DD04107-Derived neuronal exocytosis inhibitor peptides: Evidences for synaptotagmin-1 as a putative target

15 pags, 8 figs, 3 tabs. -- Supplementary data to this article can be found online at https://doi.org/10.1016/j.bioorg.2021.105231.The analgesic peptide DD04107 (Pal-EEMQRR-NH2) and its acetylated analogue inhibit α-calcitonin gene-related peptide (α-CGRP) exocytotic release from primary sensory neurons. Examining the crystal structure of the SNARE-Synaptotagmin-1(Syt1) complex, we hypothesized that these peptides could inhibit neuronal exocytosis by binding to Syt1, hampering at least partially its interaction with the SNARE complex. To address this hypothesis, we first interrogate the role of individual side-chains on the inhibition of α-CGRP release, finding that E1, M3, Q4 and R6 residues were crucial for activity. CD and NMR conformational analysis showed that linear peptides have tendency to adopt α-helical conformations, but the results with cyclic analogues indicated that this secondary structure is not needed for activity. Isothermal titration calorimetry (ITC) measurements demonstrate a direct interaction of some of these peptides with Syt1-C2B domain, but not with Syt7-C2B region, indicating selectivity. As expected for a compound able to inhibit α-CGRP release, cyclic peptide derivative Pal-E-cyclo[EMQK]R-NH2 showed potent in vivo analgesic activity, in a model of inflammatory pain. Molecular dynamics simulations provided a model consistent with KD values for the interaction of peptides with Syt1-C2B domain, and with their biological activity. Altogether, these results identify Syt1 as a potential new analgesic target.This work was supported by the Spanish Ministerio de Economía y Competitividad (MINECO-FEDER), RTI2018-097189-C2 and CTQ2017-84371-P), and the Spanish National Research Council (CSIC, 201880E109, 201980E030). The NMR experiments were performed in the “Manuel Rico” NMR laboratory, LMR, CSIC, a node of the Spanish Large-Scale National Facility ICTS R-LRB. We thank Prof. Josep Rizo and R. Voleti (Dept. Biophysics, Biochemistry and Pharmacology, UT Southwestern Medical Center, Dallas, USA) for providing the clones required for expressing Syt1 and Syt7 proteins. SG-R and AB belong to the Instituto de Investigación Sanitaria del Principado de Asturias (ISPA).Peer reviewe

Diseño para el consumo cultural, la innovación y la inclusión social

Esta obra presenta diversos trabajos de investigación que tienen en común propuestas de diseño desde la cultura, la inclusión y la innovación social, desarrolladas por investigadores nacionales e internacionales adscritos a diversas universidades, así como a programas de posgrado

Ciencia Odontológica 2.0

Libro que muestra avances de la Investigación Odontológica en MéxicoEs para los integrantes de la Red de Investigación en Estomatología (RIE) una enorme alegría presentar el segundo de una serie de 6 libros sobre casos clínicos, revisiones de la literatura e investigaciones. La RIE está integrada por cuerpos académicos de la UAEH, UAEM, UAC y UdeG

Fiestas nupciales en el Madrid de Felipe II

Material no publicadoTrabajo que obtuvo un primer premio en el VI Certamen de Materiales Curriculares adaptados a la Comunidad de Madrid. Estudio interdisciplinar que conmemora el cuarto centenario de la muerte de Felipe II. Se centra en el recorrido festivo que la reina doña Ana de Austria, cuarta esposa de Felipe II, realizó a su llegada a Madrid en 1570. Se dirige a alumnos de tercero y cuarto de ESO que cursan Geografía e Historia, Latín y Cultura Clásica por los aspectos que se tratan: el humanismo cristiano de la época de Felipe II y su transmisión popular; el marco histórico de la boda entre el monarca español y la archiduquesa Ana de Austria y el estudio de la morfología de Madrid y de sus transformaciones utilizando como referencia el plano de Witt y otro de la época actual.MadridES

Fiestas nupciales en el Madrid de Felipe II : estudio interdisciplinar del recorrido festivo realizado por la reina Doña Ana de Austria, cuarta esposa de Felipe II, con motivo de su llegada a Madrid el 26 de noviembre de 1570

