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La gerencia sustentable en la producción ovina es fundamental para asegurar la viabilidad a largo plazo de esta actividad ganadera, integrando beneficios ambientales, económicos y sociales. El manejo responsable de los recursos naturales, como el suelo y el agua, a través de prácticas como el pastoreo rotacional y la conservación de forrajes nativos, contribuye a la salud del ecosistema y previene la degradación ambiental. Tecnologías como la inseminación artificial, cuando se aplican de manera ética, pueden optimizar la genética y el rendimiento reproductivo, reduciendo la necesidad de intervenciones médicas. El presente estudio tiene como objetivo evaluar el impacto de prácticas de manejo sustentable en la eficiencia reproductiva y bienestar animal de ovejas criollas mediante la aplicación de protocolos de inseminación artificial a tiempo fijo utilizando gonadotropina coriónica equina (eCG) y progesterona (P4). El estudio es de tipo cuali-cuantitativo experimental con muestra de 248 ovejas criollas adultas, con variables de estudio: tasa de preñez y tasa de natalidad de la región Ayacucho, Perú. Los resultados indican que la gonadotropina coriónica equina (eCG) junto al tratamiento con progesterona (P4) induce celo-ovulación en ovejas criollas en anestro con alto porcentaje de preñez y natalidad. La capacidad de manipular el comportamiento reproductivo de las ovejas no solo mejora la tasa de preñez y prolificidad, sino que también contribuye a un uso más eficiente y responsable de los recursos naturales.

Abstract Background Quality control of DNA sequences is an important data preprocessing step in many genomic analyses. However, all existing parallel tools for this purpose are based on a batch processing model, needing to have the complete genetic dataset before processing can even begin. This limitation clearly hinders quality control performance in those scenarios where the dataset must be downloaded from a remote repository and/or copied to a distributed file system for its parallel processing. Results In this paper we present SeQual-Stream, a streaming tool that allows performing multiple quality control operations on genomic datasets in a fast, distributed and scalable way. To do so, our approach relies on the Apache Spark framework and the Hadoop Distributed File System (HDFS) to fully exploit the stream paradigm and accelerate the preprocessing of large datasets as they are being downloaded and/or copied to HDFS. The experimental results have shown significant improvements in the execution times of SeQual-Stream when compared to a batch processing tool with similar quality control features, providing a maximum speedup of 2.7 $$\times$$ × when processing a dataset with more than 250 million DNA sequences, while also demonstrating good scalability features. Conclusion Our solution provides a more scalable and higher performance way to carry out quality control of large genomic datasets by taking advantage of stream processing features. The tool is distributed as free open-source software released under the GNU AGPLv3 license and is publicly available to download at https://github.com/UDC-GAC/SeQual-Stream .

Abstract Context: Marine ecosystems are sources of bioactive compounds. Thirty-eight microorganism strains from the Cuban platform were screened, which allowed us to identify an extract from Bacillus amyloliquefaciens, strain CBM-116, as a source for obtaining bioproducts with biomedical applications. Aims: To physiologically characterize the culture of Bacillus amyloliquefaciens (CBM-116 strain) and to evaluate the antioxidant and toxic potentialities in vitro of the M116 extract obtained from CBM-116. Methods: The growth and metabolite production of the culture were evaluated at a sieve scale. The chemical composition of the M116 extract obtained from the fermented CBM-116 culture was qualitatively characterized. The extract antioxidant activity was measured by DPPH• and FRAP assays, while cytotoxicity was evaluated in MDCK, J774, CT26, 4T1, MCF-7, A549 cell lines and in Caulobacter crescentus, as well as the effects on genetic material by SOS colorimetric and Rifampicin Resistance, in the last model. Results: Grow kinetic parameters of CBM-116 showed the formation of protein metabolites, while the extract revealed antioxidant capacity, which was evidenced by its iron-reducing capacity. M116 was not cytotoxic up to 2000 μg/mL in C. crescentus; however, it induced mutagenicity and primary damage to the DNA of the bacteria. The extract significantly inhibited cell viability of CT26, 4T1, MCF-7, A549 cells after 48 hours’ exposure. Mean inhibitory concentration (IC50) was calculated for CT26 and 4T1 cells with values of 384 and 488 µg/mL, respectively, in the MTT assay. In the neutral red assay, the values were 478.6 and 398 µg/mL, respectively. Meanwhile, the selectivity index showed values above 2 for both assays. MDCK and J774 cells were not affected. Conclusions: The M116 extract obtained from B. amyloliquefaciens showed bioactive properties with potential application for developing new anti-tumor agents.

Abstract Introduction This article analyzes experiences of antibiotic use and bacterial infections among Primary Health Care users of the Brazilian Unified Health System (SUS) and the possible implications for antimicrobial resistance (AMR). The aim is to map aspects that shape users' lay knowledge regarding antibiotics use and AMR. Methods This is an exploratory study, which consists primarily of individual in‐depth interviews with 19 respondents. Recurrent interview topics were coded and analysed according to thematic content analysis. Results Our findings show users' lived experiences constitute three dimensions related to users' previous antibiotic use: (1) lay knowledge about medicines; (2) previous bacterial infections and (3) communication during the consultation. Lay knowledge encompasses the users' understanding of how antibiotics work in comparison to other drugs and experimentations they make with medication. Users' narratives about bacterial infections are divided into situations of urinary tract infections and antibiotic treatments for other conditions. Communication during the consultation is mainly characterized by a lack of shared knowledge and trust in the doctor–patient relationship. Discussion Users bring together knowledge learned from their own experiences to create the rationale, which shapes how they understand antibiotic use, bacterial infections and medical advice. These experiences are interwoven with information received from healthcare professionals (HPs) on these topics, creating a scenario that goes beyond professional information about antibiotic use. Users have knowledge about medication, antibiotics use and bacterial infection but do not have room to share it with HP, allowing lived experiences to take precedence over professional information. Conclusion Users ascribe symbolic meanings to antibiotics creating a lay knowledge frame, even if this knowledge is not scientifically correct. The personal experiences of bacterial infections and their treatment are also an important source of knowledge about antibiotic use and AMR among users. Users demand from their HPs both trust and willingness to listen to their health narratives and experiences. By considering lay knowledge as part of the assessment of a user's health condition, rather than dismissing it as erroneous and therefore unworthy of attention, HPs may enhance the compliance of users. Patient or Public Contribution Patients or community members did not participate in the design stage of the study. Primary Care patients were invited to participate as respondents of in‐depth interviews, which were carried out by the first author at a Primary Care Unit (PCU) in the suburb of Campo Limpo, Southern region of São Paulo, Brazil. Patients were interviewed after reading and signing a Free and Informed Consent Form, holding with them a copy of the Form. Among the final activities of the project, a feedback session at the same PCU is planned to report on the results of the study. All respondents will have the opportunity to contribute further information regarding their antibiotic use and exchange knowledge and experiences on antimicrobial resistance.

