bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploring the Relationship between Attitudes, Risk Perceptions, Fatalistic Beliefs, and Pedestrian Behaviors in China
Authors: Liu Mingyu , Wu Jianping , Yousaf Adnan , Wang Linyang , Hu Kezhen , Plant Katherine L. , McIlroy Rich C. , Stanton Neville A.
Published: March 2021

Road safety has become a worldwide public health concern. Although many factors contribute to collisions, pedestrian behaviors can strongly influence road safety outcomes. This paper presents results of a survey investigating the effects of age, gender, attitudes towards road safety, fatalistic beliefs and risk perceptions on self-reported pedestrian behaviors in a Chinese example. The study was carried out on 543 participants (229 men and 314 women) from 20 provinces across China. Pedestrian behaviors were assessed by four factors: errors, violations, aggressions, and lapses. Younger people reported performing riskier pedestrian behaviors compared to older people. Gender was not an influential factor. Of the factors explored, attitudes towards road safety explained the most amount of variance in self-reported behaviors. Significant additional variance in risky pedestrian behaviors was explained by the addition of fatalistic beliefs. The differences among the effects, and the implications for road safety intervention design, are discussed. In particular, traffic managers can provide road safety education and related training activities to influence pedestrian behaviors positively.
Evaluation of the Soft Tissue Changes after Rapid Maxillary Expansion Using a Handheld Three-Dimensional Scanner: A Prospective Study
Authors: Alkhayer Ali , Becsei Roland , Hegedűs László , Párkányi László , Piffkó József , Braunitzer Gábor , Segatto Emil
Published: March 2021

Facial soft tissue esthetics is a priority in orthodontic treatment, and emerging of the digital technologies can offer new methods to help the orthodontist toward an esthetic outcome. This prospective study aimed to assess the soft tissue changes of the face after six months of retention following Rapid Maxillary Expansion (RME). The sample consisted of 25 patients (13 females, 12 males, mean age: 11.6 years) who presented with unilateral or bilateral posterior crossbite requiring RME, which was performed with a Hyrax expander. 3D facial images were obtained before treatment (T0) and at the end of a six-month retention period after the treatment (T1) using a structured-light 3D handheld scanner. Linear and angular measurements were performed and 3D deviation analyses were done for six morphological regions of the face. Significant changes in various areas of the nasal and the upper lip regions were observed. Based on the results of the study and within the limitations of the study, RME with a Hyrax expander results in significant morphological changes of the face after a six-month retention period.
Health Workforce Development in Health Emergency and Disaster Risk Management: The Need for Evidence-Based Recommendations
Authors: Hung Kevin K. C. , Mashino Sonoe , Chan Emily Y. Y. , MacDermot Makiko K. , Balsari Satchit , Ciottone Gregory R. , Della Corte Francesco , Dell’Aringa Marcelo F. , Egawa Shinichi , Evio Bettina D. , Hart Alexander , Hu Hai , Ishii Tadashi , Ragazzoni Luca , Sasaki Hiroyuki , Walline Joseph H. , Wong Chi S. , Bhattarai Hari K. , Dalal Saurabh , Kayano Ryoma , Abrahams Jonathan , Graham Colin A.
Published: March 2021

The Sendai Framework for Disaster Risk Reduction 2015–2030 placed human health at the centre of disaster risk reduction, calling for the global community to enhance local and national health emergency and disaster risk management (Health EDRM). The Health EDRM Framework, published in 2019, describes the functions required for comprehensive disaster risk management across prevention, preparedness, readiness, response, and recovery to improve the resilience and health security of communities, countries, and health systems. Evidence-based Health EDRM workforce development is vital. However, there are still significant gaps in the evidence identifying common competencies for training and education programmes, and the clarification of strategies for workforce retention, motivation, deployment, and coordination. Initiated in June 2020, this project includes literature reviews, case studies, and an expert consensus (modified Delphi) study. Literature reviews in English, Japanese, and Chinese aim to identify research gaps and explore core competencies for Health EDRM workforce training. Thirteen Health EDRM related case studies from six WHO regions will illustrate best practices (and pitfalls) and inform the consensus study. Consensus will be sought from global experts in emergency and disaster medicine, nursing, public health and related disciplines. Recommendations for developing effective health workforce strategies for low- and middle-income countries and high-income countries will then be disseminated.
A Precision Evaluation Index System for Remote Sensing Data Sampling Based on Hexagonal Discrete Grids
Authors: Ma Yue , Li Guoqing , Yao Xiaochuang , Cao Qianqian , Zhao Long , Wang Shuang , Zhang Lianchong
Published: March 2021

