Lysophosphatidic acid LPA1-3 receptors: signaling, regulation and in silico analysis of their putative phosphorylation sites

Lysophosphatidic acid (LPA) is a bioactive lipid with a plethora of roles in the normal function of our organism as well as in the pathogenesis of many diseases. The actions of LPA are mainly mediated through a family of G protein-coupled receptors, which currently is composed of six members; other receptors might participate in LPA actions including a nuclear receptor. In this work, we mainly focus on three of these receptors, i. e.,  LPA1-3; those that were initially discovered which, have been more extensively studied and that are phylogenetically related among themselves,  as well as with receptors for other bioactive phospholipids, such as those for spingosine 1-phosphate.  The characteristics of these receptors, their patterns of tissue expression, and some of the actions in which they are involved are presented. Regulation of receptor function, including desensitization, internalization and phosphorylation has only been studied for the LPA1 subtype. However, in silico analysis of potential phosphorylation sites indicate that all of these three receptors are putatively regulated by agonist activation and heterologous stimuli. We think LPA1-3 receptor regulation constitutes a niche of investigation that is potentially of great importance considering the physiological and pathophysiological actions in which they are involved.&nbsp

Fuentes fosfóricas de diferente solubilidad para frijol común evaluadas por método isotópico.

Se condujeron experimentos en casa de cristales de la Estación Experimental La Renée ubicada en la provincia Habana en el año 2003. El objetivo fue evaluar fuentes fosfóricas de diferente solubilidad para frijol común (Phaseolus vulgaris L.) utilizando dos suelos, Acrisol y Ferralsol ródico, y la técnica de dilución isotópica con 32P. Las fuentes fosfóricas evaluadas fueron roca fosfórica (RF) Trinidad de Guedes, RF parcialmente solubilizada al 50 % con H2SO4 (producto denominado comercialmente FPA 50) y superfosfato simple (SS) en el Acrisol y superfosfato triple (SFT) en el Ferralsol ródico. Los genotipos de frijol empleados en el Acrisol fueron BAT 477, DOR 364, DOR 390 y Censa, mientras que en el Ferralsol fueron BAT 58, BAT 477, DOR 364 y CC-25-9(N). Se evaluó producción de materia seca y extracción de P y se determinó la fracción (%) y cantidad de P en planta derivado de los portadores y % de eficiencia de uso del fertilizante. La RF en aplicación directa fue poco efectiva mientras que los superfosfatos y el FPA 50 resultaron efectivos en ambos suelos. Hubo diferencia varietal en la respuesta vegetal y en la utilización del P de las fuentes, que también dependió de las características del suelo

Late-onset thymidine kinase 2 deficiency: a review of 18 cases

Background: TK2 gene encodes for mitochondrial thymidine kinase, which phosphorylates the pyrimidine nucleosides thymidine and deoxycytidine. Recessive mutations in the TK2 gene are responsible for the ‘myopathic form’ of the mitochondrial depletion/multiple deletions syndrome, with a wide spectrum of severity. Methods: We describe 18 patients with mitochondrial myopathy due to mutations in the TK2 gene with absence of clinical symptoms until the age of 12. Results: The mean age of onset was 31 years. The first symptom was muscle limb weakness in 10/18, eyelid ptosis in 6/18, and respiratory insufficiency in 2/18. All patients developed variable muscle weakness during the evolution of the disease. Half of patients presented difficulty in swallowing. All patients showed evidence of respiratory muscle weakness, with need for non-invasive Mechanical Ventilation in 12/18. Four patients had deceased, all of them due to respiratory insufficiency. We identified common radiological features in muscle magnetic resonance, where the most severely affected muscles were the gluteus maximus, semitendinosus and sartorius. On muscle biopsies typical signs of mitochondrial dysfunction were associated with dystrophic changes. All mutations identified were previously reported, being the most frequent the in-frame deletion p.Lys202del. All cases showed multiple mtDNA deletions but mtDNA depletion was present only in two patients. Conclusions: The late-onset is the less frequent form of presentation of the TK2 deficiency and its natural history is not well known. Patients with late onset TK2 deficiency have a consistent and recognizable clinical phenotype and a poor prognosis, due to the high risk of early and progressive respiratory insufficiency