Abstract Background In recent years, huge improvements have been made in the context of sequencing genomic data under what is called Next Generation Sequencing (NGS). However, the DNA reads generated by current NGS platforms are not free of errors, which can affect the quality of downstream analysis. Although error correction can be performed as a preprocessing step to overcome this issue, it usually requires long computational times to analyze those large datasets generated nowadays through NGS. Therefore, new software capable of scaling out on a cluster of nodes with high performance is of great importance. Results In this paper, we present SparkEC, a parallel tool capable of fixing those errors produced during the sequencing process. For this purpose, the algorithms proposed by the CloudEC tool, which is already proved to perform accurate corrections, have been analyzed and optimized to improve their performance by relying on the Apache Spark framework together with the introduction of other enhancements such as the usage of memory-efficient data structures and the avoidance of any input preprocessing. The experimental results have shown significant improvements in the computational times of SparkEC when compared to CloudEC for all the representative datasets and scenarios under evaluation, providing an average and maximum speedups of 4.9 $$\times$$ × and 11.9 $$\times$$ × , respectively, over its counterpart. Conclusion As error correction can take excessive computational time, SparkEC provides a scalable solution for correcting large datasets. Due to its distributed implementation, SparkEC speed can increase with respect to the number of nodes in a cluster. Furthermore, the software is freely available under GPLv3 license and is compatible with different operating systems (Linux, Windows and macOS).

Background Chagas disease (CD) presents an ominous prognosis. The predictive value of biomarkers and new echocardiogram parameters in adjusted models have not been well studied. Methods and Results There were 361 patients with chronic CD (57.6% men, 61±11 years of age, clinical forms: indeterminate 27.1%, cardiac 56.6%, digestive 3.6%, cardiodigestive 12.7%) included in this single‐center, observational, prospective longitudinal study. Echocardiographic evaluation included strain analyses of left atrial, left ventricular (LV), and right ventricular and 3‐dimensional analyses of left atrial and LV volumes. Biomarkers included cardiac troponin I, brain natriuretic peptide, transforming growth factor β1, tumor necrosis factor, matrix metalloproteinases, and Trypanosoma cruzi polymerase chain reaction. The studied end point was a composite of CD‐related mortality, heart transplant, hospital admission due to worsening heart failure, or new cardiac device insertion. Event‐free survival was analyzed by multivariable regression analyses adjusted for competing risks. P values

Previous studies have found increases in nonfatal opioid overdoses during the COVID-19 pandemic, which created difficult conditions for people with substance use disorders. We assessed changes in nonfatal opioid-related overdoses in Florida during the onset of the COVID-19 pandemic. Emergency medical service data was obtained from the Florida Department of Health. Naloxone administration with documented improvement was used as a proxy for nonfatal opioid-related overdoses. Age-adjusted rates were estimated per 100,000 population for April-September 2020 (n = 9,377) and compared to the same time period during 2019 (n = 6,765) using rate ratios. Age-adjusted rates were estimated by sex, race/ethnicity, and metro/nonmetro county classification, as well as county-level measures of medications for opioid use disorder (MOUD) availability, rates of COVID-19 deaths, and unemployment during 2020. The age-adjusted rate of nonfatal opioid-related overdoses increased from 32.41 (95 % CL: 31.64–33.19) during 2019 to 45.35 (95 % CL: 44.42–46.27) during 2020 (RR = 1.40; 95 % CL: 1.36–1.44). The rate for males increased most in metro counties (RR = 1.47, 95 % CL: 1.41–1.53); the rate for females increased most in nonmetro counties (RR = 1.51, 95 % CL: 1.10–2.06). The largest increases were observed among Hispanics (males: RR = 1.56, 95 % CL: 1.37–1.78; females: RR = 1.44, 95 % CL: 1.14–1.81), counties with no MOUD treatment options (RR = 1.66, 95 % CL: 1.14–2.44) and counties with the lowest rates of buprenorphine prescribers (RR = 1.70, 95 % CL: 1.29–2.22). Nonfatal opioid-related overdoses increased in Florida during the first six months of the COVID-19 pandemic. Expanding access to services that support treatment and recovery is critical to addressing the ongoing opioid crisis in Florida.

The present study examined the influence of the specialization onset on the magnitude and patterns of changes in basketball-specific physical fitness within a competitive season and developmental fitness trends between 11 and 17 years in young basketball players. Repeated measures of 181 young basketball players (female, n = 40; male, n = 141) were examined. Anthropometry, age, estimated maturity status, and basketball-specific physical fitness (assessed with the countermovement jump, line drill, and yo-yo intermittent recovery level-1 and fitness score) were considered. Players were grouped by the onset of specialization as related to biological maturation milestones (pre-puberty, mid-puberty, and late-puberty specialization). The within-season and developmental changes in physical fitness were fitted using multilevel modeling in a fully Bayesian framework. The fitness outcomes were similar between-player and within-player changes when grouped by specialization across a season. Fitness improvements across a season were apparent for female players, while male players maintained their performance levels. There was no variation in the patterns of physical fitness development between 11 and 17 years associated with the onset of specialization. Conditional on our data and models, the assumption that early sport specialization provides a physical fitness advantage for future athletic success does not hold.

Leukemia inhibitory factor receptor (LIFR) is frequently downregulated in liver cancer. Here the authors show that loss of LIFR promotes liver tumorigenesis and confers resistance to drug-induced ferroptosis through NF-κB-mediated upregulation of iron-sequestering cytokine LCN2.

