Genome-Wide Association Study of Fiber Diameter in Alpacas.

The aim of this study was the identification of candidate genomic regions associated with fiber diameter in alpacas. DNA samples were collected from 1011 female Huacaya alpacas from two geographical Andean regions in Peru (Pasco and Puno), and three alpaca farms within each region. The samples were genotyped using an Affymetrix Custom Alpaca genotyping array containing 76,508 SNPs. After the quality controls, 960 samples and 51,742 SNPs were retained. Three association study methodologies were performed. The GWAS based on a linear model allowed us to identify 11 and 35 SNPs (-log10(p-values) > 4) using information on all alpacas and alpacas with extreme values of fiber diameter, respectively. The haplotype and marker analysis method allowed us to identify nine haplotypes with standardized haplotype heritability higher than six standard deviations. The selection signatures based on cross-population extended haplotype homozygosity (XP-EHH) allowed us to identify 180 SNPs with XP-EHH values greater than |3|. Four candidate regions with adjacent SNPs identified via two association methods of analysis are located on VPA6, VPA9, VPA29 and one chromosomally unassigned scaffold. This study represents the first analysis of alpaca whole genome association with fiber diameter, using a recently assembled alpaca SNP microarray.

Genetic diversity in creole pigs in south central Peru.

The creole pigs represent 67% of the national population in Peru. They are a source of economic income in rural communities, and due to their rusticity, they are not much labor demanding. However, knowledge about its genetic diversity remains scarce. The objective of this study was to determine the population structure and genetic diversity of creole pigs from rural communities in south central Peru. Thirteen microsatellites were used to characterize 120 creole pigs from the departments of Ayacucho (57) and Apurimac (63). The samples were taken from hair follicles and ear tissue. Nine microsatellites were highly polymorphic and informative (PIC > 0.5) for both departments. The Ayacucho population had a mean number of alleles (MNA) and expected heterozygosity (HE) of 8.8 and 0.68, respectively, while in the Apurimac population, these were 8.9 and 0.71, respectively. Both populations showed in less than 50% of their loci a deviation from Hardy-Weinberg equilibrium. There was a moderate genetic structure according to the analysis of molecular variance and the FST statistics (0.06), which was corroborated by Bayesian methods. In conclusion, the genetic diversity was mostly due to the intrapopulation variance (91%). Some individuals from Ayacucho shared similar alleles with those from Apurimac. This latter result may be due to their geographic proximity and the introduction of the same new exotic breeds. This is the first research on the genetic diversity of creole pigs in south central Peru. In fact, this study could serve as a basis for conservation strategies and actions in this region.

Scarce Evidence of Heterosis for Growth Traits in Peruvian Guinea Pigs.

This study aimed to estimate the heterosis for productive traits in a two-way crossbreeding scheme. Four guinea pig lines were originally selected for the following traits: line P1 for the growth rate, P2 for the partial feed conversion rate, M1 for the growth rate of the litter at 10 days of age, and M2 for the litter size at birth. The comparison included 176 purebreds (P1: 46, P2: 43, M1: 54 and M2: 33) and 150 crosses (P1P2: 42, P2P1: 38, M1M2: 11 and M2M1: 59); body weights at birth, 10 days, weaning and 60 days of age were analyzed. A linear fixed-effect model was used, and heterosis was estimated as the difference between the average performance of the crossbred and pure-line animals. The pure line comparisons showed that P2 was lower than P1 for weight at 10 days and weaning weight, while all other comparisons between the paternal and maternal pure lines were not significant. The results indicated significant positive heterosis effects for both types of crosses, but only for birth weight: 3.7% for paternal crosses and 12.7% for maternal crosses. The heterosis estimates were mostly positive but not significant for all other traits. A reason for the low levels of heterosis could be that the lines are not very genetically differentiated. These results suggest that applying a two-way crossbreeding scheme within paternal and maternal guinea pig lines for meat production is not recommended due to the absence of heterosis for growth traits.

Inhibition of PLK1 Destabilizes EGFR and Sensitizes EGFR-Mutated Lung Cancer Cells to Small Molecule Inhibitor Osimertinib.

