better viscoelastic characteristics. Despite the gains, higher thermal conductivity and lower flammability were reported for the developed RPUF composites, related to the high content of cellulose and hemicellulose on the bleached CF chemical composition. This work shows the possibility of using a Brazilian vegetable fiber, with low exploration for the manufacturing of composite materials with improved properties. The developed RPUF presents high applicability as enhanced cores for the manufacturing of structural sandwich panels, mainly used in civil, aircraft, and marine industries.
Noncoding-RNA-Mediated Regulation in Response to Macronutrient Stress in Plants
Authors: Li Ziwei , Tian Peng , Huang Tengbo , Huang Jianzi
Published: October 2021

Macronutrient elements including nitrogen (N), phosphorus (P), potassium (K), calcium (Ca), magnesium (Mg), and sulfur (S) are required in relatively large and steady amounts for plant growth and development. Deficient or excessive supply of macronutrients from external environments may trigger a series of plant responses at phenotypic and molecular levels during the entire life cycle. Among the intertwined molecular networks underlying plant responses to macronutrient stress, noncoding RNAs (ncRNAs), mainly microRNAs (miRNAs) and long ncRNAs (lncRNAs), may serve as pivotal regulators for the coordination between nutrient supply and plant demand, while the responsive ncRNA-target module and the interactive mechanism vary among elements and species. Towards a comprehensive identification and functional characterization of nutrient-responsive ncRNAs and their downstream molecules, high-throughput sequencing has produced massive omics data for comparative expression profiling as a first step. In this review, we highlight the recent findings of ncRNA-mediated regulation in response to macronutrient stress, with special emphasis on the large-scale sequencing efforts for screening out candidate nutrient-responsive ncRNAs in plants, and discuss potential improvements in theoretical study to provide better guidance for crop breeding practices.
Long Term Immune Response Produced by the SputnikV Vaccine
Authors: Martynova Ekaterina , Hamza Shaimaa , Garanina Ekaterina E. , Kabwe Emmanuel , Markelova Maria , Shakirova Venera , Khaertynova Ilsiyar M. , Kaushal Neha , Baranwal Manoj , Rizvanov Albert A. , Urbanowicz Richard A. , Khaiboullina Svetlana F.
Published: October 2021

SputnikV is a vaccine against SARS-CoV-2 developed by the Gamaleya National Research Centre for Epidemiology and Microbiology. The vaccine has been shown to induce both humoral and cellular immune responses, yet the mechanisms remain largely unknown. Forty SputnikV vaccinated individuals were included in this study which aimed to demonstrate the location of immunogenic domains of the SARS-CoV-2 S protein using an overlapping peptide library. Additionally, cytokines in the serum of vaccinated and convalescent COVID-19 patients were analyzed. We have found antibodies from both vaccinated and convalescent sera bind to immunogenic regions located in multiple domains of SARS-CoV-2 S protein, including Receptor Binding Domain (RBD), N-terminal Domain (NTD), Fusion Protein (FP) and Heptad Repeats (HRs). Interestingly, many peptides were recognized by immunized and convalescent serum antibodies and correspond to conserved regions in circulating variants of SARS-CoV-2. This breadth of reactivity was still evident 90 days after the first dose of the vaccine, showing that the vaccine has induced a prolonged response. As evidenced by the activation of T cells, cellular immunity strongly suggests the high potency of the SputnikV vaccine against SARS-CoV-2 infection.
Modifications in Gene Expression in the Process of Osteoblastic Differentiation of Multipotent Bone Marrow-Derived Human Mesenchymal Stem Cells Induced by a Novel Osteoinductive Porous Medical-Grade 3D-Printed Poly(ε-caprolactone)/β-tricalcium Phosphate Composite
Authors: López-González Ivan , Zamora-Ledezma Camilo , Sanchez-Lorencio María Isabel , Tristante Barrenechea Elena , Gabaldón-Hernández José Antonio , Meseguer-Olmo Luis
Published: October 2021