With the rapid development of earth observation, satellite navigation, mobile communication, and other technologies, the order of magnitude of the spatial data we acquire and accumulate is increasing, and higher requirements are put forward for the application and storage of spatial data. As a new form of data management, the global discrete grid can be used for the efficient storage and application of large-scale global spatial data, which is a digital multiresolution georeference model that helps to establish a new model of data association and fusion. It is expected to make up for the shortcomings in the organization, processing, and application of current spatial data. There are different types of grid systems according to the grid division form, including global discrete grids with equal latitude and longitude, global discrete grids with variable latitude and longitude, and global discrete grids based on regular polyhedrons. However, there is no accuracy evaluation index system for remote sensing images expressed on the global discrete grid to solve this problem. This paper is dedicated to finding a suitable way to express remote sensing data on discrete grids, as well as establishing a suitable accuracy evaluation system for modeling remote sensing data based on hexagonal grids to evaluate modeling accuracy. The results show that this accuracy evaluation method can evaluate and analyze remote sensing data based on hexagonal grids from multiple levels, and the comprehensive similarity coefficient of the images before and after conversion is greater than 98%, which further proves the availability of the hexagonal-grid-based remote sensing data of remote sensing images. This evaluation method is generally applicable to all raster remote sensing images based on hexagonal grids, and it can be used to evaluate the availability of hexagonal grid images.
Determination of Environmental Factors for the Implementation of the Exploitability Index in Industrial Aggregate Mining Using Multi-Criteria Analysis
Authors: de Luis-Ruiz Julio Manuel , Salas-Menocal Benito Ramiro , Fernández-Maroto Gema , Pérez-Álvarez Rubén , Pereda-García Raúl
Published: March 2021

The quality of human life is linked to the exploitation of mining resources. The Exploitability Index (EI) assesses the actual possibilities to enable a mine according to several factors. The environment is one of the most constraining ones, but its analysis is made in a shallow way. This research is focused on its determination, according to a new preliminary methodology that sets the main components of the environmental impact related to the development of an exploitation of industrial minerals and its weighting according to the Analytic Hierarchy Process (AHP). It is applied to the case of the ophitic outcrops in Cantabria (Spain). Twelve components are proposed and weighted with the AHP and an algorithm that allows for assigning a normalized value for the environmental factor to each deposit. Geographic Information Systems (GISs) are applied, allowing us to map a large number of components of the environmental factors. This provides a much more accurate estimation of the environmental factor, with respect to reality, and improves the traditional methodology in a substantial way. It can be established as a methodology for mining spaces planning, but it is suitable for other contexts, and it raises developing the environmental analysis before selecting the outcrop to be exploited.
Osmolality Effects on CHO Cell Growth, Cell Volume, Antibody Productivity and Glycosylation
Authors: Alhuthali Sakhr , Kotidis Pavlos , Kontoravdi Cleo
Published: March 2021

The addition of nutrients and accumulation of metabolites in a fed-batch culture of Chinese hamster ovary (CHO) cells leads to an increase in extracellular osmolality in late stage culture. Herein, we explore the effect of osmolality on CHO cell growth, specific monoclonal antibody (mAb) productivity and glycosylation achieved with the addition of NaCl or the supplementation of a commercial feed. Although both methods lead to an increase in specific antibody productivity, they have different effects on cell growth and antibody production. Osmolality modulation using NaCl up to 470 mOsm kg−1 had a consistently positive effect on specific antibody productivity and titre. The addition of the commercial feed achieved variable results: specific mAb productivity was increased, yet cell growth rate was significantly compromised at high osmolality values. As a result, Feed C addition to 410 mOsm kg−1 was the only condition that achieved a significantly higher mAb titre compared to the control. Additionally, Feed C supplementation resulted in a significant reduction in galactosylated antibody structures. Cell volume was found to be positively correlated to osmolality; however, osmolality alone could not account for observed changes in average cell diameter without considering cell cycle variations. These results help delineate the overall effect of osmolality on titre and highlight the potentially negative effect of overfeeding on cell growth.
Effect of MgCl2 and GdCl3 on ORAI1 Expression and Store-Operated Ca2+ Entry in Megakaryocytes
Authors: Zhou Kuo , Zhu Xuexue , Ma Ke , Liu Jibin , Nürnberg Bernd , Gawaz Meinrad , Lang Florian
Published: March 2021

In chronic kidney disease, hyperphosphatemia upregulates the Ca2+ channel ORAI and its activating Ca2+ sensor STIM in megakaryocytes and platelets. ORAI1 and STIM1 accomplish store-operated Ca2+ entry (SOCE) and play a key role in platelet activation. Signaling linking phosphate to upregulation of ORAI1 and STIM1 includes transcription factor NFAT5 and serum and glucocorticoid-inducible kinase SGK1. In vascular smooth muscle cells, the effect of hyperphosphatemia on ORAI1/STIM1 expression and SOCE is suppressed by Mg2+ and the calcium-sensing receptor (CaSR) agonist Gd3+. The present study explored whether sustained exposure to Mg2+ or Gd3+ interferes with the phosphate-induced upregulation of NFAT5, SGK1, ORAI1,2,3, STIM1,2 and SOCE in megakaryocytes. To this end, human megakaryocytic Meg-01 cells were treated with 2 mM ß-glycerophosphate for 24 h in the absence and presence of either 1.5 mM MgCl2 or 50 µM GdCl3. Transcript levels were estimated utilizing q-RT-PCR, protein abundance by Western blotting, cytosolic Ca2+ concentration ([Ca2+]i) by Fura-2 fluorescence and SOCE from the increase in [Ca2+]i following re-addition of extracellular Ca2+ after store depletion with thapsigargin (1 µM). As a result, Mg2+ and Gd3+ upregulated CaSR and blunted or virtually abolished the phosphate-induced upregulation of NFAT5, SGK1, ORAI1,2,3, STIM1,2 and SOCE in megakaryocytes. In conclusion, Mg2+ and the CaSR agonist Gd3+ interfere with phosphate-induced dysregulation of [Ca2+]i in megakaryocytes.
The Long Linker Region of Telomere-Binding Protein TRF2 Is Responsible for Interactions with Lamins
Authors: Travina Aleksandra O. , Ilicheva Nadya V. , Mittenberg Alexey G. , Shabelnikov Sergey V. , Kotova Anastasia V. , Podgornaya Olga I.
Published: March 2021