Tyrosine kinase inhibitors (TKI) targeting the epidermal growth factor receptor (EGFR) have significantly prolonged survival in EGFR-mutant non-small cell lung cancer patients. However, the development of resistance mechanisms prohibits the curative potential of EGFR TKIs. Combination therapies emerge as a valuable approach to preventing or delaying disease progression. Here, we investigated the combined inhibition of polo-like kinase 1 (PLK1) and EGFR in TKI-sensitive EGFR-mutant NSCLC cells. The pharmacological inhibition of PLK1 destabilized EGFR levels and sensitized NSCLC cells to Osimertinib through induction of apoptosis. In addition, we found that c-Cbl, a ubiquitin ligase of EGFR, is a direct phosphorylation target of PLK1 and PLK1 impacts the stability of c-Cbl in a kinase-dependent manner. In conclusion, we describe a novel interaction between mutant EGFR and PLK1 that may be exploited in the clinic. Co-targeting PLK1 and EGFR may improve and prolong the clinical response to EGFR TKI in patients with an EGFR-mutated NSCLC.

The EGFR-STYK1-FGF1 axis sustains functional drug tolerance to EGFR inhibitors in EGFR-mutant non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) patients harboring activating mutations in epidermal growth factor receptor (EGFR) are sensitive to therapy with EGFR tyrosine kinase inhibitors (TKI). Despite remarkable clinical responses using EGFR TKI, surviving drug tolerant cells serve as a reservoir from which drug resistant tumors may emerge. This study addresses the need for improved efficacy of EGFR TKI by identifying targets involved in functional drug tolerance against them. To this aim, a high-throughput siRNA kinome screen was performed using two EGFR TKI-sensitive EGFR-mutant NSCLC cell lines in the presence/absence of the second-generation EGFR TKI afatinib. From the screen, Serine/Threonine/Tyrosine Kinase 1 (STYK1) was identified as a target that when downregulated potentiates the effects of EGFR inhibition in vitro. We found that chemical inhibition of EGFR combined with the siRNA-mediated knockdown of STYK1 led to a significant decrease in cancer cell viability and anchorage-independent cell growth. Further, we show that STYK1 selectively interacts with mutant EGFR and that the interaction is disrupted upon EGFR inhibition. Finally, we identified fibroblast growth factor 1 (FGF1) as a downstream effector of STYK1 in NSCLC cells. Accordingly, downregulation of STYK1 counteracted the afatinib-induced upregulation of FGF1. Altogether, we unveil STYK1 as a valuable target to repress the pool of surviving drug tolerant cells arising upon EGFR inhibition. Co-targeting of EGFR and STYK1 could lead to a better overall outcome for NSCLC patients.

Infección por SARS - CoV-2 posterior a la inmunización artificial e híbrida en el personal de salud / SARS-CoV-2 breakthrough infection after artificial and hybrid immunization in healthcare workers

Reportes actuales sugieren que el antecedente de infección por SARS - CoV-2 y completar un esquema de vacunación otorga mayor protección contra la presentación sintomática de COVID -19. Se comparó el riesgo de enfermar de COVID -19 entre el personal de salud con esquema completo de vacuna contra SARS - CoV-2 BNT162b2 y el antecedente de infección por SARS - CoV-2. Estudio de cohorte histórica en 1874 trabajadores de la salud del Nuevo Hospital Civil de Guadalajara inmunizados con la vacuna BNT162b2 entre enero y marzo de 2021. Después de seis meses de seguimiento, el grupo de no expuestos (sin antecedente de infección) fue de 1397 y el grupo expuesto (con antecedente de infección), de 477 sujetos. La incidencia de infección por SARS - CoV-2 fue de 39 casos. El riesgo de infección en la cohorte posterior a la inmunización fue de 0,021. El grupo de inmunización híbrida presentó un riesgo menor de infección comparado con el grupo de inmunización artificial (0,015 y 0,243). La inmunización híbrida contribuyó a una reducción del riesgo atribuible a la población de 0,003 (R0 0,024; Rp 0,020). La hospitalización se presentó en el 7,69 % de los casos confirmados con SARS - CoV-2. El riesgo de hospitalización en inmunización híbrida es de 0,210 y de 0,143 en el grupo de inmunización artificial (RR 1,46 IC95 % 0,13 -16,11). Se llegó a la conclusión que la inmunización híbrida podría contribuir a reducir el riesgo de infección por SARS - CoV-2, potenciando la inmunidad generada por la vacuna contra COVID -19

