bluuebunny/crossref_metadata_2025 huggingface dataset:
Development of Cellular Models to Study Efficiency and Safety of Gene Edition by Homologous Directed Recombination Using the CRISPR/Cas9 System
Authors: Sánchez-Hernández Sabina , Aguilar-González Araceli , Guijarro-Albaladejo Beatriz , Maldonado-Pérez Noelia , Ramos-Hernández Iris , Cortijo-Gutiérrez Marina , Sánchez Martín Rosario María , Benabdellah Karim , Martin Francisco
Published: June 2020

In spite of the enormous potential of CRISPR/Cas in basic and applied science, the levels of undesired genomic modifications cells still remain mostly unknown and controversial. Nowadays, the efficiency and specificity of the cuts generated by CRISPR/Cas is the main concern. However, there are also other potential drawbacks when DNA donors are used for gene repair or gene knock-ins. These GE strategies should take into account not only the specificity of the nucleases, but also the fidelity of the DNA donor to carry out their function. The current methods to quantify the fidelity of DNA donor are costly and lack sensitivity to detect illegitimate DNA donor integrations. In this work, we have engineered two reporter cell lines (K562_SEWAS84 and K562GWP) that efficiently quantify both the on-target and the illegitimate DNA donor integrations in a WAS-locus targeting setting. K562_SEWAS84 cells allow the detection of both HDR-and HITI-based donor integration, while K562GWP cells only report HDR-based GE. To the best of our knowledge, these are the first reporter systems that allow the use of gRNAs targeting a relevant locus to measure efficacy and specificity of DNA donor-based GE strategies. By using these models, we have found that the specificity of HDR is independent of the delivery method and that the insertion of the target sequence into the DNA donor enhances efficiency but do not affect specificity. Finally, we have also shown that the higher the number of the target sites is, the higher the specificity and efficacy of GE will be.
Unilateral Cleavage Furrows in Multinucleate Cells
Authors: Bindl Julia , Molnar Eszter Sarolta , Ecke Mary , Prassler Jana , Müller-Taubenberger Annette , Gerisch Günther
Published: June 2020

Multinucleate cells can be produced in Dictyostelium by electric pulse-induced fusion. In these cells, unilateral cleavage furrows are formed at spaces between areas that are controlled by aster microtubules. A peculiarity of unilateral cleavage furrows is their propensity to join laterally with other furrows into rings to form constrictions. This means cytokinesis is biphasic in multinucleate cells, the final abscission of daughter cells being independent of the initial direction of furrow progression. Myosin-II and the actin filament cross-linking protein cortexillin accumulate in unilateral furrows, as they do in the normal cleavage furrows of mononucleate cells. In a myosin-II-null background, multinucleate or mononucleate cells were produced by cultivation either in suspension or on an adhesive substrate. Myosin-II is not essential for cytokinesis either in mononucleate or in multinucleate cells but stabilizes and confines the position of the cleavage furrows. In fused wild-type cells, unilateral furrows ingress with an average velocity of 1.7 µm × min−1, with no appreciable decrease of velocity in the course of ingression. In multinucleate myosin-II-null cells, some of the furrows stop growing, thus leaving space for the extensive broadening of the few remaining furrows.
Imprinting the Polytype Structure of Silicon Carbide by Rapid Thermal Processing
Authors: Pezoldt Jörg , Cimalla Volker
Published: June 2020

Silicon carbide is a material with a multistable crystallographic structure, i.e., a polytypic material. Different polytypes exhibit different band gaps and electronic properties with nearly identical basal plane lattice constants, making them interesting for heterostructures without concentration gradients. The controlled formation of this heterostructure is still a challenge. The ability to adjust a defined temperature–time profile using rapid thermal processing was used to imprint the polytype transitions by controlling the nucleation and structural evolution during the temperature ramp-up and the steady state. The influence of the linear heating-up rate velocity during ramp-up and steady-state temperature on the crystal structure of amorphized ion-implanted silicon carbide layers was studied and used to form heteropolytype structures. Integrating the structural selection properties of the non-isothermal annealing stage of the ion-implanted layers into an epitaxial growth process allows the imprinting of polytype patterns in epitaxial layers due to the structural replication of the polytype pattern during epitaxial growth. The developed methodology paves the way for structural selection and vertical and lateral polytype patterning. In rapid thermal chemical vapor deposition, the adjustment of the process parameters or the buffer layer allowed the nucleation and growth of wurtzite silicon carbide.
Power and Efficiency Optimization for Open Combined Regenerative Brayton and Inverse Brayton Cycles with Regeneration before the Inverse Cycle
Authors: Chen Lingen , Feng Huijun , Ge Yanlin
Published: June 2020

