bluuebunny/crossref_metadata_2025 huggingface dataset:
The Effects of Red Light on Mammalian Sperm Rely upon the Color of the Straw and the Medium Used
Authors: Catalán Jaime , Yánez-Ortiz Iván , Gacem Sabrina , Papas Marion , Bonet Sergi , Rodríguez-Gil Joan E. , Yeste Marc , Miró Jordi
Published: January 2021

Previous research has determined that irradiation of mammalian sperm with red light increases motility, mitochondrial activity, and fertilization capacity. In spite of this, no study has considered the potential influence of the color of the straw and the extender used. Therefore, this study tests the hypothesis that the response of mammalian sperm to red light is influenced by the color of the straw and the turbidity/composition of the extender. Using the horse as a model, 13 ejaculates from 13 stallions were split into two equal fractions, diluted with Kenney or Equiplus extender, and stored at 4 °C for 24 h. Thereafter, each diluted fraction was split into five equal aliquots and subsequently packed into 0.5-mL straws of red, blue, yellow, white, or transparent color. Straws were either nonirradiated (control) or irradiated with a light–dark–light pattern of 3–3–3 (i.e., light: 3 min, dark: 3 min; light: 3 min) prior to evaluating sperm motility, acrosome and plasma membrane integrity, mitochondrial membrane potential, and intracellular ROS and calcium levels. Our results showed that irradiation increased some motion variables, mitochondrial membrane potential, and intracellular ROS without affecting the integrities of the plasma membrane and acrosome. Remarkably, the extent of those changes varied with the color of the straw and the extender used; the effects of irradiation were more apparent when sperm were diluted with Equiplus extender and packed into red-colored straws or when samples were diluted with Kenney extender and packed into transparent straws. As the increase in sperm motility and intracellular ROS levels was parallel to that of mitochondrial activity, we suggest that the impact of red light on sperm function relies upon the specific rates of energy provided to the mitochondria, which, in turn, vary with the color of the straw and the turbidity/composition of the extender.
The Impact of the Sex of Handlers and Riders on the Reported Social Confidence, Compliance and Touch Sensitivity of Horses in Their Care
Authors: Anzulewicz Ashley , Fenner Kate , Hyde Michelle , Heald Susan , Burattini Bibiana , Romness Nicole , McKenzie Jessica , Wilson Bethany , McGreevy Paul
Published: January 2021

Current evidence of how human sex-related differences in riders and handlers may influence horse behaviour is limited. The Equine Behaviour Assessment and Research Questionnaire (E-BARQ) was used to collect demographic data on riders and handlers (n = 1420) and behavioural data on their horses. It includes demographic items about the sex of the respondent and how frequently the horse has been ridden or handled by male and female humans. The questionnaire then gathers observations on the horse’s behaviour on the ground and under saddle or when driven. Using E-BARQ’s battery of 97 questions, the current study showed differences in ridden and non-ridden horse behaviour that were related to the sex of the rider or handler. Data were evaluated using multivariate analysis and revealed that horses handled by male humans were significantly more difficult to catch (t-value = −3.11; p = 0.002) and significantly more defensive when approached (t-value = −2.104; p = 0.035), but significantly less likely to pull on the reins/brace the neck or toss their head (t-value 1.980; p = 0.048) than horses handled more frequently by female humans. The differences found between male and female horse handlers suggest that sex is an important factor to consider when understanding equine behaviour. Our study explored reported differences in confidence, handling and working compliance and touch sensitivity among horses ridden and handled by male and female humans and suggested further research into how these differences are gendered.
An Immunoregulatory Role for Complement Receptors in Murine Models of Breast Cancer
Authors: Akhir Fazrena Nadia Md , Noor Mohd Hezmee Mohd , Leong Keith Weng Kit , Nabizadeh Jamileh A. , Manthey Helga D. , Sonderegger Stefan E. , Fung Jenny Nga Ting , McGirr Crystal E. , Shiels Ian A. , Mills Paul C. , Woodruff Trent M. , Rolfe Barbara E.
Published: January 2021

The complement system has demonstrated roles in regulating tumor growth, although these may differ between tumor types. The current study used two murine breast cancer models (EMT6 and 4T1) to investigate whether pharmacological targeting of receptors for complement proteins C3a (C3aR) and C5a (C5aR1) is protective in murine breast cancer models. In contrast to prior studies in other tumor models, treatment with the selective C5aR1 antagonist PMX53 had no effect on tumor growth. However, treatment of mice with a dual C3aR/C5aR1 agonist (YSFKPMPLaR) significantly slowed mammary tumor development and progression. Examination of receptor expression by quantitative polymerase chain reaction (qPCR) analysis showed very low levels of mRNA expression for either C3aR or C5aR1 by EMT6 or 4T1 mammary carcinoma cell lines compared with the J774 macrophage line or bone marrow-derived macrophages. Moreover, flow cytometric analysis found no evidence of C3aR or C5aR1 protein expression by either EMT6 or 4T1 cells, leading us to hypothesize that the tumor inhibitory effects of the dual agonist are indirect, possibly via regulation of the anti-tumor immune response. This hypothesis was supported by flow cytometric analysis of tumor infiltrating leukocyte populations, which demonstrated a significant increase in T lymphocytes in mice treated with the C3aR/C5aR1 agonist. These results support an immunoregulatory role for complement receptors in primary murine mammary carcinoma models. They also suggest that complement activation peptides can influence the anti-tumor response in different ways depending on the cancer type, the host immune response to the tumor and levels of endogenous complement activation within the tumor microenvironment.
Long-Term Use of Tedizolid in Osteoarticular Infections: Benefits among Oxazolidinone Drugs
Authors: Benavent Eva , Morata Laura , Escrihuela-Vidal Francesc , Reynaga Esteban Alberto , Soldevila Laura , Albiach Laia , Pedro-Botet Maria Luisa , Padullés Ariadna , Soriano Alex , Murillo Oscar
Published: January 2021