Current reports suggest that a history of SARS - CoV-2 infection and completing a vaccination schedule provides greater protection against the symptomatic presentation of COVID -19. The risk of becoming ill with COVID -19 was compared between health personnel with a complete SARS - CoV-2 BNT162b2 vaccine schedule and a history of SARS - CoV-2 infection. Historical cohort study in 1874 health workers of the New Civil Hospital of Guadalajara immunized with the BNT162b2 vaccine between January and March 2021. After six months of follow-up, the non-exposed group (without a history of infection) was 1397 and the exposed group (with a history of infection), of 477 subjects. The incidence of SARS - CoV-2 infection was 39 cases. The risk of infection in the post-immunization cohort was 0.021. The hybrid immunization group had a lower risk of infection compared to the artificial immunization group (0.015 and 0.243). Hybrid immunization contributed to a population-attributable risk reduction of 0.003 (R0 0.024, Rp 0.020). Hospitalization occurred in 7.69% of confirmed cases with SARS - CoV-2. The risk of hospitalization in hybrid immunization is 0.210 and 0.143 in the artificial immunization group (RR 1.46 CI95% 0.13 -16.11). It was concluded that hybrid immunization could help reduce the risk of SARS - CoV-2 infection, enhancing the immunity generated by the vaccine against COVID -19

Artes escénicas como metodología de enseñanza para la comunicación efectiva en estudiantes de Enfermería en la Universidad de La Frontera, Chile / Performing arts as a teaching methodology for effective communication in Nursing students, Universidad de La Frontera, Chile

Introducción: La capacidad comunicativa es factible de mejorar en sujetos que reciben preparación sociopsicológica. Las escuelas de Enfermería han recurrido a variadas formas de arte, entre ellas las escénicas, como parte de esta instrucción. Los objetivos son: desvelar la vivencia con respecto a los talleres basados en artes escénicas, descubrir los aportes de éstos para la formación y la competencia de comunicación, e indagar aspectos que deben mejorar posterior a la experiencia.Material y métodos.Es una investigación cualitativa exploratoria, mediante sistematización de experiencia, con una muestra no probabilística, intencionada de casos por criterio, conveniencia, conformada por 36 estudiantes. La intervención se basó en la pedagogía de Jacques Lecoq, y se desarrollaron 11 talleres en el primer semestre de 2019. La recolección de datos se hizo con un instrumento con preguntas abiertas, y el análisis, mediante comparación constante y reducción progresiva de forma manual. El estudio fue aprobado por Coordinación de Desarrollo Docente e Innovación Tecnológica, Vicerrectoría de Pregrado, Universidad de La Frontera.Resultados.En el primer nivel, se obtuvieron 400 unidades de significado agrupadas en 58 categorías emergentes que originaron un dominio cualitativo en el tercer nivel: 'representa opiniones de estudiantes en relación con la potenciación del desarrollo personal y de la competencia de comunicación asociada a metodología de aprendizaje basado en artes escénicas en el ámbito personal y académico para los cuidados'.Conclusiones.Los participantes reconocen el desarrollo de competencias genéricas, especialmente comunicación, e identifican los beneficios de la experiencia en el ámbito personal, académico y futuro profesional. (AU)

Introduction: The communicative ability is feasible to improve in subjects receiving socio-psychological training. Nursing schools have used a variety of art forms, including theatrical skills, as part of this instruction. The objectives are: to reveal the experience concerning the workshops based on performing arts, to discover its contributions to training and communication skills, and to investigate aspects that should be improved after the experience.Material and methods.Exploratory qualitative research, through the systematization of experience. Non-probabilistic, intentional sample of cases by criterion, convenience, made up of 36 students. The intervention was based on the pedagogy of Jacques Lecoq, developing 11 workshops in the first semester of 2019. Data collection with an instrument with open questions. Analysis by constant comparison and manual progressive reduction. Study approved by the Coordination of Teaching Development and Technological Innovation, Undergraduate Vice-Rectory, Universidad de La Frontera.Results.First level, 400 units of meaning grouped into 58 emerging categories that originated a qualitative domain in the third level: 'represents students' opinions about the enhancement of personal development and communication competence associated with learning methodology based on performing arts in the personal and academic sphere for care'.Conclusions.Participants recognize the development of generic skills, especially communication, identify the benefits of the experience in the personal, academic, and professional future. (AU)

USP13 modulates the stability of the APC/C adaptor CDH1.

