Fibroblast Stromal Support Model for Predicting Human Papillomavirus-Associated Cancer Drug Responses.

Currently, there are no specific antiviral therapeutic approaches targeting Human papillomaviruses (HPVs), which cause around 5% of all human cancers. Specific antiviral reagents are particularly needed for HPV-related oropharyngeal cancers (HPV + OPCs) whose incidence is increasing and for which there are no early diagnostic tools available. We and others have demonstrated that the estrogen receptor alpha (ERα) is overexpressed in HPV + OPCs, compared to HPV-negative cancers in this region, and that these elevated levels are associated with an improved disease outcome. Utilizing this HPV + specific overexpression profile, we previously demonstrated that estrogen attenuates the growth and cell viability of HPV + keratinocytes and HPV + cancer cells in vitro . Expansion of this work in vivo failed to replicate this sensitization. The role of stromal support from the tumor microenvironment (TME) has previously been tied to both the HPV lifecycle and in vivo therapeutic responses. Our investigations revealed that in vitro co-culture with fibroblasts attenuated HPV + specific estrogen growth responses. Continuing to monopolize on the HPV + specific overexpression of ERα, our co-culture models then assessed the suitability of the selective estrogen receptor modulators (SERMs), raloxifene and tamoxifen, and showed growth attenuation in a variety of our models to one or both of these drugs in vitro. Utilization of these SERMs in vivo closely resembled the sensitization predicted by our co-culture models. Therefore, the in vitro fibroblast co-culture model better predicts in vivo responses. We propose that utilization of our co-culture in vitro model can accelerate cancer therapeutic drug discovery. Importance: Human papillomavirus-related cancers (HPV + cancers) remain a significant public health concern, and specific clinical approaches are desperately needed. In translating drug response data from in vitro to in vivo , the fibroblasts of the adjacent stromal support network play a key role. Our study presents the utilization of a fibroblast 2D co-culture system to better predict translational drug assessments for HPV + cancers. We also suggest that this co-culture system should be considered for other translational approaches. Predicting even a portion of treatment paradigms that may fail in vivo with a co-culture model will yield significant time, effort, resource, and cost efficiencies.

Testing quantum electrodynamics in extreme fields using helium-like uranium.

Quantum electrodynamics (QED), the quantum field theory that describes the interaction between light and matter, is commonly regarded as the best-tested quantum theory in modern physics. However, this claim is mostly based on extremely precise studies performed in the domain of relatively low field strengths and light atoms and ions1-6. In the realm of very strong electromagnetic fields such as in the heaviest highly charged ions (with nuclear charge Z ≫ 1), QED calculations enter a qualitatively different, non-perturbative regime. Yet, the corresponding experimental studies are very challenging, and theoretical predictions are only partially tested. Here we present an experiment sensitive to higher-order QED effects and electron-electron interactions in the high-Z regime. This is achieved by using a multi-reference method based on Doppler-tuned X-ray emission from stored relativistic uranium ions with different charge states. The energy of the 1s1/22p3/2 J = 2 → 1s1/22s1/2 J = 1 intrashell transition in the heaviest two-electron ion (U90+) is obtained with an accuracy of 37 ppm. Furthermore, a comparison of uranium ions with different numbers of bound electrons enables us to disentangle and to test separately the one-electron higher-order QED effects and the bound electron-electron interaction terms without the uncertainty related to the nuclear radius. Moreover, our experimental result can discriminate between several state-of-the-art theoretical approaches and provides an important benchmark for calculations in the strong-field domain.

Percepción del Aprendizaje Activo Virtual de la Anatomía Humana, por Estudiantes de la Universidad Austral de Chile / Student Perceptions of Active Learning for the Practice of Virtual Human Anatomy, a Study at the Universidad Austral de Chile