Telomere-binding factor 2 (TRF2) is part of the shelterin protein complex found at chromosome ends. Lamin A/C interacts with TRF2 and influences telomere position. TRF2 has an intrinsically disordered region between the ordered dimerization and DNA-binding domains. This domain is referred to as the long linker region of TRF2, or udTRF2. We suggest that udTRF2 might be involved in the interaction between TRF2 and lamins. The recombinant protein corresponding to the udTRF2 region along with polyclonal antibodies against this region were used in co-immunoprecipitation with purified lamina and nuclear extracts. Co-immunoprecipitation followed by Western blots and mass spectrometry indicated that udTRF2 interacts with lamins, preferably lamins A/C. The interaction did not involve any lamin-associated proteins, was not dependent on the post-translation modification of lamins, nor did it require their higher-order assembly. Besides lamins, a number of other udTRF2-interacting proteins were identified by mass spectrometry, including several heterogeneous nuclear ribonucleoproteins (hnRNP A2/B1, hnRNPA1, hnRNP A3, hnRNP K, hnRNP L, hnRNP M), splicing factors (SFPQ, NONO, SRSF1, and others), helicases (DDX5, DHX9, and Eif4a3l1), topoisomerase I, and heat shock protein 71, amongst others. Some of the identified interactors are known to be involved in telomere biology; the roles of the others remain to be investigated. Thus, the long linker region of TRF2 (udTRF2) is a regulatory domain responsible for the association between TRF2 and lamins and is involved in interactions with other proteins.
Selective Activation of CNS and Reference PPARGC1A Promoters Is Associated with Distinct Gene Programs Relevant for Neurodegenerative Diseases
Authors: Kwik Markus , Hainzl Stefan , Oppelt Jan , Tichy Boris , Koller Ulrich , Bernardinelli Emanuele , Steiner Markus , Zara Greta , Nofziger Charity , Weis Serge , Paulmichl Markus , Dossena Silvia , Patsch Wolfgang , Soyal Selma M.
Published: March 2021

The transcriptional regulator peroxisome proliferator activated receptor gamma coactivator 1A (PGC-1α), encoded by PPARGC1A, has been linked to neurodegenerative diseases. Recently discovered CNS-specific PPARGC1A transcripts are initiated far upstream of the reference promoter, spliced to exon 2 of the reference gene, and are more abundant than reference gene transcripts in post-mortem human brain samples. The proteins translated from the CNS and reference transcripts differ only at their N-terminal regions. To dissect functional differences between CNS-specific isoforms and reference proteins, we used clustered regularly interspaced short palindromic repeats transcriptional activation (CRISPRa) for selective endogenous activation of the CNS or the reference promoters in SH-SY5Y cells. Expression and/or exon usage of the targets was ascertained by RNA sequencing. Compared to controls, more differentially expressed genes were observed after activation of the CNS than the reference gene promoter, while the magnitude of alternative exon usage was comparable between activation of the two promoters. Promoter-selective associations were observed with canonical signaling pathways, mitochondrial and nervous system functions and neurological diseases. The distinct N-terminal as well as the shared downstream regions of PGC-1α isoforms affect the exon usage of numerous genes. Furthermore, associations of risk genes of amyotrophic lateral sclerosis and Parkinson’s disease were noted with differentially expressed genes resulting from the activation of the CNS and reference gene promoter, respectively. Thus, CNS-specific isoforms markedly amplify the biological functions of PPARGC1A and CNS-specific isoforms and reference proteins have common, complementary and selective functions relevant for neurodegenerative diseases.
Possibility for Transcriptional Targeting of Cancer-Associated Fibroblasts—Limitations and Opportunities
Authors: Antonova Dina V. , Zinovyeva Marina V. , Kondratyeva Liya G. , Sass Alexander V. , Alekseenko Irina V. , Pleshkan Victor V.
Published: March 2021

Cancer-associated fibroblasts (CAF) are attractive therapeutic targets in the tumor microenvironment. The possibility of using CAFs as a source of therapeutic molecules is a challenging approach in gene therapy. This requires transcriptional targeting of transgene expression by cis-regulatory elements (CRE). Little is known about which CREs can provide selective transgene expression in CAFs. We hypothesized that the promoters of FAP, CXCL12, IGFBP2, CTGF, JAG1, SNAI1, and SPARC genes, the expression of whose is increased in CAFs, could be used for transcriptional targeting. Analysis of the transcription of the corresponding genes revealed that unique transcription in model CAFs was characteristic for the CXCL12 and FAP genes. However, none of the promoters in luciferase reporter constructs show selective activity in these fibroblasts. The CTGF, IGFBP2, JAG1, and SPARC promoters can provide higher transgene expression in fibroblasts than in cancer cells, but the nonspecific viral promoters CMV, SV40, and the recently studied universal PCNA promoter have the same features. The patterns of changes in activity of various promoters relative to each other observed for human cell lines were similar to the patterns of activity for the same promoters both in vivo and in vitro in mouse models. Our results reveal restrictions and features for CAF transcriptional targeting.
Biological and Physico-Chemical Characteristics of Arginine-Rich Peptide Gemini Surfactants with Lysine and Cystine Spacers
Authors: Neubauer Damian , Jaśkiewicz Maciej , Bauer Marta , Olejniczak-Kęder Agata , Sikorska Emilia , Sikora Karol , Kamysz Wojciech
Published: March 2021