BACKGROUND: The cell division cycle is a process that is exquisitely controlled by a complex interplay between E3 ubiquitin ligases and deubiquitinating enzymes (DUBs). We have previously reported that the DUB USP13 regulates Aurora B levels along the cell cycle. That observation prompted us to explore any possible connection between USP13 and the APC/CCDH1, the major E3 controlling Aurora B levels in cells. METHODS: We performed immunoprecipitation assays followed by western-blotting to assess the interaction between USP13 and CDH1. The cellular effects of USP13 gain or loss of function were analyzed by transfection of FLAG-tagged USP13 plasmid or small interfering RNAs and short hairpin RNAs directed against USP13. The levels of CDH1 and other proteins were quantified in cell extracts by western-blotting. RESULTS: We found that USP13 binds to the APC/C adaptor CDH1. In addition, we report for the first time that USP13 controls CDH1 protein levels in cells: overexpression of USP13 increased CDH1 levels, whereas depletion of USP13 decreased CDH1 levels. CONCLUSIONS: We unveil the existing interplay between USP13 and CDH1: USP13 is capable of stabilizing CDH1 levels. We previously reported that USP13 stabilizes Aurora B in cells, a known substrate of the APC/CCDH1 E3 ubiquitin ligase, before their entry into mitosis. Altogether, our data identify and establish the USP13-CDH1-Aurora B axis as a new regulatory module required for flawless cell cycle progression in mammalian cells, whose misfunction may be involved in the rewiring of cell cycle pathways linked to cancer development.

Efectividad de la flexibilidad activa y pasiva en el entrenamiento de gimnasia rítmica / Efetividade da flexibilidade ativa e passiva no treino da ginástica rítmica / Effectiveness of active and passive flexibility in rhythmic gymnastics training

RESUMEN La flexibilidad es la capacidad de articular, de realizar movimientos a máxima amplitud, siendo una capacidad determinante en deportes como la Gimnasia Rítmica, por lo cual los modelos de planificación del entrenamiento deportivo priorizan su contenido como parte del proceso de dirección. Este trabajo tiene como objetivo: valorar el efecto de un entrenamiento pasivo y activo de flexibilidad en los miembros inferiores de gimnastas rítmicas de la Liga Deportiva Cantonal de Rumiñahui. El tipo de investigación utilizada es el cuasiexperimental de orden correlacional. En dicho estudio, se incluyen a 35 deportistas de gimnasia rítmica de la Liga Deportiva Cantonal de Rumiñahui (5-15 años). Se implementa un modelo de periodización de la flexibilidad en tres mesociclos, con 30 ejercicios de flexibilidad pasiva y activa, la cual se aplica en dos momentos de la preparación y un test de Split lateral y frontal. En el pretest del Split Lateral, se obtiene 1.74 cm. y en el postest 6.86 cm. (p=0.000), mientras que en el pretest del Split Frontal se obtiene 1.11 cm. y el postest 8.03 cm. (p=0.000). Los anteriores son indicativos superiores al combinar ambos métodos de flexibilidad, que los realizados aisladamente al comparar resultados con otra obra. En la investigación, se evidencian mejoras significativas en el Split Lateral y Frontal para el presente estudio. Esto confirma que la combinación de diversos métodos de entrenamiento de la flexibilidad articular puede mejorar la capacidad de forma óptima.

RESUMO A flexibilidade é a capacidade de articular, de realizar movimentos à máxima amplitude, sendo uma capacidade determinante em desportos como a ginástica rítmica, razão pela qual os modelos de planejamento do treino desportivo dão prioridade ao seu conteúdo como parte do processo de gestão. O objetivo deste trabalho é avaliar o efeito do treino de flexibilidade passivo e ativo nos membros inferiores dos ginastas rítmicos da Liga Desportiva Cantonal de Rumiñahui. O tipo de investigação utilizada é quase-experimental e correlacional. Neste estudo estão incluídos 35 ginastas rítmicos da Liga Desportiva Cantonal de Rumiñahui (5-15 anos de idade). Um modelo de periodização da flexibilidade é implementado em três mesociclos, com 30 exercícios de flexibilidade passivos e ativos, que são aplicados em dois momentos da preparação e um teste Split lateral e frontal. No pré-teste da Fenda Lateral, obtém-se 1,74 cm e no pós-teste 6,86 cm. (p=0,000), enquanto no pré-teste da fenda frontal 1,11 cm. e no pós-teste 8,03 cm. (p=0.000). Os acima referidos são indicadores superiores quando se combinam ambos os métodos de flexibilidade, do que aqueles realizados isoladamente quando se comparam resultados com outros trabalhos. Na investigação, melhorias significativas na Divisão Lateral e Frontal são evidentes no presente estudo. Isto confirma que a combinação de vários métodos de treino de flexibilidade conjunta pode melhorar de forma óptima a capacidade.