Understanding leaf generation dynamics, their seasonal changes, and their responses to nitrogen fertilization (NF) is key to improving pasture utilization efficiency. The objectives of this research were to determine structural and morphogenetic variables underlying changes in herbage mass on a set of Paspalum notatum genotypes. Ten P. notatum genotypes were evaluated in experimental plots following a completely randomized block design under a split-plot arrangement for two N-rates during four periods. Increased herbage mass (HM) after N-fertilization was explained by a higher tiller density (TD) (41.8%) and tiller weight (TW) (22.1%). The increment of TW after NF was due to the increase in leaf blade length (LBL) and width (LBW). During the flowering season, NF increases the reproductive tiller density by 262.5%. Seasonal variation in HM was mainly explained by changes in LBL that modified TW. Morphogenetic traits differed between genotypes of different growth habits; therefore, different management practices are suggested. The average increase in leaf elongation rate in response to NF was about 36.7%, generating longer leaves despite reductions in leaf elongation time (LET). The depletion in LBL and consequently in TW and HM during the autumn was attributed to the reduction in LET.

Abstract Background Plasmodium knowlesi is now the major cause of human malaria in Malaysia, complicating malaria control efforts that must attend to the elimination of multiple Plasmodium species. Recent advances in the cultivation of P. knowlesi erythrocytic-stage parasites in vitro, transformation with exogenous DNA, and infection of mosquitoes with gametocytes from culture have opened up studies of this pathogen without the need for resource-intensive and costly non-human primate (NHP) models. For further understanding and development of methods for parasite transformation in malaria research, this study examined the activity of various trans-species transcriptional control sequences and the influence of Plasmodium vivax centromeric (pvcen) repeats in plasmid-transfected P. knowlesi parasites. Methods In vitro cultivated P. knowlesi parasites were transfected with plasmid constructs that incorporated Plasmodium vivax or Plasmodium falciparum 5′ UTRs driving the expression of bioluminescence markers (firefly luciferase or Nanoluc). Promoter activities were assessed by bioluminescence, and parasites transformed with human resistant allele dihydrofolate reductase-expressing plasmids were selected using antifolates. The stability of transformants carrying pvcen-stabilized episomes was assessed by bioluminescence over a complete parasite life cycle through a rhesus macaque monkey, mosquitoes, and a second rhesus monkey. Results Luciferase expression assessments show that certain P. vivax promoter regions, not functional in the more evolutionarily-distant P. falciparum, can drive transgene expression in P. knowlesi. Further, pvcen repeats may improve the stability of episomal plasmids in P. knowlesi and support detection of NanoLuc-expressing elements over the full parasite life cycle from rhesus macaque monkeys to Anopheles dirus mosquitoes and back again to monkeys. In assays of drug responses to chloroquine, G418 and WR9910, anti-malarial half-inhibitory concentration (IC50) values of blood stages measured by NanoLuc activity proved comparable to IC50 values measured by the standard SYBR Green method. Conclusion All three P. vivax promoters tested in this study functioned in P. knowlesi, whereas two of the three were inactive in P. falciparum. NanoLuc-expressing, centromere-stabilized plasmids may support high-throughput screenings of P. knowlesi for new anti-malarial agents, including compounds that can block the development of mosquito- and/or liver-stage parasites.

International universities often promote inclusive learning environments to aid their sojourners' social integration and improve their well-being. However, little is known about how social experiences with inclusion and integration (SEII) unfold for international PhD candidates in Dutch research universities (DRUs). This study uses the narratives of twenty IPCs to understand the factors that play a role in their SEII in a DRU. Findings suggest that nine factors may define SEII among the participants. Two factors--prior experiences in an ILE and identity in PhD role--played a role in participants' early SEII, while seven factors played a role in participants' early and later SEII. These included IPCs' social participation level, intercultural interaction dynamics, shared language adaptation, cultural events, university's international campus climate, social support, and perceived prejudice and stereotypes. IPCs and their international universities should align expectations to promote an inclusive social climate to foster social integration of IPCs.

Resumo Fundamento O maior risco de se desenvolver diabetes com o uso de estatinas é um desafio para a segurança do uso dessa classe de medicamentos em longo prazo. No entanto, poucos estudos analisaram essa questão durante síndromes coronarianas agudas (SCA). Objetivos Investigar a associação entre início precoce da terapia com estatina e níveis de glicemia em pacientes admitidos com SCA. Métodos Este foi um estudo retrospectivo de pacientes hospitalizados por SCA. Pacientes que nunca haviam usado estatinas foram incluídos e divididos segundo uso ou não de estatina nas primeiras 24 horas de internação. O desfecho primário foi a incidência de hiperglicemia na internação (definida como pico de glicemia > 200mg/dL). Modelos de regressão logística e modelos lineares multivariados foram usados para ajuste quanto a fatores de confusão e um modelo de pareamento por escore de propensão foi desenvolvido para comparações entre os dois grupos de interesses. Um valor de p menor que 0,05 foi considerado estatisticamente significativo. Resultados Um total de 2357 pacientes foram incluídos, 1704 deles alocados no grupo que receberam estatinas e 653 no grupo que não receberam estatinas nas primeiras 24 horas de internação. Após os ajustes, uso de estatina nas primeiras 24 horas foi associado com uma menor incidência de hiperglicemia durante a internação (OR ajustado = 0,61, IC95% 0,46-0,80; p < 0,001) e menor necessidade de uso de insulina (OR ajustado = 0,56, IC 95% 0,41-0,76; p < 0,001). Essas associações mantiveram-se similares nos modelos de pareamento por escore de propensão, bem como após análises de sensibilidade, como exclusão de pacientes que desenvolveram choque cardiogênico, infecção grave ou pacientes que foram a óbito durante a internação hospitalar. Conclusões Entre os pacientes internados com SCA que não receberam estatinas previamente, a terapia precoce com estatina associou-se independentemente com menor incidência de hiperglicemia durante a internação. (Arq Bras Cardiol. 2021; 116(2):285-294)

The obtainment of a dynamical logic gate (DLG), which is a device capable of implementing several logic functions using the same model, has been one of the goals of the scientific community. Dynamical systems, specifically those that display chaotic behavior, have been widely used to emulate different logic gates which are the basis of general-purpose computing. In this study, we present a methodology based on unstable dissipative systems of type 1 (UDS-1), a kind of dynamical system capable of generating multi-scrolls and multi-stability. Using these two features, we codify inputs, subsequently, we get the adequate output, developing in this way a dynamical (reconfigurable) logic gate that performs any of the sixteen possible logic functions of two inputs. A highlight of the proposed methodology is that the selection of the desired logic gate is realized just by varying a couple of parameters.