Ultrashort cationic lipopeptides (USCLs) and gemini cationic surfactants are classes of potent antimicrobials. Our recent study has shown that the branching and shortening of the fatty acids chains with the simultaneous addition of a hydrophobic N-terminal amino acid in USCLs result in compounds with enhanced selectivity. Here, this approach was introduced into arginine-rich gemini cationic surfactants. l-cystine diamide and l-lysine amide linkers were used as spacers. Antimicrobial activity against planktonic and biofilm cultures of ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) strains and Candida sp. as well as hemolytic and cytotoxic activities were examined. Moreover, antimicrobial activity in the presence of human serum and the ability to form micelles were evaluated. Membrane permeabilization study, serum stability assay, and molecular dynamics were performed. Generally, critical aggregation concentration was linearly correlated with hydrophobicity. Gemini surfactants were more active than the parent USCLs, and they turned out to be selective antimicrobial agents with relatively low hemolytic and cytotoxic activities. Geminis with the l-cystine diamide spacer seem to be less cytotoxic than their l-lysine amide counterparts, but they exhibited lower antibiofilm and antimicrobial activities in serum. In some cases, geminis with branched fatty acid chains and N-terminal hydrophobic amino acid resides exhibited enhanced selectivity to pathogens over human cells.
Co-Transcriptional RNA Processing in Plants: Exploring from the Perspective of Polyadenylation
Authors: Yang Jing , Cao Ying , Ma Ligeng
Published: March 2021

Most protein-coding genes in eukaryotes possess at least two poly(A) sites, and alternative polyadenylation is considered a contributing factor to transcriptomic and proteomic diversity. Following transcription, a nascent RNA usually undergoes capping, splicing, cleavage, and polyadenylation, resulting in a mature messenger RNA (mRNA); however, increasing evidence suggests that transcription and RNA processing are coupled. Plants, which must produce rapid responses to environmental changes because of their limited mobility, exhibit such coupling. In this review, we summarize recent advances in our understanding of the coupling of transcription with RNA processing in plants, and we describe the possible spatial environment and important proteins involved. Moreover, we describe how liquid–liquid phase separation, mediated by the C-terminal domain of RNA polymerase II and RNA processing factors with intrinsically disordered regions, enables efficient co-transcriptional mRNA processing in plants.
Adenovirus Terminal Protein Contains a Bipartite Nuclear Localisation Signal Essential for Its Import into the Nucleus
Authors: Al-Wassiti Hareth A. , Thomas David R. , Wagstaff Kylie M. , Fabb Stewart A. , Jans David A. , Johnston Angus P. , Pouton Colin W.
Published: March 2021

Adenoviruses contain dsDNA covalently linked to a terminal protein (TP) at the 5′end. TP plays a pivotal role in replication and long-lasting infectivity. TP has been reported to contain a nuclear localisation signal (NLS) that facilitates its import into the nucleus. We studied the potential NLS motifs within TP using molecular and cellular biology techniques to identify the motifs needed for optimum nuclear import. We used confocal imaging microscopy to monitor the localisation and nuclear association of GFP fusion proteins. We identified two nuclear localisation signals, PV(R)6VP and MRRRR, that are essential for fully efficient TP nuclear entry in transfected cells. To study TP–host interactions further, we expressed TP in Escherichia coli (E. coli). Nuclear uptake of purified protein was determined in digitonin-permeabilised cells. The data confirmed that nuclear uptake of TP requires active transport using energy and shuttling factors. This mechanism of nuclear transport was confirmed when expressed TP was microinjected into living cells. Finally, we uncovered the nature of TP binding to host nuclear shuttling proteins, revealing selective binding to Imp β, and a complex of Imp α/β but not Imp α alone. TP translocation to the nucleus could be inhibited using selective inhibitors of importins. Our results show that the bipartite NLS is required for fully efficient TP entry into the nucleus and suggest that this translocation can be carried out by binding to Imp β or Imp α/β. This work forms the biochemical foundation for future work determining the involvement of TP in nuclear delivery of adenovirus DNA.
A Distinct Cytokine Profile and Stromal Vascular Fraction Metabolic Status without Significant Changes in the Lipid Composition Characterizes Lipedema
Authors: Wolf Stefan , Deuel Jeremy W. , Hollmén Maija , Felmerer Gunther , Kim Bong-Sung , Vasella Mauro , Grünherz Lisanne , Giovanoli Pietro , Lindenblatt Nicole , Gousopoulos Epameinondas
Published: March 2021

Lipedema is an adipose tissue disorder characterized by the disproportionate increase of subcutaneous fat tissue in the lower and/or upper extremities. The underlying pathomechanism remains unclear and no molecular biomarkers to distinguish the disease exist, leading to a large number of undiagnosed and misdiagnosed patients. To unravel the distinct molecular characteristic of lipedema we performed lipidomic analysis of the adipose tissue and serum of lipedema versus anatomically- and body mass index (BMI)-matched control patients. Both tissue groups showed no significant changes regarding lipid composition. As hyperplastic adipose tissue represents low-grade inflammation, the potential systemic effects on circulating cytokines were evaluated in lipedema and control patients using the Multiplex immunoassay system. Interestingly, increased systemic levels of interleukin 11 (p = 0.03), interleukin 28A (p = 0.04) and interleukin 29 (p = 0.04) were observed. As cytokines can influence metabolic activity, the metabolic phenotype of the stromal vascular fraction was examined, revealing significantly increased mitochondrial respiration in lipedema. In conclusion, despite sharing a comparable lipid profile with healthy adipose tissue, lipedema is characterized by a distinct systemic cytokine profile and metabolic activity of the stromal vascular fraction.
Insights into the Role of Transcriptional Gene Silencing in Response to Herbicide-Treatments in Arabidopsis thaliana
Authors: Markus Catarine , Pecinka Ales , Merotto Aldo
Published: March 2021