A theoretical model of an open combined cycle is researched in this paper. In this combined cycle, an inverse Brayton cycle is introduced into regenerative Brayton cycle by resorting to finite-time thermodynamics. The constraints of flow pressure drop and plant size are taken into account. Thirteen kinds of flow resistances in the cycle are calculated. On the one hand, four isentropic efficiencies are used to evaluate the friction losses in the blades and vanes. On the other hand, nine kinds of flow resistances are caused by the cross-section variances of flowing channels, which exist at the entrance of top cycle compressor (TCC), the entrance and exit of regenerator, the entrance and exit of combustion chamber, the exit of top cycle turbine, the exit of bottom cycle turbine, the entrance of heat exchanger, as well as the entrance of bottom cycle compressor (BCC). To analyze the thermodynamic indexes of power output, efficiency along with other coefficients, the analytical formulae of these indexes related to thirteen kinds of pressure drop losses are yielded. The thermodynamic performances are optimized by varying the cycle parameters. The numerical results reveal that the power output presents a maximal value when the air flow rate and entrance pressure of BCC change. In addition, the power output gets its double maximal value when the pressure ratio of TCC further changes. In the premise of constant flow rate of working fuel and invariant power plant size, the thermodynamic indexes can be optimized further when the flow areas of the components change. The effect of regenerator on thermal efficiency is further analyzed in detail. It is reported that better thermal efficiency can be procured by introducing the regenerator into the combined cycle in contrast with the counterpart without the regenerator as the cycle parameters change in the critical ranges.
Concrete Messages Increase Healthy Eating Preferences
Authors: Balcetis Emily , Manivannan Madhumitha , Cox E. Blair
Published: June 2020

Public health campaigns utilize messaging to encourage healthy eating. The present experimental study investigated the impact of three components of health messages on preferences for healthy foods. We exposed 1676 online, American study participants to messages that described the gains associated with eating healthy foods or the costs associated with not eating healthy foods. Messages also manipulated the degree to which they included abstract and concrete language and the temporal distance to foreshadowed outcomes. Analysis of variance statistical tests indicated that concrete rather than abstract language increased the frequency of choosing healthy over unhealthy foods when indicating food preferences. However, manipulations of proximity to outcomes and gain rather than loss frame did not affect food preferences. We discuss implications for effective public health campaigns, and economic and social cognitive theories of persuasion, and our data suggest that describing health outcomes in concrete rather than abstract terms may motivate healthier choices.
Real-Time and Deep Learning Based Vehicle Detection and Classification Using Pixel-Wise Code Exposure Measurements
Authors: Kwan Chiman , Gribben David , Chou Bryan , Budavari Bence , Larkin Jude , Rangamani Akshay , Tran Trac , Zhang Jack , Etienne-Cummings Ralph
Published: June 2020

One key advantage of compressive sensing is that only a small amount of the raw video data is transmitted or saved. This is extremely important in bandwidth constrained applications. Moreover, in some scenarios, the local processing device may not have enough processing power to handle object detection and classification and hence the heavy duty processing tasks need to be done at a remote location. Conventional compressive sensing schemes require the compressed data to be reconstructed first before any subsequent processing can begin. This is not only time consuming but also may lose important information in the process. In this paper, we present a real-time framework for processing compressive measurements directly without any image reconstruction. A special type of compressive measurement known as pixel-wise coded exposure (PCE) is adopted in our framework. PCE condenses multiple frames into a single frame. Individual pixels can also have different exposure times to allow high dynamic ranges. A deep learning tool known as You Only Look Once (YOLO) has been used in our real-time system for object detection and classification. Extensive experiments showed that the proposed real-time framework is feasible and can achieve decent detection and classification performance.
Analytical Drain Current Model for a-SiGe:H Thin Film Transistors Considering Density of States
Authors: Salas-Rodríguez Silvestre , López-Huerta Francisco , Herrera-May Agustín L. , Molina-Reyes Joel , Martínez-Castillo Jaime
Published: June 2020

Thin film transistors (TFTs) fabricated on flexible and large area substrates have been studied with great interest due to their future applications. Recent studies have developed new semiconductors such as a-SiGe:H for fabrication of high performance TFTs. These films have important advantages, including deposition at low temperatures and low pressures, and higher carrier mobilities. Due to these advantages, the a-SiGe:H films can be used in the fabrication of TFTs. In this work, we present an analytical drain current model for a-SiGe:H TFTs considering density of states and free charges, which describes the current behavior at sub-and above- threshold region. In addition, 2D numerical simulations of a-SiGe:H TFTs are developed. The results of the analytical drain current model agree well with those of the 2D numerical simulations. For all characteristics of the drain current curves, the average absolute error of the analytical model is close to 5.3%. This analytical drain current model can be useful to estimate the performance of a-SiGe:H TFTs for applications in large area electronics.
Add-On Anomaly Threshold Technique for Improving Unsupervised Intrusion Detection on SCADA Data
Authors: Almalawi Abdulmohsen , Fahad Adil , Tari Zahir , Khan Asif Irshad , Alzahrani Nouf , Bakhsh Sheikh Tahir , Alassafi Madini O. , Alshdadi Abdulrahman , Qaiyum Sana
Published: June 2020

Supervisory control and data acquisition (SCADA) systems monitor and supervise our daily infrastructure systems and industrial processes. Hence, the security of the information systems of critical infrastructures cannot be overstated. The effectiveness of unsupervised anomaly detection approaches is sensitive to parameter choices, especially when the boundaries between normal and abnormal behaviours are not clearly distinguishable. Therefore, the current approach in detecting anomaly for SCADA is based on the assumptions by which anomalies are defined; these assumptions are controlled by a parameter choice. This paper proposes an add-on anomaly threshold technique to identify the observations whose anomaly scores are extreme and significantly deviate from others, and then such observations are assumed to be ”abnormal”. The observations whose anomaly scores are significantly distant from ”abnormal” ones will be assumed as ”normal”. Then, the ensemble-based supervised learning is proposed to find a global and efficient anomaly threshold using the information of both ”normal”/”abnormal” behaviours. The proposed technique can be used for any unsupervised anomaly detection approach to mitigate the sensitivity of such parameters and improve the performance of the SCADA unsupervised anomaly detection approaches. Experimental results confirm that the proposed technique achieved a significant improvement compared to the state-of-the-art of two unsupervised anomaly detection algorithms.
Partial Pilot Allocation Scheme in Multi-Cell Massive MIMO Systems for Pilot Contamination Reduction
Authors: Al-hubaishi Ahmed S. , Noordin Nor Kamariah , Sali Aduwati , Subramaniam Shamala , Mansoor Ali Mohammed , Ghaleb Safwan M.
Published: June 2020

