bluuebunny/crossref_metadata_2025 huggingface dataset:
Dental Nurses’ Mental Health in Germany: A Nationwide Survey during the COVID-19 Pandemic
Authors: Mekhemar Mohamed , Attia Sameh , Dörfer Christof , Conrad Jonas
Published: July 2021

Several studies have found a rise in the rate of psychological discomfort among healthcare personnel since the COVID-19 pandemic outbreak. In this study, we analyzed the relationship between psychological variables of anxiety, depression, stress, avoidance, intrusion and hyperarousal and several factors among German dental nurses. For this poll, dental nurses were asked nationwide to take part via an online-based survey from July 2020 to January 2021. This survey gathered data on demographics, as well as psychological assessments through the Impact of Events Scale-Revised (IES-R) instrument, and the Depression Anxiety Stress Scales (DASS-21). The correlations between DASS-21/IES-R ratings and sociodemographic data were investigated using univariate analyses (Kruskal–Wallis and Mann–Whitney U tests). Single comparisons were performed using the Dunn–Bonferroni post hoc test if a relevant test result was significant followed by multiple linear regressions. Furthermore, 252 dental nurses took part in the study and showed overall normal or mild results of all psychological variables. Having immune-deficiency or chronic diseases, employment at a dental practice, being married, having no children and seeing the pandemic as a financial threat were presented as significant risk factors (p ≤ 0.05) with higher DASS-21 and IES-R scores. These results emphasize the aspects that must be considered to safeguard German dental nurses’ mental wellbeing during the crisis.
Deepening Well-Being Evaluation with Different Data Sources: A Bayesian Networks Approach
Authors: Cugnata Federica , Salini Silvia , Siletti Elena
Published: July 2021

In this paper, we focus on a Bayesian network s approach to combine traditional survey and social network data and official statistics to evaluate well-being. Bayesian networks permit the use of data with different geographical levels (provincial and regional) and time frequencies (daily, quarterly, and annual). The aim of this study was twofold: to describe the relationship between survey and social network data and to investigate the link between social network data and official statistics. Particularly, we focused on whether the big data anticipate the information provided by the official statistics. The applications, referring to Italy from 2012 to 2017, were performed using ISTAT’s survey data, some variables related to the considered time period or geographical levels, a composite index of well-being obtained by Twitter data, and official statistics that summarize the labor market.
Quantifying the Contributions of Environmental Factors to Wind Characteristics over 2000–2019 in China
Authors: Lu Yuming , Wu Bingfang , Yan Nana , Zhu Weiwei , Zeng Hongwei , Ma Zonghan , Xu Jiaming , Wu Xinghua , Pang Bo
Published: July 2021

Global climate change and human activities have resulted in immense changes in the Earth’s ecosystem, and the interaction between the land surface and the atmosphere is one of the most important processes. Wind is a reference for studying atmospheric dynamics and climate change, analyzing the wind speed change characteristics in historical periods, and studying the influence of wind on the Earth-atmosphere interaction; additionally, studying the wind, contributes to analyzing and alleviating a series of problems, such as the energy crisis, environmental pollution, and ecological deterioration facing human beings. In this study, data from 697 meteorological stations in China from 2000 to 2019 were used to study the distribution and trend of wind speed over the past two decades. The relationships between wind speed and climate factors were explored using statistical methods; furthermore, combined with terrain, climate change, and human activities, we quantified the contribution of environmental factors to wind speed. The results show that a downward trend was recorded before 2011, but overall, there was an increasing trend that was not significant; moreover, the wind speed changes showed obvious seasonality and were more complicated on the monthly scale. The wind speed trend mainly increased in the western region, decreased in the eastern region, was higher in the northeastern, northwestern, and coastal areas, and was lower in the central area. Temperature, bright sunshine duration, evaporation, and precipitation had a strong influence, in which wind speed showed a significant negative correlation with temperature and precipitation and vice versa for sunshine and evapotranspiration. The influence of environmental factors is diverse, and these results could help to develop environmental management strategies across ecologically fragile areas and improve the design of wind power plants to make better use of wind energy.
Accuracy Evaluation of Ionospheric Delay from Multi-Scale Reference Networks and Its Augmentation to PPP during Low Solar Activity
Authors: Zhao Lewen , Douša Jan , Václavovic Pavel
Published: July 2021

The Precise Point Positioning (PPP) with fast integer ambiguity resolution (PPP-RTK) is feasible only if the solution is augmented with precise ionospheric parameters. The vertical ionospheric delays together with the receiver hardware biases, are estimated simultaneously based on the uncombined PPP model. The performance of the ionospheric delays was evaluated and applied in the PPP-RTK demonstration during the low solar activity period. The processing was supported by precise products provided by Deutsches GeoForschungsZentrum Potsdam (GFZ) and also by real-time products provided by the National Centre for Space Studies (CNES). Since GFZ provides only precise orbits and clocks, other products needed for ambiguity resolution, such as phase biases, were estimated at the Geodetic Observatory Pecny (GOP). When ambiguity parameters were resolved as integer values in the GPS-only solution, the initial convergence period was reduced from 30 and 20 min to 24 and 13 min when using CNES and GFZ/GOP products, respectively. The accuracy of ionospheric delays derived from the ambiguity fixed PPP, and the CODE global ionosphere map were then assessed. Comparison of ambiguity fixed ionospheric delay obtained at two collocated stations indicated the accuracy of 0.15 TECU for different scenarios with more than 60% improvement compared to the ambiguity float PPP. However, a daily periodic variation can be observed from the multi-day short-baseline ionospheric residuals. The accuracy of the interpolated ionospheric delay from global maps revealed a dependency on the location of the stations, ranging from 1 to 3 TECU. Precise ionospheric delays derived from the EUREF permanent network with an inter-station distance larger than 73 km were selected for ionospheric modeling at the user location. Results indicated that the PPP ambiguity resolution could be achieved within three minutes. After enlarging the inter-station distance to 209 km, ambiguity resolution could also be achieved within several minutes.
Cell Types and Synapses Expressing the SNARE Complex Regulating Proteins Complexin 1 and Complexin 2 in Mammalian Retina
Authors: Lux Uwe Thorsten , Ehrenberg Johanna , Joachimsthaler Anneka , Atorf Jenny , Pircher Bianca , Reim Kerstin , Kremers Jan , Gießl Andreas , Brandstätter Johann Helmut
Published: July 2021

