'Lalis' Business Plan

Treball Final de Grau en Administració d'Empreses. Codi: AE1049. Curs 2020/2021"Lalis" is a company whose activity consists of selling an experience, an experience that is divided into hosting and carrying out activities. "Lalis" arises from the needs of families who spent a long time in confinement in small spaces, such as city flats, and after so long their family relationships have deteriorated and they want to do something different in their next holiday. Families who live the "Lalis" experience will be introduced to the rural world through accommodation and activities of all kinds in an unbeatable setting, Benassal. The main characteristics that define "Lalis" and therefore, what differentiates them from the competition is that their mission is to educate through activities in sustainability values for both children and adults and to strengthen family bonds. Lalis' target segment is families, but families with children from 5 to 18 years old, with their main residence in the city, with an income above the Spanish average, and with parents involved in the education of their children in values. Throughout this document, the different plans will be developed to make the operation of "Lalis" viable, as the idea and the business opportunity have already been validated through different processes. Starting with the strategic study of the external and internal environment, studying the rural tourism sector, the competition and the resources and capacities of "Lalis". Next, a marketing plan has been designed and quantified in order to achieve the sales, positioning and profitability objectives. Another important part of the document is the operations plan, where the design of processes and services can be observed. We also find the part that refers to human resources, where we find the organisation chart of the company, the recruitment and selection process with the main functions and characteristics that the employees of "Lalis" must fulfil. Finishing, we find the financial plan, with which we know the initial investment that "Lalis" needs, the forecast of costs and income throughout the first year of operation of the company. We must not forget the contingency plans, which provide guidelines for eight possible changes that may occur during the course of the economic activity and how to solve them. The main legal aspects to be taken into account by "Lalis" are also discussed. And finally we have a chronogram for the planning of the actions to be carried out in the first months of the company's operation

Decidualización defectuosa durante y después de un embarazo con preeclampsia revela una contribución materna en la etiología de la enfermedad