Background: To evaluate the efficacy and safety of long-term use of tedizolid in osteoarticular infections. Methods: Multicentric retrospective study (January 2017–March 2019) of osteoarticular infection cases treated with tedizolid. Failure: clinical worsening despite antibiotic treatment or the need of suppressive treatment. Results: Cases (n = 51; 59% women, mean age of 65 years) included osteoarthritis (n = 27, 53%), prosthetic joint infection (n = 17, 33.3%), and diabetic foot infections (n = 9, 18%); where, 59% were orthopedic device-related. Most frequent isolates were Staphylococcus spp. (65%, n = 47; S. aureus, 48%). Reasons for choosing tedizolid were potential drug-drug interaction (63%) and cytopenia (55%); median treatment duration was 29 days (interquartile range -IQR- 15–44), 24% received rifampicin (600 mg once daily) concomitantly, and adverse events were scarce (n = 3). Hemoglobin and platelet count stayed stable throughout treatment (from 108.6 g/L to 116.3 g/L, p = 0.079; and 240 × 109/L to 239 × 109/L, p = 0.942, respectively), also in the subgroup of cases with cytopenia. Among device-related infections, 33% were managed with implant retention. Median follow-up was 630 days and overall cure rate 83%; among failures (n = 8), 63% were device-related infections. Conclusions: Long-term use of tedizolid was effective, showing a better safety profile with less myelotoxicity and lower drug-drug interaction than linezolid. Confirmation of these advantages could make tedizolid the oxazolidinone of choice for most of osteoarticular infections.
Carbapenem-Resistant Klebsiella pneumoniae Clinical Isolates: In Vivo Virulence Assessment in Galleria mellonella and Potential Therapeutics by Polycationic Oligoethyleneimine
Authors: Mil-Homens Dalila , Martins Maria , Barbosa José , Serafim Gabriel , Sarmento Maria J. , Pires Rita F. , Rodrigues Vitória , Bonifácio Vasco D.B. , Pinto Sandra N.
Published: January 2021

Klebsiella pneumoniae, one of the most common pathogens found in hospital-acquired infections, is often resistant to multiple antibiotics. In fact, multidrug-resistant (MDR) K. pneumoniae producing KPC or OXA-48-like carbapenemases are recognized as a serious global health threat. In this sense, we evaluated the virulence of K. pneumoniae KPC(+) or OXA-48(+) aiming at potential antimicrobial therapeutics. K. pneumoniae carbapenemase (KPC) and the expanded-spectrum oxacillinase OXA-48 isolates were obtained from patients treated in medical care units in Lisbon, Portugal. The virulence potential of the K. pneumonia clinical isolates was tested using the Galleria mellonella model. For that, G. mellonella larvae were inoculated using patients KPC(+) and OXA-48(+) isolates. Using this in vivo model, the KPC(+) K. pneumoniae isolates showed to be, on average, more virulent than OXA-48(+). Virulence was found attenuated when a low bacterial inoculum (one magnitude lower) was tested. In addition, we also report the use of a synthetic polycationic oligomer (L-OEI-h) as a potential antimicrobial agent to fight infectious diseases caused by MDR bacteria. L-OEI-h has a broad-spectrum antibacterial activity and exerts a significantly bactericidal activity within the first 5-30 min treatment, causing lysis of the cytoplasmic membrane. Importantly, the polycationic oligomer showed low toxicity against in vitro models and no visible cytotoxicity (measured by survival and health index) was noted on the in vivo model (G. mellonella), thus L-OEI-h is foreseen as a promising polymer therapeutic for the treatment of MDR K. pneumoniae infections.
Evaluation of IL1β and IL6 Gingival Crevicular Fluid Levels during the Early Phase of Orthodontic Tooth Movement in Adolescents and Young Adults
Authors: Chelărescu Simina , Șurlin Petra , Decusară Mioara , Oprică Mădălina , Bud Eugen , Teodorescu Elina , Elsaafin Mahmoud Nabil , Păcurar Mariana
Published: January 2021

Background: The crevicular fluid analysis represents a useful diagnosis tool, with the help of which noninvasive cellular metabolic activity can be analyzed. The aim of the study is to investigate comparatively IL1β and IL6 in the gingival crevicular fluid of clinically healthy adolescents and young adults during the acute phase of orthodontic treatment. Methods: Gingival crevicular fluid was collected from 20 patients (aged between 11 and 28) undergoing orthodontic treatment. Measurements were taken before (T0) and after 24 h after distalization forces were activated (T1). IL1β and IL 6 were analyzed using Elisa tests. The statistical tests used were two-sided t tests. Results: Between the two time periods there was a significant raise both in the crevicular fluid rate (0.57 µL at T0 vs. 0.95 µL at T1, p = 0.001) and in IL1β levels (15.67 pg/µL at T0 vs. 27.94 pg/µL at T1, p = 0.009). We were able to identify IL6 only in a third of the sites. There is a significantly increased level of ILβ at T1 in adolescents, more than in young adults (42.96 pg/µL vs. 17.93 pg/µL, p = 0.006). Conclusions: In the early stage of orthodontic treatment, the periodontal tissues of adolescents are more responsive to orthodontic forces than those of young adults.
Numerical Modeling of the Motion and Interaction of a Droplet of an Inkjet Printing Process with a Flat Surface
Authors: Tofan Tim , Kruggel-Emden Harald , Turla Vytautas , Jasevičius Raimondas
Published: January 2021