Generations No.6: Towards a global university

Apreciados graduados UNAB. En esta edición de “Generaciones” les presentamos los aspectos más relevantes del Plan de Desarrollo 2013-2018 que tiene como base los principios y valores institucionales que han marcado nuestro rumbo durante estas seis décadas de trabajo ininterrumpido por la región y el país. Dicho Plan se logró gracias a la realización de un trabajo conjunto y minucioso por parte de todos los integrantes de las dependencias de la UNAB. Es así como el rumbo que seguiremos en los próximos seis años está marcado por la noción clara de cómo será nuestro crecimiento en número de estudiantes y en la ampliación de nuestra oferta académica, entre otros factores.Editorial; Por Alberto Montoya Puyana…3 Saludo; Por Marcela Peralta Bautista…4 La voz del graduado…6 Institucional Plan de desarrollo 2013-2018; Por Carolina Toscano Vargas…7 Ruta del Empleo 2013; Por Luz Yaqueline Hernández Castañeda…10 El graduado UNAB, un profesional integral y competitivo; Por Adolfo Segura Moya…12 Planeta Joven 2013; Por Marcela Peralta Bautista…14 La literatura enredada; Por Santiago Gómez Mejía…20 Embarazo adolescente problema de salud pública; Por Bernardo Useche Aldana…22 Educación siglo XXI; Por Iliana Restrepo Hernández…24 ¿Usar las TIC o dejarse usar por ellas?; Por Julio Eduardo Mejía Gómez…26 Colombia tiene un estado laico; Por Alejandro Alvarado Bedoya…28 Mecatrónica: el rombo de la ingeniería actual; Por Omar Lengerke Pérez…30 Ocho años en la ‘Onda’ de la investigación; Por César Aurelio Rojas Carvajal…32 Emprendimiento Perseverancia, la clave del éxito; Por Redacción Generaciones UNAB…34 Graduados destacados; Por Redacción Generaciones UNAB…36 Generaciones en cifras…42 Conociendo el CPA; Por Luis Fernando Rueda Vivas…43Dear UNAB graduates. In this edition of "Generations" we present the most relevant aspects of the 2013-2018 Development Plan, which is based on the principles and institutional values ​​that have set our course during these six decades of uninterrupted work in the region and the country. Said Plan was achieved thanks to the accomplishment of a joint and meticulous work on the part of all the members of the dependencies of the UNAB. This is how the course that we will follow in the next six years is marked by a clear notion of how our growth in number of students will be and in the expansion of our academic offer, among other factors

Multicentric study of cervical cancer screening with human papillomavirus testing and assessment of triage methods in Latin America : the ESTAMPA screening study protocol

Q1Q1Introduction Human papillomavirus (HPV) testing is replacing cytology in primary screening. Its limited specificity demands using a second (triage) test to better identify women at high-risk of cervical disease. Cytology represents the immediate triage but its low sensitivity might hamper HPV testing sensitivity, particularly in low-income and middle-income countries (LMICs), where cytology performance has been suboptimal. The ESTAMPA (EStudio multicéntrico de TAMizaje y triaje de cáncer de cuello uterino con pruebas del virus del PApiloma humano; Spanish acronym) study will: (1) evaluate the performance of different triage techniques to detect cervical precancer and (2) inform on how to implement HPV-based screening programmes in LMIC. Methods and analysis Women aged 30–64 years are screened with HPV testing and Pap across 12 study centres in Latin America. Screened positives have colposcopy with biopsy and treatment of lesions. Women with no evident disease are recalled 18 months later for another HPV test; those HPV-positive undergo colposcopy with biopsy and treatment as needed. Biological specimens are collected in different visits for triage testing, which is not used for clinical management. The study outcome is histological high-grade squamous intraepithelial or worse lesions (HSIL+) under the lower anogenital squamous terminology. About 50 000 women will be screened and 500 HSIL+ cases detected (at initial and 18 months screening). Performance measures (sensitivity, specificity and predictive values) of triage techniques to detect HSIL+ will be estimated and compared with adjustment by age and study centre. Ethics and dissemination The study protocol has been approved by the Ethics Committee of the International Agency for Research on Cancer (IARC), of the Pan American Health Organisation (PAHO) and by those in each participating centre. A Data and Safety Monitoring Board (DSMB) has been established to monitor progress of the study, assure participant safety, advice on scientific conduct and analysis and suggest protocol improvements. Study findings will be published in peer-reviewed journals and presented at scientific meetings. Trial registration number NCT01881659Revista Internacional - Indexad

