RESUMEN
OBJECTIVE: High levels of stress and fatigue are associated with decreased academic success, well-being, and quality of life. The objective of this research was to quantify levels of perceived stress and fatigue among chiropractic students to identify sources of and student coping mechanisms for perceived stress and fatigue and to identify the relationship between students' perceived stress and fatigue. METHODS: A survey comprised of the Perceived Stress Scale, the Undergraduate Sources of Stress Survey, and the Piper Fatigue Scale was administered to chiropractic students in their 2nd, 5th, and 8th trimesters of doctoral study. Data were analyzed by descriptive statistics, 1-way analysis of variance, and linear correlation tests. RESULTS: Students reported having moderate to high levels of stress and fatigue, with higher levels of stress and fatigue seen in women than in men. A nonsignificant difference among stress scores and a significant difference among fatigue scores were observed based on program term. Levels of stress predicted levels of fatigue, and stress was strongly correlated with psychological health, relationships with family members, mood, and need for learning accommodations. Fatigue was strongly correlated with psychological health, academic demands, and conflicts between studies and other activities. CONCLUSION: There are differences in the reporting of perceived stress and fatigue levels in this chiropractic student population based on gender. The correlation between fatigue and stress also suggests that measures that may alleviate one may likely affect the other.
RESUMEN
Aberrant FGFR4 signaling has been documented abundantly in various human cancers. The majority of FGFR inhibitors display significantly reduced potency toward FGFR4 compared to FGFR1-3. However, LY2874455 has similar inhibition potency for FGFR1-4 with IC50 less than 6.4 nM. To date, there is no published crystal structure of LY2874455 in complex with any kinase. To better understand the pan-FGFR selectivity of LY2874455, we have determined the crystal structure of the FGFR4 kinase domain bound to LY2874455 at a resolution of 2.35 Å. LY2874455, a type I inhibitor for FGFR4, binds to the ATP-binding pocket of FGFR4 in a DFG-in active conformation with three hydrogen bonds and a number of van der Waals contacts. After alignment of the kinase domain sequence of 4 FGFRs, and superposition of the ATP binding pocket of 4 FGFRs, our structural analyses reveal that the interactions of LY2874455 to FGFR4 are largely conserved in 4 FGFRs, explaining at least partly, the broad inhibitory activity of LY2874455 toward 4 FGFRs. Consequently, our studies reveal new insights into the pan-FGFR selectivity of LY2874455 and provide a structural basis for developing novel FGFR inhibitors that target FGFR1-4 broadly.
Asunto(s)
Indazoles/metabolismo , Receptor Tipo 4 de Factor de Crecimiento de Fibroblastos/metabolismo , Adenosina Trifosfato/metabolismo , Secuencia de Aminoácidos , Cristalización , Cristalografía por Rayos X , Humanos , Enlace de Hidrógeno , Indazoles/química , Estructura Molecular , Receptor Tipo 4 de Factor de Crecimiento de Fibroblastos/química , Homología de Secuencia de AminoácidoRESUMEN
Enzymes that modify the epigenetic status of cells provide attractive targets for therapy in various diseases. The therapeutic development of epigenetic modulators, however, has been largely limited to direct targeting of catalytic active site conserved across multiple members of an enzyme family, which complicates mechanistic studies and drug development. Class IIa histone deacetylases (HDACs) are a group of epigenetic enzymes that depends on interaction with Myocyte Enhancer Factor-2 (MEF2) for their recruitment to specific genomic loci. Targeting this interaction presents an alternative approach to inhibiting this class of HDACs. We have used structural and functional approaches to identify and characterize a group of small molecules that indirectly target class IIa HDACs by blocking their interaction with MEF2 on DNA.Weused X-ray crystallography and (19)F NMRto show that these compounds directly bind to MEF2. We have also shown that the small molecules blocked the recruitment of class IIa HDACs to MEF2-targeted genes to enhance the expression of those targets. These compounds can be used as tools to study MEF2 and class IIa HDACs in vivo and as leads for drug development.