In this work, we evaluated the influence of a novel hybrid 3D-printed porous composite scaffold based on poly(ε-caprolactone) (PCL) and β-tricalcium phosphate (β-TCP) microparticles in the process of adhesion, proliferation, and osteoblastic differentiation of multipotent adult human bone marrow mesenchymal stem cells (ah-BM-MSCs) cultured under basal and osteogenic conditions. The in vitro biological response of ah-BM-MSCs seeded on the scaffolds was evaluated in terms of cytotoxicity, adhesion, and proliferation (AlamarBlue Assay®) after 1, 3, 7, and 14 days of culture. The osteogenic differentiation was assessed by alkaline phosphatase (ALP) activity, mineralization (Alizarin Red Solution, ARS), expression of surface markers (CD73, CD90, and CD105), and reverse transcription–quantitative polymerase chain reaction (qRT-PCR) after 7 and 14 days of culture. The scaffolds tested were found to be bioactive and biocompatible, as demonstrated by their effects on cytotoxicity (viability) and extracellular matrix production. The mineralization and ALP assays revealed that osteogenic differentiation increased in the presence of PCL/β-TCP scaffolds. The latter was also confirmed by the gene expression levels of the proteins involved in the ossification process. Our results suggest that similar bio-inspired hybrid composite materials would be excellent candidates for osteoinductive and osteogenic medical-grade scaffolds to support cell proliferation and differentiation for tissue engineering, which warrants future in vivo research.
Progranulin A Promotes Compensatory Hepatocyte Proliferation via HGF/c-Met Signaling after Partial Hepatectomy in Zebrafish
Authors: Chiang Keng-Yu , Li Ya-Wen , Li Yen-Hsing , Huang Shin-Jie , Wu Chih-Lu , Gong Hong-Yi , Wu Jen-Leih
Published: October 2021

Compensatory hepatocyte proliferation and other liver regenerative processes are activated to sustain normal physiological function after liver injury. A major mitogen for liver regeneration is hepatocyte growth factor (HGF), and a previous study indicated that progranulin could modulate c-met, the receptor for HGF, to initiate hepatic outgrowth from hepatoblasts during embryonic development. However, a role for progranulin in compensatory hepatocyte proliferation has not been shown previously. Therefore, this study was undertaken to clarify whether progranulin plays a regulatory role during liver regeneration. To this end, we established a partial hepatectomy regeneration model in adult zebrafish that express a liver-specific fluorescent reporter. Using this model, we found that loss of progranulin A (GrnA) function by intraperitoneal-injection of a Vivo-Morpholino impaired and delayed liver regeneration after partial hepatectomy. Furthermore, transcriptome analysis and confirmatory quantitative real-time PCR suggested that cell cycle progression and cell proliferation was not as active in the morphants as controls, which may have been the result of comparative downregulation of the HGF/c-met axis by 36 h after partial hepatectomy. Finally, liver-specific overexpression of GrnA in transgenic zebrafish caused more abundant cell proliferation after partial hepatectomy compared to wild types. Thus, we conclude that GrnA positively regulates HGF/c-met signaling to promote hepatocyte proliferation during liver regeneration.
Dopamine Transporter Imaging, Current Status of a Potential Biomarker: A Comprehensive Review
Authors: Palermo Giovanni , Giannoni Sara , Bellini Gabriele , Siciliano Gabriele , Ceravolo Roberto
Published: October 2021

A major goal of current clinical research in Parkinson’s disease (PD) is the validation and standardization of biomarkers enabling early diagnosis, predicting outcomes, understanding PD pathophysiology, and demonstrating target engagement in clinical trials. Molecular imaging with specific dopamine-related tracers offers a practical indirect imaging biomarker of PD, serving as a powerful tool to assess the status of presynaptic nigrostriatal terminals. In this review we provide an update on the dopamine transporter (DAT) imaging in PD and translate recent findings to potentially valuable clinical practice applications. The role of DAT imaging as diagnostic, preclinical and predictive biomarker is discussed, especially in view of recent evidence questioning the incontrovertible correlation between striatal DAT binding and nigral cell or axon counts.
Antileukemic Natural Product Induced Both Apoptotic and Pyroptotic Programmed Cell Death and Differentiation Effect
Authors: Leu Wohn-Jenn , Chang Hsun-Shuo , Chen Ih-Sheng , Guh Jih-Hwa , Chan She-Hung
Published: October 2021