Translational research (TR) is an interdisciplinary branch of the biomedical field that seeks to connect its three supporting pillars: basic research on the bench, the hospital beds and other health system services, and the delivery of products for the well-being and health of the community. Here, we review the five transition stages of the TR spectrum, registering the lessons learned during > 20 years leading to the first clinical trial designed and performed in Brazil for testing a complementary treatment for Chagas disease (CD): the selenium trial (STCC). Lessons learned were: (1) to consider all the TR spectrum since the beginning of the project; (2) to start simultaneously animal studies and translation to humans; (3) to ensure a harmonious interaction between clinical and basic research teams; (4) to include MSc and PhD students only in pre-clinical and basic studies (TR0) or vertical clinical studies using retrospective samples and data (TR1); (5) to identify potential suppliers in the national commercial market for a future final treatment since the pre-clinical stage; (6) to keep an international network of experts as permanent advisers on the project. In the whole process, some perspectives were created: a complementary clinical trial for the opened questions and the construction of a Brazilian clinical CD platform.

Abstract Metaplastic breast cancer (MpBC) is an exceedingly rare breast cancer variant that is therapeutically challenging and aggressive. MpBC is defined by the histological presence of at least two cellular types, typically epithelial and mesenchymal components. This variant harbors a triple-negative breast cancer (TNBC) phenotype, yet has a worse prognosis and decreased survival compared to TNBC. There are currently no standardized treatment guidelines specifically for MpBC. However, prior studies have found that MpBC typically has molecular alterations in epithelial-to-mesenchymal transition, amplification of epidermal growth factor receptor, PI3K/Akt signaling, nitric oxide signaling, Wnt/β-catenin signaling, altered immune response, and cell cycle dysregulation. Some of these molecular alterations have been studied as therapeutic targets, in both the preclinical and clinical setting. This current review discusses the histological organization and cellular origins of MpBC, molecular alterations, the role of radiation therapy, and current clinical trials for MpBC.

During the early Eocene, Patagonia had highly diverse floras that are primarily known from compression and pollen fossils. Fossil wood studies from this epoch are scarce in the region and largely absent from the Laguna del Hunco flora, which has a highly diverse and excellently preserved compression assemblage. A collection of 26 conifer woods from the Laguna del Hunco fossil-lake beds (early Eocene, ca. 52 Ma) from central-western Patagonia was studied, of which 12 could be identified to genus. The dominant species is Phyllocladoxylon antarcticum, which has affinity with early-diverging Podocarpaceae such as Phyllocladus and Prumnnopitys. A single specimen of Protophyllocladoxylon francisiae probably represents an extinct group of Podocarpaceae. In addition, two taxonomic units of cf. Cupressinoxylon with putative affinity to Podocarpaceae were found. Diverse Podocarpaceae taxa consistent with the affinities of these woods were previously reported from vegetative and reproductive macrofossils as well as pollen grains from the same source unit. Some of the woods have galleries filled with frass. Distinct growth ring boundaries indicate seasonality, inferred to represent seasonal light availability. Growth ring widths suggest that the woods came from mature trees, whereas the widths and types of some rings denote near-uniform temperature and water availability conditions.

Los precios de venta de primera mano del gas natural (GN) en México tuvieron una relación dinámica, pero con retrasos, con los precios internacionales de los futuros de GN durante el periodo de enero de 2012 a junio de 2017. A partir de una estrategia de cobertura en la que se emplean futuros de GN y utilizando un modelo MGARCH VCC para estimar las variaciones condicionales con retrasos de 20 y 40 días de los precios de los futuros, se muestra cómo se comportan las coberturas dinámicas de GN, suponiendo precios teóricos futuros del dólar estadounidense en pesos mexicanos. A través de una prueba retrospectiva, se halló que las predicciones de las razones de cobertura óptima mejoran con períodos cortos de pronóstico y períodos cercanos de observación. El modelo de cobertura dinámica propuesto puede extenderse a otros mercados de combustibles. Se destaca la importancia de la cobertura de los precios del GN dado el tamaño del mercado y la magnitud del riesgo al que se encuentran expuestos los participantes.

The aim of this work is to design an integrated optical ring resonator to be implemented in LiNbO3 with a 2.5 mm radius and an operating wavelength of 1550 nm. Considering these ring parameters, a free spectral range of 71.54 pm and a quality factor of ∼5×105 were calculated. The authors apply results to improve the implementation of femtosecond laser writing in lithium niobate crystals. As it is well‐known finite difference time domain method requires large memory and time for processing circuits with large footprint (few square mm), in contrast, the beam propagation method allows to simulate large bends in a simple way. RSoft suite design tools commonly represent circles by closed polygons whose geometrical parameters are not optimised to obtain bending losses as least as possible, as suggested by coherent coupling theory. In this sense, the suitable determination of a splice angle (in this case 1.44°), shape and length for segments are key parameters in the ring design. For this purpose, an ad hoc software was implemented to overcome this drawback. In summary, a 250 sided polygon side showed a suitable coupling performance and established a new layout approach for middle range rings.