ABSTRACT Flexibility is the joint capacity to perform movements at maximum amplitude, being a determining capacity in sports such as rhythmic gymnastics, for which the sports training planning models prioritize its content as part of the management process. This paper research is aimed at assessing the effect of passive and active flexibility training on the lower limbs of rhythmic gymnasts from the Liga Deportiva Cantonal of Rumiñahui. This is a Quasi-experimental research of a correlational order, studying 35 rhythmic gymnastics athletes from the Rumiñahui Cantonal Sports League (5-15 years). A flexibility periodization model is implemented in three mesocycles, with 30 passive and active flexibility exercises, applying a lateral and frontal split test at two preparation moments. In the Lateral Split pretest, 1.74cm is achieved, and in the posttest 6.86cm (p=0.000), while in the Front Split pretest it is obtained 1.11cm, and the posttest 8.03cm (p=0.000). They are superior indicative when combining both methods of flexibility than those carried out separately when comparing results with another work. Significant improvements in the Lateral and Frontal Split are evidenced for the present research, indicating that the combination of various joint flexibility training methods can optimally improve capacity.

ssGBLUP Method Improves the Accuracy of Breeding Value Prediction in Huacaya Alpaca.

Improving textile characteristics is the main objective of alpaca breeding. A recently developed SNP chip for alpacas could potentially be used to implement genomic selection and accelerate genetic progress. Therefore, this study aimed to compare the increase in prediction accuracy of three important fiber traits: fiber diameter (FD), standard deviation of fiber diameter (SD), and percentage of medullation (PM) in Huacaya alpacas. The data contains a total pedigree of 12,431 animals, 24,169 records for FD and SD, and 8386 records for PM and 60,624 SNP markers for each of the 431 genotyped animals of the Pacomarca Genetic Center. Prediction accuracy of breeding values was compared between a classical BLUP and a single-step Genomic BLUP (ssGBLUP). Deregressed phenotypes were predicted. The accuracies of the genetic and genomic values were calculated using the correlation between the predicted breeding values and the deregressed values of 100 randomly selected animals from the genotyped ones. Fifty replicates were carried out. Accuracies with ssGBLUP improved by 2.623%, 6.442%, and 1.471% on average for FD, SD, and PM, respectively, compared to the BLUP method. The increase in accuracy was relevant, suggesting that adding genomic data could benefit alpaca breeding programs.

Community-Based Livestock Breeding: Coordinated Action or Relational Process?

Over the past decade, community-based breeding programs (CBBPs) have been promoted as a viable approach to improving smallholder livelihoods through a systematic livestock breeding. CBBPs aim to initiate systematic breeding at the community level, including an organized animal identification and recording of performance and pedigree data. To ensure the breeding programs' continuity, building capacities, and ownership among participants are essential to the approach. This study's purpose was to understand how CBBPs have evolved in specific institutional settings and which dynamics occur in the course of implementation. We addressed these questions in reflective conversations with six coordinators of a diverse sample of CBBPs: goats (Malawi, Uganda, and Mexico), sheep (Ethiopia), alpaca (Peru), and cattle (Burkina Faso). The interviews and analysis were guided by categories of the multi-level perspective. The respondents considered lack of funding and weak institutionalization as the main constraints on the CBBPs. While the idea of participation and localized ownership was at the center of the programs, linear paradigms of knowledge transfer prevailed. In all cases, the impulse to start a CBBP came from individual researchers, who relied on intermediaries, such as extension agents, for implementation. Personal relations and trust were seen as both a factor in the success and a positive outcome of CBBPs. We conclude that these findings have different implications depending on how rural development is conceptualized: proponents of the innovation systems perspective would call for stakeholders to further align their interests and coordinate their actions. Proponents of process-relational concepts, in contrast, would not consider the CBBP a product but a starting-point for initiators and participants to continuously discover new ways of collaboration and engagement.

Development of a 76k Alpaca (Vicugna pacos) Single Nucleotide Polymorphisms (SNPs) Microarray.

Small farm producers' sustenance depends on their alpaca herds and the production of fiber. Genetic improvement of fiber characteristics would increase their economic benefits and quality of life. The incorporation of molecular marker technology could overcome current limitations for the implementation of genetic improvement programs. Hence, the aim of this project was the generation of an alpaca single nucleotide polymorphism (SNP) microarray. A sample of 150 Huacaya alpacas from four farms, two each in Puno and Cerro de Pasco were used for SNP discovery by genotyping by sequencing (GBS). Reduced representation libraries, two per animal, were produced after DNA digestion with ApeK1 and double digestion with Pst1-Msp1. Ten alpaca genomes, sequenced at depths between 12× to 30×, and the VicPac3.1 reference genome were used for read alignments. Bioinformatics analysis discovered 76,508 SNPs included in the microarray. Candidate genes SNPs (302) for fiber quality and color are also included. The microarray SNPs cover 90.5% of the genome length with a density of about 39 ± 2.51 SNPs/Mb of DNA at an average interval of 26.45 ± 18.57 kbp. The performance was evaluated by genotyping 30 family trios and comparing them to their pedigrees, as well as comparing microarray to GBS genotypes. Concordance values of 0.93 and 0.94 for ApeK1 and Pst1-Msp1 generated SNPs were observed. Similarly, 290 fiber quality and color candidate gene SNPs were validated. Availability of this microarray will facilitate genome-wide association studies, marker-assisted selection and, in time, genomic selection.