Acute myeloid leukemia (AML) is one of the most common forms of leukemia. Despite advances in the management of such malignancies and the progress of novel therapies, unmet medical needs still exist in AML because of several factors, including poor response to chemotherapy and high relapse rates. Ardisianone, a plant-derived natural component with an alkyl benzoquinone structure, induced apoptosis in leukemic HL-60 cells. The determination of dozens of apoptosis-related proteins showed that ardisianone upregulated death receptors and downregulated the inhibitor of apoptosis protein (IAPs). Western blotting showed that ardisianone induced a dramatic increase in tumor necrosis factor receptor 2 (TNFR2) protein expression. Ardisianone also induced downstream signaling by activating caspase-8 and -3 and degradation in Bid, a caspase-8 substrate. Furthermore, ardisianone induced degradation in DNA fragmentation factor 45 kDa (DFF45), a subunit of inhibitors of caspase-activated DNase (ICAD). Q-VD-OPh (a broad-spectrum caspase inhibitor) significantly diminished ardisianone-induced apoptosis, confirming the involvement of caspase-dependent apoptosis. Moreover, ardisianone induced pyroptosis. Using transmission electron microscopic examination and Western blot analysis, key markers including gasdermin D, high mobility group box1 (HMGB1), and caspase-1 and -5 were detected. Notably, ardisianone induced the differentiation of the remaining survival cells, which were characterized by an increase in the expression of CD11b and CD68, two markers of macrophages and monocytes. Wright–Giemsa staining also showed the differentiation of cells into monocyte and macrophage morphology. In conclusion, the data suggested that ardisianone induced the apoptosis and pyroptosis of leukemic cells through downregulation of IAPs and activation of caspase pathways that caused gasdermin D cleavage and DNA double-stranded breaks and ultimately led to programmed cell death. Ardisianone also induced the differentiation of leukemic cells into monocyte-like and macrophage-like cells. The data suggested the potential of ardisianone for further antileukemic development.
AK-I-190, a New Catalytic Inhibitor of Topoisomerase II with Anti-Proliferative and Pro-Apoptotic Activity on Androgen-Negative Prostate Cancer Cells
Authors: Jeon Kyung-Hwa , Park Seojeong , Jang Hae Jin , Hwang Soo-Yeon , Shrestha Aarajana , Lee Eung-Seok , Kwon Youngjoo
Published: October 2021

Castration-resistant prostate cancer (CRPC) is a clinical challenge in treatment because of its aggressive nature and resistance to androgen deprivation therapy. Topoisomerase II catalytic inhibitors have been suggested as a strategy to overcome these issues. We previously reported AK-I-190 as a novel topoisomerase II inhibitor. In this study, the mechanism of AK-I-190 was clarified using various types of spectroscopic and biological evaluations. AK-I-190 showed potent topoisomerase II inhibitory activity through intercalating into DNA without stabilizing the DNA-enzyme cleavage complex, resulting in significantly less DNA toxicity than etoposide, a clinically used topoisomerase II poison. AK-I-190 induced G1 arrest and effectively inhibited cell proliferation and colony formation in combination with paclitaxel in an androgen receptor–negative CRPC cell line. Our results confirmed that topoisomerase II catalytic inhibition inhibited proliferation and induced apoptosis of AR-independently growing prostate cancer cells. These findings indicate the clinical relevance of topoisomerase II catalytic inhibitors in androgen receptor-negative prostate cancer.
Myelodysplastic Syndromes and Metabolism
Authors: Balaian Ekaterina , Wobus Manja , Bornhäuser Martin , Chavakis Triantafyllos , Sockel Katja
Published: October 2021