Herbicide resistance is broadly recognized as the adaptive evolution of weed populations to the intense selection pressure imposed by the herbicide applications. Here, we tested whether transcriptional gene silencing (TGS) and RNA-directed DNA Methylation (RdDM) pathways modulate resistance to commonly applied herbicides. Using Arabidopsis thaliana wild-type plants exposed to sublethal doses of glyphosate, imazethapyr, and 2,4-D, we found a partial loss of TGS and increased susceptibility to herbicides in six out of 11 tested TGS/RdDM mutants. Mutation in REPRESSOR OF SILENCING 1 (ROS1), that plays an important role in DNA demethylation, leading to strongly increased susceptibility to all applied herbicides, and imazethapyr in particular. Transcriptomic analysis of the imazethapyr-treated wild type and ros1 plants revealed a relation of the herbicide upregulated genes to chemical stimulus, secondary metabolism, stress condition, flavonoid biosynthesis, and epigenetic processes. Hypersensitivity to imazethapyr of the flavonoid biosynthesis component TRANSPARENT TESTA 4 (TT4) mutant plants strongly suggests that ROS1-dependent accumulation of flavonoids is an important mechanism for herbicide stress response in A. thaliana. In summary, our study shows that herbicide treatment affects transcriptional gene silencing pathways and that misregulation of these pathways makes Arabidopsis plants more sensitive to herbicide treatment.
Graphene-Based Sensors for the Detection of Bioactive Compounds: A Review
Authors: Sainz-Urruela Carlos , Vera-López Soledad , San Andrés María Paz , Díez-Pascual Ana M.
Published: March 2021

Over the last years, different nanomaterials have been investigated to design highly selective and sensitive sensors, reaching nano/picomolar concentrations of biomolecules, which is crucial for medical sciences and the healthcare industry in order to assess physiological and metabolic parameters. The discovery of graphene (G) has unexpectedly impulsed research on developing cost-effective electrode materials owed to its unique physical and chemical properties, including high specific surface area, elevated carrier mobility, exceptional electrical and thermal conductivity, strong stiffness and strength combined with flexibility and optical transparency. G and its derivatives, including graphene oxide (GO) and reduced graphene oxide (rGO), are becoming an important class of nanomaterials in the area of optical and electrochemical sensors. The presence of oxygenated functional groups makes GO nanosheets amphiphilic, facilitating chemical functionalization. G-based nanomaterials can be easily combined with different types of inorganic nanoparticles, including metals and metal oxides, quantum dots, organic polymers, and biomolecules, to yield a wide range of nanocomposites with enhanced sensitivity for sensor applications. This review provides an overview of recent research on G-based nanocomposites for the detection of bioactive compounds, providing insights on the unique advantages offered by G and its derivatives. Their synthesis process, functionalization routes, and main properties are summarized, and the main challenges are also discussed. The antioxidants selected for this review are melatonin, gallic acid, tannic acid, resveratrol, oleuropein, hydroxytyrosol, tocopherol, ascorbic acid, and curcumin. They were chosen owed to their beneficial properties for human health, including antibiotic, antiviral, cardiovascular protector, anticancer, anti-inflammatory, cytoprotective, neuroprotective, antiageing, antidegenerative, and antiallergic capacity. The sensitivity and selectivity of G-based electrochemical and fluorescent sensors are also examined. Finally, the future outlook for the development of G-based sensors for this type of biocompounds is outlined.
A Combined Activity of Thrombin and P-Selectin Is Essential for Platelet Activation by Pancreatic Cancer Cells
Authors: Haschemi Reza , Gockel Lukas Maria , Bendas Gerd , Schlesinger Martin
Published: March 2021

Pancreatic cancer patients have an elevated risk of suffering from venous thrombosis. Among several risk factors that contribute to hypercoagulability of this malignancy, platelets possess a key role in the initiation of clot formation. Although single mechanisms of platelet activation are well-known in principle, combinations thereof and their potential synergy to mediate platelet activation is, in the case of pancreatic cancer, far from being clear. Applying an inhibitor screening approach using light transmission aggregometry, dense granule release, and thrombin formation assays, we provide evidence that a combination of tissue factor-induced thrombin formation by cancer cells and their platelet P-selectin binding is responsible for AsPC-1 and Capan-2 pancreatic cancer cell-mediated platelet activation. While the blockade of one of these pathways leads to a pronounced inhibition of platelet aggregation and dense granule release, the simultaneous blockade of both pathways is inevitable to prevent platelet aggregation completely and minimize ATP release. In contrast, MIA PaCa-2 pancreatic cancer cells express reduced levels of tissue factor and P-selectin ligands and thus turn out to be poor platelet activators. Consequently, a simultaneous blockade of thrombin and P-selectin binding seems to be a powerful approach, as mediated by heparin to crucially reduce the hypercoagulable state of pancreatic cancer patients.
Xyloglucan Oligosaccharides Hydrolysis by Exo-Acting Glycoside Hydrolases from Hyperthermophilic Microorganism Saccharolobus solfataricus
Authors: Curci Nicola , Strazzulli Andrea , Iacono Roberta , De Lise Federica , Maurelli Luisa , Di Fenza Mauro , Cobucci-Ponzano Beatrice , Moracci Marco
Published: March 2021

