RESUMEN
Diabetes and hypertension are the most common diseases and often coexist. Currently, hypertension is the most widespread chronic disease in China. To explore the value of three-dimensional team management in improving the effect of the management of primary diabetes and hypertension in patients in the medical community model, the expert team at the Department of Cardiology and Endocrinology of Anji County People's Hospital is selected to train 59 community general practitioners in the medical community model (the study group adopts the three-dimensional team management model in the medical community model), and another 59 community medical general practitioners adopts the conventional training method (the control group). The two groups of doctors managed patients with diabetes and hypertension who are registered in the jurisdiction (200 patients per group) as per the respective training methods. The three-dimensional management of the team under the medical community model significantly improves the diagnostic and treatment capabilities of grassroot general practitioners to better control patients' diabetes and hypertension levels.
Asunto(s)
Cardiología , Diabetes Mellitus , Endocrinología , Hipertensión , Médicos , Diabetes Mellitus/terapia , Humanos , Hipertensión/terapiaRESUMEN
In the vertebrate ventral spinal cord, p2 progenitors give rise to two interneuron subtypes: excitatory V2a interneurons and inhibitory V2b interneurons. In the differentiation of V2a and V2b cells, Notch signaling promotes V2b fate at the expense of V2a fate. Later, V2b cells extend axons along the ipsilateral side of the spinal cord and express the inhibitory transmitter GABA. Notch signaling has been reported to inhibit the axonal outgrowth of mature neurons of the central nervous system; however, it remains unknown how Notch signaling modulates V2b neurite outgrowth and maturation into GABAergic neurons. Here, we have investigated neuron-specific Notch functions regarding V2b axon growth and maturation into zebrafish GABAergic neurons. We found that continuous neuron-specific Notch activation enhanced V2b fate determination but inhibited V2b axonal outgrowth and maturation into GABAergic neurons. These results suggest that Notch signaling activation is required for V2b fate determination, whereas its downregulation at a later stage is essential for V2b maturation. Accordingly, we found that a Notch signaling downstream gene, her15.1, showed biased expression in V2 linage cells and downregulated expression during the maturation of V2b cells, and continuous expression of her15.1 repressed V2b axogenesis. Our data suggest that spatiotemporal control of Notch signaling activity is required for V2b fate determination, maturation and axogenesis.
Asunto(s)
Axones/metabolismo , Neuronas GABAérgicas/metabolismo , Interneuronas/metabolismo , Receptores Notch/metabolismo , Transducción de Señal , Proteínas de Pez Cebra/metabolismo , Pez Cebra/embriología , Animales , Receptores Notch/genética , Pez Cebra/genética , Proteínas de Pez Cebra/genéticaRESUMEN
Cytosine methylation of genomic DNA controls gene expression and maintains genome stability. How a specific DNA sequence is targeted for methylation by a methyltransferase is largely unknown. Here, we show that histone H3 tails lacking lysine 4 (K4) methylation function as an allosteric activator for methyltransferase Dnmt3a by binding to its plant homeodomain (PHD). In vitro, histone H3 peptides stimulated the methylation activity of Dnmt3a up to 8-fold, in a manner reversely correlated with the level of K4 methylation. The biological significance of allosteric regulation was manifested by molecular modeling and identification of key residues in both the PHD and the catalytic domain of Dnmt3a whose mutations impaired the stimulation of methylation activity by H3 peptides but not the binding of H3 peptides. Significantly, these mutant Dnmt3a proteins were almost inactive in DNA methylation when expressed in mouse embryonic stem cells while their recruitment to genomic targets was unaltered. We therefore propose a two-step mechanism for de novo DNA methylation - first recruitment of the methyltransferase probably assisted by a chromatin- or DNA-binding factor, and then allosteric activation depending on the interaction between Dnmt3a and the histone tails - the latter might serve as a checkpoint for the methylation activity.
Asunto(s)
ADN (Citosina-5-)-Metiltransferasas/metabolismo , Metilación de ADN , Histonas/metabolismo , Regulación Alostérica , Animales , Línea Celular , Inmunoprecipitación de Cromatina , ADN (Citosina-5-)-Metiltransferasas/química , ADN (Citosina-5-)-Metiltransferasas/genética , ADN Metiltransferasa 3A , Células Madre Embrionarias/citología , Células Madre Embrionarias/metabolismo , Activación Enzimática , Histonas/química , Humanos , Ratones , Mutación , Unión Proteica , Estructura Terciaria de ProteínaRESUMEN
Propionylation has been identified recently as a new type of protein post-translational modification. Bacterial propionyl-CoA synthetase and human histone H4 are propionylated at specific lysine residues that have been known previously to be acetylated. However, other proteins subject to this modification remain to be identified, and the modifying enzymes involved need to be characterized. In this work, we report the discovery of histone H3 propionylation in mammalian cells. Propionylation at H3 lysine Lys(23) was detected in the leukemia cell line U937 by mass spectrometry and Western analysis using a specific antibody. In this cell line, the propionylated form of Lys(23) accounted for 7%, a level at least 6-fold higher than in other leukemia cell lines (HL-60 and THP-1) or non-leukemia cell lines (HeLa and IMR-90). The propionylation level in U937 cells decreased remarkably during monocytic differentiation, indicating that this modification is dynamically regulated. Moreover, in vitro assays demonstrated that histone acetyltransferase p300 can catalyze H3 Lys(23) propionylation, whereas histone deacetylase Sir2 can remove this modification in the presence of NAD(+). These results suggest that histone propionylation might be generated by the same set of enzymes as for histone acetylation and that selection of donor molecules (propionyl-CoA versus acetyl-CoA) may determine the difference of modifications. Because like acetyl-CoA, propionyl-CoA is an important intermediate in biosynthesis and energy production, histone H3 Lys(23) propionylation may provide a novel epigenetic regulatory mark for cell metabolism.