Pentacyclic Triterpene Profile and Its Biosynthetic Pathway in Cecropia telenitida as a Prospective Dietary Supplement.

Promising research over the past decades has shown that some types of pentacyclic triterpenes (PTs) are associated with the prevention of type 2 diabetes (T2D), especially those found in foods. The most abundant edible sources of PTs are those belonging to the ursane and oleanane scaffold. The principal finding is that Cecropia telenitida contains abundant oleanane and ursane PT types with similar oxygenation patterns to those found in food matrices. We studied the compositional profile of a rich PT fraction (DE16-R) and carried out a viability test over different cell lines. The biosynthetic pathway connected to the isolated PTs in C. telenitida offers a specific medicinal benefit related to the modulation of T2D. This current study suggests that this plant can assemble isobaric, positional isomers or epimeric PT. Ursane or oleanane scaffolds with the same oxygenation pattern are always shared by the PTs in C. telenitida, as demonstrated by its biosynthetic pathway. Local communities have long used this plant in traditional medicine, and humans have consumed ursane and oleanane PTs in fruits since ancient times, two key points we believe useful in considering the medicinal benefits of C. telenitida and explaining how a group of molecules sharing a closely related scaffold can express effectiveness.

Structure-Activity Relationship (SAR) Study of Spautin-1 to Entail the Discovery of Novel NEK4 Inhibitors.

Lung cancer is one of the most frequently diagnosed cancers accounting for the highest number of cancer-related deaths in the world. Despite significant progress including targeted therapies and immunotherapy, the treatment of advanced lung cancer remains challenging. Targeted therapies are highly efficacious at prolonging life, but not curative. In prior work we have identified Ubiquitin Specific Protease 13 (USP13) as a potential target to significantly enhance the efficacy of mutant EGFR inhibition. The current study aimed to develop lead molecules for the treatment of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) by developing potent USP13 inhibitors initially starting from Spautin-1, the only available USP13 inhibitor. A SAR study was performed which revealed that increasing the chain length between the secondary amine and phenyl group and introducing a halogen capable of inducing a halogen bond at position 4' of the phenyl group, dramatically increased the activity. However, we could not confirm the binding between Spautin-1 (or its analogues) and USP13 using isothermal titration calorimetry (ITC) or thermal shift assay (TSA) but do not exclude binding under physiological conditions. Nevertheless, we found that the anti-proliferative activity displayed by Spautin-1 towards EGFR-mutant NSCLC cells in vitro was at least partially associated with kinase inhibition. In this work, we present N-[2-(substituted-phenyl)ethyl]-6-fluoro-4-quinazolinamines as promising lead compounds for the treatment of NSCLC. These analogues are significantly more effective towards EGFR-mutant NSCLC cells than Spautin-1 and act as potent never in mitosis A related kinase 4 (NEK4) inhibitors (IC50~1 µM) with moderate selectivity over other kinases.

Polimorfismos de nucleótido simple (PNSs) del gen MC1R en alpacas negras y marrones / Single nucleotide polymorphisms (SNPs) of the MC1R gene in black and brown alpacas