Abstract Background The human epidermal growth factor receptor (HER) family, notably EGFR, is overexpressed in most triple-negative breast cancer (TNBC) cases and provides cancer cells with compensatory signals that greatly contribute to the survival and development of resistance in response to therapy. This study investigated the effects of Pan-HER (Symphogen, Ballerup, Denmark), a novel mixture of six monoclonal antibodies directed against members of the HER family EGFR, HER2, and HER3, in a preclinical trial of TNBC patient-derived xenografts (PDXs). Methods Fifteen low passage TNBC PDX tumor samples were transferred into the right mammary fat pad of mice for engraftment. When tumors reached an average size of 100–200 mm3, mice were randomized (n ≥ 6 per group) and treated following three 1-week cycles consisting of three times/week intraperitoneal (IP) injection of either formulation buffer (vehicle control) or Pan-HER (50 mg/kg). At the end of treatment, tumors were collected for Western blot, RNA, and immunohistochemistry analyses. Results All 15 TNBC PDXs were responsive to Pan-HER treatment, showing significant reductions in tumor growth consistent with Pan-HER-mediated tumor downmodulation of EGFR and HER3 protein levels and significantly decreased activation of associated HER family signaling pathways AKT and ERK. Tumor regression was observed in five of the models, which corresponded to those PDX tumor models with the highest level of HER family activation. Conclusions The marked effect of Pan-HER in numerous HER family-dependent TNBC PDX models justifies further studies of Pan-HER in TNBC clinical trials as a potential therapeutic option.

The thermodynamic behavior of the pseudo-binary Al2O3 – MnO is of high value for the steel industry. However, its phase diagram has been associated with some controversy regarding the equilibrium conditions involving the spinel phase (MnAl2O4) at higher temperatures. One way to handle this issue would be the development of a more accurate Gibbs energy models for this mixed oxide, which by itself demands high precision heat capacity data. In the present article, Al2MnO4 samples are synthesized at 1373 K under a reduced atmosphere (C/CO) and characterized through different methods: transmission electron microscopy (TEM) and X-ray diffraction (XRD). The volumetric behavior of Al2MnO4 has next been addressed through XRD analysis with synchrotron radiation during cooling between 300 and 20 K. Finally, selected samples have been studied in a relaxation calorimeter for measuring CP in the range between 2 to 300 K. A reversible thermal anomaly has been detected, with a peak centered around 33 K. Such phenomena resulted in a measurable contribution to the molar entropy of the spinel phase (4.7 ± 0.05 J/mol.K). Considering this contribution, the mean molar entropy of Al2MnO4 at 298.15 K has shown to be equal to 118.7 ± 0.5 J/mol.K.

This paper presents SeQual, a scalable tool to efficiently perform quality control of large genomic datasets. Our tool currently supports more than 30 different operations (e.g., filtering, trimming, formatting) that can be applied to DNA/RNA reads in FASTQ/FASTA formats to improve subsequent downstream analyses, while providing a simple and user-friendly graphical interface for non-expert users. Furthermore, SeQual takes full advantage of Big Data technologies to process massive datasets on distributed-memory systems such as clusters by relying on the open-source Apache Spark cluster computing framework. Our scalable Spark-based implementation allows to reduce the runtime from more than three hours to less than 20 minutes when processing a paired-end dataset with 251 million reads per input file on an 8-node multi-core cluster.

Abstract Background Cancer stem cells (CSCs) are purported to be responsible for tumor initiation, treatment resistance, disease recurrence, and metastasis. CXCR1, one of the receptors for CXCL8, was identified on breast cancer (BC) CSCs. Reparixin, an investigational allosteric inhibitor of CXCR1, reduced the CSC content of human BC xenograft in mice. Methods In this multicenter, single-arm trial, women with HER-2-negative operable BC received reparixin oral tablets 1000 mg three times daily for 21 days before surgery. Primary objectives evaluated the safety of reparixin and the effects of reparixin on CSC and tumor microenvironment in core biopsies taken at baseline and at treatment completion. Signal of activity was defined as a reduction of ≥ 20% in ALDH+ or CD24−/CD44+ CSC by flow cytometry, with consistent reduction by immunohistochemistry. Results Twenty patients were enrolled and completed the study. There were no serious adverse reactions. CSC markers ALDH+ and CD24−/CD44+ measured by flow cytometry decreased by ≥ 20% in 4/17 and 9/17 evaluable patients, respectively. However, these results could not be confirmed by immunofluorescence due to the very low number of CSC. Conclusions Reparixin appeared safe and well-tolerated. CSCs were reduced in several patients as measured by flow cytometry, suggesting targeting of CXCR1 on CSC. Clinical trial registration Clinicaltrials.gov, NCT01861054. Registered on April 18, 2013.

Recent research on the use of physical mixtures In2O3-ZrO2 has raised interesting questions as to how their combination enhances catalytic activity and selectivity. Specifically, the relationship between oxygen diffusion and defect formation and the epitaxial tension in the mixture should be further investigated. In this study, we aim to clarify some of these relationships through a molecular dynamics approach. Various potentials for the two oxides are compared and selected to describe the physical mixture of In2O3 and ZrO2. Different configurations of each single crystal and their physical mixture are simulated, and oxygen defect formation and diffusion are measured and compared. Significant oxygen defect formation is found in both crystals. In2O3 seems to be stabilized by the mixture, while ZrO2 is destabilized. Similar results were found for the ZrO2 doping with In and ln2O3 doping with Zr. The results explain the high activity and selectivity catalyst activity of the mixture for the production of isobutylene from ethanol.

The effects of testing solutions and conditions on hydroxyapatite (HAp) formation as a means of in vitro bioactivity evaluation of B2O3 containing 45S5 bioactive glasses were systematically investigated. Four glass samples prepared by the traditional melt and quench process, where SiO2 in 45S5 was gradually replaced by B2O3 (up to 30%), were studied. Two solutions: the simulated body fluid (SBF) and K2HPO4 solutions were used as the medium for evaluating in vitro bioactivity through the formation of HAp on glass surface as a function of time. It was found that addition of boron oxide delayed the HAp formation in both SBF and K2HPO4 solutions, while the reaction between glass and the K2HPO4 solution is much faster as compared to SBF. In addition to the composition and medium effects, we also studied whether the solution treatments (e.g., adjusting to maintain a pH of 7.4, refreshing solution at certain time interval, and no disturbance during immersion) affect HAp formation. Fourier transform infrared spectrometer (FTIR) equipped with an attenuated total reflection (ATR) sampling technique and scanning electron microscopy (SEM) were conducted to identify HAp formation on glass powder surfaces and to observe HAp morphologies, respectively. The results show that refreshing solution every 24 h produced the fastest HAp formation for low boron-containing samples when SBF was used as testing solution, while no significant differences were observed when K2HPO4 solution was used. This study thus suggests the testing solutions and conditions play an important role on the in vitro bioactivity testing results and should be carefully considered when study materials with varying bioactivities. Keywords: Bioactive glasses, Boron oxide, In vitro, Hydroxyapatite

