RESUMEN
Asteroids with diameters less than about 5 km have complex histories because they are small enough for radiative torques (that is, YORP, short for the Yarkovsky-O'Keefe-Radzievskii-Paddack effect)1 to be a notable factor in their evolution2. (152830) Dinkinesh is a small asteroid orbiting the Sun near the inner edge of the main asteroid belt with a heliocentric semimajor axis of 2.19 AU; its S-type spectrum3,4 is typical of bodies in this part of the main belt5. Here we report observations by the Lucy spacecraft6,7 as it passed within 431 km of Dinkinesh. Lucy revealed Dinkinesh, which has an effective diameter of only 720 m, to be unexpectedly complex. Of particular note is the presence of a prominent longitudinal trough overlain by a substantial equatorial ridge and the discovery of the first confirmed contact binary satellite, now named (152830) Dinkinesh I Selam. Selam consists of two near-equal-sized lobes with diameters of 210 m and 230 m. It orbits Dinkinesh at a distance of 3.1 km with an orbital period of about 52.7 h and is tidally locked. The dynamical state, angular momentum and geomorphologic observations of the system lead us to infer that the ridge and trough of Dinkinesh are probably the result of mass failure resulting from spin-up by YORP followed by the partial reaccretion of the shed material. Selam probably accreted from material shed by this event.
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Humans are considered as the main host for Mycobacterium leprae1, the aetiological agent of leprosy, but spillover has occurred to other mammals that are now maintenance hosts, such as nine-banded armadillos and red squirrels2,3. Although naturally acquired leprosy has also been described in captive nonhuman primates4-7, the exact origins of infection remain unclear. Here we describe leprosy-like lesions in two wild populations of western chimpanzees (Pan troglodytes verus) in Cantanhez National Park, Guinea-Bissau and Taï National Park, Côte d'Ivoire, West Africa. Longitudinal monitoring of both populations revealed the progression of disease symptoms compatible with advanced leprosy. Screening of faecal and necropsy samples confirmed the presence of M. leprae as the causative agent at each site and phylogenomic comparisons with other strains from humans and other animals show that the chimpanzee strains belong to different and rare genotypes (4N/O and 2F). These findings suggest that M. leprae may be circulating in more wild animals than suspected, either as a result of exposure to humans or other unknown environmental sources.
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Lepra/veterinaria , Pan troglodytes/microbiología , Animales , Autopsia/veterinaria , Côte d'Ivoire , Heces/microbiología , Genotipo , Guinea Bissau , Humanos , Lepra/microbiología , Mycobacterium leprae/genética , Mycobacterium leprae/aislamiento & purificación , FilogeniaRESUMEN
Urinary tract infection (UTI) commonly afflicts people with diabetes. This augmented infection risk is partly due to deregulated insulin receptor (IR) signaling in the kidney collecting duct. The collecting duct is composed of intercalated cells (ICs) and principal cells (PCs). Evidence suggests that ICs contribute to UTI defenses. Here, we interrogate how IR deletion in ICs impacts antibacterial defenses against uropathogenic Escherichia coli. We also explore how IR deletion affects immune responses in neighboring PCs with intact IR expression. To accomplish this objective, we profile the transcriptomes of IC and PC populations enriched from kidneys of wild-type and IC-specific IR knock-out mice that have increased UTI susceptibility. Transcriptomic analysis demonstrates that IR deletion suppresses IC-integrated stress responses and innate immune defenses. To define how IR shapes these immune defenses, we employ murine and human kidney cultures. When challenged with bacteria, murine ICs and human kidney cells with deregulated IR signaling cannot engage central components of the integrated stress response-including activating transcriptional factor 4 (ATF4). Silencing ATF4 impairs NFkB activation and promotes infection. In turn, NFkB silencing augments infection and suppresses antimicrobial peptide expression. In diabetic mice and people with diabetes, collecting duct cells show reduced IR expression, impaired integrated stress response engagement, and compromised immunity. Collectively, these translational data illustrate how IR orchestrates collecting duct antibacterial responses and the communication between ICs and PCs.