Myelodysplastic syndromes (MDS) are acquired clonal stem cell disorders exhibiting ineffective hematopoiesis, dysplastic cell morphology in the bone marrow, and peripheral cytopenia at early stages; while advanced stages carry a high risk for transformation into acute myeloid leukemia (AML). Genetic alterations are integral to the pathogenesis of MDS. However, it remains unclear how these genetic changes in hematopoietic stem and progenitor cells (HSPCs) occur, and how they confer an expansion advantage to the clones carrying them. Recently, inflammatory processes and changes in cellular metabolism of HSPCs and the surrounding bone marrow microenvironment have been associated with an age-related dysfunction of HSPCs and the emergence of genetic aberrations related to clonal hematopoiesis of indeterminate potential (CHIP). The present review highlights the involvement of metabolic and inflammatory pathways in the regulation of HSPC and niche cell function in MDS in comparison to healthy state and discusses how such pathways may be amenable to therapeutic interventions.
Cyclic FEE Peptide Improves Human Sperm Movement Parameters without Modification of Their Energy Metabolism
Authors: Le Foll Nathalie , Pont Jean-Christophe , L’Hostis Audrey , Guilbert Thomas , Bouillaud Frédéric , Wolf Jean-Philippe , Ziyyat Ahmed
Published: October 2021

Cyclic fertilin peptide (cFEE: phenylalanine, glutamic acid; glutamic acid) improves gamete interaction in humans. We investigate whether it could be via improvement of sperm movement parameters and their mitochondrial ATP production. Sperm movement parameters were studied using computer-assisted sperm analysis (CASA) in sperm samples from 38 patients with normal sperm in medium supplemented with cyclic fertilin against a control group. Sperm mitochondrial functions were studied using donor’s sperm, incubated or not with cFEE. It was evaluated by the measurement of their ATP production using bioluminescence, their respiration by high resolution oxygraphy, and of mitochondrial membrane potential (MMP) using potentiometric dyes and flow cytometry. cFEE significantly improved sperm movement parameters and percentage of hyperactivated sperm. Impact of inhibitors showed OXPHOS as the predominant energy source for sperm movement. However, cFEE had no significant impact on any of the analyzed mitochondrial bioenergetic parameters, suggesting that it could act via a more efficient use of its energy resources.
Liquid Biopsies for Molecular Biology-Based Radiotherapy
Authors: Blomain Erik S. , Moding Everett J.
Published: October 2021

Molecular alterations drive cancer initiation and evolution during development and in response to therapy. Radiotherapy is one of the most commonly employed cancer treatment modalities, but radiobiologic approaches for personalizing therapy based on tumor biology and individual risks remain to be defined. In recent years, analysis of circulating nucleic acids has emerged as a non-invasive approach to leverage tumor molecular abnormalities as biomarkers of prognosis and treatment response. Here, we evaluate the roles of circulating tumor DNA and related analyses as powerful tools for precision radiotherapy. We highlight emerging work advancing liquid biopsies beyond biomarker studies into translational research investigating tumor clonal evolution and acquired resistance.
Advances in Nanotechnology towards Development of Silver Nanoparticle-Based Wound-Healing Agents
Authors: Nqakala Zimkhitha B. , Sibuyi Nicole R. S. , Fadaka Adewale O. , Meyer Mervin , Onani Martin O. , Madiehe Abram M.
Published: October 2021

Since antiquity, silver-based therapies have been used in wound healing, wound care and management of infections to provide adequate healing. These therapies are associated with certain limitations, such as toxicity, skin discolouration and bacterial resistance, which have limited their use. As a result, new and innovative wound therapies, or strategies to improve the existing therapies, are sought after. Silver nanoparticles (AgNPs) have shown the potential to circumvent the limitations associated with conventional silver-based therapies as described above. AgNPs are effective against a broad spectrum of microorganisms and are less toxic, effective at lower concentrations and produce no skin discolouration. Furthermore, AgNPs can be decorated or coupled with other healing-promoting materials to provide optimum healing. This review details the history and impact of silver-based therapies leading up to AgNPs and AgNP-based nanoformulations in wound healing. It also highlights the properties of AgNPs that aid in wound healing and that make them superior to conventional silver-based wound treatment therapies.
High Mobility Group Box 1 Protein in Cerebral Thromboemboli
Authors: Essig Fabian , Babilon Lilith , Vollmuth Christoph , Kollikowski Alexander M. , Pham Mirko , Solymosi László , Haeusler Karl Georg , Kraft Peter , Stoll Guido , Schuhmann Michael K.
Published: October 2021