The numerical simulation and analysis of the ejection of an ink droplet through a nozzle as well its motion through air until its contact with a surface and taking up of a stable form is performed. The fluid flow is modeled by the incompressible Navier–Stokes equations with added surface tension. The presented model can be solved using either a level set or a phase field method to track the fluid interface. Here, the level set method is used to determinate the interface between ink and air. The presented work concentrates on the demonstration how to check the suitability of ink for inkjet printhead nozzles, for instance, for the use in printers. The results such as velocity, change of size, and volume dependence on time of an ink droplet are presented. Recommendations for the use of specific inks are also given.
Fiber-Based Sensors and Energy Systems for Wearable Electronics
Authors: Lee Jungjoon , Jeon Sungha , Seo Hyeonyeob , Lee Jung Tae , Park Seongjun
Published: January 2021

Wearable electronics have been receiving increasing attention for the past few decades. Particularly, fiber-based electronics are considered to be ideal for many applications for their flexibility, lightweight, breathability, and comfortability. Furthermore, fibers and fiber-based textiles can be 3D-molded with ease and potentially integrated with everyday clothes or accessories. These properties are especially desired in the fields of bio-related sensors and energy-storage systems. Wearable sensors utilize a tight interface with human skin and clothes for continuous environmental scanning and non-invasive health monitoring. At the same time, their flexible and lightweight properties allow more convenient and user-friendly experiences to the wearers. Similarly, for the wearable devices to be more accessible, it is crucial to incorporate energy harvesting and storage systems into the device themselves, removing the need to attach an external power source. This review summarizes the recent applications of fibers and fiber-based textiles in mechanical, photonic, and biomedical sensors. Pressure and strain sensors and their implementation as electronic skins will be explored, along with other various fiber sensors capable of imaging objects or monitoring safety and health markers. In addition, we attempt to elucidate recent studies in energy-storing fibers and their implication in self-powered and fully wireless wearable devices.
Selection of Features Based on Electric Power Quantities for Non-Intrusive Load Monitoring
Authors: Cannas Barbara , Carcangiu Sara , Carta Daniele , Fanni Alessandra , Muscas Carlo
Published: January 2021

Non-intrusive load monitoring (NILM) is a process of determining the operating states and the energy consumption of single electric devices using a single energy meter providing aggregate load measurements. Due to the large spread of power electronic-based and nonlinear devices connected to the network, the time signals of both voltage and current are typically non-sinusoidal. The effectiveness of a NILM algorithm strongly depends on determining a set of discriminative features. In this paper, voltage and current signals were combined to define, according to the definitions provided in Standard IEEE 1459, different power quantities, that can be used to distinguish different types of appliance. Multi-layer perceptron (MLP) classifiers were trained to solve the appliance detection problem as a multi-class event classification problem, varying the electric features in input. This allowed to select an optimal set of features guarantying good classification performance in identifying typical electric loads.
Suitability of the Available Options About Computer Applications to Record the Initial Assessment of the Nutritional Care Process: A Pilot Study in Spanish Software
Authors: Gomis Mario Navarro , Martínez-Sanz José Miguel , Sospedra Isabel , Romá-Ferri María Teresa
Published: January 2021

Background: Nutritional software applications are tools for professional care. These applications allow the management of relevant information, facilitating and speeding up the diet treatment, and are designed for a general population with potential nutritional problems. The aim to establish the degree to which existing nutritional software in Spanish covers the nutritional assessment aspects that dietitian needs to manage the nutritional care process (NCP). Methods: A descriptive-comparative study of four open-access and/or trial version nutritional software applications was performed, focusing on the informational content that must be recorded by the dietitian when performing a nutritional assessment. The usability and usefulness of the NCP were analyzed by means of a dichotomous scale (yes/no) and a five-level Likert scale (very complete, complete, basic, poor, very poor). Data collection was carried out from December 2018 to April 2019. Results: The software applications collect personal data in a very intuitive way, and with respect to the nutritional assessment, the applications generally comply with the collection of the basic information necessary for subsequent dietetic planning and are complete in the coinciding items, especially in Dietopro® (Valencia, Spain) and Easydiet® (Navarra, Spain). Conclusion: The applications are generally adapted to the ADA and BDA specifications, though the information is dispersed and without a sequential order for professionals.
Improving the Accuracy of Remote Sensing Land Cover Classification by GEO-ECO Zoning Coupled with Geostatistical Simulation
Authors: Zhu Ling , Li Jing , La Yixuan , Jia Tao
Published: January 2021