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Ratones Noqueados , Receptor de Insulina , Infecciones Urinarias , Escherichia coli Uropatógena , Animales , Humanos , Ratones , Infecciones por Escherichia coli/inmunología , Infecciones por Escherichia coli/metabolismo , Infecciones por Escherichia coli/microbiología , Inmunidad Innata , Riñón/metabolismo , Túbulos Renales Colectores/metabolismo , Ratones Endogámicos C57BL , Receptor de Insulina/metabolismo , Transducción de Señal , Infecciones Urinarias/microbiología , Infecciones Urinarias/metabolismo , Infecciones Urinarias/inmunología , Escherichia coli Uropatógena/inmunologíaRESUMEN
With the emergence of antibiotic-resistant bacteria, innovative approaches are needed for the treatment of urinary tract infections. Boosting antimicrobial peptide expression may provide an alternative to antibiotics. Here, we developed reporter cell lines and performed a high-throughput screen of clinically used drugs to identify compounds that boost ribonuclease 4 and 7 expression (RNase 4 and 7), peptides that have antimicrobial activity against antibiotic-resistant uropathogens. This screen identified histone deacetylase (HDAC) inhibitors as effective RNase 4 and RNase 7 inducers. Validation studies in primary human kidney and bladder cells confirmed pan-HDAC inhibitors as well as the HDAC class I inhibitor, MS-275, induce RNase 4 and RNase 7 to protect human kidney and bladder cells from uropathogenic Escherichia coli. When we administered MS-275 to mice, RNase 4 and 7 expression increased and mice were protected from acute transurethral E. coli challenge. In support of this mechanism, MS-275 treatment increased acetylated histone H3 binding to the RNASE4 and RNASE7 promoters. Overexpression and knockdown of HDAC class I proteins identified HDAC3 as a primary regulator of RNase 4 and 7. These results demonstrate the protective effects of enhancing RNase 4 and RNase 7, opening the door to repurposing medications as antibiotic conserving therapeutics for urinary tract infection.
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Inhibidores de Histona Desacetilasas , Infecciones Urinarias , Humanos , Ratones , Animales , Inhibidores de Histona Desacetilasas/farmacología , Escherichia coli/metabolismo , Reposicionamiento de Medicamentos , Ribonucleasas/metabolismo , Infecciones Urinarias/tratamiento farmacológico , Infecciones Urinarias/microbiología , AntibacterianosRESUMEN
Antimicrobial peptides (AMPs) are critical to the protection of the urinary tract of humans and other animals from pathogenic microbial invasion. AMPs rapidly destroy pathogens by disrupting microbial membranes and/or augmenting or inhibiting the host immune system through a variety of signaling pathways. We have previously demonstrated that alpha-defensins 1-3 (DEFA1A3) are AMPs expressed in the epithelial cells of the human kidney collecting duct in response to uropathogens. We also demonstrated that DNA copy number variations in the DEFA1A3 locus are associated with UTI and pyelonephritis risk. Because DEFA1A3 is not expressed in mice, we utilized human DEFA1A3 gene transgenic mice (DEFA4/4) to further elucidate the biological relevance of this locus in the murine urinary tract. We demonstrate that the kidney transcriptional and translational expression pattern is similar in humans and the human gene transgenic mouse upon uropathogenic Escherichia coli (UPEC) stimulus in vitro and in vivo. We also demonstrate transgenic human DEFA4/4 gene mice are protected from UTI and pyelonephritis under various UPEC challenges. This study serves as the foundation to start the exploration of manipulating the DEFA1A3 locus and alpha-defensins 1-3 expression as a potential therapeutic target for UTIs and other infectious diseases.
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Infecciones por Escherichia coli , Pielonefritis , Infecciones Urinarias , Escherichia coli Uropatógena , alfa-Defensinas , Animales , Variaciones en el Número de Copia de ADN , Infecciones por Escherichia coli/genética , Infecciones por Escherichia coli/inmunología , Sitios Genéticos , Humanos , Ratones , Ratones Transgénicos , Pielonefritis/genética , Pielonefritis/inmunología , Pielonefritis/microbiología , Sistema Urinario/microbiología , Infecciones Urinarias/genética , Infecciones Urinarias/inmunología , Infecciones Urinarias/microbiología , alfa-Defensinas/genéticaRESUMEN
The language environment to which children are exposed has an impact on later language abilities as well as on brain development; however, it is unclear how early such impacts emerge. This study investigates the effects of children's early language environment and socioeconomic status (SES) on brain structure in infancy at 6 and 30 months of age (both sexes included). We used magnetic resonance imaging to quantify concentrations of myelin in specific fiber tracts in the brain. Our central question was whether Language Environment Analysis (LENA) measures from in-home recording devices and SES measures of maternal education predicted myelin concentrations over the course of development. Results indicate that 30-month-old children exposed to larger amounts of in-home adult input showed more myelination in the white matter tracts most associated with language. Right hemisphere regions also show an association with SES, with older children from more highly educated mothers and exposed to more adult input, showing greater myelin concentrations in language-related areas. We discuss these results in relation to the current literature and implications for future research.SIGNIFICANCE STATEMENT This is the first study to look at how brain myelination is impacted by language input and socioeconomic status early in development. We find robust relationships of both factors in language-related brain areas at 30 months of age.