High-mobility group box 1 protein (HMGB1) is a damage-associated molecular pattern (DAMP) involved in neutrophil extracellular trap (NET) formation and thrombosis. NETs are regularly found in cerebral thromboemboli. We here analyzed associated HMGB1 expression in human thromboemboli retrieved via mechanical thrombectomy from 37 stroke patients with large vessel occlusion. HMGB1 was detected in all thromboemboli, accounting for 1.7% (IQR 0.6–6.2%) of the total thromboemboli area and was found to be colocalized with neutrophils and NETs and in spatial proximity to platelets. Correlation analysis revealed that the detection of HMGB1 was strongly related to the number of neutrophils (r = 0.58, p = 0.0002) and platelets (r = 0.51, p = 0.001). Our results demonstrate that HMGB1 is a substantial constituent of thromboemboli causing large vessel occlusion stroke.
Differential Membrane Lipid Profiles and Vibrational Spectra of Three Edaphic Algae and One Cyanobacterium
Authors: Montero Olimpio , Velasco Marta , Miñón Jorge , Marks Evan A. N. , Sanz-Arranz Aurelio , Rad Carlos
Published: October 2021

The membrane glycerolipids of four phototrophs that were isolated from an edaphic assemblage were determined by UPLC–MS after cultivation in a laboratory growth chamber. Identification was carried out by 18S and 16S rDNA sequencing. The algal species were Klebsormidium flaccidum (Charophyta), Oocystis sp. (Chlorophyta), and Haslea spicula (Bacillariophyta), and the cyanobacterium was Microcoleus vaginatus (Cyanobacteria). The glycerolipid profile of Oocystis sp. was dominated by monogalactosyldiacylglycerol (MGDG) species, with MGDG(18:3/16:4) accounting for 68.6%, whereas MGDG(18:3/16:3) was the most abundant glycerolipid in K. flaccidum (50.1%). A ratio of digalactosyldiacylglycerol (DGDG) species to MGDG species (DGDG/MGDG) was shown to be higher in K. flaccidum (0.26) than in Oocystis sp. (0.14). This ratio increased under high light (HL) as compared to low light (LL) in all the organisms, with its highest value being shown in cyanobacterium (0.38–0.58, LL−HL). High contents of eicosapentaenoic acid (EPA, C20:5) and hexadecenoic acid were observed in the glycerolipids of H. spicula. Similar Fourier transform infrared (FTIR) and Raman spectra were found for K. flaccidum and Oocystis sp. Specific bands at 1629.06 and 1582.78 cm−1 were shown by M. vaginatus in the Raman spectra. Conversely, specific bands in the FTIR spectrum were observed for H. spicula at 1143 and 1744 cm−1. The results of this study point out differences in the membrane lipid composition between species, which likely reflects their different morphology and evolutionary patterns.
What Do We Know about Classical and Non-Classical Progesterone Receptors in the Human Female Reproductive Tract? A Review
Authors: Medina-Laver Yassmin , Rodríguez-Varela Cristina , Salsano Stefania , Labarta Elena , Domínguez Francisco
Published: October 2021

The progesterone hormone regulates the human menstrual cycle, pregnancy, and parturition by its action via the different progesterone receptors and signaling pathways in the female reproductive tract. Progesterone actions can be exerted through classical and non-classical receptors, or even a combination of both. The former are nuclear receptors whose activation leads to transcriptional activity regulation and thus in turn leads to slower but long-lasting responses. The latter are composed of progesterone receptors membrane components (PGRMC) and membrane progestin receptors (mPRs). These receptors rapidly activate the appropriate intracellular signal transduction pathways, and they can subsequently initiate specific cell responses or even modulate genomic cell responses. This review covers our current knowledge on the mechanisms of action and the relevance of classical and non-classical progesterone receptors in female reproductive tissues ranging from the ovary and uterus to the cervix, and it exposes their crucial role in female infertility.
Investigating Pathogenetic Mechanisms of Alzheimer’s Disease by Systems Biology Approaches for Drug Discovery
Authors: Yeh Shan-Ju , Chung Ming-Hsun , Chen Bor-Sen
Published: October 2021