Complexins (Cplxs) 1 to 4 are components of the presynaptic compartment of chemical synapses where they regulate important steps in synaptic vesicle exocytosis. In the retina, all four Cplxs are present, and while we know a lot about Cplxs 3 and 4, little is known about Cplxs 1 and 2. Here, we performed in situ hybridization experiments and bioinformatics and exploited Cplx 1 and Cplx 2 single-knockout mice combined with immunocytochemistry and light microscopy to characterize in detail the cell type and synapse-specific distribution of Cplx 1 and Cplx 2. We found that Cplx 2 and not Cplx 1 is the main isoform expressed in normal and displaced amacrine cells and ganglion cells in mouse retinae and that amacrine cells seem to operate with a single Cplx isoform at their conventional chemical synapses. Surprising was the finding that retinal function, determined with electroretinographic recordings, was altered in Cplx 1 but not Cplx 2 single-knockout mice. In summary, the results provide an important basis for future studies on the function of Cplxs 1 and 2 in the processing of visual signals in the mammalian retina.
Receptor-Dependent and Independent Regulation of Voltage-Gated Ca2+ Channels and Ca2+-Permeable Channels by Endocannabinoids in the Brain
Authors: Boczek Tomasz , Zylinska Ludmila
Published: July 2021

The activity of specific populations of neurons in different brain areas makes decisions regarding proper synaptic transmission, the ability to make adaptations in response to different external signals, as well as the triggering of specific regulatory pathways to sustain neural function. The endocannabinoid system (ECS) appears to be a very important, highly expressed, and active system of control in the central nervous system (CNS). Functionally, it allows the cells to respond quickly to processes that occur during synaptic transmission, but can also induce long-term changes. The endocannabinoids (eCBs) belong to a large family of bioactive lipid mediators that includes amides, esters, and ethers of long-chain polyunsaturated fatty acids. They are produced “on demand” from the precursors located in the membranes, exhibit a short half-life, and play a key role as retrograde messengers. eCBs act mainly through two receptors, CB1R and CB2R, which belong to the G-protein coupled receptor superfamily (GPCRs), but can also exert their action via multiple non-receptor pathways. The action of eCBs depends on Ca2+, but eCBs can also regulate downstream Ca2+ signaling. In this short review, we focus on the regulation of neuronal calcium channels by the most effective members of eCBs-2-arachidonoylglycerol (2-AG), anandamide (AEA) and originating from AEA-N-arachidonoylglycine (NAGly), to better understand the contribution of ECS to brain function under physiological conditions.
Nanovesicles from Organic Agriculture-Derived Fruits and Vegetables: Characterization and Functional Antioxidant Content
Authors: Logozzi Mariantonia , Di Raimo Rossella , Mizzoni Davide , Fais Stefano
Published: July 2021

Dietary consumption of fruits and vegetables is related to a risk reduction in a series of leading human diseases, probably due to the plants’ antioxidant content. Plant-derived nanovesicles (PDNVs) have been recently receiving great attention regarding their natural ability to deliver several active biomolecules and antioxidants. To investigate the presence of active antioxidants in fruits, we preliminarily analyzed the differences between nanovesicles from either organic or conventional agriculture-derived fruits, at equal volumes, showing a higher yield of nanovesicles with a smaller size from organic agriculture-derived fruits as compared to conventional ones. PDNVs from organic agriculture also showed a higher antioxidant level compared to nanovesicles from conventional agriculture. Using the PDNVs from fruit mixes, we found comparable levels of Total Antioxidant Capacity, Ascorbic Acid, Catalase, Glutathione and Superoxide Dismutase 1. Finally, we exposed the nanovesicle mixes to either chemical or physical lytic treatments, with no evidence of effects on the number, size and antioxidant capacity of the treated nanovesicles, thus showing a marked resistance of PDNVs to external stimuli and a high capability to preserve their content. Our study provides for the first time a series of data supporting the use of plant-derived nanovesicles in human beings’ daily supplementation, for both prevention and treatment of human diseases.
An Experimental Workflow for Studying Barrier Integrity, Permeability, and Tight Junction Composition and Localization in a Single Endothelial Cell Monolayer: Proof of Concept
Authors: Bartosova Maria , Ridinger David , Marinovic Iva , Heigwer Jana , Zhang Conghui , Levai Eszter , Westhoff Jens H. , Schaefer Franz , Terjung Stefan , Hildenbrand Georg , Krunic Damir , Bestvater Felix , Hausmann Michael , Schmitt Claus Peter , Zarogiannis Sotirios G.
Published: July 2021