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Encéfalo , Lenguaje , Niño , Masculino , Femenino , Adulto , Humanos , Adolescente , Preescolar , Clase Social , Desarrollo del Lenguaje , Imagen por Resonancia MagnéticaRESUMEN
Semiochemicals can be used to manipulate insect behaviour for sustainable pest management strategies, but their high volatility is a major issue for their practical implementation. Inclusion of these molecules within porous materials is a potential solution to this issue, as it can allow for a slower and more controlled release. In this work, we demonstrate that a series of Zr(IV) and Al(III) metal-organic frameworks (MOFs) with channel-type pores enable controlled release of three semiochemicals over 100â days by pore size design, with the uptake and rate of release highly dependent on the pore size. Insight from grand canonical Monte Carlo simulations indicates that this is due to weaker MOF-guest interactions per guest molecule as the pore size increases. These MOFs are all stable post-release and can be reloaded to show near-identical re-release profiles. These results provide valuable insight on the diffusion behaviour of volatile guests in MOFs, and for the further development of porous materials for sustainable agriculture applications.
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A prompt diagnosis of urinary tract infection (UTI) is necessary to minimize its symptoms and limit sequelae. The current UTI screening by urine test strip analysis and microscopic examination has suboptimal diagnostic accuracy. A definitive diagnosis of UTI by urine culture takes two to three days for the results. These limitations necessitate a need for better biomarkers for the diagnosis and subsequent management of UTI in children. Here, we review the value of currently available UTI biomarkers and highlight the potential of emerging biomarkers that can facilitate a more rapid and accurate UTI diagnosis. Of the newer UTI biomarkers, the most promising are blood procalcitonin (PCT) and urinary neutrophil gelatinase-associated lipocalin (NGAL). PCT can provide diagnostic benefits and should be considered in patients who have a blood test for other reasons. NGAL, which is on the threshold of clinical care, needs more research to address its scope and utilization, including point-of-care application. Employment of these and other biomarkers may ultimately improve UTI diagnosis, guide UTI therapy, reduce antibiotic use, and mitigate UTI complications.
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Biomarcadores , Lipocalina 2 , Polipéptido alfa Relacionado con Calcitonina , Infecciones Urinarias , Humanos , Infecciones Urinarias/diagnóstico , Infecciones Urinarias/microbiología , Biomarcadores/orina , Biomarcadores/sangre , Polipéptido alfa Relacionado con Calcitonina/sangre , Lipocalina 2/orina , Lipocalina 2/sangre , NiñoRESUMEN
BACKGROUND: An alternative surgical approach for hypoplastic left heart syndrome is the Hybrid pathway, which delays the risk of acute kidney injury outside of the newborn period. We sought to determine the incidence, and associated morbidity, of acute kidney injury after the comprehensive stage 2 and the cumulative incidence after the first two operations in the Hybrid pathway. DESIGN: A single centre, retrospective study was conducted of hypoplastic left heart patients completing the second-stage palliation in the Hybrid pathway from 2009 to 2018. Acute kidney injury was defined utilising Kidney Diseases Improving Global Outcomes criteria. Perioperative and post-operative characteristics were analysed. RESULTS: Sixty-one patients were included in the study cohort. The incidence of acute kidney injury was 63.9%, with 36.1% developing severe injury. Cumulatively after the Hybrid Stage 1 and comprehensive stage 2 procedures, 69% developed acute kidney injury with 36% developing severe injury. The presence of post-operative acute kidney injury was not associated with an increase in 30-day mortality (acute kidney injury 7.7% versus none 9.1%; p = > 0.9). There was a significantly longer median duration of intubation among those with acute kidney injury (acute kidney injury 32 (8, 155) hours vs. no injury 9 (0, 94) hours; p = 0.018). CONCLUSIONS: Acute kidney injury after the comprehensive stage two procedure is common and accounts for most of the kidney injury in the first two operations of the Hybrid pathway. No difference in mortality was detected between those with acute kidney injury and those without, although there may be an increase in morbidity.