Alzheimer’s disease (AD) is the most common cause of dementia, characterized by progressive cognitive decline and neurodegenerative disorder. Abnormal aggregations of intracellular neurofibrillary tangles (NFTs) and unusual accumulations of extracellular amyloid-β (Aβ) peptides are two important pathological features in AD brains. However, in spite of large-scale clinical studies and computational simulations, the molecular mechanisms of AD development and progression are still unclear. In this study, we divided all of the samples into two groups: early stage (Braak score I–III) and later stage (Braak score IV–VI). By big database mining, the candidate genetic and epigenetic networks (GEN) have been constructed. In order to find out the real GENs for two stages of AD, we performed systems identification and system order detection scheme to prune false positives with the help of corresponding microarray data. Applying the principal network projection (PNP) method, core GENs were extracted from real GENs based on the projection values. By the annotation of KEGG pathway, we could obtain core pathways from core GENs and investigate pathogenetic mechanisms for the early and later stage of AD, respectively. Consequently, according to pathogenetic mechanisms, several potential biomarkers are identified as drug targets for multiple-molecule drug design in the treatment of AD.
8-Hydroxyquinoline-Amino Acid Hybrids and Their Half-Sandwich Rh and Ru Complexes: Synthesis, Anticancer Activities, Solution Chemistry and Interaction with Biomolecules
Authors: Pivarcsik Tamás , Dömötör Orsolya , Mészáros János P. , May Nóra V. , Spengler Gabriella , Csuvik Oszkár , Szatmári István , Enyedy Éva A.
Published: October 2021

Solution chemical properties of two novel 8-hydroxyquinoline-D-proline and homo-proline hybrids were investigated along with their complex formation with [Rh(η5-C5Me5)(H2O)3]2+ and [Ru(η6-p-cymene)(H2O)3]2+ ions by pH-potentiometry, UV-visible spectrophotometry and 1H NMR spectroscopy. Due to the zwitterionic structure of the ligands, they possess excellent water solubility as well as their complexes. The complexes exhibit high solution stability in a wide pH range; no significant dissociation occurs at physiological pH. The hybrids and their Rh(η5-C5Me5) complexes displayed enhanced cytotoxicity in human colon adenocarcinoma cell lines and exhibited multidrug resistance selectivity. In addition, the Rh(η5-C5Me5) complexes showed increased selectivity to the chemosensitive cancer cells over the normal cells; meanwhile, the Ru(η6-p-cymene) complexes were inactive, most likely due to arene loss. Interaction of the complexes with human serum albumin (HSA) and calf-thymus DNA (ct-DNA) was investigated by capillary electrophoresis, fluorometry and circular dichroism. The complexes are able to bind strongly to HSA and ct-DNA, but DNA cleavage was not observed. Changing the five-membered proline ring to the six-membered homoproline resulted in increased lipophilicity and cytotoxicity of the Rh(η5-C5Me5) complexes while changing the configuration (L vs. D) rather has an impact on HSA or ct-DNA binding.
Probiotic Supplements: Their Strategies in the Therapeutic and Prophylactic of Human Life-Threatening Diseases
Authors: Youssef Mahmoud , Ahmed Hanaa Y. , Zongo Abel , Korin Ali , Zhan Fuchao , Hady Essam , Umair Muhammad , Shahid Riaz Rajoka Muhammad , Xiong Yongai , Li Bin
Published: October 2021

Chronic diseases and viral infections have threatened human life over the ages and constitute the main reason for increasing death globally. The rising burden of these diseases extends to negatively affecting the economy and trading globally, as well as daily life, which requires inexpensive, novel, and safe therapeutics. Therefore, scientists have paid close attention to probiotics as safe remedies to combat these morbidities owing to their health benefits and biotherapeutic effects. Probiotics have been broadly adopted as functional foods, nutraceuticals, and food supplements to improve human health and prevent some morbidity. Intriguingly, recent research indicates that probiotics are a promising solution for treating and prophylactic against certain dangerous diseases. Probiotics could also be associated with their essential role in animating the immune system to fight COVID-19 infection. This comprehensive review concentrates on the newest literature on probiotics and their metabolism in treating life-threatening diseases, including immune disorders, pathogens, inflammatory and allergic diseases, cancer, cardiovascular disease, gastrointestinal dysfunctions, and COVID-19 infection. The recent information in this report will particularly furnish a platform for emerging novel probiotics-based therapeutics as cheap and safe, encouraging researchers and stakeholders to develop innovative treatments based on probiotics to prevent and treat chronic and viral diseases.
Genome-Wide Identification and Expression Analysis of R2R3-MYB Family Genes Associated with Petal Pigment Synthesis in Liriodendron
Authors: Yang Lichun , Liu Huanhuan , Hao Ziyuan , Zong Yaxian , Xia Hui , Shen Yufang , Li Huogen
Published: October 2021