Endothelial and epithelial barrier function is crucial for the maintenance of physiological processes. The barrier paracellular permeability depends on the composition and spatial distribution of the cell-to-cell tight junctions (TJ). Here, we provide an experimental workflow that yields several layers of physiological data in the setting of a single endothelial cell monolayer. Human umbilical vein endothelial cells were grown on Transwell filters. Transendothelial electrical resistance (TER) and 10 kDa FITC dextran flux were measured using Alanyl-Glutamine (AlaGln) as a paracellular barrier modulator. Single monolayers were immunolabelled for Zonula Occludens-1 (ZO-1) and Claudin-5 (CLDN5) and used for automated immunofluorescence imaging. Finally, the same monolayers were used for single molecule localization microscopy (SMLM) of ZO-1 and CLDN5 at the nanoscale for spatial clustering analysis. The TER increased and the paracellular dextran flux decreased after the application of AlaGln and these functional changes of the monolayer were mediated by an increase in the ZO-1 and CLDN5 abundance in the cell–cell interface. At the nanoscale level, the functional and protein abundance data were accompanied by non-random increased clustering of CLDN5. Our experimental workflow provides multiple data from a single monolayer and has wide applicability in the setting of paracellular studies in endothelia and epithelia.
Mitochondrial Modulations, Autophagy Pathways Shifts in Viral Infections: Consequences of COVID-19
Authors: Singh Shailendra Pratap , Amar Salomon , Gehlot Pinky , Patra Sanjib K. , Kanwar Navjot , Kanwal Abhinav
Published: July 2021

Mitochondria are vital intracellular organelles that play an important role in regulating various intracellular events such as metabolism, bioenergetics, cell death (apoptosis), and innate immune signaling. Mitochondrial fission, fusion, and membrane potential play a central role in maintaining mitochondrial dynamics and the overall shape of mitochondria. Viruses change the dynamics of the mitochondria by altering the mitochondrial processes/functions, such as autophagy, mitophagy, and enzymes involved in metabolism. In addition, viruses decrease the supply of energy to the mitochondria in the form of ATP, causing viruses to create cellular stress by generating ROS in mitochondria to instigate viral proliferation, a process which causes both intra- and extra-mitochondrial damage. SARS-COV2 propagates through altering or changing various pathways, such as autophagy, UPR stress, MPTP and NLRP3 inflammasome. Thus, these pathways act as potential targets for viruses to facilitate their proliferation. Autophagy plays an essential role in SARS-COV2-mediated COVID-19 and modulates autophagy by using various drugs that act on potential targets of the virus to inhibit and treat viral infection. Modulated autophagy inhibits coronavirus replication; thus, it becomes a promising target for anti-coronaviral therapy. This review gives immense knowledge about the infections, mitochondrial modulations, and therapeutic targets of viruses.
Electrochemical Sensors for Detection of Markers on Tumor Cells
Authors: Zhou Han , Du Xin , Zhang Zhenguo
Published: July 2021

In recent years, the increasing incidence and mortality of cancer have inspired the development of accurate and rapid early diagnosis methods in order to successfully cure cancer; however, conventional methods used for detecting tumor cells, including histopathological and immunological methods, often involve complex operation processes, high analytical costs, and high false positive rates, in addition to requiring experienced personnel. With the rapid emergence of sensing techniques, electrochemical cytosensors have attracted wide attention in the field of tumor cell detection because of their advantages, such as their high sensitivity, simple equipment, and low cost. These cytosensors are not only able to differentiate tumor cells from normal cells, but can also allow targeted protein detection of tumor cells. In this review, the research achievements of various electrochemical cytosensors for tumor cell detection reported in the past five years are reviewed, including the structures, detection ranges, and detection limits of the cytosensors. Certain trends and prospects related to the electrochemical cytosensors are also discussed.
Indomethacin Disrupts the Formation of β-Amyloid Plaques via an α2-Macroglobulin-Activating lrp1-Dependent Mechanism
Authors: Guan Pei-Pei , Yang Liu-Qing , Xu Guo-Biao , Wang Pu
Published: July 2021

Epidemiological studies have implied that the nonsteroidal anti-inflammatory drug (NSAID) indomethacin slows the development and progression of Alzheimer’s disease (AD). However, the underlying mechanisms are notably understudied. Using a chimeric mouse/human amyloid precursor protein (Mo/HuAPP695swe) and a mutant human presenilin 1 (PS1-dE9) (APP/PS1) expressing transgenic (Tg) mice and neuroblastoma (N) 2a cells as in vivo and in vitro models, we revealed the mechanisms of indomethacin in ameliorating the cognitive decline of AD. By screening AD-associated genes, we observed that a marked increase in the expression of α2-macroglobulin (A2M) was markedly induced after treatment with indomethacin. Mechanistically, upregulation of A2M was caused by the inhibition of cyclooxygenase-2 (COX-2) and lipocalin-type prostaglandin D synthase (L-PGDS), which are responsible for the synthesis of prostaglandin (PG)H2 and PGD2, respectively. The reduction in PGD2 levels induced by indomethacin alleviated the suppression of A2M expression through a PGD2 receptor 2 (CRTH2)-dependent mechanism. Highly activated A2M not only disrupted the production and aggregation of β-amyloid protein (Aβ) but also induced Aβ efflux from the brain. More interestingly, indomethacin decreased the degradation of the A2M receptor, low-density lipoprotein receptor-related protein 1 (LRP1), which facilitated the brain efflux of Aβ. Through the aforementioned mechanisms, indomethacin ameliorated cognitive decline in APP/PS1 Tg mice by decreasing Aβ production and clearing Aβ from the brains of AD mice.
A Short-Type Peptidoglycan Recognition Protein 1 (PGRP1) Is Involved in the Immune Response in Asian Corn Borer, Ostrinia furnacalis (Guenée)
Authors: Shen Dongxu , Ji Jiayue , Zhang Shasha , Liu Jiahui , An Chunju
Published: July 2021