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Lesión Renal Aguda , Síndrome del Corazón Izquierdo Hipoplásico , Recién Nacido , Humanos , Síndrome del Corazón Izquierdo Hipoplásico/complicaciones , Síndrome del Corazón Izquierdo Hipoplásico/cirugía , Estudios Retrospectivos , Lesión Renal Aguda/epidemiología , Lesión Renal Aguda/etiología , Periodo PosoperatorioRESUMEN
We present two cases of cricoid chondronecrosis treated with hyperbaric oxygen (HBO2) therapy. Both patients presented with biphasic stridor and dyspnea several weeks after an intubation event. Tracheostomy was ultimately performed for airway protection, followed by antibiotic treatment and outpatient HBO2 therapy. Both patients were decannulated within six months of presentation and after at least 20 HBO2 therapy sessions. Despite a small sample size, our findings are consistent with data supporting HBO2 therapy's effects on tissue edema, neovascularization, and HBO2 potentiation of antibiotic treatment and leukocyte function. We suggest HBO2 therapy may have accelerated airway decannulation by way of infection resolution as well as the revitalization of upper airway tissues, ultimately renewing the structural integrity of the larynx. When presented with this rare but significant clinical challenge, physicians should be aware of the potential benefits of HBO2 therapy.
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Oxigenoterapia Hiperbárica , Médicos , Humanos , Oxígeno , Investigación , AntibacterianosRESUMEN
Despite the American Academy of Pediatrics guidelines for the evaluation, treatment, and management of urinary tract infections (UTIs), UTI diagnosis and management remains challenging for clinicians. Challenges with acute UTI management stem from vague presenting signs and symptoms, diagnostic uncertainty, limitations in laboratory testing, and selecting appropriate antibiotic therapy in an era with increasing rates of antibiotic-resistant uropathogens. Recurrent UTI management remains difficult due to an incomplete understanding of the factors contributing to UTI, when to assess a child with repeated infections for kidney and urinary tract anomalies, and limited prevention strategies. To help reduce these uncertainties, this review provides a comprehensive overview of UTI epidemiology, risk factors, diagnosis, treatment, and prevention strategies that may help pediatricians overcome the challenges associated with acute and recurrent UTI management.
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Antibacterianos , Infecciones Urinarias , Humanos , Infecciones Urinarias/diagnóstico , Infecciones Urinarias/tratamiento farmacológico , Infecciones Urinarias/terapia , Infecciones Urinarias/epidemiología , Niño , Antibacterianos/uso terapéutico , Factores de RiesgoRESUMEN
Detecting multiple enzyme activities simultaneously with high spatial specificity is a promising strategy to investigate complex biological phenomena, and Raman imaging would be an excellent tool for this purpose due to its high multiplexing capabilities. We previously developed activatable Raman probes based on 9CN-pyronins, but specific visualization of cells with target enzyme activities proved difficult due to leakage of the hydrolysis products from the target cells after activation. Here, focusing on rhodol bearing a nitrile group at the position of 9 (9CN-rhodol), we established a novel mechanism for Raman signal activation based on a combination of aggregate formation (to increase local dye concentration) and the resonant Raman effect along with the bathochromic shift of the absorption, and utilized it to develop Raman probes. We selected the 9CN-rhodol derivative 9CN-JCR as offering a suitable combination of increased stimulated Raman scattering (SRS) signal intensity and high aggregate-forming ability, resulting in good retention in target cells after probe activation. By using isotope-edited 9CN-JCR-based probes, we could simultaneously detect ß-galactosidase, γ-glutamyl transpeptidase, and dipeptidyl peptidase-4 activities in live cultured cells and distinguish cell regions expressing target enzyme activity in Drosophila wing disc and fat body ex vivo.