Land cover products obtained from remote sensing image classification inevitably contain a large number of false classification or uncertain pixels because of spectral confusion, image resolution limitation, and ground object complexity. The confusion matrix used to evaluate the classification accuracy cannot reflect the spatial variation. The information provided to users of land cover products is incomplete and uncertain. In this study, a method is presented to evaluate and improve the accuracy of land cover classification products by coupling Geo-Eco zoning and Markov chain geoscience statistical simulation. Validation points collected from various sources are used in the model calculation and accuracy verification of results. The pre-classified image that needs to be improved and Geo-Eco zoning attribute data are used as auxiliary data for co-simulation. Results show that the accuracy of Globeland30 data can be improved by more than 10% by coupling Geo-Eco zoning and Markov chain geostatistical simulation.
Impulsive Noise Removal with an Adaptive Weighted Arithmetic Mean Operator for Any Noise Density
Authors: González-Hidalgo Manuel , Massanet Sebastia , Mir Arnau , Ruiz-Aguilera Daniel
Published: January 2021

Many computer vision algorithms which are not robust to noise incorporate a noise removal stage in their workflow to avoid distortions in the final result. In the last decade, many filters for salt-and-pepper noise removal have been proposed. In this paper, a novel filter based on the weighted arithmetic mean aggregation function and the fuzzy mathematical morphology is proposed. The performance of the proposed filter is highly competitive when compared with other state-of-the-art filters regardless of the amount of salt-and-pepper noise present in the image, achieving notable results for any noise density from 5% to 98%. A statistical analysis based on some objective restoration measures supports that this filter surpasses several state-of-the-art filters for most of the noise levels considered in the comparison experiments.
Finite Elements for Higher Order Steel–Concrete Composite Beams
Authors: Gara Fabrizio , Carbonari Sandro , Leoni Graziano , Dezi Luigino
Published: January 2021

This paper presents finite elements for a higher order steel–concrete composite beam model developed for the analysis of bridge decks. The model accounts for the slab–girder partial interaction, the overall shear deformability, and the shear-lag phenomenon in steel and concrete components. The theoretical derivation of the solving balance conditions, in both weak and strong form, is firstly addressed. Then, three different finite elements are proposed, which are characterised by (i) linear interpolating functions, (ii) Hermitian polynomial interpolating functions, and (iii) interpolating functions, respectively, derived from the analytical solution expressed by means of exponential matrices. The performance of the finite elements is analysed in terms of the solution convergence rate for realistic steel–concrete composite beams with different restraints and loading conditions. Finally, the efficiency of the beam model is shown by comparing the results obtained with the proposed finite elements and those achieved with a refined 3D shell finite element model.
An Identifier and Locator Decoupled Multicast Approach (ILDM) Based on ICN
Authors: Li Bo , Wang Jinlin
Published: January 2021

Many bandwidth-intensive applications (such as online live, online games, etc.) are more suitable for using multicast to transmit information. Due to the advantages in scalability, Shared Tree (ST) is more suitable for large-scale deployment than Source-Based Tree (SBT). However, in ST-based multicast, all multicast sources need to send multicast data to a center node called a core, which will lead to core overload and traffic concentration. Besides, most existing multicast protocols use the shortest path between the source or the core and each receiver to construct the multicast tree, which will result in traffic overload on some links. In this paper, we propose an Identifier and Locator Decoupled Multicast approach (ILDM) based on Information-Centric Networking (ICN). ILDM uses globally unique names to identify multicast services. For each multicast service, the mapping between the multicast service name and the addresses of multicast tree nodes is stored in the Name Resolution System (NRS). To avoid core overload and traffic aggregation, we presented a dynamic core management and selection mechanism, which can dynamically select a low-load core for each multicast service. Furthermore, we designed a path state-aware multicast tree node selection mechanism to achieve traffic load balancing by using low-load links more effectively. Experimental results showed that our proposed multicast approach outperformed some other multicast methods in terms of core load, number of join requests, link load, traffic concentration, and routing state.
Long-Term Variability of Relationships between Potential Large-Scale Drivers and Summer Precipitation in North China in the CERA-20C Reanalysis
Authors: Dai Lan , Wright Jonathon S.
Published: January 2021

Although much progress has been made in identifying the large-scale drivers of recent summer precipitation variability in North China, the evolution of these drivers over longer time scales remains unclear. We investigate multidecadal and interannual variability in North China summer precipitation in the 110-year Coupled ECMWF Reanalysis of the Twentieth Century (CERA-20C), considering changes in regional moisture and surface energy budgets along with nine circulation indices linked to anomalous precipitation in this region. The CERA-20C record is separated into three distinct periods according to the running climatology of summer precipitation: 1901–1944 (neutral), 1945–1979 (wet), and 1980–2010 (dry). CERA-20C reproduces expected relationships between large-scale drivers and regional summer precipitation anomalies well during 1980–2010, but these relationships generally do not extend to earlier periods. For example, a strong relationship with the Eurasian teleconnection pattern only emerges in the late 1970s, while correlations with the El Niño-Southern Oscillation and the Pacific–Japan pattern change sign in the mid-twentieth century. We evaluate two possible reasons for this nonstationarity: (1) the underlying atmospheric model may require strong data assimilation constraints to capture large-scale circulation influences on North China, or (2) large-scale drivers inferred from recent records may be less general than expected. Our analysis indicates that both factors contribute to the identified nonstationarity in CERA-20C, with implications for the reliability of seasonal forecasts and climate projections based on current models.
Temporal Changes in Ozone Concentrations and Their Impact on Vegetation
Authors: Juráň Stanislav , Grace John , Urban Otmar
Published: January 2021