In the field of biocatalysis and the development of a bio-based economy, hemicellulases have attracted great interest for various applications in industrial processes. However, the study of the catalytic activity of the lignocellulose-degrading enzymes needs to be improved to achieve the efficient hydrolysis of plant biomasses. In this framework, hemicellulases from hyperthermophilic archaea show interesting features as biocatalysts and provide many advantages in industrial applications thanks to their stability in the harsh conditions encountered during the pretreatment process. However, the hemicellulases from archaea are less studied compared to their bacterial counterpart, and the activity of most of them has been barely tested on natural substrates. Here, we investigated the hydrolysis of xyloglucan oligosaccharides from two different plants by using, both synergistically and individually, three glycoside hydrolases from Saccharolobus solfataricus: a GH1 β-gluco-/β-galactosidase, a α-fucosidase belonging to GH29, and a α-xylosidase from GH31. The results showed that the three enzymes were able to release monosaccharides from xyloglucan oligosaccharides after incubation at 65 °C. The concerted actions of β-gluco-/β-galactosidase and the α-xylosidase on both xyloglucan oligosaccharides have been observed, while the α-fucosidase was capable of releasing all α-linked fucose units from xyloglucan from apple pomace, representing the first GH29 enzyme belonging to subfamily A that is active on xyloglucan.
Personalized Development of Antisense Oligonucleotides for Exon Skipping Restores Type XVII Collagen Expression in Junctional Epidermolysis Bullosa
Authors: Ablinger Michael , Lettner Thomas , Friedl Nicole , Potocki Hannah , Palmetzhofer Theresa , Koller Ulrich , Illmer Julia , Liemberger Bernadette , Hainzl Stefan , Klausegger Alfred , Reisenberger Manuela , Lambert Jo , Van Gele Mireille , Desmet Eline , Van Maelsaeke Els , Wimmer Monika , Zauner Roland , Bauer Johann W. , Wally Verena
Published: March 2021

Intermediate junctional epidermolysis bullosa caused by mutations in the COL17A1 gene is characterized by the frequent development of blisters and erosions on the skin and mucous membranes. The rarity of the disease and the heterogeneity of the underlying mutations renders therapy developments challenging. However, the high number of short in-frame exons facilitates the use of antisense oligonucleotides (AON) to restore collagen 17 (C17) expression by inducing exon skipping. In a personalized approach, we designed and tested three AONs in combination with a cationic liposomal carrier for their ability to induce skipping of COL17A1 exon 7 in 2D culture and in 3D skin equivalents. We show that AON-induced exon skipping excludes the targeted exon from pre-mRNA processing, which restores the reading frame, leading to the expression of a slightly truncated protein. Furthermore, the expression and correct deposition of C17 at the dermal–epidermal junction indicates its functionality. Thus, we assume AON-mediated exon skipping to be a promising tool for the treatment of junctional epidermolysis bullosa, particularly applicable in a personalized manner for rare genotypes.
Examining the Impact of Squaric Acid as a Crosslinking Agent on the Properties of Chitosan-Based Films
Authors: Olewnik-Kruszkowska Ewa , Gierszewska Magdalena , Grabska-Zielińska Sylwia , Skopińska-Wiśniewska Joanna , Jakubowska Ewelina
Published: March 2021

Hydrogels based on chitosan are very versatile materials which can be used for tissue engineering as well as in controlled drug delivery systems. One of the methods for obtaining a chitosan-based hydrogel is crosslinking by applying different components. The objective of the present study was to obtain a series of new crosslinked chitosan-based films by means of solvent casting method. Squaric acid—3,4-dihydroxy-3-cyclobutene-1,2-dione—was used as a safe crosslinking agent. The effect of the squaric acid on the structural, mechanical, thermal, and swelling properties of the formed films was determined. It was established that the addition of the squaric acid significantly improved Young’s modulus, tensile strength, and thermal stability of the obtained materials. Moreover, it should be stressed that the samples consisting of chitosan and squaric acid were characterized by a higher swelling than pure chitosan. The detailed characterization proved that squaric acid could be used as a new effective crosslinking agent.
Alzheimer’s Disease Pathogenesis: Role of Autophagy and Mitophagy Focusing in Microglia
Authors: Eshraghi Mehdi , Adlimoghaddam Aida , Mahmoodzadeh Amir , Sharifzad Farzaneh , Yasavoli-Sharahi Hamed , Lorzadeh Shahrokh , Albensi Benedict C. , Ghavami Saeid
Published: March 2021

