Moving From Transactional to Relational: How Funders Can Work in Partnership With Black, Indigenous and People of Color Communities.

BACKGROUND: The Racial Equity Coalition (REC) formed to address persistent educational disparities. The coalition was composed of 14 Black, Indigenous and People of Color (BIPOC) organizations that provide culturally integrative youth services. OBJECTIVES: REC, with support from United Way of King County, engaged in participatory research to identify commonalities and shared struggles to inform collective action. Participatory research aligns with REC's commitment to equitable participatory processes. This article focuses on REC's experiences with funders. The objective was to understand what creates positive and challenging experiences with funders, and to identify recommendations for funders to become more culturally responsive. METHODS: A research committee was formed including representatives of nine REC organizations and United Way of King County staff. The committee conducted interviews with each of the 14 REC organizations and conducted thematic analysis of interview transcripts. Through participatory analysis, the committee drafted narratives that were further refined through a series of research retreats attended by all REC organizations. RESULTS: Recommendations were to incentivize collaboration, listen to communities to create culturally responsive definitions of success and measurement strategies, arrive at mutually agreed upon approaches with organizations, honor the connections BIPOC organizations have with their communities, and provide unrestricted funding to allow BIPOC organizations greater agency. CONCLUSIONS: A major challenge for BIPOC organizations is navigating White dominant culture that too often shows up in funding requirements. Having to fit dominant culture standards stifles BIPOC organizations' abilities to meet community needs and the responsiveness of their approaches. REC identified recommendations for funders to be more culturally responsive and community centered.

Crystal structures of the DExH-box RNA helicase DHX9.

DHX9 is a DExH-box RNA helicase with versatile functions in transcription, translation, RNA processing and regulation of DNA replication. DHX9 has recently emerged as a promising target for oncology, but to date no mammalian structures have been published. Here, crystal structures of human, dog and cat DHX9 bound to ADP are reported. The three mammalian DHX9 structures share identical structural folds. Additionally, the overall architecture and the individual domain structures of DHX9 are highly conserved with those of MLE, the Drosophila orthologue of DHX9 previously solved in complex with RNA and a transition-state analogue of ATP. Due to differences in the bound substrates and global domain orientations, the localized loop conformations and occupancy of dsRNA-binding domain 2 (dsRBD2) differ between the mammalian DHX9 and MLE structures. The combined effects of the structural changes considerably alter the RNA-binding channel, providing an opportunity to compare active and inactive states of the helicase. Finally, the mammalian DHX9 structures provide a potential tool for structure-based drug-design efforts.

Thermoplastic starch/polyvinyl alcohol blends modification by citric acid-glycerol polyesters.

Thermoplastic starch/polyvinyl alcohol (TPS/PVA) films have limitations for being used in long-term applications due to starch retrogradation. This leads to plasticizer migration, especially when low molecular weight plasticizers such as glycerol, are used. In this work, we employed mixtures of oligomers based on glycerol citrates with higher molecular weight than glycerol as plasticizers for potato-based TPS/PVA blends obtained by melt-mixing. This constitutes an alternative to reduce plasticizer migration while keeping high swelling degree, and to provide high mechanical performance. The novelty lies in the usage of these oligomers by melt-mixing technique, aspect not deeply explored previously and that represents the first step towards industrial scalability. Prior to the blending process, oligomers mixtures were prepared with different molar ratios of citric acid (0-40 mol%) and added them. This minimizes the undesirable hydrolysis effect of free carboxylic groups on starch chains. The results demonstrated that the migration of plasticizers in TPS/PVA blends decreased by up to 70 % when the citric acid content increased. This reduction was attributed to the higher molecular weight (the majority in the range 764-2060 Da) and the 3D structure of the oligomers compared to using raw glycerol. Furthermore, the films exhibited a 150 % increase in Young's modulus and tensile strength without a reduction in elongation at break, while maintaining a high gel content, due to a moderate crosslinking.

Study of the Plasticization Effect of 1-Ethyl-3-methylimidazolium Acetate in TPS/PVA Biodegradable Blends Produced by Melt-Mixing.