Ante la pandemia del coronavirus, hubo que reinventar la forma de hacer las actividades prácticas de laboratorio de anatomía humana, la necesidad de que sean exclusivamente virtual, elevó la exigencia. La imposibilidad de trabajar con material orgánico demandó que al menos las imágenes a utilizar fueran de alta calidad. Para lo anterior, se usaron fotografías de disecciones del laboratorio de anatomía, más digitalizaciones de estructuras humanas de nuestro laboratorio en formato 3D disponibles en la plataforma web https://anatomiahumana3d.com. No obstante lo anterior, se detectó cierto grado de desidia por parte de los estudiantes y escasa participación en las actividades prácticas. Para resolver esto se implementó una modalidad de Aprendizaje Activo, específicamente de Aula Invertida, con el fin de que sea el propio estudiante quien genere su conocimiento. Una vez terminado el proceso de enseñanza aprendizaje bajo la nueva modalidad, se realizó un estudio descriptivo, a fin de detectar falencias y proponer mejoras respecto a la metodología aplicada. Los resultados arrojaron un nivel de satisfacción por sobre el 80 %, en tanto, que solo el 5 % de los estudiantes contestó como aceptable las diferentes dimensiones evaluadas, demostrando como el sistema de aula inversa fue bien recibida por los estudiantes. Sin embargo es prudente generar futuros estudios que ayuden a mejorar este tipo de metodología, como también seguir innovando en las estrategias didácticas que aporten a la comprensión de la anatomía humana.

SUMMARY: In the context of the COVID-19 pandemic it was necessary to reinvent the way of doing practical activities in the human anatomy laboratory and the need for these to be exclusively online, raised the requirement. Due to the impossibility of using organic samples, high-quality images had to be used. Therefore, photographs of dissections from our human anatomy laboratory were used, as well as digitalization of human structures from our laboratory in a three-dimensional (3D) format available on the web platform https://anatomiahumana3d.com. However, a certain degree of laziness on the part of the students and low participation in the practical activities was detected. To solve this problem, an Active Learning modality was implemented, specifically the Flipped Classroom, so that the students themselves generate their knowledge. Once the teaching-learning process was completed under the new modality, a descriptive study was carried out to detect shortcomings and propose improvements to the methodology applied. The results showed a level of satisfaction above 80 % and only 5 % of the students evaluated the different dimensions as acceptable demonstrating how the Flipped Classroom system was well received by the students. To conclude, it is prudent to generate future studies that help to improve this type of methodology, as well as to continue innovating in didactic strategies that contribute to the understanding of human anatomy.

Eugenia uniflora: a promising natural alternative against multidrug-resistant bacteria.

This work aimed to evaluate the chemical composition, antioxidant and antimicrobial activities from crude extract and fractions from leaves of Eugenia uniflora Linn. The crude extract was obtained by turbo extraction and their fractions by partitioning. Chromatographic analysis were performed, and the antioxidant capacity was verified by two methods (DPPH• and ABTS•+). The Minimal Inhibitory/Bactericidal Concentration were conducted against twenty-two bacteria, selecting five strains susceptible to extract/fractions and resistant to the antibiotics tested. Ampicillin, azithromycin, ciprofloxacin, and gentamicin were associated with Ethyl Acetate Fraction (EAF) against multidrug-resistant strains in modulatory and checkerboard tests. The chromatographic data showed gallic acid, ellagic acid, and myricitrin in crude extract, with enrichment in the EAF. The electron transfer activity demonstrated in the antioxidant tests is related to the presence of flavonoids. The Gram-positive strains were more susceptible to EAF, and their action spectra were improved by association, comprising Gram-negative bacilli. Synergisms were observed to ciprofloxacin and gentamicin against Pseudomonas aeruginosa colistin-resistant. The results demonstrate that the extract and enriched fraction obtained from the leaves of E. uniflora act as a promising natural alternative against multidrug-resistant bacteria.

Road networks structure analysis: A preliminary network science-based approach.

Road network studies attracted unprecedented and overwhelming interest in recent years due to the clear relationship between human existence and city evolution. Current studies cover many aspects of a road network, for example, road feature extraction from video/image data, road map generalisation, traffic simulation, optimisation of optimal route finding problems, and traffic state prediction. However, analysing road networks as a complex graph is a field to explore. This study presents comparative studies on the Porto, in Portugal, road network sections, mainly of Matosinhos, Paranhos, and Maia municipalities, regarding degree distributions, clustering coefficients, centrality measures, connected components, k-nearest neighbours, and shortest paths. Further insights into the networks took into account the community structures, page rank, and small-world analysis. The results show that the information exchange efficiency of Matosinhos is 0.8, which is 10 and 12.8% more significant than that of the Maia and Paranhos networks, respectively. Other findings stated are: (1) the studied road networks are very accessible and densely linked; (2) they are small-world in nature, with an average length of the shortest pathways between any two roads of 29.17 units, which as found in the scenario of the Maia road network; and (3) the most critical intersections of the studied network are 'Avenida da Boavista, 4100-119 Porto (latitude: 41.157944, longitude: - 8.629105)', and 'Autoestrada do Norte, Porto (latitude: 41.1687869, longitude: - 8.6400656)', based on the analysis of centrality measures.