Alzheimer’s disease (AD) is a debilitating neurological disorder, and currently, there is no cure for it. Several pathologic alterations have been described in the brain of AD patients, but the ultimate causative mechanisms of AD are still elusive. The classic hallmarks of AD, including amyloid plaques (Aβ) and tau tangles (tau), are the most studied features of AD. Unfortunately, all the efforts targeting these pathologies have failed to show the desired efficacy in AD patients so far. Neuroinflammation and impaired autophagy are two other main known pathologies in AD. It has been reported that these pathologies exist in AD brain long before the emergence of any clinical manifestation of AD. Microglia are the main inflammatory cells in the brain and are considered by many researchers as the next hope for finding a viable therapeutic target in AD. Interestingly, it appears that the autophagy and mitophagy are also changed in these cells in AD. Inside the cells, autophagy and inflammation interact in a bidirectional manner. In the current review, we briefly discussed an overview on autophagy and mitophagy in AD and then provided a comprehensive discussion on the role of these pathways in microglia and their involvement in AD pathogenesis.
Hypoxia Inducible Factor 1A Supports a Pro-Fibrotic Phenotype Loop in Idiopathic Pulmonary Fibrosis
Authors: Epstein Shochet Gali , Bardenstein-Wald Becky , McElroy Mary , Kukuy Andrew , Surber Mark , Edelstein Evgeny , Pertzov Barak , Kramer Mordechai Reuven , Shitrit David
Published: March 2021

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with poor prognosis. The IPF-conditioned matrix (IPF-CM) system enables the study of matrix–fibroblast interplay. While effective at slowing fibrosis, nintedanib has limitations and the mechanism is not fully elucidated. In the current work, we explored the underlying signaling pathways and characterized nintedanib involvement in the IPF-CM fibrotic process. Results were validated using IPF patient samples and bleomycin-treated animals with/without oral and inhaled nintedanib. IPF-derived primary human lung fibroblasts (HLFs) were cultured on Matrigel and then cleared using NH4OH, creating the IPF-CM. Normal HLF-CM served as control. RNA-sequencing, PCR and western-blots were performed. HIF1α targets were evaluated by immunohistochemistry in bleomycin-treated rats with/without nintedanib and in patient samples with IPF. HLFs cultured on IPF-CM showed over-expression of ‘HIF1α signaling pathway’ (KEGG, p < 0.0001), with emphasis on SERPINE1 (PAI-1), VEGFA and TIMP1. IPF patient samples showed high HIF1α staining, especially in established fibrous tissue. PAI-1 was overexpressed, mainly in alveolar macrophages. Nintedanib completely reduced HIF1α upregulation in the IPF-CM and rat-bleomycin models. IPF-HLFs alter the extracellular matrix, thus creating a matrix that further propagates an IPF-like phenotype in normal HLFs. This pro-fibrotic loop includes the HIF1α pathway, which can be blocked by nintedanib.
Asthma and Chronic Rhinosinusitis: How Similar Are They in Pathogenesis and Treatment Responses?
Authors: Matucci Andrea , Bormioli Susanna , Nencini Francesca , Chiccoli Fabio , Vivarelli Emanuele , Maggi Enrico , Vultaggio Alessandra
Published: March 2021

Severe asthma and rhinosinusitis represent frequent comorbidities, complicating the overall management of the disease. Both asthma and chronic rhinosinusitis (CRS) can be differentiated into endotypes: those with type 2 eosinophilic inflammation and those with a non-type 2 inflammation. A correct definition of phenotype/endotype for these diseases is crucial, taking into account the availability of novel biological therapies. Even though patients suffering from type 2 severe asthma—with or without CRS with nasal polyps—significantly benefit from treatment with biologics, the existence of different levels of patient response has been clearly demonstrated. In fact, in clinical practice, it is a common experience that patients reach a good clinical response for asthma symptoms, but not for CRS. At first glance, a reason for this could be that although asthma and CRS can coexist in the same patient, they can manifest with different degrees of severity; therefore, efficacy may not be equally achieved. Many questions regarding responders and nonresponders, predictors of response, and residual disease after blocking type 2 pathways are still unanswered. In this review, we discuss whether treatment with biological agents is equally effective in controlling both asthma and sinonasal symptoms in patients in which asthma and chronic rhinosinusitis with nasal polyps coexist.
Mitochondrial and Autophagic Regulation of Adult Neurogenesis in the Healthy and Diseased Brain
Authors: Büeler Hansruedi
Published: March 2021

Adult neurogenesis is a highly regulated process during which new neurons are generated from neural stem cells in two discrete regions of the adult brain: the subventricular zone of the lateral ventricle and the subgranular zone of the dentate gyrus in the hippocampus. Defects of adult hippocampal neurogenesis have been linked to cognitive decline and dysfunction during natural aging and in neurodegenerative diseases, as well as psychological stress-induced mood disorders. Understanding the mechanisms and pathways that regulate adult neurogenesis is crucial to improving preventative measures and therapies for these conditions. Accumulating evidence shows that mitochondria directly regulate various steps and phases of adult neurogenesis. This review summarizes recent findings on how mitochondrial metabolism, dynamics, and reactive oxygen species control several aspects of adult neural stem cell function and their differentiation to newborn neurons. It also discusses the importance of autophagy for adult neurogenesis, and how mitochondrial and autophagic dysfunction may contribute to cognitive defects and stress-induced mood disorders by compromising adult neurogenesis. Finally, I suggest possible ways to target mitochondrial function as a strategy for stem cell-based interventions and treatments for cognitive and mood disorders.
Modeling the Invasion of the Large Hive Beetle, Oplostomusfuligineus, into North Africa and South Europe under a Changing Climate
Authors: Abou-Shaara Hossam , Alashaal Sara A. , Hosni Eslam M. , Nasser Mohamed G. , Ansari Mohammad J. , Alharbi Sulaiman Ali
Published: March 2021