Inter-cell interference has been identified as one of the major challenges of multiple-input–multiple-output (MIMO)-enabled cellular systems. This problem occurs when the same pilot sets are reused across adjacent cells to save bandwidth for data transmission. As a result, so-called pilot contamination occurs, which cannot be mitigated with an increased number of serving antennas. In this work, we proposed a partial pilot allocation scheme (PPA) to tackle the pilot contamination problem and consequently improve the uplink throughput of users in multi-cell massive MIMO systems. This was achieved by using the large-scale characteristics of the fading channel to keep users with a weak channel condition out of the effect of severe interference during the pilot allocation process. Simulation results showed that the proposed scheme outperformed both smart pilot allocation (SPA) and conventional schemes. In particular, PPA improved the uplink rate by 30% compared to the SPA—a recently proposed schema. Furthermore, our simulation results clearly showed that PPA improved the cumulative distribution function (CDF) of the signal-to-interference-plus-noise ratio (SINR) and uplink throughput.
Chemistry and Sensory Characterization of a Bakery Product Prepared with Oils from African Edible Insects
Authors: Cheseto Xavier , Baleba Steve B.S. , Tanga Chrysantus M. , Kelemu Segenet , Torto Baldwyn
Published: June 2020

Globally, there is growing interest to integrate insect-derived ingredients into food products. Knowledge of consumer perception to these food products is growing rapidly in the literature, but similar knowledge on the use of oils from African edible insects remains to be established. In this study, we (1) compared the chemistry of the oils from two commonly consumed grasshoppers, the desert locust Schistocerca gregaria and the African bush-cricket Ruspolia differens with those of olive and sesame oils; (2) compared the proximate composition of a baked product (cookie) prepared from the oils; (3) identified the potential volatiles and fatty acids contributing to the aroma and taste; and (4) examined acceptance and willingness to pay (WTP) for the baked product among consumers with no previous experience of entomophagy. Our results showed that the insect oils were compositionally richer in omega-3 fatty acids, flavonoids, and vitamin E than the plant oils. Proximate analysis and volatile chemistry revealed that differences in aroma and taste of the cookies were associated with their sources of oils. Consumers’ acceptance was high for cookies prepared with R. differens (95%) and sesame (89%) oils compared to those with olive and S. gregaria oils. Notably, cookies prepared with insect oils had more than 50% dislike in aroma and taste. Consumers’ willingness to pay for cookies prepared with insect oils was 6–8 times higher than for cookies containing olive oil, but 3–4 times lower than cookies containing sesame oil. Our findings show that integrating edible insect oils into cookies, entices people to ‘‘take the first step” in entomophagy by decreasing insect-based food products neophobia, thereby, contributing to consumers’ acceptance of the baked products. However, future research should explore the use of refined or flavored insect oils for bakery products to reduce off-flavors that might have been perceived in the formulated food products
Impact of the Timing and Temperature of Malolactic Fermentation on the Aroma Composition and Mouthfeel Properties of Chardonnay Wine
Authors: Sereni Anthony , Phan Quynh , Osborne James , Tomasino Elizabeth
Published: June 2020

Malolactic fermentation (MLF) is an important process in wine production due to the resulting reduction in acidity. MLF is typically induced by the addition of Oenococcus oeni after the completion of alcoholic fermentation (AF), but can occur concurrent with AF by co-inoculation of O. oeni with Saccharomyces cerevisiae. This study investigated the effect of MLF inoculation timing and temperature (15 °C and 21 °C) and the presence of the non-Saccharomyces yeast Torulaspora delbrueckii on Chardonnay wine aroma and mouthfeel. Aroma composition was measured using headspace solid-phase microextraction-gas chromatography mass spectrometry (HS-SPME-GCMS). Mouthfeel attributes of the wines produced were assessed by a winemaker panel, using Napping® and Ultra-flash profiling. Significant differences in aroma composition and mouthfeel perception were found based on MLF timing and inoculation conditions, as well as between temperatures. Temperature had a greater impact on the aroma composition for sequential inoculations, while there were little differences based on the temperature of concurrent fermentations. Treatment type and temperature also affected the chemical composition of finished wines. Mouthfeel was impacted, although not as strongly as aroma composition. These findings demonstrate the usefulness of various MLF practices to influence the sensory qualities of a Chardonnay wine.
Exploring and Modeling the Magma–Hydrothermal Regime
Authors: Eichelberger John , Kiryukhin Alexey , Mollo Silvio , Tsuchiya Noriyoshi , Villeneuve Marlène
Published: June 2020