The insect immune response is initiated by the recognition of invading microorganisms. Peptidoglycan recognition proteins (PGRPs) function primarily as pattern recognition receptors by specifically binding to peptidoglycans expressed on microbial surfaces. We cloned a full-length cDNA for a PGRP from the Asian corn borer Ostrinia furnacalis (Guenée) and designated it as PGRP1. PGRP1 mRNA was mainly detected in the fat bodies and hemocytes. Its transcript levels increased significantly upon bacterial and fungal challenges. Purified recombinant PGRP1 exhibited binding activity to the gram-positive Micrococcus luteus, gram-negative Escherichia coli, entomopathogenic fungi Beauveria bassiana, and yeast Pichia pastoris. The binding further induced their agglutination. Additionally, PGRP1 preferred to bind to Lys-type peptidoglycans rather than DAP-type peptidoglycans. The addition of recombinant PGRP1 to O. furnacalis plasma resulted in a significant increase in phenoloxidase activity. The injection of recombinant PGRP1 into larvae led to a significantly increased expression of several antimicrobial peptide genes. Taken together, our results suggest that O. furnacalis PGRP1 potentially recognizes the invading microbes and is involved in the immune response in O. furnacalis.
Targeting DNA Damage Response and Repair to Enhance Therapeutic Index in Cisplatin-Based Cancer Treatment
Authors: Kiss Robert Csaba , Xia Fen , Acklin Scarlett
Published: July 2021

Platinum-based chemotherapies, such as cisplatin, play a large role in cancer treatment. The development of resistance and treatment toxicity creates substantial barriers to disease control, yet. To enhance the therapeutic index of cisplatin-based chemotherapy, it is imperative to circumvent resistance and toxicity while optimizing tumor sensitization. One of the primary mechanisms by which cancer cells develop resistance to cisplatin is through upregulation of DNA repair pathways. In this review, we discuss the DNA damage response in the context of cisplatin-induced DNA damage. We describe the proteins involved in the pathways and their roles in resistance development. Common biomarkers for cisplatin resistance and their utilization to improve patient risk stratification and treatment personalization are addressed. Finally, we discuss some of the current treatments and future strategies to circumvent the development of cisplatin resistance.
Role of GPR39 in Neurovascular Homeostasis and Disease
Authors: Xu Yifan , Barnes Anthony P. , Alkayed Nabil J.
Published: July 2021

GPR39, a member of the ghrelin family of G protein-coupled receptors, is zinc-responsive and contributes to the regulation of diverse neurovascular and neurologic functions. Accumulating evidence suggests a role as a homeostatic regulator of neuronal excitability, vascular tone, and the immune response. We review GPR39 structure, function, and signaling, including constitutive activity and biased signaling, and summarize its expression pattern in the central nervous system. We further discuss its recognized role in neurovascular, neurological, and neuropsychiatric disorders.
High-Density Lipoproteins in Kidney Disease
Authors: Kon Valentina , Yang Hai-Chun , Smith Loren E. , Vickers Kasey C. , Linton MacRae F.
Published: July 2021

Decades of epidemiological studies have established the strong inverse relationship between high-density lipoprotein (HDL)-cholesterol concentration and cardiovascular disease. Recent evidence suggests that HDL particle functions, including anti-inflammatory and antioxidant functions, and cholesterol efflux capacity may be more strongly associated with cardiovascular disease protection than HDL cholesterol concentration. These HDL functions are also relevant in non-cardiovascular diseases, including acute and chronic kidney disease. This review examines our current understanding of the kidneys’ role in HDL metabolism and homeostasis, and the effect of kidney disease on HDL composition and functionality. Additionally, the roles of HDL particles, proteins, and small RNA cargo on kidney cell function and on the development and progression of both acute and chronic kidney disease are examined. The effect of HDL protein modification by reactive dicarbonyls, including malondialdehyde and isolevuglandin, which form adducts with apolipoprotein A-I and impair proper HDL function in kidney disease, is also explored. Finally, the potential to develop targeted therapies that increase HDL concentration or functionality to improve acute or chronic kidney disease outcomes is discussed.
Effect of Erythropoietin on the Expression of Murine Transferrin Receptor 2
Authors: Berezovsky Betty , Báječný Martin , Frýdlová Jana , Gurieva Iuliia , Rogalsky Daniel Wayne , Přikryl Petr , Pospíšil Vít , Nečas Emanuel , Vokurka Martin , Krijt Jan
Published: July 2021

Erythropoietin (EPO) downregulates hepcidin expression to increase the availability of iron; the downregulation of hepcidin is mediated by erythroferrone (ERFE) secreted by erythroblasts. Erythroblasts also express transferrin receptor 2 (TFR2); however, the possible role of TFR2 in hepcidin downregulation is unclear. The purpose of the study was to correlate liver expression of hepcidin with the expression of ERFE and TFR2 in murine bone marrow and spleen at 4, 16, 24, 48, 72 and 96 h following administration of a single dose of EPO. Splenic Fam132b expression increased 4 h after EPO injection; liver hepcidin mRNA was decreased at 16 h. In the spleen, expression of TFR2 and transferrin receptor (TFR1) proteins increased by an order of magnitude at 48 and 72 h after EPO treatment. The EPO-induced increase in splenic TFR2 and TFR1 was associated with an increase in the number of Tfr2- and Tfr1-expressing erythroblasts. Plasma exosomes prepared from EPO-treated mice displayed increased amount of TFR1 protein; however, no exosomal TFR2 was detected. Overall, the results confirm the importance of ERFE in stress erythropoiesis, support the role of TFR2 in erythroid cell development, and highlight possible differences in the removal of TFR2 and TFR1 from erythroid cell membranes.
New Insights in Mechanisms and Therapeutics for Short- and Long-Term Impacts of Hepatic Ischemia Reperfusion Injury Post Liver Transplantation
Authors: Liu Hui , Man Kwan
Published: July 2021