Some beetle species can attack honeybee colonies, causing severe damage to beekeeping. These pests include Oplostomus fuligineus, which is also known as the Large Hive Beetle (LHB). This beetle is native to Sub-Saharan Africa and has recently also been recorded in some parts of North Africa. It feeds mainly on young bee larvae and stored food within the colonies, causing severe damage to weak colonies. The present work sheds light on the current and future distribution (from 2050 to 2070) of this beetle in Africa and South Europe using species distribution modeling. Maxent was used to model the invasion of LHB. The Shared Socioeconomic Pathways (SSPs) 126 and 585 were used to model the future distribution of LHB. The Maxent models showed satisfactory results with a high Area Under Curve (AUC) value (0.85 ± 0.02). Furthermore, the True Skill Statistics (TSS) value was equal to 0.87. The current and future maps showed a high risk of invasion because of temperature variation in most of the parts of North Africa and South Europe. The maps also predicted the future invasion of LHB into other countries, mainly through southern Europe. These predictive risk maps will help quarantine authorities in highly relevant countries to prevent the expansion of this pest outside of its natural range.
From Global to Local—New Insights into Features of Pyrethroid Detoxification in Vector Mosquitoes
Authors: Black William C. , Snell Trey K. , Saavedra-Rodriguez Karla , Kading Rebekah C. , Campbell Corey L.
Published: March 2021

The threat of mosquito-borne diseases continues to be a problem for public health in subtropical and tropical regions of the world; in response, there has been increased use of adulticidal insecticides, such as pyrethroids, in human habitation areas over the last thirty years. As a result, the prevalence of pyrethroid-resistant genetic markers in natural mosquito populations has increased at an alarming rate. This review details recent advances in the understanding of specific mechanisms associated with pyrethroid resistance, with emphasis on features of insecticide detoxification and the interdependence of multiple cellular pathways. Together, these advances add important context to the understanding of the processes that are selected in resistant mosquitoes. Specifically, before pyrethroids bind to their targets on motoneurons, they must first permeate the outer cuticle and diffuse to inner tissues. Resistant mosquitoes have evolved detoxification mechanisms that rely on cytochrome P450s (CYP), esterases, carboxyesterases, and other oxidation/reduction (redox) components to effectively detoxify pyrethroids to nontoxic breakdown products that are then excreted. Enhanced resistance mechanisms have evolved to include alteration of gene copy number, transcriptional and post-transcriptional regulation of gene expression, as well as changes to cellular signaling mechanisms. Here, we outline the variety of ways in which detoxification has been selected in various mosquito populations, as well as key gene categories involved. Pathways associated with potential new genes of interest are proposed. Consideration of multiple cellular pathways could provide opportunities for development of new insecticides.
An Agent-Based Model of Task-Allocation and Resource-Sharing for Social Internet of Things
Authors: Zia Kashif , Farooq Umar , Shafi Muhammad , Arshad Muhammad
Published: March 2021

The things in the Internet of Things are becoming more and more socially aware. What social means for these things (more often termed as “social objects”) is predominately determined by how and when objects interact with each other. In this paper, an agent-based model for Social Internet of Things is proposed, which features the realization of various interaction modalities, along with possible network structures and mobility modes, thus providing a novel model to ask interesting “what-if” questions. The scenario used, which is the acquisition of shared resources in a common spatial and temporal world, demands agents to have ad-hoc communication and a willingness to cooperate with others. The model was simulated for all possible combinations of input parameters to study the implications of competitive vs. cooperative social behavior while agents try to acquire shared resources/services in a peer-to-peer fashion. However, the main focus of the paper was to analyze the impact of profile-based mobility, which has an underpinning on parameters of extent and scale of a mobility profile. The simulation results, in addition to others, reveal that there are substantial and systematic differences among different combinations of values for extent and scale.
Association between Visceral or Subcutaneous Fat Accumulation and B-Type Natriuretic Peptide among Japanese Subjects: A Cross-Sectional Study
Authors: Hayashi Yoshinori , Yokokawa Hirohide , Fukuda Hiroshi , Saita Mizue , Miyagami Taiju , Takahashi Yuichi , Hisaoka Teruhiko , Naito Toshio
Published: March 2021

Background: Some previous studies have shown reduced levels of plasma B-type natriuretic peptide (BNP) in individuals with obesity. We aimed to estimate the relationship between BNP and abdominal fat distribution, adjusted for confounding factors. Methods: This cross-sectional study included 1806 Japanese individuals (981 men and 825 women) who underwent a medical health check-up. Analyzed data included age, sex, visceral fat area (VFA), and subcutaneous fat area (SFA) as obtained from computed tomography, blood pressure, and blood test results including BNP. Multiple linear regression analysis was used to examine the association between BNP, VFA, and SFA after adjusting for age, sex, comorbidities, and body mass index. Results: In the models analyzed separately for VFA and SFA, BNP correlated independently with VFA in multiple linear regression analysis among all subjects and in both men and women, while SFA correlated inversely with BNP in all subjects and women but not in men. In the model that included both VFA and SFA, BNP correlated independently with VFA, but SFA and BNP were not correlated in any models. Conclusion: Higher VFA showed an independent, significant association with lower BNP. In addition, the inverse correlation with BNP was stronger for VFA than for SFA.