Resumen En alpacas los fenotipos del color de vellón tienen diferentes terminologías que induce a una confusión dentro del color marrón y sus tonalidades, el que requiere de una mejor descripción y cuantificación. En consecuencia los objetivos del estudio fueron cuantificar el color de fibra e identificar los PNSs informativos del gen MC1R (receptor 1 de melanocortina) en alpacas marrones y negras. Un fenotipo vicuña (n=14) y cuatro fenotipos de alpacas (n=79), marrón claro, marrón oscuro, marrón-negro y negro fueron evaluados por colorimetría. El vellón de vicuña mostró mayor luminosidad (47.74) e intensidad de color (24.33) respecto a las alpacas marrones. Los valores obtenidos de CIE L*a*b* (luminosidad e intensidad) sugieren valores bajos en alpacas eumelánicas y altos en alpacas feomelánicas. En vicuña y alpaca la secuencia codificante del gen MC1R tiene un solo exón de 954 pb, las vicuñas no mostraron la deleción (c.224_227del). Sin embargo, esta deleción se ha observado en los tres fenotipos de alpaca (marrón claro, marrón oscuro y negro), al igual que los cinco PNSs no sinónimos que ya fueron descritos en otras poblaciones, c.82A>G, c.259G>A, c.376G>A, c.587T>C, c.901C>T (p.T28A, p.M87V, p.G126S, p.F196S y p.R301C). Para las dos especies, se identificaron un total de ocho haplotipos definidos por los cinco PNSs. No se observaron asociaciones entre los fenotipos de color y los PNSs: c.259G>A, c.376G>A y c.901C>T (p>0.05), probablemente debido a la influencia de otros genes como el ASIP en la expresión del color. Nuestros resultados, así como los estudios previos evidenciaron regiones altamente conservadas en la secuencia codificante del gen MC1R.

Abstract In alpacas color fleece phenotypes have different terminologies that induces confusion within the brown color and its shades, it requires a better description and quantification. Consequently, the aims of the study were to quantify the color of fiber and identify the informational SNPs in the MC1R gene (melanocortin 1 receptor) in brown and black alpacas. A vicuña phenotype (n=14) and four alpaca phenotypes (n=79), light brown, dark brown, brown-black and black were evaluated by colorimetry. The vicuña fleece showed greater lightness (47.74) and color intensity (24.33) compared to brown alpacas. The CIE L*a*b* values (lightness and intensity) suggest low values in eumelanic alpacas and high in pheomelanic alpacas. In vicuña and alpaca, the coding sequence of the MC1R gene has a single exon of 954 bp, in vicuñas the deletion (c.224_227del) was not observed. However, this deletion was observed in three alpaca phenotypes (light brown, dark brown and black), as well as the five non-synonymous SNPs described in other populations, c.82A>G, c.259G>A, c.376G>A, c.587T>C, c.901C>T (p.T28A, p.M87V, p.G126S, p.F196S, and p.R301C). Eight haplotypes defined by the five SNPs were identified in both species. The associations between color phenotypes and SNPs were not observed (p>0.05), probably due to the influence of other genes such as ASIP on color expression. Our results as well as previous studies showed highly conserved regions in the coding sequence of the MC1R gene.

Targeting USP13-mediated drug tolerance increases the efficacy of EGFR inhibition of mutant EGFR in non-small cell lung cancer.

In non-small cell lung cancer (NSCLC), activating mutations in the epidermal growth factor receptor (EGFR) induce sensitivity to EGFR tyrosine kinase inhibitors. Despite impressive clinical responses, patients ultimately relapse as a reservoir of drug-tolerant cells persist, which ultimately leads to acquired resistance mechanisms. We performed an unbiased high-throughput siRNA screen to identify proteins that abrogate the response of EGFR-mutant NSCLC to EGFR-targeted therapy. The deubiquitinase USP13 was a top hit resulting from this screen. Targeting USP13 increases the sensitivity to EGFR inhibition with small molecules in vitro and in vivo. USP13 selectively stabilizes mutant EGFR in a peptidase-independent manner by counteracting the action of members of the Cbl family of E3 ubiquitin ligases. We conclude that USP13 is a strong mutant EGFR-specific cotarget that could improve the treatment efficacy of EGFR-targeted therapies.

Correlation between handgrip and isokinetic strength of shoulder muscles in elite sitting volleyball players.

The aim of this study was to examine the relationships between isometric handgrip (HG) strength and isokinetic strength data of the glenohumeral rotator muscles. Twelve (Female = 50%) Brazilian Sitting Volleyball (SV) national team players volunteered. Measures of maximal grip strength were obtained by a HG dynamometer Jamar® and isokinetic measures of peak torque (PT) and total work (TW) during shoulder rotations movements were obtained with a Biodex isokinetic dynamometer at speed of 60°/s and 180°/s. Pearson correlation coefficients between isometric HG and isokinetic strength data ranged between 0.23 and 0.72 for the PT and between 0.3 and 0.76 for the isokinetic TW. Results presented positive relationships between HG isometric strength and isokinetic strength of external rotators of the shoulder in SV players. We can suggest that in the absence of isokinetic dynamometers, HG isometric strength measurements could be used to measure strength levels of the external rotator muscles of elite SV players' shoulder, particularly in the TW values.

USP13 controls the stability of Aurora B impacting progression through the cell cycle.