The first step towards the production and marketing of bioplastics based on renewable and sustainable materials is to know their behavior at a semi-industrial scale. For this reason, in this work, the properties of thermoplastic starch (TPS)/polyvinyl alcohol (PVA) films plasticized by a green solvent, as the 1-ethyl-3-methylimidazolium acetate ([Emim+][Ac-]) ionic liquid, produced by melt-mixing were studied. These blends were prepared with a different content of [Emim+][Ac-] (27.5-42.5 %wt.) as a unique plasticizer. According to the results, this ionic liquid is an excellent plasticizer due to the transformation of the crystalline structure of the starch to an amorphous state, the increase in flexibility, and the drop in Tg, as the [Emim+][Ac-] amount increases. These findings show that the properties of these biomaterials could be modified in the function of [Emim+][Ac-] content in the formulations of TPS, depending on their final use, thus becoming a functional alternative to conventional polymers.

Relación entre COVID-19 con el desarrollo de enfermedades autoinmunes / Relationship of COVID-19 with the development of autoimmune diseases / Relação da COVID-19 com o desenvolvimento de doenças autoimunes

En la actualidad existe un gran número personas diagnoticadas con SARS-CoV-2, llamando la atención la aparición de algunas enfermedades de origen autoinmunes post exposición a esta infección. Se cree que su asociación está dada por mecanismos que incluyen el mimetismo molecular, los autoanticuerpos y la estimulación de la señalización inflamatoria. Objetivo. Identificar la relación entre COVID-19 con el desarrollo de enfermedades autoinmunes. Metodología. Se realizó una revisión sistemática de la literatura, donde, se utilizó buscadores científicos en la siguiente base de datos: Pubmed, Cocharne, Scielo y Science Direct. La búsqueda de información estuvo comprendida entre 2020 al 2022, se utilizaron palabras claves y algoritmo de búsqueda con la combinación de términos: "COVID-19", "enfermedades autoinmunes", "autoinmunidad", además de esto se utilizaron operadores booleanos "And", "Or" y "Not" con la finalidad de obtener mejores resultados en la brusquedad. Conclusión. Los principales mecanismos involucrados en el desarrollo de autoinmunidad posterior a la infección por SARS-CoV-2 incluye el mimetismo molecular, la presencia de autoanticuerpos y la tormenta de citoquinas propias de la infección por COVID-19. Las enfermedades de carácter autoinmune con las que se estableció relación directa: Síndrome de Guillan-Barré, Encefalitis autoinmune, Enfermedad de Graves, Tiroiditis de Hashimoto, Purpura trombocitopenica autoinmune y Vasculitis, además también se consideró la Enfermedad similar a Kawasaki - like, Lupus Eritematoso Sistémico, mismas que aún necesitan de más estudios para establecer con exactitud su mecanismo de acciones con relación a la infección de SARS-CoV-2.

Currently there are a large number of people diagnosed with SARS-CoV-2, drawing attention to the appearance of some diseases of autoimmune origin after exposure to this infection. It is believed that their association is given by mechanisms that include molecular mimicry, autoantibodies and stimulation of inflammatory signaling. Objective. To identify the relationship between COVID-19 and the development of autoimmune diseases. Methodology. A systematic review of the literature was carried out, using scientific search engines in the following database: Pubmed, Cocharne, Scielo and Science Direct. The information search was carried out from 2020 to 2022, using keywords and search algorithm with the combination of terms: "COVID-19", "autoimmune diseases", "autoimmunity", in addition to this, Boolean operators "And", "Or" and "Not" were used in order to obtain better results in the abruptness. Conclusion. The main mechanisms involved in the development of autoimmunity following SARS-CoV-2 infection include molecular mimicry, the presence of autoantibodies and the cytokine storm characteristic of COVID-19 infection. The autoimmune diseases with which a direct relationship was established are: Guillan-Barre syndrome, autoimmune encephalitis, Graves' disease, Hashimoto's thyroiditis, autoimmune thrombocytopenic purpura and vasculitis, in addition to Kawasaki-like disease, systemic lupus erythematosus, which still need further studies to establish their exact mechanism of action in relation to SARS-CoV-2 infection.