Tropospheric concentrations of phytotoxic ozone (O3) have undergone a great increase from preindustrial 10–15 ppbv to a present-day concentration of 35–40 ppbv in large parts of the industrialised world due to increased emissions of O3 precursors including NOx, CO, CH4 and volatile organic compounds. The rate of increase in O3 concentration ranges between 1 ppbv per decade in remote locations of the Southern hemisphere and 5 ppbv per decade in the Northern hemisphere, where largest sources of O3 precursors are located. Molecules of O3 penetrating into the leaves through the stomatal apertures trigger the formation of reactive oxygen species, leading thus to the damage of the photosynthetic apparatus. Accordingly, it is assumed, that O3 increase reduces the terrestrial carbon uptake relative to the preindustrial era. Here we summarise the results of previous manipulative experiments in laboratory growth cabinets, field open-top chambers and free-air systems together with O3 flux measurements under natural growth conditions. In particular, we focus on leaf-level physiological responses in trees, variability in stomatal O3 flux and changes in carbon fluxes and biomass production in forest stands. As the results reported in the literature are highly variable, ranging from negligible to severe declines in photosynthetic carbon uptake, we also discuss the possible interactions of O3 with other environmental factors including solar radiation, drought, temperature and nitrogen deposition. Those factors were found to have great potential to modulate stomata openness and O3 fluxes.
Compound Temperature and Precipitation Events in the Czech Republic: Differences of Stratiform versus Convective Precipitation in Station and Reanalysis Data
Authors: Rulfová Zuzana , Beranová Romana , Plavcová Eva
Published: January 2021

Some natural hazards may result from the coincidences of anomalies of different climatic variables. These so-called compound events can cause extreme impacts. This study analyzes compounds of extreme temperature with notable convective and stratiform precipitation in the Czech Republic during 1982–2016. Characteristics of compound events obtained from 11 stations’ data are compared with those from the gridded ERA-Interim reanalysis. We found that notable stratiform precipitation frequently coincides with warm nights and warm days in winter but with cold days in the other seasons. While the winter stratiform precipitation coinciding with warm days and warm nights is linked to anticyclonic, southwest, northwest, and anticyclonic-northwest circulation types, the northeast type is the most crucial circulation type linked to notable stratiform precipitation coinciding with cold days in all seasons except winter. The compound events of notable convective precipitation occur most frequently in summer and they are joined mainly with warm days. These compound events are associated with anticyclonic, cyclonic, and northwest circulation types. Although the number of days with stratiform compound events is larger in ERA-Interim than in the station data, the results are qualitatively comparable. ERA-Interim is, however, not able to reproduce convective compound events obtained from the station data.
Development of EST-Molecular Markers from RNA Sequencing for Genetic Management and Identification of Growth Traits in Potato Grouper (Epinephelus tukula)
Authors: Hsu Te-Hua , Chiu Yu-Ting , Lee Hung-Tai , Gong Hong-Yi , Huang Chang-Wen
Published: January 2021

The accuracy and efficiency of marker-assisted selection (MAS) has been proven for economically critical aquaculture species. The potato grouper (Epinephelus tukula), a novel cultured grouper species in Taiwan, shows large potential in aquaculture because of its fast growth rate among other groupers. Because of the lack of genetic information for the potato grouper, the first transcriptome and expressed sequence tag (EST)-derived simple sequence repeat (SSR) and single nucleotide polymorphism (SNP) markers were developed. Initially, the transcriptome was obtained from seven cDNA libraries by using the Illumina platform. De novo transcriptome of the potato grouper yielded 51.34 Gb and 111,490 unigenes. The EST-derived SSR and SNP markers were applied in genetic management, in parentage analysis, and to discover the functional markers of economic traits. The F1 juveniles were identified as siblings from one pair of parents (80 broodstocks). Fast- and slow-growth individuals were analyzed using functional molecular markers and through their association with growth performance. The results revealed that two SNPs were correlated with growth traits. The transcriptome database obtained in this study and its derived SSR and SNP markers may be applied not only for MAS but also to maintain functional gene diversity in the novel cultured grouper.
A Modelling Framework Linking Resource-Based Stochastic Translation to the Optimal Design of Synthetic Constructs
Authors: Sarvari Peter , Ingram Duncan , Stan Guy-Bart
Published: January 2021

The effect of gene expression burden on engineered cells has motivated the use of “whole-cell models” (WCMs) that use shared cellular resources to predict how unnatural gene expression affects cell growth. A common problem with many WCMs is their inability to capture translation in sufficient detail to consider the impact of ribosomal queue formation on mRNA transcripts. To address this, we have built a “stochastic cell calculator” (StoCellAtor) that combines a modified TASEP with a stochastic implementation of an existing WCM. We show how our framework can be used to link a synthetic construct’s modular design (promoter, ribosome binding site (RBS) and codon composition) to protein yield during continuous culture, with a particular focus on the effects of low-efficiency codons and their impact on ribosomal queues. Through our analysis, we recover design principles previously established in our work on burden-sensing strategies, namely that changing promoter strength is often a more efficient way to increase protein yield than RBS strength. Importantly, however, we show how these design implications can change depending on both the duration of protein expression, and on the presence of ribosomal queues.
Plants on Rich-Magnesium Dolomite Barrens: A Global Phenomenon
Authors: Mota Juan , Merlo Encarna , Martínez-Hernández Fabián , Mendoza-Fernández Antonio J. , Pérez-García Francisco Javier , Salmerón-Sánchez Esteban
Published: January 2021