Liver transplantation has been identified as the most effective treatment for patients with end-stage liver diseases. However, hepatic ischemia reperfusion injury (IRI) is associated with poor graft function and poses a risk of adverse clinical outcomes post transplantation. Cell death, including apoptosis, necrosis, ferroptosis and pyroptosis, is induced during the acute phase of liver IRI. The release of danger-associated molecular patterns (DAPMs) and mitochondrial dysfunction resulting from the disturbance of metabolic homeostasis initiates graft inflammation. The inflammation in the short term exacerbates hepatic damage, leading to graft dysfunction and a higher incidence of acute rejection. The subsequent changes in the graft immune environment due to hepatic IRI may result in chronic rejection, cancer recurrence and fibrogenesis in the long term. In this review, we mainly focus on new mechanisms of inflammation initiated by immune activation related to metabolic alteration in the short term during liver IRI. The latest mechanisms of cancer recurrence and fibrogenesis due to the long-term impact of inflammation in hepatic IRI is also discussed. Furthermore, the development of therapeutic strategies, including ischemia preconditioning, pharmacological inhibitors and machine perfusion, for both attenuating acute inflammatory injury and preventing late-phase disease recurrence, will be summarized in the context of clinical, translational and basic research.
The Different Faces of the TDP-43 Low-Complexity Domain: The Formation of Liquid Droplets and Amyloid Fibrils
Authors: Chien Hung-Ming , Lee Chi-Chang , Huang Joseph Jen-Tse
Published: July 2021

Transactive response DNA-binding protein 43 (TDP-43) is a nucleic acid-binding protein that is involved in transcription and translation regulation, non-coding RNA processing, and stress granule assembly. Aside from its multiple functions, it is also known as the signature protein in the hallmark inclusions of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) patients. TDP-43 is built of four domains, but its low-complexity domain (LCD) has become an intense research focus that brings to light its possible role in TDP-43 functions and involvement in the pathogenesis of these neurodegenerative diseases. Recent endeavors have further uncovered the distinct biophysical properties of TDP-43 under various circumstances. In this review, we summarize the multiple structural and biochemical properties of LCD in either promoting the liquid droplets or inducing fibrillar aggregates. We also revisit the roles of the LCD in paraspeckles, stress granules, and cytoplasmic inclusions to date.
Generation of Electromagnetic Field by Microtubules
Authors: Pokorný Jan , Pokorný Jiří , Vrba Jan
Published: July 2021

The general mechanism of controlling, information and organization in biological systems is based on the internal coherent electromagnetic field. The electromagnetic field is supposed to be generated by microtubules composed of identical tubulin heterodimers with periodic organization and containing electric dipoles. We used a classical dipole theory of generation of the electromagnetic field to analyze the space–time coherence. The structure of microtubules with the helical and axial periodicity enables the interaction of the field in time shifted by one or more periods of oscillation and generation of coherent signals. Inner cavity excitation should provide equal energy distribution in a microtubule. The supplied energy coherently excites oscillators with a high electrical quality, microtubule inner cavity, and electrons at molecular orbitals and in ‘semiconduction’ and ‘conduction’ bands. The suggested mechanism is supposed to be a general phenomenon for a large group of helical systems.
Reduced Endothelin-2 and Hypoxic Signaling Pathways in Granulosa-Lutein Cells of PCOS Women
Authors: Szymanska Magdalena , Shrestha Ketan , Girsh Eliezer , Harlev Avi , Eisenberg Iris , Imbar Tal , Meidan Rina
Published: July 2021

Granulosa-lutein cells (GLCs) from PCOS women display reduced HIF-1α and EDN2 levels, suggesting their role in PCOS etiology. Here, we investigated the mechanisms involved in aberrant EDN2 expression in PCOS, and its association with HIF-1α. Various HIF-1α-dependent factors were studied in GLCs from PCOS and compared to normally ovulating women. MicroRNA-210 (miR-210), its target genes (SDHD and GPD1L), and HIF-1α-responsive genes (EDN2 and VEGFA) differed in GLCs from PCOS, compared with those of healthy women. Levels of miR-210—designated hypoxiamiR—and EDN2 were reduced in the PCOS GLCs; concomitantly, GPD1L and SDHD levels were elevated. Cultured GLCs retained low EDN2 expression and had low HIF-1α levels, providing evidence for a disrupted hypoxic response in the PCOS GLCs. However, VEGFA expression was elevated in these cells. Next, miR-210 levels were manipulated. miR-210-mimic stimulated EDN2 twice as much as the miR-NC-transfected cells, whereas miR-210-inhibitor diminished EDN2, emphasizing the importance of hypoxiamiR for EDN2 induction. Intriguingly, VEGFA transcripts were reduced by both miR-210-mimic and -inhibitor, demonstrating that EDN2 and VEGFA are distinctly regulated. Disrupted hypoxic response in the GLCs of periovulatory follicles in PCOS women may play a role in ovulation failure, and in the reduced fertility prevalent in this syndrome.
Mechanisms of Central Hypogonadism
Authors: Barber Thomas , Kyrou Ioannis , Kaltsas Gregory , Grossman Ashley , Randeva Harpal , Weickert Martin
Published: July 2021