This special issue comprises 12 papers from authors in 10 countries with new insights on the close coupling between magma as an energy and fluid source with hydrothermal systems as a primary control of magmatic behavior. Data and interpretation are provided on the rise of magma through a hydrothermal system, the relative timing of magmatic and hydrothermal events, the temporal evolution of supercritical aqueous fluids associated with ore formation, the magmatic and meteoric contributions of water to the systems, the big picture for the highly active Krafla Caldera, Iceland, as well as the implications of results from drilling at Krafla concerning the magma–hydrothermal boundary. Some of the more provocative concepts are that magma can intrude a hydrothermal system silently, that coplanar and coeval seismic events signal “magma fracking” beneath active volcanoes, that intrusive accumulations may far outlast volcanism, that arid climate favors formation of large magma chambers, and that even relatively dry rhyolite magma can convect rapidly and so lack a crystallizing mush roof. A shared theme is that hydrothermal and magmatic reservoirs need to be treated as a single system.
Association of Physical Fitness with Intelligence and Academic Achievement in Adolescents
Authors: Gil-Espinosa Francisco Javier , Chillón Palma , Fernández-García José Carlos , Cadenas-Sanchez Cristina
Published: June 2020

Physical fitness, intelligence and academic achievement are being studied from a multidisciplinary perspective. In this line, studies to advance our understanding of intelligence and academic achievement could be relevant for designing school-based programs. Our study analyzed the relationship between components of physical fitness including cardiorespiratory fitness, muscular strength and flexibility and general intelligence and academic achievement in adolescents. We recruited 403 adolescents (53.6% boys) with a mean age of 13.7 ± 1.2 years from a secondary school in Spain with a medium socioeconomic status, during the 2015/2016 school year. Cardiorespiratory fitness was assessed by the 20-m shuttle run, muscular strength with the standing long jump test and flexibility with the sit-and-reach test. General intelligence was measured by both the D48 and the Raven tests. School grades were used to determine academic achievement. Linear regression analyses showed that cardiorespiratory fitness was positively associated with intelligence in both the D48 (all β ≥ 0.184, p ≤ 0.016) and the Raven tests (all β ≥ 0.183, p ≤ 0.024). Muscular strength, flexibility and overall fitness were not associated with intelligence (all β ≤ 0.122, p ≥ 0.139). Cardiorespiratory fitness, muscular strength and flexibility were positively associated with academic achievement (all β ≥ 0.089, p ≤ 0.038), except muscular strength, which was not significantly associated with Spanish language or mathematics, (all β ≤ 0.050, p ≥ 0.200). Overall, cardiorespiratory fitness was positively associated with intelligence and academic achievement.
Characteristics of Occupational Exposure to Diesel Engine Exhaust for Shipyard Transporter Signal Workers
Authors: Shin Jungah , Kim Boowook , Kim Hyoung-Ryoul
Published: June 2020

Background: Workers performing signal work for a heavy-duty shipyard transporter are exposed to diesel engine exhaust (DEE), which is classified as a Group 1 carcinogen by the International Agency for Research on Cancer. Here, we evaluate DEE exposure levels for workers engaged in shipyard transporter signal work through measurement of respirable elemental carbon (EC), organic carbon (OC), and total carbon (TC), and identify the factors affecting exposure. Methods: Sixty signal workers were selected, and measured samples were analyzed by thermo-optical transmittance. Results: The mean EC exposure level of a transporter signal worker was 4.16 µg/m3, with a range of 0.69 to 47.81 µg/m3. EC, OC, and TC exposure levels did not show statistically significant differences for individual variables except the measurement date. This was influenced by meteorological factors such as wind speed, and it was confirmed that the work position, number carried, and load capacity in the multiple regression analysis after minimizing the meteorological effects were factors influencing the EC exposure level of the signalman. Conclusions: Meteorological conditions influenced DEE exposure of transporter signal workers who work outdoors. The mean EC exposure level was not high, but exposures to high concentrations of EC were recorded by meteorological factors.
Blockchain-Enabled Corporate Governance and Regulation
Authors: Jayasuriya Daluwathumullagamage Dulani , Sims Alexandra
Published: June 2020

There is considerable hype about blockchain in almost every industry, including finance, with significant investments globally. We conduct a systematic review of 851 records and construct a final article sample of 183 for the sample period 2012 to 2020 to identify relevant factors for blockchain adoption in corporate governance. We conduct textual and empirical analysis to develop a decentralized autonomous governance framework and link traditional corporate governance theories to blockchain adoption. Furthermore, we explore present and future use cases and implications of blockchains in corporate governance. Using our systematic review and textual analysis, we further identify gaps and common trends between prior academic and industry literature. Moreover, for our empirical analysis, we compile a unique database of blockchain investments to forecast future investments. In addition, we explore blockchain potential in corporate governance during and post COVID-19. We find prior academic articles to mostly focus on regulation (49 studies) and Initial Coin Offerings (ICOs) (46 studies), while industry articles tend to concentrate on exchanges (10 studies) and cryptocurrencies (9 articles). A significant growth in literature is observed for 2017 and 2018. Finally, we provide behavioural, regulatory, ethical and managerial perspectives of blockchain adoption in corporate governance.
Extracellular Vesicles and Cell–Cell Communication: New Insights and New Therapeutic Strategies Not Only in Oncology
Authors: Gieseler Frank , Ender Fanny
Published: June 2020

The discovery that tumors are not separated from systemic regulatory mechanisms of the body but are rather integrated into them, and even use these mechanisms for their own purposes, was one of the most important findings in tumor biology of the last few years [...]
Adaptation of the Marine Bacterium Shewanella baltica to Low Temperature Stress
Authors: Kloska Anna , Cech Grzegorz M. , Sadowska Marta , Krause Klaudyna , Szalewska-Pałasz Agnieszka , Olszewski Paweł
Published: June 2020