The MYB transcription factor family is one of the largest families in plants, and its members have various biological functions. R2R3-MYB genes are involved in the synthesis of pigments that yield petal colors. Liriodendron plants are widely cultivated as ornamental trees owing to their peculiar leaves, tulip-like flowers, and colorful petals. However, the mechanism underlying petal coloring in this species is unknown, and minimal information about MYB genes in Liriodendron is available. Herein, this study aimed to discern gene(s) involved in petal coloration in Liriodendron via genome-wide identification, HPLC, and RT-qPCR assays. In total, 204 LcMYB superfamily genes were identified in the Liriodendron chinense genome, and 85 R2R3-MYB genes were mapped onto 19 chromosomes. Chromosome 4 contained the most (10) R2R3-MYB genes, and chromosomes 14 and 16 contained the fewest (only one). MEME analysis showed that R2R3-MYB proteins in L. chinense were highly conserved and that their exon-intron structures varied. The HPLC results showed that three major carotenoids were uniformly distributed in the petals of L. chinense, while lycopene and β-carotene were concentrated in the orange band region in the petals of Liriodendron tulipifera. Furthermore, the expression profiles via RT-qPCR assays revealed that four R2R3-MYB genes were expressed at the highest levels at the S3P/S4P stage in L. tulipifera. This result combined with the HPLC results showed that these four R2R3-MYB genes might participate in carotenoid synthesis in the petals of L. tulipifera. This work laid a cornerstone for further functional characterization of R2R3-MYB genes in Liriodendron plants.
Full Length Transcriptome Highlights the Coordination of Plastid Transcript Processing
Authors: Guilcher Marine , Liehrmann Arnaud , Seyman Chloé , Blein Thomas , Rigaill Guillem , Castandet Benoit , Delannoy Etienne
Published: October 2021

Plastid gene expression involves many post-transcriptional maturation steps resulting in a complex transcriptome composed of multiple isoforms. Although short-read RNA-Seq has considerably improved our understanding of the molecular mechanisms controlling these processes, it is unable to sequence full-length transcripts. This information is crucial, however, when it comes to understanding the interplay between the various steps of plastid gene expression. Here, we describe a protocol to study the plastid transcriptome using nanopore sequencing. In the leaf of Arabidopsis thaliana, with about 1.5 million strand-specific reads mapped to the chloroplast genome, we could recapitulate most of the complexity of the plastid transcriptome (polygenic transcripts, multiple isoforms associated with post-transcriptional processing) using virtual Northern blots. Even if the transcripts longer than about 2500 nucleotides were missing, the study of the co-occurrence of editing and splicing events identified 42 pairs of events that were not occurring independently. This study also highlighted a preferential chronology of maturation events with splicing happening after most sites were edited.
Evaluation of the Antimicrobial Efficacy of N-Acetyl-l-Cysteine, Rhamnolipids, and Usnic Acid—Novel Approaches to Fight Food-Borne Pathogens
Authors: Chlumsky Ondrej , Smith Heidi J. , Parker Albert E. , Brileya Kristen , Wilking James N. , Purkrtova Sabina , Michova Hana , Ulbrich Pavel , Viktorova Jitka , Demnerova Katerina
Published: October 2021