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Espectrometría Raman , gamma-Glutamiltransferasa , Animales , Células CultivadasRESUMEN
BACKGROUND: Fluid overload leads to poor neonatal outcomes. Diuretics may lower the rates of mechanical ventilation (MV) and mortality in neonates with fluid overload. METHODS: This is a retrospective study of preterm neonates ≤ 36 weeks of gestational age (GA) in the first 14 postnatal days in a level IV NICU in 2014-2020. We evaluated the epidemiology of fluid balance in the first 14 postnatal days and its association with MV and mortality and studied the association of diuretics with fluid balance, MV, and mortality. RESULTS: In 1383 included neonates, the overall median lowest and peak fluid balances were - 7.8% (IQR: - 11.7, - 4.6) and 8% (3, 16) on days 3 (2, 5) and 13 (5, 14), respectively. Fluid balance distribution varied significantly by GA. Peak fluid balance of ≥ 10% was associated with increased odds of MV on days 7 and 14 with highest odds ratios (OR) of MV in neonates with fluid balance ≥ 15%. Peak fluid balance of ≥ 15% was associated with the greatest odds of mortality. Diuretics were used more frequently in neonates with younger GA, smaller birthweight, positive fluid balance, and those on MV. CONCLUSIONS: Positive fluid balance negatively impacts pulmonary status. The odds of MV and death increase significantly as peak fluid balance percentage increases in all GA groups. The impact of diuretics on MV and death in preterm neonates needs further evaluation. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Respiración Artificial , Desequilibrio Hidroelectrolítico , Recién Nacido , Humanos , Estudios Retrospectivos , Equilibrio Hidroelectrolítico , Edad Gestacional , Desequilibrio Hidroelectrolítico/terapia , Diuréticos/uso terapéuticoRESUMEN
The interaction of visual exploration and auditory processing is central to early cognitive development, supporting object discrimination, categorization, and word learning. Research has shown visual-auditory interactions to be complex, created from multiple processes and changing over multiple timescales. To better understand these interactions, we generalize a formal neural process model of early word learning to two studies examining how words impact 9- to 22-month-olds' attention to novelty. These simulations clarify the origin and nature of previously demonstrated effects of labels on visual exploration and the basis of mutual exclusivity effects in word learning. We use our findings to discuss key questions for this special section: what makes a good theory and how should formal theories interface with empirical paradigms and findings?
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Cognición , Aprendizaje Verbal , Humanos , Lactante , Percepción Auditiva , Desarrollo del LenguajeRESUMEN
Working with PAHO/WHO to prioritize childhood cancer in the context of systems strengthening is central to St. Jude Children's Research Hospital (SJCRH)'s role as WHO Collaborating Centre for Childhood Cancer. This manuscript focuses on how SJCRH and PAHO/WHO have partnered to apply C5 (Country Collaboration for Childhood Cancer Control) to define and implement priority actions regionally, strengthening Ministry programs for childhood cancer, while implementing the Global Initiative for Childhood Cancer since 2018. Using C5, a tool developed by SJCRH, PAHO/WHO and SJCRH co-hosted regional/national workshops engaging authorities, clinicians and other stakeholders across 10 countries to map health systems needs and prioritize strategic activities (spanning Central America, Dominican Republic, Haiti, Brazil and Uruguay). SJCRH provided English/Spanish/Portuguese C5 versions/templates for analysis/prioritization exercises, and worked with PAHO/WHO and country teams to implement C5, analyze findings, and develop outputs. In an eight-country regional workshop, countries defined priorities within national/regional initiatives and ranked their value and political will, incorporating country-specific surveys and stakeholder dialogues. Each country prioritized one strategic activity for 2022-2023, exchanged insights via storytelling, and disseminated and applied results to inform country-specific and regional action plans. National workshops analyses have been incorporated into cancer control planning activities and collaborative work regionally. Implementation success factors include engaging actors beyond the clinic, enabling flexibility, and focusing on co-design with stakeholders. Joint implementation of C5 catalyzed prioritization and accelerated strategic activities to improve policies, capacity, and quality of care for children in the Americas, supporting Ministries to integrate childhood cancer interventions as part of systems strengthening.