Atualmente, há um grande número de pessoas diagnosticadas com SARS-CoV-2, o que chama a atenção para o surgimento de algumas doenças autoimunes após a exposição a essa infecção. Acredita-se que sua associação se deva a mecanismos que incluem mimetismo molecular, autoanticorpos e estimulação da sinalização inflamatória. Objetivo. Identificar a relação entre a COVID-19 e o desenvolvimento de doenças autoimunes. Metodologia. Foi realizada uma revisão sistemática da literatura, usando mecanismos de busca científica no seguinte banco de dados: Pubmed, Cocharne, Scielo e Science Direct. A busca de informações foi realizada entre 2020 e 2022, foram utilizadas palavras-chave e algoritmo de busca com a combinação dos termos: "COVID-19", "autoimmune diseases", "autoimmunity", e também foram utilizados os operadores booleanos "And", "Or" e "Not" para obter melhores resultados na rapidez. Conclusão. Os principais mecanismos envolvidos no desenvolvimento da autoimunidade após a infecção por SARS-CoV-2 incluem mimetismo molecular, a presença de autoanticorpos e a tempestade de citocinas da infecção por COVID-19. As doenças autoimunes com as quais foi estabelecida uma relação direta são: síndrome de Guillan-Barré, encefalite autoimune, doença de Graves, tireoidite de Hashimoto, púrpura trombocitopênica autoimune e vasculite, bem como doença semelhante à Kawasaki, lúpus eritematoso sistêmico, que ainda precisam de mais estudos para estabelecer seu mecanismo exato de ação em relação à infecção por SARS-CoV-2.

FT-6876, a Potent and Selective Inhibitor of CBP/p300, is Active in Preclinical Models of Androgen Receptor-Positive Breast Cancer.

BACKGROUND: Patients with triple-negative breast cancer (TNBC) expressing the androgen receptor (AR) respond poorly to neoadjuvant chemotherapy, although AR antagonists have shown promising clinical activity, suggesting these tumors are AR-dependent. cAMP responsive element binding protein (CREB)-binding protein (CBP) and p300 are transcriptional co-activators for the AR, a key driver of AR+ breast and prostate cancer, and may provide a novel therapeutic target in AR+ TNBC. OBJECTIVES: The aim of this study was to determine the therapeutic potential of FT-6876, a new CBP/p300 bromodomain inhibitor, in breast cancer models with a range of AR levels in vitro and in vivo. METHODS: Effects of FT-6876 on the CBP/p300 pathway were determined by combining chromatin immunoprecipitation (ChIP) with precision run-on sequencing (PRO-seq) complemented with H3K27 acetylation (Ac) and transcriptional profiling. The antiproliferative effect of FT-6876 was also measured in vitro and in vivo. RESULTS: We describe the discovery of FT-6876, a potent and selective CBP/p300 bromodomain inhibitor. The combination of ChIP and PRO-seq confirmed the reduction in H3K27Ac at specific promoter sites concurrent with a decrease in CBP/p300 on the chromatin and a reduction in nascent RNA and enhancer RNA. This was associated with a time- and concentration-dependent reduction in H3K37Ac associated with a decrease in AR and estrogen receptor (ER) target gene expression. This led to a time-dependent growth inhibition in AR+ models, correlated with AR expression. Tumor growth inhibition was also observed in AR+ tumor models of TNBC and ER+ breast cancer subtypes with consistent pharmacokinetics and pharmacodynamics. CONCLUSION: Our findings demonstrate FT-6876 as a promising new CBP/p300 bromodomain inhibitor, with efficacy in preclinical models of AR+ breast cancer.

Structure-Based Design and Identification of FT-2102 (Olutasidenib), a Potent Mutant-Selective IDH1 Inhibitor.

Inhibition of mutant IDH1 is being evaluated clinically as a treatment option for oncology. Here we describe the structure-based design and optimization of quinoline lead compounds to identify FT-2102, a potent, orally bioavailable, brain penetrant, and selective mIDH1 inhibitor. FT-2102 has excellent ADME/PK properties and reduces 2-hydroxyglutarate levels in an mIDH1 xenograft tumor model. This compound has been selected as a candidate for clinical development in hematologic malignancies, solid tumors, and gliomas with mIDH1.