Marine bacteria display significant versatility in adaptation to variations in the environment and stress conditions, including temperature shifts. Shewanella baltica plays a major role in denitrification and bioremediation in the marine environment, but is also identified to be responsible for spoilage of ice-stored seafood. We aimed to characterize transcriptional response of S. baltica to cold stress in order to achieve a better insight into mechanisms governing its adaptation. We exposed bacterial cells to 8 °C for 90 and 180 min, and assessed changes in the bacterial transcriptome with RNA sequencing validated with the RT-qPCR method. We found that S. baltica general response to cold stress is associated with massive downregulation of gene expression, which covered about 70% of differentially expressed genes. Enrichment analysis revealed upregulation of only few pathways, including aminoacyl-tRNA biosynthesis, sulfur metabolism and the flagellar assembly process. Downregulation was observed for fatty acid degradation, amino acid metabolism and a bacterial secretion system. We found that the entire type II secretion system was transcriptionally shut down at low temperatures. We also observed transcriptional reprogramming through the induction of RpoE and repression of RpoD sigma factors to mediate the cold stress response. Our study revealed how diverse and complex the cold stress response in S. baltica is.
Paclitaxel Induces Upregulation of Transient Receptor Potential Vanilloid 1 Expression in the Rat Spinal Cord
Authors: Kamata Yukako , Kambe Toshie , Chiba Terumasa , Yamamoto Ken , Kawakami Kazuyoshi , Abe Kenji , Taguchi Kyoji
Published: June 2020

Painful peripheral neuropathy is a common adverse effect of paclitaxel (PTX) treatment. To analyze the contribution of transient receptor potential vanilloid 1 (TRPV1) in the development of PTX-induced mechanical allodynia/hyperalgesia and thermal hyperalgesia, TRPV1 expression in the rat spinal cord was analyzed after intraperitoneal administration of 2 and 4 mg/kg PTX. PTX treatment increased the expression of TRPV1 protein in the spinal cord. Immunohistochemistry showed that PTX (4 mg/kg) treatment increased TRPV1 protein expression in the superficial layers of the spinal dorsal horn 14 days after treatment. Behavioral assessment using the paw withdrawal response showed that PTX-induced mechanical allodynia/hyperalgesia and thermal hyperalgesia after 14 days was significantly inhibited by oral or intrathecal administration of the TRPV1 antagonist AMG9810. We found that intrathecal administration of small interfering RNA (siRNA) to knock down TRPV1 protein expression in the spinal cord significantly decreased PTX-induced mechanical allodynia/hyperalgesia and thermal hyperalgesia. Together, these results demonstrate that TRPV1 receptor expression in spinal cord contributes, at least in part, to the development of PTX-induced painful peripheral neuropathy. TRPV1 receptor antagonists may be useful in the prevention and treatment of PTX-induced peripheral neuropathic pain.
Estrogen Receptors and Estrogen-Induced Uterine Vasodilation in Pregnancy
Authors: Bai Jin , Qi Qian-Rong , Li Yan , Day Robert , Makhoul Josh , Magness Ronald R. , Chen Dong-bao
Published: June 2020

Normal pregnancy is associated with dramatic increases in uterine blood flow to facilitate the bidirectional maternal–fetal exchanges of respiratory gases and to provide sole nutrient support for fetal growth and survival. The mechanism(s) underlying pregnancy-associated uterine vasodilation remain incompletely understood, but this is associated with elevated estrogens, which stimulate specific estrogen receptor (ER)-dependent vasodilator production in the uterine artery (UA). The classical ERs (ERα and ERβ) and the plasma-bound G protein-coupled ER (GPR30/GPER) are expressed in UA endothelial cells and smooth muscle cells, mediating the vasodilatory effects of estrogens through genomic and/or nongenomic pathways that are likely epigenetically modified. The activation of these three ERs by estrogens enhances the endothelial production of nitric oxide (NO), which has been shown to play a key role in uterine vasodilation during pregnancy. However, the local blockade of NO biosynthesis only partially attenuates estrogen-induced and pregnancy-associated uterine vasodilation, suggesting that mechanisms other than NO exist to mediate uterine vasodilation. In this review, we summarize the literature on the role of NO in ER-mediated mechanisms controlling estrogen-induced and pregnancy-associated uterine vasodilation and our recent work on a “new” UA vasodilator hydrogen sulfide (H2S) that has dramatically changed our view of how estrogens regulate uterine vasodilation in pregnancy.
Secretome Analysis of Mesenchymal Stem Cell Factors Fostering Oligodendroglial Differentiation of Neural Stem Cells In Vivo
Authors: Samper Agrelo Iria , Schira-Heinen Jessica , Beyer Felix , Groh Janos , Bütermann Christine , Estrada Veronica , Poschmann Gereon , Bribian Ana , Jadasz Janusz J. , Lopez-Mascaraque Laura , Kremer David , Martini Rudolf , Müller Hans Werner , Hartung Hans Peter , Adjaye James , Stühler Kai , Küry Patrick
Published: June 2020