For botanists and ecologists, the close link between some plants and substrates, such as serpentine or gypsum, is well known. However, the relationship between dolomite and its flora has been much less studied, due to various causes. Its diffuse separation from limestone and the use of a vague approach and terminology that, until now, no one has tried to harmonize are among these reasons. After carrying out an extensive review, completed with data on the distribution of plants linked to dolomite, the territories in which this type of flora appears at a global level were mapped using a geographic information system software. In addition, data on soils were collected, as well as on their influence on the ionomic profile of the flora. These data were completed with the authors’ own information from previous research, which also served to assess these communities’ degree of conservation and the genetic diversity of some of their characteristic species. The results showed that the so-called “dolomite phenomenon” is widely represented and is clearly manifested in the appearance of a peculiar flora, very rich in endemisms, on dry soils, poor in nutrients, and with a high Mg level. Although dolomite habitats cause adaptations in plants which are even more recognizable than those of other rock types, they have not been widely studied from an ecological, evolutionary, and conservation point of view because, so far, neither their characteristics nor their universal demarcation have been precisely defined.
Bioactive Terpenes and Their Derivatives as Potential SARS-CoV-2 Proteases Inhibitors from Molecular Modeling Studies
Authors: Diniz Lúcio Ricardo Leite , Perez-Castillo Yunierkis , Elshabrawy Hatem A. , Filho Carlos da Silva Maia Bezerra , de Sousa Damião Pergentino
Published: January 2021

The coronavirus disease 2019 (COVID-19) pandemic is caused by a novel coronavirus; the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). Millions of cases and deaths to date have resulted in a global challenge for healthcare systems. COVID-19 has a high mortality rate, especially in elderly individuals with pre-existing chronic comorbidities. There are currently no effective therapeutic approaches for the prevention and treatment of COVID-19. Therefore, the identification of effective therapeutics is a necessity. Terpenes are the largest class of natural products that could serve as a source of new drugs or as prototypes for the development of effective pharmacotherapeutic agents. In the present study, we discuss the antiviral activity of these natural products and we perform simulations against the Mpro and PLpro enzymes of SARS-CoV-2. Our results strongly suggest the potential of these compounds against human coronaviruses, including SARS-CoV-2.
RNA Metabolism Guided by RNA Modifications: The Role of SMUG1 in rRNA Quality Control
Authors: Lirussi Lisa , Demir Özlem , You Panpan , Sarno Antonio , Amaro Rommie E. , Nilsen Hilde
Published: January 2021

RNA modifications are essential for proper RNA processing, quality control, and maturation steps. In the last decade, some eukaryotic DNA repair enzymes have been shown to have an ability to recognize and process modified RNA substrates and thereby contribute to RNA surveillance. Single-strand-selective monofunctional uracil-DNA glycosylase 1 (SMUG1) is a base excision repair enzyme that not only recognizes and removes uracil and oxidized pyrimidines from DNA but is also able to process modified RNA substrates. SMUG1 interacts with the pseudouridine synthase dyskerin (DKC1), an enzyme essential for the correct assembly of small nucleolar ribonucleoproteins (snRNPs) and ribosomal RNA (rRNA) processing. Here, we review rRNA modifications and RNA quality control mechanisms in general and discuss the specific function of SMUG1 in rRNA metabolism. Cells lacking SMUG1 have elevated levels of immature rRNA molecules and accumulation of 5-hydroxymethyluridine (5hmU) in mature rRNA. SMUG1 may be required for post-transcriptional regulation and quality control of rRNAs, partly by regulating rRNA and stability.
Applying Eye Movement Modeling Examples to Guide Novices’ Attention in the Comprehension of Process Models
Authors: Winter Michael , Pryss Rüdiger , Probst Thomas , Reichert Manfred
Published: January 2021

Process models are crucial artifacts in many domains, and hence, their proper comprehension is of importance. Process models mediate a plethora of aspects that are needed to be comprehended correctly. Novices especially face difficulties in the comprehension of process models, since the correct comprehension of such models requires process modeling expertise and visual observation capabilities to interpret these models correctly. Research from other domains demonstrated that the visual observation capabilities of experts can be conveyed to novices. In order to evaluate the latter in the context of process model comprehension, this paper presents the results from ongoing research, in which gaze data from experts are used as Eye Movement Modeling Examples (EMMEs) to convey visual observation capabilities to novices. Compared to prior results, the application of EMMEs improves process model comprehension significantly for novices. Novices achieved in some cases similar performances in process model comprehension to experts. The study’s insights highlight the positive effect of EMMEs on fostering the comprehension of process models.
Sleep-Related Declarative Memory Consolidation in Children and Adolescents with Developmental Dyslexia
Authors: Reda Flaminia , Gorgoni Maurizio , D'Atri Aurora , Scarpelli Serena , Carpi Matteo , Di Cola Erica , Menghini Deny , Vicari Stefano , Stella Giacomo , De Gennaro Luigi
Published: January 2021