Discovery and Optimization of Quinolinone Derivatives as Potent, Selective, and Orally Bioavailable Mutant Isocitrate Dehydrogenase 1 (mIDH1) Inhibitors.

Mutations at the arginine residue (R132) in isocitrate dehydrogenase 1 (IDH1) are frequently identified in various human cancers. Inhibition of mutant IDH1 (mIDH1) with small molecules has been clinically validated as a promising therapeutic treatment for acute myeloid leukemia and multiple solid tumors. Herein, we report the discovery and optimization of a series of quinolinones to provide potent and orally bioavailable mIDH1 inhibitors with selectivity over wild-type IDH1. The X-ray structure of an early lead 24 in complex with mIDH1-R132H shows that the inhibitor unexpectedly binds to an allosteric site. Efforts to improve the in vitro and in vivo absorption, distribution, metabolism, and excretion (ADME) properties of 24 yielded a preclinical candidate 63. The detailed preclinical ADME and pharmacology studies of 63 support further development of quinolinone-based mIDH1 inhibitors as therapeutic agents in human trials.

Discovery and optimization of novel piperazines as potent inhibitors of fatty acid synthase (FASN).

The discovery, structure-activity relationships, and optimization of a novel class of fatty acid synthase (FASN) inhibitors is reported. High throughput screening identified a series of substituted piperazines with structural features that enable interactions with many of the potency-driving regions of the FASN KR domain binding site. Derived from this series was FT113, a compound with potent biochemical and cellular activity, which translated into excellent activity in in vivo models.

Micropropagación y determinación del número cromosómico de Puya trianae con fines de conservación y uso ornamental / Micropropagation and determination of the chromosome number of Puya trianae for conservation and ornamental use

Puya trianae se caracteriza por desarrollar una vistosa inflorescencia que la caracteriza como planta de uso ornamental. Aunque actualmente no se considera amenazada, debido al rápido deterioro de los ecosistemas donde habita, la supervivencia de sus poblaciones sí está amenazada; por dichas razones se desarrolló un protocolo de micropropagación, aplicable para su conservación y para producción masiva de plántulas con fines ornamentales, así como a la determinación de su número cromosómico. Para la multiplicación se utilizaron plántulas provenientes de semillas germinadas in vitro realizando cuatro ensayos para determinar tipo, concentración y tiempo de exposición de algunos reguladores, además de la escisión parcial o total de explantes. Durante la fase de enraizamiento se cultivaron brotes en MS/2 solo y/o suplementado con AIB y ANA; la aclimatización de las plántulas obtenidas se realizó en diferentes mezclas de tierra:turba:capote, en cuarto de crecimiento e invernadero. Los resultados mostraron que en MS+2.0 mgL-1 de TDZ durante 45 días se produjo la mayor cantidad de yemas y brotes que terminaron su desarrollo después de 90 días. Los brotes enraizaron en MS/2 cuantificándose 70% de enraizamiento. Se registró una viabilidad del 90% y una longitud de plántulas de 3.6 cm en tierra:turba después de 60 días de aclimatización. El conteo cromosómico se realizó en células meristemáticas radicales tratadas con colchicina al 0.5%, fijadas en carnoy, hidrolizadas con HCL y con enzimas y teñidas con orceína acética, obteniéndose un número cromosómico de 50, con cromosomas muy pequeños (aprox. 1.2μm).