Chemotherapy or allogeneic transplantation in high-risk Philadelphia chromosome–negative adult lymphoblastic leukemia

The need for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in adults with Philadelphia chromosome–negative (Ph−) acute lymphoblastic leukemia (ALL) with high-risk (HR) features and adequate measurable residual disease (MRD) clearance remains unclear. The aim of the ALL-HR-11 trial was to evaluate the outcomes of HR Ph− adult ALL patients following chemotherapy or allo-HSCT administered based on end-induction and consolidation MRD levels. Patients aged 15 to 60 years with HR-ALL in complete response (CR) and MRD levels (centrally assessed by 8-color flow cytometry) <0.1% after induction and <0.01% after early consolidation were assigned to receive delayed consolidation and maintenance therapy up to 2 years in CR. The remaining patients were allocated to allo-HSCT. CR was attained in 315/348 patients (91%), with MRD <0.1% after induction in 220/289 patients (76%). By intention-to-treat, 218 patients were assigned to chemotherapy and 106 to allo-HSCT. The 5-year (±95% confidence interval) cumulative incidence of relapse (CIR), overall survival (OS), and event-free survival probabilities for the whole series were 43% ± 7%, 49% ± 7%, and 40% ± 6%, respectively, with CIR and OS rates of 45% ± 8% and 59% ± 9% for patients assigned to chemotherapy and of 40% ± 12% and 38% ± 11% for those assigned to allo-HSCT, respectively. Our results show that avoiding allo-HSCT does not hamper the outcomes of HR Ph− adult ALL patients up to 60 years with adequate MRD response after induction and consolidation. Better postremission alternative therapies are especially needed for patients with poor MRD clearance

Role of age and comorbidities in mortality of patients with infective endocarditis

[Purpose]: The aim of this study was to analyse the characteristics of patients with IE in three groups of age and to assess the ability of age and the Charlson Comorbidity Index (CCI) to predict mortality. [Methods]: Prospective cohort study of all patients with IE included in the GAMES Spanish database between 2008 and 2015.Patients were stratified into three age groups:<65 years,65 to 80 years,and ≥ 80 years.The area under the receiver-operating characteristic (AUROC) curve was calculated to quantify the diagnostic accuracy of the CCI to predict mortality risk. [Results]: A total of 3120 patients with IE (1327 < 65 years;1291 65-80 years;502 ≥ 80 years) were enrolled.Fever and heart failure were the most common presentations of IE, with no differences among age groups.Patients ≥80 years who underwent surgery were significantly lower compared with other age groups (14.3%,65 years; 20.5%,65-79 years; 31.3%,≥80 years). In-hospital mortality was lower in the <65-year group (20.3%,<65 years;30.1%,65-79 years;34.7%,≥80 years;p < 0.001) as well as 1-year mortality (3.2%, <65 years; 5.5%, 65-80 years;7.6%,≥80 years; p = 0.003).Independent predictors of mortality were age ≥ 80 years (hazard ratio [HR]:2.78;95% confidence interval [CI]:2.32–3.34), CCI ≥ 3 (HR:1.62; 95% CI:1.39–1.88),and non-performed surgery (HR:1.64;95% CI:11.16–1.58).When the three age groups were compared,the AUROC curve for CCI was significantly larger for patients aged <65 years(p < 0.001) for both in-hospital and 1-year mortality. [Conclusion]: There were no differences in the clinical presentation of IE between the groups. Age ≥ 80 years, high comorbidity (measured by CCI),and non-performance of surgery were independent predictors of mortality in patients with IE.CCI could help to identify those patients with IE and surgical indication who present a lower risk of in-hospital and 1-year mortality after surgery, especially in the <65-year group