The Relationship of Lightning Radio Pulse Amplitudes and Source Altitudes as Observed by LOFAR.

When a lightning flash is propagating in the atmosphere it is known that especially the negative leaders emit a large number of very high frequency (VHF) radio pulses. It is thought that this is due to streamer activity at the tip of the growing negative leader. In this work, we have investigated the dependence of the strength of this VHF emission on the altitude of such emission for two lightning flashes as observed by the Low Frequency ARray (LOFAR) radio telescope. We find for these two flashes that the extracted amplitude distributions are consistent with a power-law, and that the amplitude of the radio emissions decreases very strongly with source altitude, by more than a factor of 2 from 1 km altitude up to 5 km altitude. In addition, we do not find any dependence on the extracted power-law with altitude, and that the extracted power-law slope has an average around 3, for both flashes.

Guaranteed cost-based feedback control design for fractional-order neutral systems with input-delayed and nonlinear perturbations.

Time delay in actuators is mainly caused by electrical and mechanical components. The effect is visible in the system response particularly when changing in the input command. Therefore, input delay is a problem in the control system design that must be taken into account. Besides, ignoring uncertainty in the dynamic models may compromise the controller design. Thus, how to mitigate the effect of this issue on the system stability and performance is a challenging topic. This article deals with the stabilization of fractional neutral systems considering input-delayed and nonlinear perturbations using the guaranteed cost-based feedback control technique. The main focus is to design the state- and output-feedback controllers to achieve a good performance. The stability criteria are formulated in the Lyapunov sense, which are described in terms of matrix inequalities. The proposed idea is validated using simulations.

Modified SIQR model for the COVID-19 outbreak in several countries.

In this paper, we propose a modified Susceptible-Infected-Quarantine-Recovered (mSIQR) model, for the COVID-19 pandemic. We start by proving the well-posedness of the model and then compute its reproduction number and the corresponding sensitivity indices. We discuss the values of these indices for epidemiological relevant parameters, namely, the contact rate, the proportion of unknown infectious, and the recovering rate. The mSIQR model is simulated, and the outputs are fit to COVID-19 pandemic data from several countries, including France, US, UK, and Portugal. We discuss the epidemiological relevance of the results and provide insights on future patterns, subjected to health policies.

Optimal Solution of a Fractional HIV/AIDS Epidemic Mathematical Model.

This article presents a fractional mathematical model of the human immunodeficiency virus (HIV)/AIDS spread with a fractional derivative of the Caputo type. The model includes five compartments corresponding to the variables describing the susceptible patients, HIV-infected patients, people with AIDS but not receiving antiretroviral treatment, patients being treated, and individuals who are immune to HIV infection by sexual contact. Moreover, it is assumed that the total population is constant. We construct an optimization technique supported by a class of basis functions, consisting of the generalized shifted Jacobi polynomials (GSJPs). The solution of the fractional HIV/AIDS epidemic model is approximated by means of GSJPs with coefficients and parameters in the matrix form. After calculating and combining the operational matrices with the Lagrange multipliers, we obtain the optimization method. The theorems on the existence, unique, and convergence results of the method are proved. Several illustrative examples show the performance of the proposed method. Mathematics Subject Classification: 97M60; 41A58; 92C42.

Analysis of performance, bone characteristics, and expression of genes involved in the balance of ionic concentrations in broilers subjected to dietary electrolyte balance levels.