Puya trianae is characterized for developing a colorful inflorescence, which turned it into an ornamental plant. Is not currently considered threatened, due to the fast habitat deterioration, populations survival is threatened; due to the last, we developed a micropropagation protocol, focused on its conservation and mass production for ornamental purpose, as well as the chromosome counting. For multiplication, seedlings from germinated seeds were used in vitro and we made four tests to determine the type, concentration and time of exposure of some regulators, as well as the partial or total explants excised. Throughout the rooting phase, shoots were grown in MS/2 alone and/or supplemented with IBA and NAA; the acclimatization of the obtained seedlings was carried out in different mixtures land:peat:capote, in a growth room and a greenhouse. Buds and shoots that finished their development during 45 days in MS+2.0 mgL-1 of TDZ were the majority, after three months of development. The shoots rooted in MS/2 quantifying a 70% of rooting. A 90% viability and a plantlets length of 3.6 cm in soil: peat after 60 days of transfer. We made a radical meristematic cells chromosomal counting treated with a 0.5% of colchicine fixed in carnoy, hydrolyzed with HCL and enzymes and stained with acetic orcein, obtaining a chromosome number of 2n=50, with very small chromosomes (aprox. 1.2μm).

Knitting Mochilas: A Sociocultural, Developmental Practice in Arhuaco Indigenous Communities.

The purpose of this article is to analyze the psycho-cultural processes involved in knitting "mochilas" (traditional bags), a common craft in the Arhuaco indigenous community located in the Sierra Nevada de Santa Marta, Colombia. The article is structured in three parts, as follows: first, issues related to child development are discussed; then, the analysis method used to study the processes involved in the practice of knitting is presented and, finally, we reflect on the importance of recovering the sense and meaning of this everyday practice as a way to study child development.

Resumen desayuno de trabajo: "Manejo clínico de las metástasis óseas y sus complicaciones" / Working breakfast summary: "Clinical management of bone metastases and their complications"

Las metástasis óseas son un evento que se produce en el cáncer avanzado y pueden complicar la calidad de vida. Se presentan con dolor, fracturas patológicas, alteraciones neurológicas, hipercalcemia.

A novel mode of protein kinase inhibition exploiting hydrophobic motifs of autoinhibited kinases: discovery of ATP-independent inhibitors of fibroblast growth factor receptor.

Protein kinase inhibitors with enhanced selectivity can be designed by optimizing binding interactions with less conserved inactive conformations because such inhibitors will be less likely to compete with ATP for binding and therefore may be less impacted by high intracellular concentrations of ATP. Analysis of the ATP-binding cleft in a number of inactive protein kinases, particularly in the autoinhibited conformation, led to the identification of a previously undisclosed non-polar region in this cleft. This ATP-incompatible hydrophobic region is distinct from the previously characterized hydrophobic allosteric back pocket, as well as the main pocket. Generalized hypothetical models of inactive kinases were constructed and, for the work described here, we selected the fibroblast growth factor receptor (FGFR) tyrosine kinase family as a case study. Initial optimization of a FGFR2 inhibitor identified from a library of commercial compounds was guided using structural information from the model. We describe the inhibitory characteristics of this compound in biophysical, biochemical, and cell-based assays, and have characterized the binding mode using x-ray crystallographic studies. The results demonstrate, as expected, that these inhibitors prevent activation of the autoinhibited conformation, retain full inhibitory potency in the presence of physiological concentrations of ATP, and have favorable inhibitory activity in cancer cells. Given the widespread regulation of kinases by autoinhibitory mechanisms, the approach described herein provides a new paradigm for the discovery of inhibitors by targeting inactive conformations of protein kinases.

Estimación de riesgo cardiovascular en trabajadores de una empresa molinera: Antofagasta, 2005 / Estimation of cardiovascular risk in workers of a mill company: Atofagasta 2005

In order to detect existence of cardiovascular risk associate to the work was examined 15 workers of a mill company of Antofagasta, having identified variable personal, environmental and procedural. The obtained results indicate that more than two thirds of the studied group it presented displayed overweight and obesity type 1, in addition to high and moderately high percentage of greasy mass with a positive variable of associated cardiovascular risk to the obesity and the excessive percentage of fat. In 12 cases an index was detected waist high and moderate hip, whereas 10 workers presented displayed arterial hypertension. The physiological service load described like moderate according to rate of pulse frequency, and like low according to the intraaural corporal temperature. Occupational heat exhibition the studied according to TGBH indicated absence of exhibition to physical risk according to law 16.744. The 1,867 kilocalories per day by food ingestion was calculated, situation that are not correlated with the high index of corporal mass, the percentage of greasy mass and the demanded physical loado An ergonomic strategy based on objective indicators sets out to orient the preventive management on the part of the company and continuous qualification of the workers in the matter of own health-care.