In the food industry, the increasing antimicrobial resistance of food-borne pathogens to conventional sanitizers poses the risk of food contamination and a decrease in product quality and safety. Therefore, we explored alternative antimicrobials N-Acetyl-l-cysteine (NAC), rhamnolipids (RLs), and usnic acid (UA) as a novel approach to prevent biofilm formation and reduce existing biofilms formed by important food-borne pathogens (three strains of Salmonella enterica and two strains of Escherichia coli, Listeria monocytogenes, Staphylococcus aureus). Their effectiveness was evaluated by determining minimum inhibitory concentrations needed for inhibition of bacterial growth, biofilm formation, metabolic activity, and biofilm reduction. Transmission electron microscopy and confocal scanning laser microscopy followed by image analysis were used to visualize and quantify the impact of tested substances on both planktonic and biofilm-associated cells. The in vitro cytotoxicity of the substances was determined as a half-maximal inhibitory concentration in five different cell lines. The results indicate relatively low cytotoxic effects of NAC in comparison to RLs and UA. In addition, NAC inhibited bacterial growth for all strains, while RLs showed overall lower inhibition and UA inhibited only the growth of Gram-positive bacteria. Even though tested substances did not remove the biofilms, NAC represents a promising tool in biofilm prevention.
Machine Learning Algorithms Provide Greater Prediction of Response to SCS Than Lead Screening Trial: A Predictive AI-Based Multicenter Study
Authors: Ounajim Amine , Billot Maxime , Goudman Lisa , Louis Pierre-Yves , Slaoui Yousri , Roulaud Manuel , Bouche Bénédicte , Page Philippe , Lorgeoux Bertille , Baron Sandrine , Adjali Nihel , Nivole Kevin , Naiditch Nicolas , Wood Chantal , Rigoard Raphaël , David Romain , Moens Maarten , Rigoard Philippe
Published: October 2021

Persistent pain after spinal surgery can be successfully addressed by spinal cord stimulation (SCS). International guidelines strongly recommend that a lead trial be performed before any permanent implantation. Recent clinical data highlight some major limitations of this approach. First, it appears that patient outco mes, with or without lead trial, are similar. In contrast, during trialing, infection rate drops drastically within time and can compromise the therapy. Using composite pain assessment experience and previous research, we hypothesized that machine learning models could be robust screening tools and reliable predictors of long-term SCS efficacy. We developed several algorithms including logistic regression, regularized logistic regression (RLR), naive Bayes classifier, artificial neural networks, random forest and gradient-boosted trees to test this hypothesis and to perform internal and external validations, the objective being to confront model predictions with lead trial results using a 1-year composite outcome from 103 patients. While almost all models have demonstrated superiority on lead trialing, the RLR model appears to represent the best compromise between complexity and interpretability in the prediction of SCS efficacy. These results underscore the need to use AI-based predictive medicine, as a synergistic mathematical approach, aimed at helping implanters to optimize their clinical choices on daily practice.
Real-World Incidence of Immune-Related Adverse Events Associated with Nivolumab Plus Ipilimumab in Patients with Advanced Renal Cell Carcinoma: A Retrospective Observational Study
Authors: Washino Satoshi , Takeshita Hideki , Inoue Masaharu , Kagawa Makoto , Soma Takahiko , Yamada Hodaka , Kageyama Yukio , Miyagawa Tomoaki , Kawakami Satoru
Published: October 2021

Real-world incidence of immune-related adverse events (irAEs) associated with nivolumab plus ipilimumab in patients with renal cell carcinoma (RCC) has been rarely demonstrated. The present study aims to report the safety outcomes of this combination therapy in the real-life population. We conducted a multi-institutional retrospective observational study that assessed the incidence and severity of irAEs associated with nivolumab plus ipilimumab in 41 Japanese patients with metastatic and/or locally advanced RCC. The irAEs were classified into endocrine and non-endocrine irAEs. The median age and follow-up period were 68 years and 13.0 months, respectively. Endocrine irAEs were observed in 66% of patients, including hypopituitarism in 44%, hyperthyroidism in 41%, and primary hypothyroidism in 22%, while non-endocrine irAEs were observed in 54%. All patients experiencing hypopituitarism presented with adrenocorticotropic hormone deficiency, causing secondary adrenal insufficiency, which required permanent corticosteroid replacement therapy. There was an association between the incidence of endocrine irAEs and high-grade non-endocrine irAEs other than skin-related irAEs (p = 0.027). When patients experienced two or more endocrine irAEs, they had a 35% chance of experiencing high-grade non-endocrine irAEs other than skin-related irAEs. Nivolumab plus ipilimumab may lead to a high prevalence of endocrine irAEs in “real-world” patients. Endocrine irAEs may be associated with non-endocrine irAEs other than skin-related irAEs.