Sleep has a crucial role in memory processes, and maturational changes in sleep electrophysiology are involved in cognitive development. Albeit both sleep and memory alterations have been observed in Developmental Dyslexia (DD), their relation in this population has been scarcely investigated, particularly concerning topographical aspects. The study aimed to compare sleep topography and associated sleep-related declarative memory consolidation in participants with DD and normal readers (NR). Eleven participants with DD and 18 NR (9–14 years old) underwent a whole-night polysomnography. They were administered a word pair task before and after sleep to assess for declarative memory consolidation. Memory performance and sleep features (macro and microstructural) were compared between the groups, and the intercorrelations between consolidation rate and sleep measures were assessed. DD showed a deeper worsening in memory after sleep compared to NR and reduced slow spindles in occipito-parietal and left fronto-central areas. Our results suggest specific alterations in local sleep EEG (i.e., sleep spindles) and in sleep-dependent memory consolidation processes in DD. We highlight the importance of a topographical approach, which might shed light on potential alteration in regional cortical oscillation dynamics in DD. The latter might represent a target for therapeutic interventions aimed at enhancing cognitive functioning in DD.
HIF in Nephrotoxicity during Cisplatin Chemotherapy: Regulation, Function and Therapeutic Potential
Authors: Li Siyao , Wen Lu , Hu Xiaoru , Wei Qingqing , Dong Zheng
Published: January 2021

Cisplatin is a highly effective, broad-spectrum chemotherapeutic drug, yet its clinical use and efficacy are limited by its side effects. Particularly, cancer patients receiving cisplatin chemotherapy have high incidence of kidney problems. Hypoxia-inducible factor (HIF) is the “master” transcription factor that is induced under hypoxia to trans-activate various genes for adaptation to the low oxygen condition. Numerous studies have reported that HIF activation protects against AKI and promotes kidney recovery in experimental models of cisplatin-induced acute kidney injury (AKI). In contrast, little is known about the effects of HIF on chronic kidney problems following cisplatin chemotherapy. Prolyl hydroxylase (PHD) inhibitors are potent HIF inducers that recently entered clinical use. By inducing HIF, PHD inhibitors may protect kidneys during cisplatin chemotherapy. However, HIF activation by PHD inhibitors may reduce the anti-cancer effect of cisplatin in tumors. Future studies should test PHD inhibitors in tumor-bearing animal models to verify their effects in kidneys and tumors.
Prognostic Value and Function of KLF5 in Papillary Thyroid Cancer
Authors: Pratheeshkumar Poyil , Siraj Abdul K. , Divya Sasidharan Padmaja , Parvathareddy Sandeep Kumar , Siraj Sarah , Diaz Roxanne , Begum Rafia , Al-Sobhi Saif S. , Al-Dayel Fouad , Al-Kuraya Khawla S.
Published: January 2021

The Krüppel-like factor 5 (KLF5), a zinc-finger transcriptional factor, is highly expressed in several solid tumors, but its role in PTC remains unclear. We investigated the expression of KLF5 protein in a large cohort of PTC patient samples and explored its functional role and mechanism in PTC cell lines in vitro and in vivo. KLF5 overexpression was observed in 65.1% of all PTC cases and it was significantly associated with aggressive clinico-pathological parameters and poor outcome. Given the significant association between KLF5 and HIF-1α overexpression in PTC patients, we investigated the functional correlation between KLF5 and HIF-1α in PTC cells. Indeed, the analysis revealed the co-immunoprecipitation of KLF5 with HIF-1α in PTC cells. We also identified KLF5-binding sites in the HIF-1α promoter that specifically bound to KLF5 protein. Mechanistically, KLF5 promoted PTC cell growth, invasion, migration, and angiogenesis, while KLF5 downregulation via specific inhibitor or siRNA reverses its action in vitro. Importantly, the silencing of KLF5 decreases the self-renewal ability of spheroids generated from PTC cells. In addition, the depletion of KLF5 reduces PTC xenograft growth in vivo. These findings suggest KLF5 can be a possible new molecular therapeutic target for a subset of PTC.
Altered Spatial Composition of the Immune Cell Repertoire in Association to CD34+ Blasts in Myelodysplastic Syndromes and Secondary Acute Myeloid Leukemia
Authors: Bauer Marcus , Vaxevanis Christoforos , Al-Ali Haifa Kathrin , Jaekel Nadja , Naumann Christin Le Hoa , Schaffrath Judith , Rau Achim , Seliger Barbara , Wickenhauser Claudia
Published: January 2021

Background: Myelodysplastic syndromes (MDS) are caused by a stem cell failure and often include a dysfunction of the immune system. However, the relationship between spatial immune cell distribution within the bone marrow (BM), in relation to genetic features and the course of disease has not been analyzed in detail. Methods: Histotopography of immune cell subpopulations and their spatial distribution to CD34+ hematopoietic cells was determined by multispectral imaging (MSI) in 147 BM biopsies (BMB) from patients with MDS, secondary acute myeloid leukemia (sAML), and controls. Results: In MDS and sAML samples, a high inter-tumoral immune cell heterogeneity in spatial proximity to CD34+ blasts was found that was independent of genetic alterations, but correlated to blast counts. In controls, no CD8+ and FOXP3+ T cells and only single MUM1p+ B/plasma cells were detected in an area of ≤10 μm to CD34+ HSPC. Conclusions: CD8+ and FOXP3+ T cells are regularly seen in the 10 μm area around CD34+ blasts in MDS/sAML regardless of the course of the disease but lack in the surrounding of CD34+ HSPC in control samples. In addition, the frequencies of immune cell subsets in MDS and sAML BMB differ when compared to control BMB providing novel insights in immune deregulation.
Namodenoson in Advanced Hepatocellular Carcinoma and Child–Pugh B Cirrhosis: Randomized Placebo-Controlled Clinical Trial
Authors: Stemmer Salomon M. , Manojlovic Nebojsa S. , Marinca Mihai Vasile , Petrov Petar , Cherciu Nelly , Ganea Doina , Ciuleanu Tudor Eliade , Pusca Ioana Adriana , Beg Muhammad Shaalan , Purcell William T. , Croitoru Adina-Emilia , Ilieva Rumyana Nedyalkova , Natošević Sladjana , Nita Amedeia Lavinir , Kalev Dimitar Nikolaev , Harpaz Zivit , Farbstein Motti , Silverman Michael H. , Bristol David , Itzhak Inbal , Fishman Pnina
Published: January 2021