Background: Chagas disease (caused by Trypanosoma cruzi infection) evolves to chronic chagasic cardiomyopathy (CCC) affecting 1.8 million people worldwide. This is the first randomized, placebo-controlled, double-blinded, clinical trial designed to estimate efficacy and safety of selenium (Se) treatment in CCC. Methods: 66 patients with CCC stages B1 (left ventricular ejection fraction [LVEF] > 45% and no heart failure; n = 54) or B2 (LVEF < 45% and no heart failure; n = 12) were randomly assigned to receive 100 mcg/day sodium selenite (Se, n = 32) or placebo (Pla, n = 34) for one year (study period: May 2014-September 2018). LVEF changes over time and adverse effects were investigated. Trial registration number: NCT00875173 (clinicaltrials.gov). Findings: No significant differences between the two groups were observed for the primary outcome: mean LVEF after 6 (β= +1.1 p = 0.51 for Se vs Pla) and 12 months (β= +2.1; p = 0.23). In a subgroup analysis, statistically significant longitudinal changes were observed for mean LVEF in the stage B2 subgroup (β= +10.1; p = 0.02 for Se [n = 4] vs Pla [n = 8]). Se treatment was safe for CCC patients, and the few adverse effects observed were similarly distributed across the two groups. Interpretation: Se treatment did not improve cardiac function (evaluated from LVEF) in CCC. However, in the subgroup of patients at B2 stage, a potential beneficial influence of Se was observed. Complementary studies are necessary to explore diverse Se dose and/or associations in different CCC stages (B2 and C), as well as in A and B1 stages with longer follow-up. Funding: Brazilian Ministry of Health, Fiocruz, CNPq, FAPERJ.

Background: Patients with Coronavirus Disease 2019 (COVID-19) may present high risk features during hospitalization, including cardiovascular manifestations. However, less is known about the factors that may further increase the risk of death in these patients. Methods: We included patients with COVID-19 and high risk features according to clinical and/or laboratory criteria at 21 sites in Brazil from June 10th to October 23rd of 2020. All variables were collected until hospital discharge or in-hospital death. Results: A total of 2546 participants were included (mean age 65 years; 60.3% male). Overall, 70.8% were admitted to intensive care units and 54.2% had elevated troponin levels. In-hospital mortality was 41.7%. An interaction among sex, age and mortality was found (p = 0.007). Younger women presented higher rates of death than men (30.0% vs 22.9%), while older men presented higher rates of death than women (57.6% vs 49.2%). The strongest factors associated with in-hospital mortality were need for mechanical ventilation (odds ratio [OR] 8.2, 95% confidence interval [CI] 5.4–12.7), elevated C-reactive protein (OR 2.3, 95% CI 1.7–2.9), cancer (OR 1.8, 95 %CI 1.2–2.9), and elevated troponin levels (OR 1.8, 95% CI 1.4–2.3). A risk score was developed for risk assessment of in-hospital mortality. Conclusions: This cohort showed that patients with COVID-19 and high risk features have an elevated rate of in-hospital mortality with differences according to age and sex. These results highlight unique aspects of this population and might help identifying patients who may benefit from more careful initial surveillance and potential subsequent interventional therapies.

BackgroundChagas Disease (CD) affects 6-7 million people worldwide and is related to poverty-promoting conditions. Chronic asymptomatic cases are mostly invisible to health systems. Aiming (1) to translate CD discoveries into education/information practices to raise alertness and empowerment of affected people; and (2) to perform an active search of CD cases, articulating intersectoral actions to improve the access of infected people to the local health service for the treatment of CD; our research group developed and tested under field conditions as innovative social technology: an itinerant education interdisciplinary setting named "Chagas Express XXI" (CE21).MethodologyCE21 was created as an "imaginary train" with ~40 ArtScience workshops, games, laboratory activities and conversation circles. An entry/exit plus six activity modules combined associations of affected people, microscopic observations, One Health education, and wellness activities. CE21 was conceived as a social technology, since all the processes were co-created with CD patients and inter-sector local partners. Descriptive statistics showed quantitative data collected throughout the expeditions (CD knowledge, serological results). Qualitative data accessed the public perceptions about the education activities.Principal findingsCE21 was exhibited in local educational institutions (schools, universities) in four cities, engaging 2,117 people that evaluated the 41 activities carried out. Citizens and health professionals enjoyed acquisition of information related to blood, parasites, vectors, reservoirs, environmental changes, and social determinants of CD. Further, local legacies of 600 participants volunteer for health promotion groups and CD associations, local empowerment groups to fight for better health conditions, and 05 mural paintings. We observed that 81% of the participants ignored the possibility of treating CD while 52% of the participants requested a blood test for CD showing seropositivity in 20% of them.ConclusionsCE21 is a social technology potentially useful for health and science education and active search of asymptomatic CD chronic cases. Moreover, this technology may be adapted to understand and to cooperate in other potentially epidemic situations, especially NTDs related.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare but serious disease with poorly understood mechanisms. Here, we report that patients with EGPA have elevated levels of TSLP, IL-25, and soluble ST2, which are well-characterized cytokine “alarmins” that activate or modulate type 2 innate lymphoid cells (ILC2s). Patients with active EGPA have a concurrent reduction in circulating ILC2s, suggesting a role for ILC2s in the pathogenesis of this disease. To explore the mechanism of these findings in patients, we established a model of EGPA in which active vasculitis and pulmonary hemorrhage were induced by IL-33 administration in predisposed, hypereosinophilic mice. In this model, induction of pulmonary hemorrhage and vasculitis was dependent on ILC2s and signaling through IL4Rα. In the absence of IL4Rα or STAT6, IL-33–treated mice had less vascular leak and pulmonary edema, less endothelial activation, and reduced eotaxin production, cumulatively leading to a reduction of pathologic eosinophil migration into the lung parenchyma. These results offer a mouse model for use in future mechanistic studies of EGPA, and they suggest that IL-33, ILC2s, and IL4Rα signaling may be potential targets for further study and therapeutic targeting in patients with EGPA.