También en biblioteca material no publicado R. 4702 y R.4703Trabajo que obtuvo un primer premio en el VI Certamen de Materiales Curriculares adaptados a la Comunidad de Madrid. Realiza un estudio interdisciplinar que conmemora el cuarto centenario de la muerte de Felipe II. Se centra en el recorrido festivo que la reina doña Ana de Austria, cuarta esposa de Felipe II, realizó a su llegada a Madrid en 1570. Se dirige a alumnos de tercero y cuarto de ESO que cursan Geografía e Historia, Latín y Cultura Clásica por los aspectos que se tratan: el humanismo cristiano de la época de Felipe II y su transmisión popular; el marco histórico de la boda entre el monarca español y la archiduquesa Ana de Austria y el estudio de la morfología de Madrid y de sus transformaciones utilizando como referencia el plano de Witt y otro de la época actual..MadridES

Primary Immunodeficiency Diseases at Reference and High-Specialty Hospitals in the State of Guanajuato, Mexico

Background. In general, primary immunodeficiency diseases (PIDs) are underdiagnosed in most countries. The objective of this study was to describe the frequency and clinical spectrum of PID in the most important tertiary hospitals in our region. Methods. An observational, cross-sectional, with retrospective chart, review study was conducted. A total of 26 patients were included and grouped according to the updated classification of PIDs. Results. PIDs spectra were as follows: predominantly antibody deficiency diseases were the most common category (65.38%), followed by other well-defined immunodeficiency syndromes (11.55%), congenital defects of phagocyte number and/or function (7.69%), complement deficiencies (3.85%), combined T- and B-cell immunodeficiencies (3.85%), and defects in innate immunity (3.85%). The mean time elapsed from the onset of symptoms to the reference and diagnosis by a tertiary hospital was of 4.65 ± 6.95 years. Conclusions. Predominant antibody deficiency disease was the most common group of PIDs, agreeing with international reports. Awareness of underdiagnosis by physicians is crucial for a prompt diagnosis and treatment, which in turn should improve the quality of life among patients with PIDs

Disease burden for patients with primary immunodeficiency diseases identified at reference hospitals in Guanajuato, Mexico.

In addition to the deleterious effect on health, there is considerable economic and psychosocial morbidity associated with primary immunodeficiency diseases (PID). Also, the cost of a late diagnosis frequently results in a heavy disease burden on the patient. The objective of this study was to collect and analyze data on patients with PID in the state of Guanajuato in Mexico, to indirectly estimate the burden of the disease.An observational, longitudinal, and comparative study was conducted. A total of 44 patients were included and grouped according to the updated classification of PID.The median time elapsed from the onset of symptoms to the reference and diagnosis by a tertiary hospital was of 2.17 (IQR = 6.44) years. Before diagnosis, the number of hospitalizations/year per patient was 0.86 (IQR = 2.28), the number of visit to emergency room/year per patient was 0.92 (IQR = 1.77), the number of doctor's visits/year per patient was 15 (IQR = 11.25), whereas the school/work absence days per patient were reported in 52.72 (IQR = 56.35) days per year. After diagnosis, 20 patients (45.45%) received IVIG replacement therapy, and all of them presented a significant improvement (p <0.05) in all the mentioned variables. Characteristically, even when patients with PID received IVIG, there was still an important disease burden when comparing them against healthy controls. Complications secondary to PID were detected in 19 patients (43.18%). The reported overall mortality rate was 6.82% (n = 3).We were able to indirectly estimate an important disease burden in patients with PID; which is considered to be preventable, at least in part, with effective interventions like health planning, research, collaboration with primary care providers, and generation of policies and practices, in order to improve the quality of life and care of families with PID

Spectrum of PID at reference and high specialty hospitals in Guanajuato Sate.

<p>Spectrum of PID at reference and high specialty hospitals in Guanajuato Sate.</p

Burden of disease between patients with PID, before and after the treatment with IVIG, matched healthy controls.

<p>Burden of disease between patients with PID, before and after the treatment with IVIG, matched healthy controls.</p