Reproductive function depends upon an operational hypothalamo–pituitary–gonadal (HPG) axis. Due to its role in determining survival versus reproductive strategies, the HPG axis is vulnerable to a diverse plethora of signals that ultimately manifest with Central Hypogonadism (CH) in all its many guises. Acquired CH can result from any pituitary or hypothalamic lesion, including its treatment (such as surgical resection and/or radiotherapy). The HPG axis is particularly sensitive to the suppressive effects of hyperprolactinaemia that can occur for many reasons, including prolactinomas, and as a side effect of certain drug therapies. Physiologically, prolactin (combined with the suppressive effects of autonomic neural signals from suckling) plays a key role in suppressing the gonadal axis and establishing temporary CH during lactation. Leptin is a further key endocrine regulator of the HPG axis. During starvation, hypoleptinaemia (from diminished fat stores) results in activation of hypothalamic agouti-related peptide neurons that have a dual purpose to enhance appetite (important for survival) and concomitantly suppresses GnRH neurons via effects on neural kisspeptin release. Obesity is associated with hyperleptinaemia and leptin resistance that may also suppress the HPG axis. The suppressibility of the HPG axis also leaves it vulnerable to the effects of external signals that include morphine, anabolic-androgenic steroids, physical trauma and stress, all of which are relatively common causes of CH. Finally, the HPG axis is susceptible to congenital malformations, with reports of mutations within >50 genes that manifest with congenital CH, including Kallmann Syndrome associated with hyposmia or anosmia (reduction or loss of the sense of smell due to the closely associated migration of GnRH with olfactory neurons during embryogenesis). Analogous to the HPG axis itself, patients with CH are often vulnerable, and their clinical management requires both sensitivity and empathy.
Early Life Febrile Seizures Impair Hippocampal Synaptic Plasticity in Young Rats
Authors: Postnikova Tatyana Y. , Griflyuk Alexandra V. , Amakhin Dmitry V. , Kovalenko Anna A. , Soboleva Elena B. , Zubareva Olga E. , Zaitsev Aleksey V.
Published: July 2021

Febrile seizures (FSs) in early life are significant risk factors of neurological disorders and cognitive impairment in later life. However, existing data about the impact of FSs on the developing brain are conflicting. We aimed to investigate morphological and functional changes in the hippocampus of young rats exposed to hyperthermia-induced seizures at postnatal day 10. We found that FSs led to a slight morphological disturbance. The cell numbers decreased by 10% in the CA1 and hilus but did not reduce in the CA3 or dentate gyrus areas. In contrast, functional impairments were robust. Long-term potentiation (LTP) in CA3-CA1 synapses was strongly reduced, which we attribute to the insufficient activity of N-methyl-D-aspartate receptors (NMDARs). Using whole-cell recordings, we found higher desensitization of NMDAR currents in the FS group. Since the desensitization of NMDARs depends on subunit composition, we analyzed NMDAR current decays and gene expression of subunits, which revealed no differences between control and FS rats. We suggest that an increased desensitization is due to insufficient activation of the glycine site of NMDARs, as the application of D-serine, the glycine site agonist, allows the restoration of LTP to a control value. Our results reveal a new molecular mechanism of FS impact on the developing brain.
Caveolin-1 Expression in the Dorsal Striatum Drives Methamphetamine Addiction-Like Behavior
Authors: Avchalumov Yosef , Kreisler Alison D. , Trenet Wulfran , Nayak Mahasweta , Head Brian P. , Piña-Crespo Juan C. , Mandyam Chitra D.
Published: July 2021

Dopamine D1 receptor (D1R) function is regulated by membrane/lipid raft-resident protein caveolin-1 (Cav1). We examined whether altered expression of Cav1 in the dorsal striatum would affect self-administration of methamphetamine, an indirect agonist at the D1Rs. A lentiviral construct expressing Cav1 (LV-Cav1) or containing a short hairpin RNA against Cav1 (LV-shCav1) was used to overexpress or knock down Cav1 expression respectively, in the dorsal striatum. Under a fixed-ratio schedule, LV-Cav1 enhanced and LV-shCav1 reduced responding for methamphetamine in an extended access paradigm compared to LV-GFP controls. LV-Cav1 and LV-shCav1 also produced an upward and downward shift in a dose–response paradigm, generating a drug vulnerable/resistant phenotype. LV-Cav1 and LV-shCav1 did not alter responding for sucrose. Under a progressive-ratio schedule, LV-shCav1 generally reduced positive-reinforcing effects of methamphetamine and sucrose as seen by reduced breakpoints. Western blotting confirmed enhanced Cav1 expression in LV-Cav1 rats and reduced Cav1 expression in LV-shCav1 rats. Electrophysiological findings in LV-GFP rats demonstrated an absence of high-frequency stimulation (HFS)-induced long-term potentiation (LTP) in the dorsal striatum after extended access methamphetamine self-administration, indicating methamphetamine-induced occlusion of plasticity. LV-Cav1 prevented methamphetamine-induced plasticity via increasing phosphorylation of calcium calmodulin kinase II, suggesting a mechanism for addiction vulnerability. LV-shCav1 produced a marked deficit in the ability of HFS to produce LTP and, therefore, extended access methamphetamine was unable to alter striatal plasticity, indicating a mechanism for resistance to addiction-like behavior. Our results demonstrate that Cav1 expression and knockdown driven striatal plasticity assist with modulating addiction to drug and nondrug rewards, and inspire new strategies to reduce psychostimulant addiction.
Modulation of Nrf2 and NF-κB Signaling Pathways by Naturally Occurring Compounds in Relation to Cancer Prevention and Therapy. Are Combinations Better Than Single Compounds?
Authors: Krajka-Kuźniak Violetta , Baer-Dubowska Wanda
Published: July 2021