The objective of this paper is to assess the sustainability of the agricultural production chain of rice (Oryza sativa L.) in Brazil and Cuba, using a conceptual model that considers five sectors of sustainability supported in the Goals Programming philosophy as multicriteria analysis tools. A synthetic sustainability indicator is constructed to support decision-making through the benchmarking process to contribute the environmental, economic and social sustainability of rice farming. As results, Brazil shows a greater sustainability based on better availability of environmental resources for rice cultivation, a lower relative environmental load, better economic and productive performance, poorer employment and wage policies and higher satisfaction of the social demand for rice. On the other hand, Cuba shows a deficit of environmental resources, higher relative environmental load, low economic and productive performance, better employment and wage policies, and unsatisfied social demand for rice.

Abstract Background Neoadjuvant dual human epidermal growth factor receptor (HER2) blockade with trastuzumab and pertuzumab plus paclitaxel leads to an overall pathologic complete response (pCR) rate of 46%. Dual HER2 blockade with ado-trastuzumab emtansine (T-DM1) and lapatinib plus nab-paclitaxel has shown efficacy in patients with metastatic HER2-positive breast cancer. To test neoadjuvant effectiveness of this regimen, an open-label, multicenter, randomized, phase II trial was conducted comparing T-DM1, lapatinib, and nab-paclitaxel with trastuzumab, pertuzumab, and paclitaxel in patients with early-stage HER2-positive breast cancer. Methods Stratification by estrogen receptor (ER) status occurred prior to randomization. Patients in the experimental arm received 6 weeks of targeted therapies (T-DM1 and lapatinib) followed by T-DM1 every 3 weeks, lapatinib daily, and nab-paclitaxel weekly for 12 weeks. In the standard arm, patients received 6 weeks of trastuzumab and pertuzumab followed by trastuzumab weekly, pertuzumab every 3 weeks, and paclitaxel weekly for 12 weeks. The primary objective was to evaluate the proportion of patients with residual cancer burden (RCB) 0 or I. Key secondary objectives included pCR rate, safety, and change in tumor size at 6 weeks. Hypothesis-generating correlative assessments were also performed. Results The 30 evaluable patients were well-balanced in patient and tumor characteristics. The proportion of patients with RCB 0 or I was higher in the experimental arm (100% vs. 62.5% in the standard arm, p = 0.0035). In the ER-positive subset, all patients in the experimental arm achieved RCB 0-I versus 25% in the standard arm (p = 0.0035). Adverse events were similar between the two arms. Conclusion In early-stage HER2-positive breast cancer, the neoadjuvant treatment with T-DM1, lapatinib, and nab-paclitaxel was more effective than the standard treatment, particularly in the ER-positive cohort. Trial registration Clinicaltrials.gov NCT02073487, February 27, 2014.

Here, a cross of Plasmodium vivax malaria parasites links a chloroquine resistance (CQR) phenotype to a 76 kb region of chromosome 1 and greater expression of pvcrt, an ortholog of the Plasmodium falciparum CQR transporter gene.

Approximate computing has been exploited for many years in application-specific architectures. Recently, it has also been proposed for low-power programmable processors. However, this poses some challenges as, in a microprocessor, the energy consumed by fetching and decoding an instruction may be significantly higher than that of the execution itself. Therefore, approximate computing would be advisable only for those instructions, in which the execution stage is significantly expensive in terms of energy consumption. In this paper, we present new architectures for truncated SIMD multipliers able to calculate signed and unsigned products from 8 × 8 to 64× 64 bits. Next, we analyze the precision loss incurred by truncation for all product sizes. We implement accurate and truncated architectures for both scalar and SIMD products and find that truncation allows area savings of up to 27%. The proposed design is experimentally evaluated in different scenarios, showing potential energy savings ranging from 29% to 42%. Finally, this paper analyzes the overall convenience of introducing truncated SIMD architectures with respect to accurate SIMD and scalar architectures.

Malaria is a parasitic disease caused by protozoan parasites from the genus Plasmodium. Plasmodium falciparum is the most prevalent species worldwide and the causative agent of severe malaria. The spread of resistance to the currently available antimalarial therapy is a major concern. Therefore, it is imperative to discover and develop new antimalarial drugs, which not only treat the disease but also control the emerging resistance. Brussonol is an icetexane derivative and a member of a family of diterpenoids that have been isolated from several terrestrial plants. Here, the synthesis and antiplasmodial profiling of a series of brussonol derivatives are reported. The compounds showed inhibitory activities in the low micromolar range against a panel of sensitive and resistant P. falciparum strains (IC50s = 5–16 μM). Moreover, brussonol showed fast-acting in vitro inhibition and an additive inhibitory behavior when combined with the antimalarial artesunate (FICindex~1). The mode of action investigation indicated that brussonol increased the cytosolic calcium levels within the parasite. Hence, the discovery of brussonol as a new scaffold endowed with antiplasmodial activity will enable us to design derivatives with improved properties to deliver new lead candidates for malaria.

Se traza aquí una panorámica del itinerario intelectual de Cassirer, enfatizando el creciente compromiso político de su pensamiento, al querer combatir la ideología nacionalsocialista desde la historia de las ideas y su filosofía de la cultura simbólica, invocando para ello al espíritu de la Ilustración en general y a Kant muy en particular. Su refutación ideológica del nazismo comienza en 1928 con su homenaje a la República de Weimar y llega hasta 1945 con El mito del Estado, pero aquí se presenta su interpretación del significado peligrosamente moral que tuvo el judaísmo para la ideología totalitaria del nacionalsocialismo.