La Preeclampsia (PE) es una enfermedad obstétrica caracterizada por hipertensión arterial en gestante previamente normotensa a partir de la semana 20 de gestación con o sin síntomas asociados y con importante morbimortalidad materno-fetal y neonatal asociada. La única cura actual es el alumbramiento. La etiología es desconocida pero hay una decidualización endometrial alterada y una invasión trofoblástica superficial involucrada que produce placentación anómala y desencadena el fenotipo clínico característico. Estudios recientes in vitro demuestran alteración en la expresión de genes involucrados en decidualización como anexina A2 (ANXA2). Esta proteína está presente en la mayoría de células eucariotas y a nivel endometrial y decidual, se encuentra sobreexpresada durante la fase secretora implicándose en los cambios morfológicos de las células endometriales y en la adhesión celular. Se plantea la posibilidad de que exista una decidualización endometrial alterada previa a la llegada del blastocisto y responsable de la invasión superficial trofoblástica así como de la mala interacción entre ambos. Se obtienen células endometriales de biopsias procedentes de 13 mujeres con antecedente de gestación normal y 13 de preeclampsia severa y se induce a decidualización in vitro bajo estímulo hormonal durante 5 días con adenosín monofosfato cíclico y medroxiprogesterona esperando observar los cambios morfológicos y bioquímicos característicos de este proceso fisiológico. Sin embargo, las células endometriales estromales del grupo Preeclampsia severa con fenotipo fibrinoide no cambian a conformación poligonal ni secretan moléculas de señalización características de decidualización como son la prolactina (PRL) y la proteína de unión al factor de crecimiento de la insulina 1 (IGFBP-1). Se compara el perfil transcripcional de ambos grupos tanto antes como después de la decidualización y se demuestra la presencia de hasta 129 genes diferencialmente expresados en las células endometriales estromales decidualizadas respecto al control, 22 de los cuales forman parte de rutas biológicas implicadas en la decidualización. Entre estos genes, se evidencia el que codifica para anexina A2 (ANXA2), proteína implicada en la implantación del blastocisto sobre la decidua. Su contribución en el proceso de decidualización queda demostrado mediante un modelo in vitro con ARN de interferencia para ANXA2 que inhibe su expresión en las células estromales endometriales y las impide decidualizar. Finalmente se aplica un modelo in vivo mediante ratones silenciados para ANXA-2 que, tras iniciar gestación, reproduce el fenotipo clínico de la preeclampsia severa en los animales modificados genéticamente. El estudio demuestra una resistencia a la decidualización de las células endometriales estromales procedentes de mujeres con antecedentes de Preeclampsia severa que no depende de la presencia de un concepto, como en este caso el blastocisto aunque sí puede condicionar su correcta invasión sobre la decidua, por lo que se demuestra la contribución materna en la etiología de la enfermedad. La relevancia de ANXA2 sobre la correcta decidualización queda demostrada, tanto in vitro, como in vivo en el modelo animal, y por tanto, su utilidad como herramienta de marcador predictivo o de diagnóstico precoz sería de gran impacto para reducir la incidencia y morbimortalidad de la enfermedad, sobretodo en la población con factores de riesgo elevados para desarrollarla.Pre-eclampsia (PE) is an obstetric disorder characterized by high blood pressure in previously normotensive pregnant women after 20 weeks of pregnancy with or without associated symptoms and with important maternal, fetal and neonatal morbimortality. The etiology of preeclampsia is unknown, but there is involved a disturbed endometrial decidualization and a superficial trophoblastic invasion that produces abnormal placentation and, thus, unchains the typical clinical phenotype. Recent in vitro studies show some disturbance in the expression of the decidualization involved genes, such as annexin A2 (ANXA2). This protein is, in fact, present in most of the eukaryote cells. It is, as well, overexpressed in endometrial and decidual cells during the secretory phase, implicating morphological changes in both endometrial cells and cell adhesion. This fact arises the possibility of the existence of a disturbance during the process of endometrial decidualization, previously to the arrival of the blastocyst, and that this is, actually, the responsible of the superficial trophoblastic invasion as well as the altered interaction between them. Endometrial cells are obtained from biopsies from 13 women with previous normal pregnancies and other 13 women with severe pre-eclampsia, and decidualization is induced in vitro under hormonal stimulation during 5 days with cyclic adenosine monophosphate (cAMP) and medroxyprogesterone, expecting the characteristic morphological and biochemical changes of this process to be observed. However, endometrial stromal cells of the severe pre-eclampsia group with fibrinoid phenotype do not change to polygonal conformation nor secrete the characteristic signalling molecules of decidualization, such us prolactin (PRL) or insulin growth factor binding protein 1 (IGFBP-1). The transcriptional profile from the two groups is compared, both before and after decidualization, and it is proved the presence of up to 129 differentially expressed genes in the endometrial stromal cells compared to the control group, 22 of which are part of biological pathways involved in decidualization. Among these, the presence of the gene that codifies for annexin A2 (ANXA2) is demonstrated, protein involved in the implantation of the blastocyst in the decidua. Its contribution to the process of decidualization is shown through an in vitro model with interfering RNA for the ANXA2, that inhibits its expression in the endometrial stromal cells and prevents them from decidualize. Lastly, and in vivo model with silenced ANXA2 mice is applied, which, after starting gestation, reproduces the clinical phenotype of the severe pre-eclampsia in the genetically modified animals. The study shows a resistance to decidualization of the endometrial stromal cells coming from women with severe pre-eclampsia that does not depend on the presence of a concept, like, in this case, the blastocyst. However, it can determine the correct invasion on the decidua, so the maternal contribution to the etiology of the syndrome is evidenced. The importance of ANXA2 on the correct decidualization is proved, both in vitro and in the in vivo animal model and, therefore, its use as a predictive or early diagnose tool would be of great impact to reduce the incidence and morbimortality of the disease, especially among the population with high risk factors for its development

Metabolomics Approaches and their Hidden Potential for Explaining the Mycotoxin Contamination Problem

Food is essential for life. On the basis of the previous sentence, consumers have a right to expect that the foods they purchase and consume will be safe, authentic and of high quality. On these premises, target compounds, such as mycotoxins, pesticides or antibiotics, have been commonly investigated on the food chain, and subsequently, were regulated by authorities. This raises the following question: may consumer be prevented to these risk exposures? Probably not, food chain is step-by-step longer and more complex than ever before. Note that food chain is affected by globalized trade, culture, travel and migration, an ageing population, changing consumer trends and habits, new technologies, emergencies, climate change and extreme weather events which are increasing foodborne health risks, especially for mycotoxins. Because of the fact that mycotoxins are natural toxic compounds produced by certain filamentous fungi on many agricultural communities. In fact, these toxins have adverse effects on humans, animals and crops that result in illnesses and economic losses. Nevertheless, so far mycotoxins and their modified forms have been mainly monitored in cereal and cereal-based products, however, may an early detection of mycotoxins be considered a reliable strategy? In this chapter, recent metabolomics approaches have been reviewed in order to answer this question and to understand future strategies in the field of mycotoxin contamination

Correlación entre natalidad y mortalidad nacional

This article aims to raise a correlation between birth and death rates in Colombia. According to public data, it seeks to make known the meaning of the numbers, their possible interrelationship, and the various statistics obtained by the different sources of demographic data. The related data in the national census and civil registry platforms will be valuable since these sources provide the necessary material for in-depth research on population changes.Este artículo tiene como objetivo plantear una correlación entre los índices de natalidad y mortalidad en Colombia. De acuerdo a los datos públicos, se busca dar a conocer el significado de las cifras, su posible interrelación, y las diversas estadísticas obtenidas por las diferentes fuentes de datos demográficos. Serán de utilidad los datos relacionados en las plataformas de los censos nacionales y el registro civil, ya que estas fuentes proporcionan el material necesario para la investigación profunda sobre los cambios de población