Nrf2 (nuclear factor erythroid 2-related factor 2) and NF-κB (nuclear factor–kappa B) signaling pathways play a central role in suppressing or inducing inflammation and angiogenesis processes. Therefore, they are involved in many steps of carcinogenesis through cooperation with multiple signaling molecules and pathways. Targeting both transcription factors simultaneously may be considered an equally important strategy for cancer chemoprevention and therapy. Several hundreds of phytochemicals, mainly edible plant and vegetable components, were shown to activate Nrf2 and mediate antioxidant response. A similar number of phytochemicals was revealed to affect NF-κB. While activation of Nrf2 and inhibition of NF-κB may protect normal cells against cancer initiation and promotion, enhanced expression and activation in cancer cells may lead to resistance to conventional chemo- or radiotherapy. Most phytochemicals, through different mechanisms, activate Nrf2, but others, such as luteolin, can act as inhibitors of both Nrf2 and NF-κB. Despite many experimental data confirming the above mechanisms currently, limited evidence exists demonstrating such activity in humans. Combinations of phytochemicals resembling that in a natural food matrix but allowing higher concentrations may improve their modulating effect on Nrf2 and NF-κB and ultimately cancer prevention and therapy. This review presents the current knowledge on the effect of selected phytochemicals and their combinations on Nrf2 and NF-κB activities in the above context.
Improving Human Induced Pluripotent Stem Cell-Derived Megakaryocyte Differentiation and Platelet Production
Authors: Krisch Linda , Brachtl Gabriele , Hochmann Sarah , Andrade André Cronemberger , Oeller Michaela , Ebner-Peking Patricia , Schallmoser Katharina , Strunk Dirk
Published: July 2021

Several protocols exist for generating megakaryocytes (MKs) and platelets from human induced pluripotent stem cells (hiPSCs) with limited efficiency. We observed previously that mesoderm induction improved endothelial and stromal differentiation. We, therefore, hypothesized that a protocol modification prior to hemogenic endothelial cell (HEC) differentiation will improve MK progenitor (MKP) production and increase platelet output. We further asked if basic media composition affects MK maturation. In an iterative process, we first compared two HEC induction protocols. We found significantly more HECs using the modified protocol including activin A and CHIR99021, resulting in significantly increased MKs. MKs released comparable platelet amounts irrespective of media conditions. In a final validation phase, we obtained five-fold more platelets per hiPSC with the modified protocol (235 ± 84) compared to standard conditions (51 ± 15; p < 0.0001). The regenerative potency of hiPSC-derived platelets was compared to adult donor-derived platelets by profiling angiogenesis-related protein expression. Nineteen of 24 angiogenesis-related proteins were expressed equally, lower or higher in hiPSC-derived compared to adult platelets. The hiPSC-platelet’s coagulation hyporeactivity compared to adult platelets was confirmed by thromboelastometry. Further stepwise improvement of hiPSC-platelet production will, thus, permit better identification of platelet-mediated regenerative mechanisms and facilitate manufacture of sufficient amounts of functional platelets for clinical application.
The Effects of Aβ1-42 Binding to the SARS-CoV-2 Spike Protein S1 Subunit and Angiotensin-Converting Enzyme 2
Authors: Hsu John Tsu-An , Tien Chih-Feng , Yu Guann-Yi , Shen Santai , Lee Yi-Hsuan , Hsu Pei-Chien , Wang Yun , Chao Po-Kuan , Tsay Huey-Jen , Shie Feng-Shiun
Published: July 2021

Increasing evidence suggests that elderly people with dementia are vulnerable to the development of severe coronavirus disease 2019 (COVID-19). In Alzheimer’s disease (AD), the major form of dementia, β-amyloid (Aβ) levels in the blood are increased; however, the impact of elevated Aβ levels on the progression of COVID-19 remains largely unknown. Here, our findings demonstrate that Aβ1-42, but not Aβ1-40, bound to various viral proteins with a preferentially high affinity for the spike protein S1 subunit (S1) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the viral receptor, angiotensin-converting enzyme 2 (ACE2). These bindings were mainly through the C-terminal residues of Aβ1-42. Furthermore, Aβ1-42 strengthened the binding of the S1 of SARS-CoV-2 to ACE2 and increased the viral entry and production of IL-6 in a SARS-CoV-2 pseudovirus infection model. Intriguingly, data from a surrogate mouse model with intravenous inoculation of Aβ1-42 show that the clearance of Aβ1-42 in the blood was dampened in the presence of the extracellular domain of the spike protein trimers of SARS-CoV-2, whose effects can be prevented by a novel anti-Aβ antibody. In conclusion, these findings suggest that the binding of Aβ1-42 to the S1 of SARS-CoV-2 and ACE2 may have a negative impact on the course and severity of SARS-CoV-2 infection. Further investigations are warranted to elucidate the underlying mechanisms and examine whether reducing the level of Aβ1-42 in the blood is beneficial to the fight against COVID-19 and AD.
In Vitro Evaluation of Rigosertib Antitumoral and Radiosensitizing Effects against Human Cholangiocarcinoma Cells
Authors: Malacrida Alessio , Rigolio Roberta , Celio Luigi , Damian Silvia , Cavaletti Guido , Mazzaferro Vincenzo , Miloso Mariarosaria
Published: July 2021