OBJECTIVES: Returning to work after an episode of acute coronary syndrome (ACS) is challenging for many patients, and has both personal and social impacts. There are limited data regarding the working status in the very long-term after ACS. METHODS: We retrospectively analyzed 1,632 patients who were working prior to hospitalization for ACS in a quaternary hospital and were followed-up for up to 17 years. Adjusted models were developed to analyze the variables independently associated with actively working at the last contact, and a prognostic predictive index for not working at follow-up was developed. RESULTS: The following variables were significantly and independently associated with actively working at the last contact: age>median (hazard-ratio [HR], 0.76, p

Summary: Inflammatory response heterogeneity has impeded high-resolution dissection of diverse immune cell populations during activation. We characterize mouse cutaneous immune cells by single-cell RNA sequencing, after inducing inflammation using imiquimod and oxazolone dermatitis models. We identify 13 CD45+ subpopulations, which broadly represent most functionally characterized immune cell types. Oxazolone pervasively upregulates Jak2/Stat3 expression across T cells and antigen-presenting cells (APCs). Oxazolone also induces Il4/Il13 expression in newly infiltrating basophils, and Il4ra and Ccl24, most prominently in APCs. In contrast, imiquimod broadly upregulates Il17/Il22 and Ccl4/Ccl5. A comparative analysis of single-cell inflammatory transcriptional responses reveals that APC response to oxazolone is tightly restricted by cell identity, whereas imiquimod enforces shared programs on multiple APC populations in parallel. These global molecular patterns not only contrast immune responses on a systems level but also suggest that the mechanisms of new sources of inflammation can eventually be deduced by comparison to known signatures.

We first provide a critical review of the existing findings on bilingualism as a contributor to cognitive reserve from moderator-mediator warranting cause-effect research conclusions. We next address the question of direct or indirect effects between bilingualism and neurocognitive protective factors influencing the associated age-related mental deficits. The existing findings support bilingualism as a predictor and as a moderator. Third, we propose cognitive reserve models of bilingualism describing analytical approaches that allow testing of these models and hypotheses related to path strength and causal relationships between predictors, moderators, and mediators. Lastly and most importantly, we suggest using large datasets available via open repositories. This can aid in the testing of theoretical models, clarifying the roles of moderators and mediators, and assessing the research viability of multi-causal paths that can influence cognitive reserve. Creating collaborative datasets to test these models would greatly advance our field and identify critical variables in the study of the bilingual aging brain.

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For over 60 years, selenium (Se) has been known as an essential microelement to many biological functions, including cardiovascular homeostasis. This review presents a compilation of studies conducted in the past 20 years related to chronic Chagas disease cardiomyopathy (CCC), caused by Trypanosoma cruzi infection, a neglected disease that represents a global burden, especially in Latin America. Experimental and clinical data indicate that Se may be used as a complementary therapy to prevent heart failure and improve heart function. Starting from the main questions “Is Se deficiency related to heart inflammation and arrhythmogenesis in CCC?” and “Could Se be recommended as a therapeutic strategy for CCC?”, we show evidence implicating the complex and multidetermined CCC physiopathology, discussing its possible interplays with the multifunctional cytokine TGF-β as regulators of immune response and fibrosis. We present two new proposals to face this global public health challenge in vulnerable populations affected by this parasitic disease: fibrosis modulation mediated by TGF-β pathways and the possible use of selenoproteins as antioxidants regulating the increased reactive oxygen stress present in CCC inflammatory environments. We assess the opportunity to consider the beneficial effects of Se in preventing heart failure as a concept to be applied for CCC patients.

The demand for bromelian and pineapple fruit has been increasing substantially in the world because of their benefits for the human health and use in diverse areas. In this context, this work aimed to study the capacity of higher retention (concentration); bromelain activity underwent ultrafiltration from pineapple juice (Ananas comusus L. Merrill). All assays were carried out at pH 7.0 and 7.5, and at 0.05 and 0.40 bar of transmembrane pressures. Results have shown that at the best operating conditions, between 85 and 87% of bromelain activity was recovered using the plain membrane separation process at 0.05 bar. The ultrafiltration has shown the capacity to retain 100% of proteolytic activity of the bromelain extracted. The samples have kept the same physics properties after ultrafiltration, and the result was verified via electrophoresis. The bromelain enzyme obtained was characterized, and pH 7 and between 30 and 40 °C were the best conditions. Therefore, this work shows that the use of both polymeric membranes has shown high efficiency, and can be used in the purification of bromelain enzymes.

Abstract Background Breast cancer has been considered not highly immunogenic, and few patients benefit from current immunotherapies. However, new strategies are aimed at changing this paradigm. In the present study, we examined the in vivo activity of a humanized anti-programmed cell death protein 1 (anti-PD-1) antibody against triple-negative breast cancer (TNBC) patient-derived xenograft (PDX) tumor models. Methods To circumvent some of the limitations posed by the lack of appropriate animal models in preclinical studies of immunotherapies, partially human leukocyte antigen-matched TNBC PDX tumor lines from our collection, as well as human melanoma cell lines, were engrafted in humanized nonobese diabetic/severe combined immunodeficiency IL2Rγ null (hNSG) mice obtained by intravenous injection of CD34+ hematopoietic stem cells into nonlethally irradiated 3–4-week-old mice. After both PDXs and melanoma cell xenografts reached ~ 150–200 mm3, animals were treated with humanized anti-PD-1 antibody or anti-CTLA-4 and evaluated for tumor growth, survival, and potential mechanism of action. Results Human CD45+, CD20+, CD3+, CD8+, CD56+, CD68+, and CD33+ cells were readily identified in blood, spleen, and bone marrow collected from hNSG, as well as human cytokines in blood and engrafted tumors. Engraftment of TNBC PDXs in hNSG was high (~ 85%), although they grew at a slightly slower pace and conserved their ability to generate lung metastasis. Human CD45+ cells were detectable in hNSG-harbored PDXs, and consistent with clinical observations, anti-PD-1 antibody therapy resulted in both a significant reduction in tumor growth and increased survival in some of the hNSG PDX tumor lines, whereas no such effects were observed in the corresponding non-hNSG models. Conclusions This study provides evidence associated with anti-PD-1 immunotherapy against TNBC tumors supporting the use of TNBC PDXs in humanized mice as a model to overcome some of the technical difficulties associated with the preclinical investigation of immune-based therapies.