EDUCACIÓN AMBIENTAL Y SOCIEDAD. SABERES LOCALES PARA EL DESARROLLO Y LA SUSTENTABILIDAD

Este texto contribuye al análisis científico de varias áreas del conocimiento como la filosofía social, la patología, la educación para el cuidado del medio ambiente y la sustentabilidad que inciden en diversas unidades de aprendizaje de la Licenciatura en Educación para la Salud y de la Maestría en Sociología de la SaludLas comunidades indígenas de la sierra norte de Oaxaca México, habitan un territorio extenso de biodiversidad. Sin que sea una área protegida y sustentable, la propia naturaleza de la región ofrece a sus visitantes la riqueza de la vegetación caracterizada por sus especies endémicas que componen un paisaje de suma belleza

Lysophosphatidic acid LPA1-3 receptors: signaling, regulation and in silico analysis of their putative phosphorylation sites

Lysophosphatidic acid (LPA) is a bioactive lipid with a plethora of roles in the normal function of our organism as well as in the pathogenesis of many diseases. The actions of LPA are mainly mediated through a family of G protein-coupled receptors, which currently is composed of six members; other receptors might participate in LPA actions including a nuclear receptor. In this work, we mainly focus on three of these receptors, i. e.,&nbsp; LPA1-3; those that were initially discovered which, have been more extensively studied and that are phylogenetically related among themselves,&nbsp; as well as with receptors for other bioactive phospholipids, such as those for spingosine 1-phosphate.&nbsp; The characteristics of these receptors, their patterns of tissue expression, and some of the actions in which they are involved are presented. Regulation of receptor function, including desensitization, internalization and phosphorylation has only been studied for the LPA1 subtype. However, in silico analysis of potential phosphorylation sites indicate that all of these three receptors are putatively regulated by agonist activation and heterologous stimuli. We think LPA1-3 receptor regulation constitutes a niche of investigation that is potentially of great importance considering the physiological and pathophysiological actions in which they are involved.&nbsp

Phosphorylation and Internalization of Lysophosphatidic Acid Receptors LPA1, LPA2, and LPA3.

The lysophosphatidic acid receptors LPA1, LPA2, and LPA3 were individually expressed in C9 cells and their signaling and regulation were studied. Agonist-activation increases intracellular calcium concentration in a concentration-dependent fashion. Phorbol myristate acetate markedly inhibited LPA1- and LPA3-mediated effect, whereas that mediated by LPA2 was only partially diminished; the actions of the phorbol ester were inhibited by bisindolylmaleimide I and by overnight incubation with the protein kinase C activator, which leads to down regulation of this protein kinase. Homologous desensitization was also observed for the three LPA receptors studied, with that of LPA2 receptors being consistently of lesser magnitude; neither inhibition nor down-regulation of protein kinase C exerted any effect on homologous desensitization. Activation of LPA1-3 receptors induced ERK 1/2 phosphorylation; this effect was markedly attenuated by inhibition of epidermal growth factor receptor tyrosine kinase activity, suggesting growth factor receptor transactivation in this effect. Lysophosphatidic acid and phorbol myristate acetate were able to induce LPA1-3 phosphorylation, in time- and concentration-dependent fashions. It was also clearly observed that agonists and protein kinase C activation induced internalization of these receptors. Phosphorylation of the LPA2 subtype required larger concentrations of these agents and its internalization was less intense than that of the other subtypes.Our data show that these three LPA receptors are phosphoproteins whose phosphorylation state is modulated by agonist-stimulation and protein kinase C-activation and that differences in regulation and cellular localization exist, among the subtypes