Cholangiocarcinoma is the first most common cancer of the biliary tract. To date, surgical resection is the only potentially curative option, but it is possible only for a limited percentage of patients, and in any case survival rate is quite low. Moreover, cholangiocarcinoma is often chemotherapy-resistant, and the only drug with a significant benefit for patient’s survival is Gemcitabine. It is necessary to find new drugs or combination therapies to treat nonresectable cholangiocarcinoma and improve the overall survival rate of patients. In this work, we evaluate in vitro the antitumoral effects of Rigosertib, a multi-kinase inhibitor in clinical development, against cholangiocarcinoma EGI-1 cell lines. Rigosertib impairs EGI-1 cell viability in a dose- and time-dependent manner, reversibility is dose-dependent, and significant morphological and nuclear alterations occur. Moreover, Rigosertib induces the arrest of the cell cycle in the G2/M phase, increases autophagy, and inhibits proteasome, cell migration, and invasion. Lastly, Rigosertib shows to be a stronger radiosensitizer than Gemcitabine and 5-Fluorouracil. In conclusion, Rigosertib could be a potential therapeutic option, alone or in combination with radiations, for nonresectable patients with cholangiocarcinoma.
What Drives Authorization in Mobile Applications? A Perspective of Privacy Boundary Management
Authors: Tang Jie , Zhang Bin , Akram Umair
Published: July 2021

Personal information has been likened to “golden data”, which companies have chased using every means possible. Via mobile apps, the incidents of compulsory authorization and excessive data collection have evoked privacy concerns and strong repercussions among app users. This manuscript proposes a privacy boundary management model, which elaborates how such users can demarcate and regulate their privacy boundaries. The survey data came from 453 users who authorized certain operations through mobile apps. The partial least squares (PLS) analysis method was used to validate the instrument and the proposed model. Results indicate that information relevance and transparency play a significant role in shaping app users’ control–risk perceptions, while government regulation is more effective than industry self-discipline in promoting the formation of privacy boundaries. Unsurprisingly, privacy risk control perceptions significantly affect users’ privacy concerns and trust beliefs, which are two vital factors that ultimately influence their willingness to authorize. The implications of conducting a thorough inquiry into app users’ willingness to authorize their privacy information are far-reaching. In relation to this, app vendors should probe into the privacy-relevant beliefs of their users and enact effective privacy practices to intercept the economic and reputational damages induced by improper information collection. More significantly, a comprehensive understanding of users’ willingness to authorize their information can serve as an essential reference for relevant regulatory bodies to formulate reasonable privacy protection policies in the future.
Evolution of Additive Manufacturing in Civil Infrastructure Systems: A Ten-Year Review
Authors: Jamali Koosha , Kaushal Vinayak , Najafi Mohammad
Published: July 2021

As human beings, we have a moral responsibility to act in a manner that takes the wellbeing of humans and Earth into consideration. When building, we must consider two things: the health of the workforce associated with construction and the state of the planet after building. Many engineers in the past have made groundbreaking achievements to revolutionize the civil infrastructure systems (CIS) industry. However, additive manufacturing (AM) has yet to be significantly recognized throughout the CIS industry. In this review, the use of all fundamental materials utilized by AM in CIS like concrete, metals, and polymers, are discussed. The objective of this study is to expand upon the technology of AM, specifically in CIS and to provide a review on the evolution of AM from 2011 to 2021. The different AM techniques that are utilized to construct said structures are also included. The review study suggests that AM can be useful in the CIS industry, as homes, bridges, and benches were manufactured with this technique. To enhance the reader’s visualization, pictures of the related built structures are also presented. It can be concluded that adopting AM techniques in the CIS industry can save material, speed up the construction process, and create a safer environment for the people that work in the CIS industry. Since the research on this subject is limited, further research on polymer printing along with metal printing is recommended.
Japanese Honeybees (Apis cerana japonica Radoszkowski, 1877) May Be Resilient to Land Use Change
Authors: Donkersley Philip , Covell Lucy , Ota Takahiro
Published: July 2021

Pollinators are being threatened globally by urbanisation and agricultural intensification, driven by a growing human population. Understanding these impacts on landscapes and pollinators is critical to ensuring a robust pollination system. Remote sensing data on land use attributes have previously linked honeybee nutrition to land use in the Western Honeybee (Apis mellifera L.). Here, we instead focus on the less commonly studied Apis cerana japonica—the Japanese Honeybee. Our study presents preliminary data comparing forage (honey and pollen) with land use across a rural-urban gradient from 22 sites in Kyushu, southern Japan. Honey samples were collected from hives between June 2018 and August 2019. Pollen were collected and biotyped from hives in urban and rural locations (n = 4). Previous studies of honey show substantial variation in monosaccharide content. Our analysis of A. cerana japonica honey found very little variation in glucose and fructose (which accounted for 97% of monosaccharides), despite substantial differences in surrounding forage composition. As expected, we observed temporal variation in pollen foraged by A. cerana japonica, likely dependent on flowering phenology. These preliminary results suggest that the forage and nutrition of A. cerana japonica may not be negatively affected by urban land use. This highlights the need for further comparative studies between A. cerana japonica and A. mellifera as it could suggest a resilience in pollinators foraging in their native range.