Mesenchymal stem cell (MSC)-secreted factors have been shown to significantly promote oligodendrogenesis from cultured primary adult neural stem cells (aNSCs) and oligodendroglial precursor cells (OPCs). Revealing underlying mechanisms of how aNSCs can be fostered to differentiate into a specific cell lineage could provide important insights for the establishment of novel neuroregenerative treatment approaches aiming at myelin repair. However, the nature of MSC-derived differentiation and maturation factors acting on the oligodendroglial lineage has not been identified thus far. In addition to missing information on active ingredients, the degree to which MSC-dependent lineage instruction is functional in vivo also remains to be established. We here demonstrate that MSC-derived factors can indeed stimulate oligodendrogenesis and myelin sheath generation of aNSCs transplanted into different rodent central nervous system (CNS) regions, and furthermore, we provide insights into the underlying mechanism on the basis of a comparative mass spectrometry secretome analysis. We identified a number of secreted proteins known to act on oligodendroglia lineage differentiation. Among them, the tissue inhibitor of metalloproteinase type 1 (TIMP-1) was revealed to be an active component of the MSC-conditioned medium, thus validating our chosen secretome approach.
Synphilin-1 Interacts with AMPK and Increases AMPK Phosphorylation
Authors: Li Tianxia , Liu Jingnan , Guo Gongbo , Ning Bo , Li Xueping , Zhu Guangjing , Yang Dejun , Moran Timothy H. , Smith Wanli W.
Published: June 2020

A role for the cytoplasmic protein synphilin-1 in regulating energy balance has been demonstrated recently. Expression of synphilin-1 increases ATP levels in cultured cells. However, the mechanism by which synphilin-1 alters cellular energy status is unknown. Here, we used cell models and biochemical approaches to investigate the cellular functions of synphilin-1 on the AMP-activated protein kinase (AMPK) signaling pathway, which may affect energy balance. Overexpression of synphilin-1 increased AMPK phosphorylation (activation). Moreover, synphilin-1 interacted with AMPK by co-immunoprecipitation and GST (glutathione S-transferase) pull-down assays. Knockdown of synphilin-1 reduced AMPK phosphorylation. Overexpression of synphilin-1 also altered AMPK downstream signaling, i.e., a decrease in acetyl CoA carboxylase (ACC) phosphorylation, and an increase in p70S6K phosphorylation. Treatment of compound C (an AMPK inhibitor) reduced synphilin-1 binding with AMPK. In addition, compound C diminished synphilin-1-induced AMPK phosphorylation, and the increase in cellular ATP (adenosine triphosphate) levels. Our results demonstrated that synphilin-1 couples with AMPK, and they exert mutual effects on each other to regulate cellular energy status. These findings not only identify novel cellular actions of synphilin-1, but also provide new insights into the roles of synphilin-1 in regulating energy currency, ATP.
Has Drug Repurposing Fulfilled Its Promise in Acute Myeloid Leukaemia?
Authors: Valli Debora , Gruszka Alicja M. , Alcalay Myriam
Published: June 2020

Drug repurposing is a method of drug discovery that consists of finding a new therapeutic context for an old drug. Compound identification arises from screening of large libraries of active compounds, through interrogating databases of cell line gene expression response upon treatment or by merging several types of information concerning disease–drug relationships. Although, there is a general consensus on the potential and advantages of this drug discovery modality, at the practical level to-date no non-anti-cancer repurposed compounds have been introduced into standard acute myeloid leukaemia (AML) management, albeit that preclinical validation yielded several candidates. The review presents the state-of-the-art drug repurposing approach in AML and poses the question of what has to be done in order to take a full advantage of it, both at the stage of screening design and later when progressing from the preclinical to the clinical phases of drug development. We argue that improvements are needed to model and read-out systems as well as to screening technologies, but also to more funding and trust in drug repurposing strategies.
CAR-T Cell Therapy—An Overview of Targets in Gastric Cancer
Authors: Bębnowska Dominika , Grywalska Ewelina , Niedźwiedzka-Rystwej Paulina , Sosnowska-Pasiarska Barbara , Smok-Kalwat Jolanta , Pasiarski Marcin , Góźdź Stanisław , Roliński Jacek , Polkowski Wojciech
Published: June 2020

Gastric cancer (GC) is one of the most commonly diagnosed malignancies and, unfortunately, still has a high mortality rate. Recent research points to CAR-T immunotherapy as a promising treatment for this disease. Using genetically engineered T cells designed to target a previously selected antigen, researchers are able to harness the natural anti-tumor activity of T cells. For therapy to be successful, however, it is essential to choose antigens that are present on tumor cells but not on healthy cells. In this review, we present an overview of the most important targets for CAR-T therapy in the context of GC, including their biologic function and therapeutic application. A number of clinical studies point to the following as important markers in GC: human epidermal growth factor receptor 2, carcinoembryonic antigen, mucin 1, epithelial cell adhesion molecule, claudin 18.2, mesothelin, natural-killer receptor group 2 member D, and folate receptor 1. Although these markers have been met with some success, the search for new and improved targets continues. Key among these novel biomarkers are the B7H6 ligand, actin-related protein 2/3 (ARP 2/3), neuropilin-1 (NRP-1), desmocollin 2 (DSC2), anion exchanger 1 (AF1), and cancer-related antigens CA-72-4 and CA-19-9.
Using Bayesian Networks to Predict Long-Term Health-Related Quality of Life and Comorbidity after Bariatric Surgery: A Study Based on the Scandinavian Obesity Surgery Registry
Authors: Cao Yang , Raoof Mustafa , Szabo Eva , Ottosson Johan , Näslund Ingmar
Published: June 2020