La colaboración con la OPS/OMS para priorizar el cáncer infantil en el contexto del fortalecimiento de los sistemas es fundamental para la labor del St. Jude Children's Research Hospital (SJCRH) como centro colaborador de la OMS contra el cáncer infantil. Este artículo se centra en la alianza entre el SJCRH y la OPS/OMS en la aplicación de la herramienta C5 (colaboración nacional para el control del cáncer infantil) para definir y ejecutar medidas prioritarias a nivel regional, fortalecer los programas contra el cáncer infantil del ministerio y poner en marcha la Iniciativa Mundial contra el Cáncer Infantil desde el 2018. Con C5, una herramienta elaborada por el SJCRH, la OPS/OMS y este hospital organizaron conjuntamente talleres regionales y nacionales con autoridades, personal médico y otras partes interesadas en diez países para determinar cuáles son las necesidades de los sistemas de salud y priorizar las actividades estratégicas (en América Central, República Dominicana, Haití, Brasil y Uruguay). El SJCRH proporcionó versiones y plantillas de C5 en inglés, español y portugués para actividades de análisis y priorización y trabajó con la OPS/OMS y los equipos de país para ejecutar la herramienta C5, analizar los resultados y elaborar productos. En un taller regional de ocho países, se definieron las prioridades en las iniciativas regionales y nacionales, se clasificó su valor y la voluntad política y se incorporaron encuestas específicas para cada país y diálogos con las partes interesadas. Cada país priorizó una actividad estratégica para el período 2022-2023, intercambió ideas por medio de narrativas, y difundió y aplicó los resultados para fundamentar planes de acción tanto regionales como específicos para el país. Los análisis de los talleres nacionales se han incorporado a las actividades de planificación del control del cáncer y al trabajo colaborativo a nivel regional. Entre los factores de éxito de la ejecución se encuentra involucrar a los agentes más allá de lo clínico, permitir que haya flexibilidad y centrarse en un diseño elaborado en colaboración con las partes interesadas. La ejecución conjunta de la herramienta C5 catalizó la priorización y aceleró las actividades estratégicas para mejorar las políticas, la capacidad y la calidad de la atención infantil en la Región de las Américas y brindó apoyo a los ministerios para integrar las intervenciones contra el cáncer infantil en el fortalecimiento de los sistemas.
A colaboração com a OPAS/OMS para priorizar o câncer infantil no contexto do fortalecimento dos sistemas é fundamental para o papel do St. Jude Children's Research Hospital (SJCRH) como Centro Colaborador da OMS para o Câncer Infantil. Este artigo mostra como o SJCRH e a OPAS/OMS se associaram para aplicar a ferramenta C5 (Colaboração Nacional para Controle do Câncer Infantil), com o propósito de definir e implementar ações prioritárias regionalmente, fortalecendo programas ministeriais para o câncer na infância, durante a implementação da Iniciativa Global para o Câncer Infantil desde 2018. Com auxílio da C5, uma ferramenta desenvolvida pelo SJCRH, a OPAS/OMS e o SJCRH organizaram conjuntamente oficinas regionais/nacionais com a participação de autoridades, profissionais de saúde e outras partes interessadas em 10 países, com a finalidade de mapear as necessidades dos sistemas de saúde e priorizar atividades estratégicas (abrangendo América Central, República Dominicana, Haiti, Brasil e Uruguai). O SJCRH forneceu versões/modelos da C5 em inglês, espanhol e português para exercícios de análise/priorização e colaborou com a OPAS/OMS e as equipes dos países para implementar a C5, analisar resultados e desenvolver produtos. Em uma oficina regional com oito países, foram definidas as prioridades das iniciativas nacionais/regionais e classificados seu valor e vontade política, incorporando levantamentos nacionais e diálogos entre as partes interessadas. Cada país priorizou uma atividade estratégica para 2022-2023, trocou conhecimentos por meio da narração de histórias e disseminou e aplicou os resultados para informar planos de ação nacionais e regionais. As análises das oficinas nacionais foram incorporadas às atividades de planejamento para controle do câncer e ao trabalho conjunto no âmbito regional. Entre os fatores de êxito da implementação estão o engajamento de agentes de fora do segmento da saúde, a oferta de flexibilidade e a ênfase no planejamento conjunto com as partes interessadas. A implementação conjunta da C5 catalisou a priorização e acelerou atividades estratégicas para aprimorar as políticas, a capacidade e a qualidade da atenção às crianças nas Américas, apoiando os ministérios na integração das intervenções contra o câncer infantil como parte do fortalecimento dos sistemas.