Prognostic role of minimal residual disease before and after hematopoietic stem cell transplantation in childhood acute lymphoblastic leukemia

More than 80% of children with acute lymphoblastic leukemia (ALL) can be cured through intensive and risk-oriented chemotherapy protocols. Allogeneic hematopoietic stem cell transplantation (HSCT) is considered bene\ufb01cial for approximately 10% of the patients who are at veryhigh risk at frontline therapy and for the majority of patients after relapse. Consequently, it is critically important to identify prognostic factors in this group of patients in order to tailor risk-adapted therapy. In this retrospective study, we aimed to assess the prognostic role of minimal residual disease (MRD) before HSCT and at di\ufb00erent time points after transplantation in children with ALL

FARMACOGENÉTICA E FARMACOGENÔMICA: UM FUTURO EM MEIO A ATUALIDADE

As companhias farmacêuticas têm investido em pesquisas proteômicas, visando determinar a estrutura, expressão, atividade bioquímica, interações e funções de grande parte das proteínas para o desenvolvimento de fármacos com bases genéticas, dando a expectativa de que a medicina personalizada pode ser alcançada usando biomarcadores farmacogenômicos. Sendo assim, o objetivo do presente estudo foi descrever as aplicações atuais da farmacogenética e farmacogenômica através de uma revisão integrativa de literatura. Foram encontrados 3025 artigos através da utilização dos descritores. Destes, 2853 foram excluídos por não atenderem os critérios de inclusão e 161 foram excluídos por não contemplarem o objetivo da pesquisa, totalizando 10 artigos selecionados para compor a amostra. Os estudos selecionados evidenciaram que as diferenças genéticas e farmacogenéticas de cada indivíduo podem afetar o desempenho dos fármacos. Doenças como depressão, diabetes, epilepsia, artroplastia total do joelho ou toxicodependência podem ser beneficiadas pela farmacogenética e farmacogenômica devido aplicação personalizada a fim de melhorar a eficácia, segurança e diminuir efeitos adversos do tratamento medicamentoso

Plasma and dried blood spot lysosphingolipids for the diagnosis of different sphingolipidoses: a comparative study.

Abstract Background Lysosphingolipids, the N-deacylated forms of sphingolipids, have been identified as potential biomarkers of several sphingolipidoses, such as Gaucher, Fabry, Krabbe and Niemann-Pick diseases and in GM1 and GM2 gangliosidoses. To date, different methods have been developed to measure various lysosphingolipids (LysoSLs) in plasma. Here, we present a novel liquid chromatography tandem mass spectrometry (LC-MS/MS) assay for a simultaneous quantification of LysoSLs (HexSph, LysoGb3, LysoGM1, LysoGM2, LysoSM and LysoSM509) in dried blood spot (DBS). This LC-MS/MS method was used to compare the levels of LysoSLs in DBS and plasma in both affected patients and healthy controls. Methods Lysosphingolipids were extracted from a 3.2 mm diameter DBS with a mixture of methanol:acetonitrile:water (80:15:5, v/v) containing internal stable isotope standards. Chromatographic separation was performed using a C18 column with a gradient of water and acetonitrile both with 0.1% formic acid in a total run time of 4 min. The compounds were detected in the positive ion mode electrospray ionization (ESI)-MS/MS by multiple reaction monitoring (MRM). Results The method was validated on DBS to demonstrate specificity, linearity, lowest limit of quantification, accuracy and precision. The reference ranges were determined in pediatric and adult populations. The elevated levels of LysoSLs were identified in Gaucher disease (HexSph), Fabry disease (LysoGb3), prosaposin deficiency (HexSph and LysoGb3) and Niemann-Pick disease types A/B and C (LysoSM and LysoSM509). The correlation in the levels between DBS and plasma was excellent for LysoGb3 and HexSph but poor for LysoSM and LysoSM509. Conclusions Despite the fact that plasma LysoSLs determination remains the gold standard, our LC-MS/MS method allows a rapid and reliable quantification of lysosphingolipids in DBS. The method is a useful tool for the diagnosis of different sphingolipidoses except for Niemann-Pick type C

Diferencias entre los métodos de determinación de 2.a y 3.a generación de la parathormona sérica sobre la mortalidad en el paciente en hemodiálisis