1. Sodium bicarbonate (NaHCO3), potassium carbonate (K2CO3), and ammonium chloride (NH4Cl) are commonly used to correct dietary electrolyte balance (DEB) in birds. However, there are many gaps in the knowledge of their effects when used simultaneously. This study investigated the effect of DEB levels on performance, femur bone characteristics and the expression of genes related to the balance of ionic concentrations in broilers at 21 days of age.2. Male Cobb broiler chickens (n = 245), aged 1-21 d, were divided into groups based on a completely randomised design with five DEB levels (110 mEq/kg, 175 mEq/kg, 240 mEq/kg, 305 mEq/kg, and 370 mEq/kg).3. The performance characteristics measured included body weight (BW), body weight gain (BWG), feed intake (FI), feed conversion (FCR) and body weight birds slaughtered (BWS).4. The bone variables assessed in the femur were weight (WE), relative bone weight (RBWE), length (L), width (WI), maximum load supported (MLS), bone-breaking resistance (BR), and Seedor index (SI). In addition, the expression of CHP1, SLC9A1, and SLC24A3 in the livers, intestines and kidneys of birds was evaluated.5. The DEB level of 370 mEq/kg, at Na+ content of 0.48%, resulted in the highest averages for L, MLS, and BR of the femur. This DEB level increased the expression of SLC9A1 in the liver and SLC24A3 in the intestine. A 240 mEq/kg DEB level decreased the expression of CHP1 in the liver, while supplementation with 110 mEq/kg increased the expression of SLC24A3 in the kidney.6. In conclusion, 370 mEq/kg DEB improved FCR and increased the mean bone characteristics of the femur (L, MLS, and BR) and the expression of SLC9A1 and SLC24A3 in the liver and intestine, respectively. These findings should be considered in future assessments of the effects of DEB levels on broilers.

A local stabilized approach for approximating the modified time-fractional diffusion problem arising in heat and mass transfer.

INTRODUCTION: During the last years the modeling of dynamical phenomena has been advanced by including concepts borrowed from fractional order differential equations. The diffusion process plays an important role not only in heat transfer and fluid flow problems, but also in the modelling of pattern formation that arises in porous media. The modified time-fractional diffusion equation provides a deeper understanding of several dynamic phenomena. OBJECTIVES: The purpose of the paper is to develop an efficient meshless technique for approximating the modified time-fractional diffusion problem formulated in the Riemann-Liouville sense. METHODS: The temporal discretization is performed by integrating both sides of the modified time-fractional diffusion model. The unconditional stability of the time discretization scheme and the optimal convergence rate are obtained. Then, the spatial derivatives are discretized through a local hybridization of the cubic and Gaussian radial basis function. This hybrid kernel improves the condition of the system matrix. Therefore, the solution of the linear system can be obtained using direct solvers that reduce significantly computational cost. The main idea of the method is to consider the distribution of data points over the local support domain where the number of points is almost constant. RESULTS: Three examples show that the numerical procedure has good accuracy and applicable over complex domains with various node distributions. Numerical results on regular and irregular domains illustrate the accuracy, efficiency and validity of the technique. CONCLUSION: This paper adopts a local hybrid kernel meshless approach to solve the modified time-fractional diffusion problem. The main results of the research is the numerical technique with non-uniform distribution in irregular grids.

Fractional and fractal processes applied to cryptocurrencies price series.

Introduction: Cryptocurrencies have been attracting the attention from media, investors, regulators and academia during the last years. In spite of some scepticism in the financial area, cryptocurrencies are a relevant subject of academic research. Objectives: In this paper, several tools are adopted as an instrument that can help market agents and investors to more clearly assess the cryptocurrencies price dynamics and, thus, guide investment decisions more assertively while mitigating risks. Methods: We consider three methods, namely the Auto-Regressive Integrated Moving Average (ARIMA), Auto-Regressive Fractionally Integrated Moving Average (ARFIMA) and Detrended Fluctuation Analysis, and three indices given by the Hurst and Lyapunov exponents or the Fractal Dimension. This information allows assessing the behaviour of the time series, such as their persistence, randomness, predictability and chaoticity. Results: The results suggest that, except for the Bitcoin, the other cryptocurrencies exhibit the characteristic of mean reverting, showing a lower predictability when compared to the Bitcoin. The results for the Bitcoin also indicate a persistent behavior that is related to the long memory effect. Conclusions: The ARFIMA reveals better predictive performance than the ARIMA for all cryptocurrencies. Indeed, the obtained residual values for the ARFIMA are smaller for the auto and partial auto correlations functions, as well as for confidence intervals.

Advances in the computational analysis of SARS-COV2 genome.