Previously published literature has identified a few predictors of health-related quality of life (HRQoL) after bariatric surgery. However, performance of the predictive models was not evaluated rigorously using real world data. To find better methods for predicting prognosis in patients after bariatric surgery, we examined performance of the Bayesian networks (BN) method in predicting long-term postoperative HRQoL and compared it with the convolution neural network (CNN) and multivariable logistic regression (MLR). The patients registered in the Scandinavian Obesity Surgery Registry (SOReg) were used for the current study. In total, 6542 patients registered in the SOReg between 2008 and 2012 with complete demographic and preoperative comorbidity information, and preoperative and postoperative 5-year HROoL scores and comorbidities were included in the study. HRQoL was measured using the RAND-SF-36 and the obesity-related problems scale. Thirty-five variables were used for analyses, including 19 predictors and 16 outcome variables. The Gaussian BN (GBN), CNN, and a traditional linear regression model were used for predicting 5-year HRQoL scores, and multinomial discrete BN (DBN) and MLR were used for 5-year comorbidities. Eighty percent of the patients were randomly selected as a training dataset and 20% as a validation dataset. The GBN presented a better performance than the CNN and the linear regression model; it had smaller mean squared errors (MSEs) than those from the CNN and the linear regression model. The MSE of the summary physical scale was only 0.0196 for GBN compared to the 0.0333 seen in the CNN. The DBN showed excellent predictive ability for 5-year type 2 diabetes and dyslipidemia (area under curve (AUC) = 0.942 and 0.917, respectively), good ability for 5-year hypertension and sleep apnea syndrome (AUC = 0.891 and 0.834, respectively), and fair ability for 5-year depression (AUC = 0.750). Bayesian networks provide useful tools for predicting long-term HRQoL and comorbidities in patients after bariatric surgery. The hybrid network that may involve variables from different probability distribution families deserves investigation in the future.
Sacubitril/Valsartan Improves Autonomic Function and Cardiopulmonary Parameters in Patients with Heart Failure with Reduced Ejection Fraction
Authors: Giallauria Francesco , Vitale Giuseppe , Pacileo Mario , Di Lorenzo Anna , Oliviero Alessandro , Passaro Francesco , Calce Roberta , Parlato Alessandro , Testa Crescenzo , D’Ambrosio Giuseppe , Romano Giuseppe , Clemenza Francesco , Sarullo Silvia , Venturini Elio , Gentile Marco , Nugara Cinzia , Iannuzzo Gabriella , D’Andrea Antonello , Vigorito Carlo , Sarullo Filippo M.
Published: June 2020

Background: Heart rate recovery (HRR) is a marker of vagal tone, which is a powerful predictor of mortality in patients with cardiovascular disease. Sacubitril/valsartan (S/V) is a treatment for heart failure with reduced ejection fraction (HFrEF), which impressively impacts cardiovascular outcome. This study aims at evaluating the effects of S/V on HRR and its correlation with cardiopulmonary indexes in HFrEF patients. Methods: Patients with HFrEF admitted to outpatients’ services were screened out for study inclusion. S/V was administered according to guidelines. Up-titration was performed every 4 weeks when tolerated. All patients underwent laboratory measurements, Doppler-echocardiography, and cardiopulmonary exercise stress testing (CPET) at baseline and at 12-month follow-up. Results: Study population consisted of 134 HFrEF patients (87% male, mean age 57.9 ± 9.6 years). At 12-month follow-up, significant improvement in left ventricular ejection fraction (from 28% ± 5.8% to 31.8% ± 7.3%, p < 0.0001), peak exercise oxygen consumption (VO2peak) (from 15.3 ± 3.7 to 17.8 ± 4.2 mL/kg/min, p < 0.0001), the slope of increase in ventilation over carbon dioxide output (VE/VCO2 slope )(from 33.4 ± 6.2 to 30.3 ± 6.5, p < 0.0001), and HRR (from 11.4 ± 9.5 to 17.4 ± 15.1 bpm, p = 0.004) was observed. Changes in HRR were significantly correlated to changes in VE/VCO2slope (r = −0.330; p = 0.003). After adjusting for potential confounding factors, multivariate analysis showed that changes in HRR were significantly associated to changes in VE/VCO2slope (Beta (B) = −0.975, standard error (SE) = 0.364, standardized Beta coefficient (Bstd) = −0.304, p = 0.009). S/V showed significant reduction in exercise oscillatory ventilation (EOV) detection at CPET (28 EOV detected at baseline CPET vs. 9 EOV detected at 12-month follow-up, p < 0.001). HRR at baseline CPET was a significant predictor of EOV at 12-month follow-up (B = −2.065, SE = 0.354, p < 0.001). Conclusions: In HFrEF patients, S/V therapy improves autonomic function, functional capacity, and ventilation. Whether these findings might translate into beneficial effects on prognosis and outcome remains to be elucidated.
Comparison of Three Nutritional Screening Tools with the New Glim Criteria for Malnutrition and Association with Sarcopenia in Hospitalized Older Patients
Authors: Bellanti Francesco , Lo Buglio Aurelio , Quiete Stefano , Pellegrino Giuseppe , Dobrakowski Michał , Kasperczyk Aleksandra , Kasperczyk Sławomir , Vendemiale Gianluigi
Published: June 2020