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Recently, the oncogenic role of lemur tyrosine kinase 3 (LMTK3) has been well established in different tumor types, highlighting it as a viable therapeutic target. In the present study, using in vitro and cell-based assays coupled with biophysical analyses, we identify a highly selective small molecule LMTK3 inhibitor, namely C36. Biochemical/biophysical and cellular studies revealed that C36 displays a high in vitro selectivity profile and provides notable therapeutic effect when tested in the National Cancer Institute (NCI)-60 cancer cell line panel. We also report the binding affinity between LMTK3 and C36 as demonstrated via microscale thermophoresis (MST). In addition, C36 exhibits a mixed-type inhibition against LMTK3, consistent with the inhibitor overlapping with both the adenosine 5'-triphosphate (ATP)- and substrate-binding sites. Treatment of different breast cancer cell lines with C36 led to decreased proliferation and increased apoptosis, further reinforcing the prospective value of LMTK3 inhibitors for cancer therapy.
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Inhibidores de Proteínas Quinasas , Proteínas Serina-Treonina Quinasas , Línea Celular Tumoral , Estudios Prospectivos , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , HumanosRESUMEN
Nine-banded armadillos (Dasypus novemcinctus) are naturally infected with Mycobacterium leprae and are implicated in the zoonotic transmission of leprosy in the United States. In Mexico, the existence of such a reservoir remains to be characterized. We describe a wild armadillo infected by M. leprae in the state of Nuevo León, Mexico.
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Armadillos , Lepra , Animales , Armadillos/microbiología , Reservorios de Enfermedades/microbiología , Lepra/diagnóstico , Lepra/epidemiología , Lepra/veterinaria , México/epidemiología , Mycobacterium leprae/genéticaRESUMEN
The current review describes advances in the use of fluorescent 2,1,3-benzothiadiazole (BTD) derivatives after nearly one decade since the first description of bioimaging experiments using this class of fluorogenic dyes. The review describes the use of BTD-containing fluorophores applied as, inter alia, bioprobes for imaging cell nuclei, mitochondria, lipid droplets, sensors, markers for proteins and related events, biological processes and activities, lysosomes, plasma membranes, multicellular models, and animals. A number of physicochemical and photophysical properties commonly observed for BTD fluorogenic structures are also described.
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Imagen Óptica , Tiadiazoles , Colorantes Fluorescentes , LisosomasRESUMEN
Solvent-free synthesis by using a vibratory ball mill (VBM) offers the chance to access new chemical reactivity, whilst reducing solvent waste and minimising reaction times. Herein, we report the core functionalisation of N,N'-bis(2-ethylhexyl)-2,6-dibromo-1,4,5,8-naphthalenetetracarboxylic acid (Br2 -NDI) by using Suzuki, Sonogashira and Buchwald-Hartwig coupling reactions. The products of these reactions are important building blocks in many areas of organic electronics including organic light-emitting diodes (OLEDs), organic field-effect transistors (OFETs) and organic photovoltaic cells (OPVCs). The reactions proceed in as little as 1â h, use commercially available palladium sources (frequently Pd(OAc)2 ) and are tolerant to air and atmospheric moisture. Furthermore, the real-world potential of this green VBM protocol is demonstrated by the double Suzuki coupling of a monobromo(NDI) residue to a bis(thiophene) pinacol ester. The resulting dimeric NDI species has been demonstrated to behave as an electron acceptor in functioning OPVCs.
RESUMEN
ISOX-DUAL is a dual inhibitor of CBP/p300 (IC50 = 0.65 µM) and BRD4 (IC50 = 1.5 µM) bromodomains, and a useful chemical probe for epigenetic research. Aspects of the published synthetic route to this compound and its analogues are small-scale, poor-yielding or simply unamenable to scale-up without optimization. Herein we describe the development of a refined synthesis that circumvents the challenges of the original report, with notable improvements to several of the key synthetic transformations. Moreover, a general Suzuki Miyaura protocol for the late stage installation of alternative dimethyl-isoxazole acetyl-lysine (KAc) binding motifs is presented.