Given a data-set of Ribonucleic acid (RNA) sequences we can infer the phylogenetics of the samples and tackle the information for scientific purposes. Based on current data and knowledge, the SARS-CoV-2 seemingly mutates much more slowly than the influenza virus that causes seasonal flu. However, very recent evolution poses some doubts about such conjecture and shadows the out-coming light of people vaccination. This paper adopts mathematical and computational tools for handling the challenge of analyzing the data-set of different clades of the severe acute respiratory syndrome virus-2 (SARS-CoV-2). On one hand, based on the mathematical paraphernalia of tools, the concept of distance associated with the Kolmogorov complexity and Shannon information theories, as well as with the Hamming scheme, are considered. On the other, advanced data processing computational techniques, such as, data compression, clustering and visualization, are borrowed for tackling the problem. The results of the synergistic approach reveal the complex time dynamics of the evolutionary process and may help to clarify future directions of the SARS-CoV-2 evolution.

Optimal solution of the fractional order breast cancer competition model.

In this article, a fractional order breast cancer competition model (F-BCCM) under the Caputo fractional derivative is analyzed. A new set of basis functions, namely the generalized shifted Legendre polynomials, is proposed to deal with the solutions of F-BCCM. The F-BCCM describes the dynamics involving a variety of cancer factors, such as the stem, tumor and healthy cells, as well as the effects of excess estrogen and the body's natural immune response on the cell populations. After combining the operational matrices with the Lagrange multipliers technique we obtain an optimization method for solving the F-BCCM whose convergence is investigated. Several examples show that a few number of basis functions lead to the satisfactory results. In fact, numerical experiments not only confirm the accuracy but also the practicability and computational efficiency of the devised technique.

Management of defoliation in Trifolium vesiculosum S. for the production of seeds / [Manejo da desfolha em Trifolium vesiculosum Savi para a produção de sementes]

The present study aims to determine the appropriate defoliation management for the production of seeds and forage in arrowleaf clover via trail analysis. The results obtained demonstrated that defoliation practices have a great influence on the composition of seed yield and germination power. In addition, when the goal is the maximum balance between dry matter production and seed yield, this can be achieved in up to two defoliation practices. These results are confirmed by analyzing the positive association between the weight of a thousand seeds and the seed yield. When the third defoliation practice is performed, it negatively correlates with the weight of a thousand seeds, suggesting that, with the increase in defoliation frequency, there is a lower weight of a thousand seeds, and, therefore, lower seed yield. Therefore, management planning in Trifolium vesiculosum Savi that aims at natural reseeding, maximum yield and seed germination must prioritize one to two defoliation practices, aiming to promote favorable conditions for the perennialization of the species. In this context, the trail analysis proved to be a useful tool as a criterion for obtaining the ideal management aiming at the production of seeds and forage in vesicular clover.(AU)

O presente estudo visa determinar o manejo de desfolha adequado para a produção de sementes e de forragem em trevo-vesiculoso via análise de trilha. Os resultados obtidos demonstraram que as práticas de desfolha possuem grande influência na composição do rendimento de sementes e no poder germinativo. Além disso, quando o objetivo for o máximo equilíbrio entre a produção de matéria seca e o rendimento de sementes, esse pode ser alcançado em até duas práticas de desfolha. Esses resultados são confirmados ao se analisar a associação positiva entre o peso de mil sementes e o rendimento de sementes. Quando realizada a terceira prática de desfolha, esta se correlaciona negativamente com o peso de mil sementes, sugerindo que, com o aumento da frequência de desfolha, ocorre menor peso de mil sementes e, por conseguinte, menor rendimento de sementes. Portanto, o planejamento do manejo em T. vesiculosum Savi que objetive a ressemeadura natural, o máximo rendimento e a germinação de sementes deve priorizar até duas práticas de desfolha, visando promover condições favoráveis para a perenização da espécie. Nesse contexto, a análise de trilha demonstrou ser uma ferramenta útil como critério para obtenção do manejo ideal visando à produção de sementes e de forragem em trevo-vesiculoso.(AU)

Genetic parameters and genetic trends of conformation and management traits in Dairy Gir cattle / [Parâmetros genéticos e tendências genéticas de características de conformação e manejo de bovinos Gir Leiteiro]