Namodenoson, an A3 adenosine-receptor agonist, showed promising results in advanced hepatocellular carcinoma (HCC) and moderate hepatic dysfunction (Child–Pugh B; CPB) in a phase I/II clinical study. This phase II study investigated namodenoson as second-line therapy in such patients. Patients were randomized 2:1 to twice a day (BID) namodenoson (25 mg; n = 50) or placebo (n = 28). The primary endpoint (overall survival [OS]) was not met. Median OS was 4.1/4.3 months for namodenoson/placebo (hazard ratio [HR], 0.82; 95% confidence interval [CI] 0.49–1.38; p = 0.46). Pre-planned subgroup analysis of CPB7 patients (34 namodenoson-treated, 22 placebo-treated) showed a nonsignificant improvement in OS/progression-free survival (PFS). OS: 6.9 versus 4.3 months; HR, 0.81; 95% CI: 0.45–1.43, p = 0.46. PFS: 3.5 versus 1.9 months; HR, 0.89; 95% CI: 0.51–1.55, p = 0.67 (log-rank test). The difference in 12-month OS was significant (44% versus 18%, p = 0.028). Response rates were determined in patients for whom ≥ 1 assessment post-baseline was available (34 namodenoson-treated, 21 placebo-treated). Partial response was achieved by 3/34 (8.8%) and 0/21 (0%) patients, respectively. Namodenoson was well-tolerated, with a safety profile comparable to that of the placebo group. No treatment-related deaths were reported; no patients withdrew due to toxicity. In conclusion, namodenoson demonstrated a favorable safety profile and a preliminary efficacy signal in HCC CPB.
The Caspase-1/IL-18 Axis of the Inflammasome in Tumor Cells: A Modulator of the Th1/Tc1 Response of Tumor-Infiltrating T Lymphocytes in Colorectal Cancer
Authors: Mutala Linda Bilonda , Deleine Cécile , Karakachoff Matilde , Dansette Delphine , Ducoin Kathleen , Oger Romain , Rousseau Olivia , Podevin Juliette , Duchalais Emilie , Fourquier Pierre , Thomas Wassila El Alami , Gourraud Pierre-Antoine , Bennouna Jaafar , Brochier Camille , Gervois Nadine , Bossard Céline , Jarry Anne
Published: January 2021

In colorectal cancer (CRC), a high density of T lymphocytes represents a strong prognostic marker in subtypes of CRC. Optimized immunotherapy strategies to boost this T-cell response are still needed. A good candidate is the inflammasome pathway, an emerging player in cancer immunology that bridges innate and adaptive immunity. Its effector protein caspase-1 matures IL-18 that can promote a T-helper/cytotoxic (Th1/Tc1) response. It is still unknown whether tumor cells from CRC possess a functional caspase-1/IL-18 axis that could modulate the Th1/Tc1 response. We used two independent cohorts of CRC patients to assess IL-18 and caspase-1 expression by tumor cells in relation to the density of TILs and the microsatellite status of CRC. Functional and multiparametric approaches at the protein and mRNA levels were performed on an ex vivo CRC explant culture model. We show that, in the majority of CRCs, tumor cells display an activated and functional caspase-1/IL-18 axis that contributes to drive a Th1/Tc1 response elicited by TILs expressing IL-18Rα. Furthermore, unsupervised clustering identified three clusters of CRCs according to the caspase-1/IL-18/TIL density/interferon gamma (IFNγ) axis and microsatellite status. Together, our results strongly suggest that targeting the caspase-1/IL-18 axis can improve the anti-tumor immune response in subgroups of CRC.
Cold-Shock Domains—Abundance, Structure, Properties, and Nucleic-Acid Binding
Authors: Heinemann Udo , Roske Yvette
Published: January 2021

The cold-shock domain has a deceptively simple architecture but supports a complex biology. It is conserved from bacteria to man and has representatives in all kingdoms of life. Bacterial cold-shock proteins consist of a single cold-shock domain and some, but not all are induced by cold shock. Cold-shock domains in human proteins are often associated with natively unfolded protein segments and more rarely with other folded domains. Cold-shock proteins and domains share a five-stranded all-antiparallel β-barrel structure and a conserved surface that binds single-stranded nucleic acids, predominantly by stacking interactions between nucleobases and aromatic protein sidechains. This conserved binding mode explains the cold-shock domains’ ability to associate with both DNA and RNA strands and their limited sequence selectivity. The promiscuous DNA and RNA binding provides a rationale for the ability of cold-shock domain-containing proteins to function in transcription regulation and DNA-damage repair as well as in regulating splicing, translation, mRNA stability and RNA sequestration.