Para detectar existencia de riesgo cardiovascular asociado al trabajo se examinó 15 trabajadores de una empresa molinera de Antofagasta, identificando variables personales, ambientales y procedimentales. Se determinó sobrepeso y obesidad tipo 1 en más de dos tercios del grupo estudiado, además de porcentajes altos y moderadamente altos de masa grasa con una variable positiva de riesgo cardiovascular asociado a la obesidad y al porcentaje de grasa excesivo. En 12 casos se detectó un índice cintura cadera alto y moderado, en tanto que 10 trabajadores presentaron hipertensión arterial. La carga de trabajo fisiológico calificó como moderada según tasa de frecuencia de pulso, y como baja según la temperatura corporal intraaural. La exposición a calor ocupacional estudiada según temperatura de globo y bulbo húmedo indicó ausencia de exposición a riesgo físico según la ley 16.744. La ingesta de alimentos calculada fue de 1.867 kilocalorías por día, situación que no se correlaciona con el alto índice de masa corporal, el porcentaje de masa grasa y la carga física demandada.

Shortwave diathermy and prolonged stretching increase hamstring flexibility more than prolonged stretching alone.

STUDY DESIGN: A randomized, counterbalanced 2x3x5 repeated-measures design. OBJECTIVE: To compare changes in hamstring flexibility after treatments of pulsed shortwave diathermy and prolonged stretch, sham diathermy and prolonged stretch, and control. BACKGROUND: Heat and stretch techniques have been touted for years. To date, the effect of shortwave diathermy and hamstring stretching has not been studied. Because diathermy heats a large area and penetrates deep into the muscle, use of this device prior to or during hamstring stretching may increase flexibility. METHODS AND MEASURES: Thirty college-age students (mean age, 21.5 years) with tight hamstrings (inability to achieve greater than 160 degrees knee extension at 90 degrees hip flexion) participated. Subjects were assigned to 1 of 3 groups: diathermy and stretch, sham diathermy and stretch, and control). Range of motion was recorded before and after each treatment for 5 days and on day 8. A straight leg-raise stretch was performed using a mechanical apparatus. Subjects in the diathermy-and-stretch group received 10 minutes of diathermy (distal hamstrings) followed by 5 minutes of simultaneous diathermy and stretch, followed by 5 minutes of stretching only. Subjects in the sham-diathermy-and-stretch group followed the same protocol, but with the diathermy unit turned off. Subjects in the control group lay on the table for 20 minutes. Data were analyzed using an ANOVA and post hoc t tests. RESULTS: Mean (+/- pooled SE) increases in knee extension after 5 days were 15.8 degrees 2.2 degrees for the diathermy-and-stretch group, 5.2 degrees +/- 2.2 degrees for the sham-diathermy-and-stretch group, and -0.3 degrees +/- 2.2 degrees for the control group. Seventy-two hours after the last treatment, the diathermy-and-stretch group lost 1.9 degrees +/- 2.2 degrees, the sham-diathermy-and-stretch group lost 3.0 degrees +/- 2.2 degrees, and the control group changed -0.4 degrees +/- 2.2 degrees. CONCLUSION: These results suggest that hamstring flexibility can be greatly improved when shortwave diathermy is used in conjunction with prolonged stretching.

Perfectionism and ethnicity: implications for depressive symptoms and self-reported academic achievement.

Ethnic differences in perfectionism were examined among Asian American, African American, and Caucasian American college students. Analyses revealed that Asian American students scored significantly higher than the other groups on 3 of 6 perfectionism subscales. Minority students reported significantly higher parental expectations than Caucasian students. Significant correlations emerged for all 3 groups between depressive symptoms and concerns about making mistakes, perceived criticism from parents, and self-doubt. In regression analyses, perfectionism explained significant variance in depressive symptoms for Asian Americans and Caucasians and explained significant variance in cumulative grade point average for Asian Americans and African Americans. Self-doubt emerged as a robust individual predictor in these analyses.