The objective of this study was to estimate genetic parameters and genetic trends of different conformation and management traits regularly measured within the context of the National Dairy Gir Breeding Program (PNMGL). The estimation of genetic and residual variances for each trait was performed using average information restricted maximum likelihood (AI-REML) procedure in AIREMLF90 program software. The population was divided into three subpopulations constituted by measured females (with phenotype records), all females, and males. Linear regressions were applied for each trait, considering two periods of birth (1st period: 1938-1996; 2nd period: 1997-2012). The estimated heritability of conformation and management traits varied from 0.01 to 0.53, denoting a perspective of genetic improvement through selection and corrective matings for purebred Dairy Gir populations. The average genetic changes in conformation and management traits were, in general, variable and inexpressive, showing that the selection of Dairy Gir may have had been directed essentially to increase milk yield. The analysis of the two periods of birth indicated that some linear traits present progress (although inexpressive) in the 2nd period (more recent period).(AU)

O objetivo deste estudo foi estimar os parâmetros genéticos e as tendências genéticas para diferentes características de conformação e manejo de animais puros da raça Gir Leiteiro, pertencentes ao Programa Nacional de Melhoramento do Gir Leiteiro (PNMGL). A estimativa das variâncias genéticas e residuais para cada característica foi realizada usando-se o procedimento de máxima verossimilhança restrita (AI-REML), por meio do programa AIREMLF90. A população foi dividida em três subpopulações, constituídas por fêmeas mensuradas (com registros de fenótipo), todas fêmeas e machos. As regressões lineares para cada característica foram ainda divididas em dois períodos de anos de nascimento (1º período: 1938 a 1996; 2º período: 1997 a 2012). As herdabilidades estimadas variaram de 0,01 a 0,53 para as características de conformação e manejo, possibilitando a perspectiva de melhoramento mediante seleção e acasalamentos corretivos na população pura da raça Gir Leiteiro. As mudanças genéticas nas características conformação e manejo foram, em geral, variáveis e inexpressivas, sugerindo que a seleção no Gir Leiteiro possa ter sido direcionada essencialmente para maior produção de leite. Ao serem observados os dois períodos distintos de anos de nascimento, infere-se que algumas características lineares apresentaram progresso (embora inexpressivo) no 2º período analisado.(AU)

Autophosphorylation of the KaiC-like protein ArlH inhibits oligomerization and interaction with ArlI, the motor ATPase of the archaellum.

Motile archaea are propelled by the archaellum, whose motor complex consists of the membrane protein ArlJ, the ATPase ArlI, and the ATP-binding protein ArlH. Despite its essential function and the existence of structural and biochemical data on ArlH, the role of ArlH in archaellum assembly and function remains elusive. ArlH is a structural homolog of KaiC, the central component of the cyanobacterial circadian clock. Since autophosphorylation and dephosphorylation of KaiC are central properties for the function of KaiC, we asked whether autophosphorylation is also a property of ArlH proteins. We observed that both ArlH from the euryarchaeon Pyrococcus furiosus (PfArlH) and from the crenarchaeon Sulfolobus acidocaldarius (SaArlH) have autophosphorylation activity. Using a combination of single-molecule fluorescence measurements and biochemical assays, we show that autophosphorylation of ArlH is closely linked to its oligomeric state when bound to hexameric ArlI. These experiments also strongly suggest that ArlH is a hexamer in its ArlI-bound state. Mutagenesis of the putative catalytic residue (Glu-57 in SaArlH) in ArlH results in a reduced autophosphorylation activity and abolished archaellation and motility in S. acidocaldarius, indicating that optimum phosphorylation activity of ArlH is essential for archaellation and motility.

Entropy analysis of human death uncertainty.

Uncertainty about the time of death is part of one's life, and plays an important role in demographic and actuarial sciences. Entropy is a measure useful for characterizing complex systems. This paper analyses death uncertainty through the concept of entropy. For that purpose, the Shannon and the cumulative residual entropies are adopted. The first may be interpreted as an average information. The second was proposed more recently and is related to reliability measures such as the mean residual lifetime. Data collected from the Human Mortality Database and describing the evolution of 40 countries during several decades are studied using entropy measures. The emerging country and inter-country entropy patterns are used to characterize the dynamics of mortality. The locus of the two entropies gives a deeper insight into the dynamical evolution of the human mortality data series.