Aurora B kinase plays essential roles in mitosis. Its protein levels increase before the onset of mitosis and sharply decrease during mitosis exit. The latter decrease is due to a balance between the actions of the E3 ubiquitin ligase anaphase-promoting complex or cyclosome (activated by the Cdh1 adapter), and the deubiquitinating enzyme USP35. Aurora B also executes important functions in interphase. Abnormal modulation of Aurora B in interphase leads to cell cycle defects often linked to aberrant chromosomal condensation and segregation. Very little is however known about how Aurora B levels are regulated in interphase. Here we found that USP13-associates with and stabilizes Aurora B in cells, especially before their entry into mitosis. In order for USP13 to exert its stabilizing effect on Aurora B, their association is promoted by the Aurora B-mediated phosphorylation of USP13 at Serine 114. We also present evidence that USP13 instigates Aurora B deubiquitination and/or protect it from degradation in a non-catalytic manner. In addition, we report that genetic or chemical modulation of the cellular levels/activity of USP13 affects unperturbed cell-cycle progression. Overall our study unveils the molecular and cellular connections of the USP13-Aurora B axis, which potentially participates in the rewiring of the cell cycle happening in cancer cells.

Emphysematous Pyelonephritis in a Horseshoe kidney.

Emphysematous pyelonephritis is a necrotizing renal infection that results in the presence of gas in renal parenchyma, collecting system, and surrounding tissues. Ninety-five percent of the patients have underlying uncontrolled diabetes mellitus, but non-diabetic patients may be affected due to ureteral obstruction and infection with gas forming pathogens. Several poor prognostic factors have been described, such as thrombocytopenia, acute kidney failure, impaired consciousness, and shock. We present a case of a 41-year-old female who attends to the emergency department with signs of septic shock and diffuse abdominal pain. The diagnosis of emphysematous pyelonephritis in a horseshoe kidney was confirmed.

Comitê paralímpico brasileiro: análise do ambiente, estratégia e estrutura organizacional / Brazilian paralympic committee: analysis of the environment, strategy and organizational structure / Comité paralímpico brasileño: análisis del ambiente, estrategia y estructura organizativa

O desenvolvimento do esporte paralímpico brasileiro, esportivo e administrativo, está concatenado com a evolução do Comitê Paralímpico Brasileiro. As transformações ocorridas na estrutura, ambiente e estratégia organizacionais ao longo da trajetória da entidade possibilitou à organização construir um ciclo virtuoso de estabilidade. Isto posto, este estudo tem o objetivo de caracterizar esse processo de estruturação organizacional do CPB. Para tanto, investigará como o mesmo está inserido no desporto paralímpico brasileiro, por meio da análise de três dimensões organizacionais do órgão:ambiente, estratégia, estrutura. Este trabalho consiste em um estudo de caso de natureza qualitativa de caráter exploratório e descritivo. De modo a triangular os dados obtidos por meio de entrevistas semi estruturadas, fez-se necessária uma revisão bibliográfica e documental. Por fim, os resultados obtidos apresentam que a estrutura organizacional atual do CPB é caracterizada com uma lógica de funcionamento profissional.

The development of the Brazilian sportive and administrative Paralympics is related to the evolution of the Brazilian Paralympic Committee. Due to the transformation in the organizational structure, environment and strategy of the entity along its trajectory, the organization has made it possible to build up a virtuous cycle of stability. This study aimed at characterizing the CPB organizational structuring process and investigated how this process is inserted in the Brazilian Paralympic sports. An analysis of three CPB organizational dimensions: environment, strategy, structure was made. This is a qualitative study totriangulate the data obtained through semi-structured interviews, a bibliographic and documentary review was developed. The results showed that the current CPB organizational structure is characterized by a professional manner.

El desarrollo del deporte paralímpico brasileño, deportivo y administrativo, está coherente con la evolución del Comité Paralímpico Brasileño (CPB). Las transformaciones ocurridas en la estructura organizacional, el ambiente y las estrategias a lo largo de la trayectoria de la entidad permitieron a la organización generar un ciclo virtuoso de estabilidad. De esa manera, este estudio atisba el objetivo de caracterizar el proceso de estructuración organizacional del CPB (ambiente, estrategia, estructura). Este trabajo consiste em un estudio) de caso cualitativo de naturaleza exploratoria y descriptiva. Al fin y al cabo triangular datos obtenidos por medio de entrevistas semi estructuradas, se realizó una revisión bibliográfica y documental. Finalmente, los resultados mostraron que la estructura organizativa actual del CPB se caracteriza por una lógica de funcionamiento profesional.