The integrated assessment of nutritional status and presence of sarcopenia would help improve clinical outcomes of in-hospital aged patients. We compared three common nutritional screening tools with the new Global Leadership Initiative on Malnutrition (GLIM) diagnostic criteria among hospitalized older patients. To this, 152 older patients were assessed consecutively at hospital admission by the Malnutrition Universal Screening Tool (MUST), the Subjective Global Assessment (SGA), and the Nutritional Risk Screening 2002 (NRS-2002). A 46% prevalence of malnutrition was reported according to GLIM. Sensitivity was 64%, 96% and 47%, and specificity was 82%, 15% and 76% with the MUST, SGA, and NRS-2002, respectively. The concordance with GLIM criteria was 89%, 53% and 62% for the MUST, SGA, and NRS-2002, respectively. All the screening tools had a moderate value to diagnose malnutrition. Moreover, patients at high nutritional risk by MUST were more likely to present with sarcopenia than those at low risk (OR 2.5, CI 1.3-3.6). To conclude, MUST is better than SGA and NRS-2002 at detecting malnutrition in hospitalized older patients diagnosed by the new GLIM criteria. Furthermore, hospitalized older patients at high risk of malnutrition according to MUST are at high risk of presenting with sarcopenia. Nutritional status should be determined by MUST in older patients at hospital admission, followed by both GLIM and the European Working Group on Sarcopenia in Older People (EWGSOP2) assessment.
Regular Training Increases sTWEAK and Its Decoy Receptor sCD163–Does Training Trigger the sTWEAK/sCD163-Axis to Induce an Anti-Inflammatory Effect?
Authors: Schönbauer Robert , Lichtenauer Michael , Paar Vera , Emich Michael , Fritzer-Szekeres Monika , Schukro Christoph , Strametz-Juranek Jeanette , Sponder Michael
Published: June 2020

Background: Low levels of soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) were reported in patients with coronary artery disease, heart failure, chronic kidney disease and diabetes mellitus. Soluble cluster differentiation 163 (sCD163) serum levels are related to M2 macrophages, having anti-inflammatory attributes. As sport is well-known for its anti-inflammatory and cardioprotective effects we aimed to investigate the influence of eight months of physical activity on serum sCD163 and sTWEAK levels. Methods: In total, 109 subjects with at least one cardiovascular risk factor were asked to perform endurance training within the calculated training pulse for eight months. Overall, 98 finished the study. The performance gain was measured/quantified by bicycle stress tests at the beginning and end of the observation period. The cohort was divided into four groups, dependent on their baseline performance and performance gain. sCD163 and sTWEAK were measured at baseline and after two, six and eight months by ELISA. Results: Those participants who had a performance gain of ≤2.9% (mean gain 12%) within eight months showed a significant increase in sTWEAK (group 2: from 133 to 200 pg/mL, p = 0.002 and group 4: from 166 to 212 pg/mL, p = 0.031) and sCD163 levels (group 2: from 255 to 348 ng/mL, p = 0.035 and group 4: from 247 to 288 ng/mL, p = 0.025) in contrast to subjects without performance gain (sTWEAK: group 1: from 161 to 177 pg/mL, p = 0.953 and group 3: from 153 to 176 pg/mL, p = 0.744; sCD163: group 1: from 289 to 256 ng/mL, p = 0.374 and group 4: from 291 to 271 ng/mL, p = 0.913). Baseline sCD163 correlated with erythrocyte count, hematocrit, ASAT and lipoprotein a, the presence of hypertension and a BMI > 30 kg/m2. Conclusion: Regular physical activity leads to a significant increase in sCD163 and sTWEAK levels of up to 37% and 50%, respectively. It is well-known that physical activity prevents or retards the onset and genesis of chronic inflammatory disease. One possible way of how training evolves its beneficial effect might be by modifying the inflammation status using the sTWEAK–sCD163 axis. Brief Summary: Regular physical activity leads to a significant increase in sTWEAK and sCD163 levels. Both factors are diminished in patients with chronic (inflammation-based) diseases, such as coronary artery disease, heart failure, pulmonary artery hypertension, chronic kidney disease and diabetes mellitus. It seems that the amounts of soluble TWEAK and CD163 are essential for a healthy balance and modulation between pro- and anti-inflammatory processes, and regular physical training could use the sCD163–sTWEAK axis to unfold its beneficial effect.
Small-Diameter Subchondral Drilling Improves DNA and Proteoglycan Content of the Cartilaginous Repair Tissue in a Large Animal Model of a Full-Thickness Chondral Defect
Authors: Orth Patrick , Eldracher Mona , Cucchiarini Magali , Madry Henning
Published: June 2020

This study quantified changes in the DNA content and extracellular matrix composition of both the cartilaginous repair tissue and the adjacent cartilage in a large animal model of a chondral defect treated by subchondral drilling. Content of DNA, proteoglycans, and Type II and Type I collagen, as well as their different ratios were assessed at 6 months in vivo after treatment of full-thickness cartilage defects in the femoral trochlea of adult sheep with six subchondral drill holes, each of either 1.0 mm or 1.8 mm in diameter by biochemical analyses of the repair tissue and the adjacent cartilage and compared with the original cartilage. Only subchondral drilling which were 1.0 mm in diameter significantly increased both DNA and proteoglycan content of the repair tissue compared to the original cartilage. DNA content correlated with the proteoglycan and Type II collagen content within the repair tissue. Significantly higher amounts of Type I collagen within the repair tissue and significantly increased DNA, proteoglycan, and Type I collagen content in the adjacent cartilage were identified. These translational data support the use of small-diameter bone-cutting devices for marrow stimulation. Signs of early degeneration were present within the cartilaginous repair tissue and the adjacent cartilage.