Parathormone plays a key role in controlling mineral metabolism. PTH is considered a uremic toxin causing cardiovascular damage and cardiovascular mortality in dialysis patients. There are two different assays to measure PTH called 2nd generation or intact PTH (iPTH) and 3rd generation or bioPTH (PTHbio). Objective: To evaluate the differences in mortality of dialysis patients between both assays to measure PTH, as well as the possible prognostic role of the PTHbio/iPTH ratio. Methods: 145 haemodialysis patients were included with 2-year monitoring including baseline laboratory test and annually thereafter. Results: 21 patients died in the first year and 28 in the second. No correlation was found between PTH, PTHbio and PTHbio/iPTH ratio with mortality. Both PTH have a perfect correlation between them and correlate similarly with other molecules of the mineral metabolism. The extreme baseline values of PTH are those of higher mortality. In survival by iPTH intervals (according to guidelines and COSMOS study), a J curve is observed. When iPTH increases, the ratio decreases, possibly when increasing fragments no. 1–84. There is no greater prognostic approximation on mortality with PTHbio than PTHi. There was also no difference in mortality when progression ratio PTHbio/PTHi was analysed. Conclusions: We didn’t find any advantages to using bioPTH vs. PTHi as a marker of mortality. BioPTH limits of normality must be reevaluated because its relationship with iPTH is not consistent. Not knowing these limits affects its prognostic valueLa paratohormona tiene un papel fundamental en el control del metabolismo mineral. Además es considerada como una toxina urémica al originar dan˜ o cardiovascular e influir en la mortalidad cardiovascular del paciente en diálisis. Existen dos métodos de medición denominados de 2.a generación o PTH intacta (PTHi) y de 3.a generación o bioPTH (PTHbio). Objetivo: Evaluar las diferencias en la mortalidad del paciente en diálisis entre ambas formas de medición de PTH, así como el posible papel pronóstico de su cociente. Métodos: Se incluyeron 145 pacientes en hemodiálisis con un seguimiento de 2 an˜ os con determinación analítica basal y posteriormente de forma anual. Resultados: Veintiún pacientes fallecieron el primer an˜ o y 28 el segundo. No se encontró correlación entre PTHi, PTHbio y cociente PTHbio/PTHi con la mortalidad. Ambas PTH tienen una buena correlación entre ellas y correlacionan de manera similar con otras moléculas del metabolismo mineral. Los valores basales de PTH extremos son los de mayor mortalidad. En la supervivencia por tramos de PTHi (según guías y estudio COSMOS) se observa una curva en J. A mayor aumento de PTHi el cociente desciende, posiblemente al aumentar los fragmentos no 1-84. No existe una mayor aproximación pronóstica sobre mortalidad con PTHbio que con PTHi. No se observan diferencias en el valor predictivo del cociente sobre la mortalidad. Tampoco hubo diferencias en mortalidad cuando se analiza la progresión del cociente PTHbio/PTHi. Conclusiones: No encontramos ventajas en la utilización de PTHbio sobre la PTHi como marcador de mortalidad. Se deben reevaluar los límites de la PTHbio pues su relación con la PTHi no es constante. El no conocer esos límites condiciona su utilidad pronósticaOur thanks to Maribel Villarino for the help with the development of the study. L.R.-O. is a Health Professional on Research Training “Rio Hortega r” (CM13/00131), Ministry of Education, Government of Spain. R.V.B. is a professional with postdoctoral contract “Sara Borrell” (CD14/00198) and a project (SAF2014- 60699-JIN) of the Ministry of Economy (MINECO) and FEDER funds. PI14/00386. PI16/01298. FEDER funds ISCIII-RETIC REDinREN/ RD06/0016, RD12/002

N-Acetylglutamate Synthase Deficiency Due to a Recurrent Sequence Variant in the N-acetylglutamate Synthase Enhancer Region

N-acetylglutamate synthase deficiency (NAGSD, MIM #237310) is an autosomal recessive disorder of the urea cycle that results from absent or decreased production of N-acetylglutamate (NAG) due to either decreased NAGS gene expression or defective NAGS enzyme. NAG is essential for the activity of carbamylphosphate synthetase 1 (CPS1), the first and rate-limiting enzyme of the urea cycle. NAGSD is the only urea cycle disorder that can be treated with a single drug, N-carbamylglutamate (NCG), which can activate CPS1 and completely restore ureagenesis in patients with NAGSD. We describe a novel sequence variant NM_153006.2:c.-3026C > T in the NAGS enhancer that was found in three patients from two families with NAGSD; two patients had hyperammonemia that resolved upon treatment with NCG, while the third patient increased dietary protein intake after initiation of NCG therapy. Two patients were homozygous for the variant while the third patient had the c.-3026C > T variant and a partial uniparental disomy that encompassed the NAGS gene on chromosome 17. The c.-3026C > T sequence variant affects a base pair that is highly conserved in vertebrates; the variant is predicted to be deleterious by several bioinformatics tools. Functional assays in cultured HepG2 cells demonstrated that the c.-3026C > T substitution could result in reduced expression of the NAGS gene. These findings underscore the importance of analyzing NAGS gene regulatory regions when looking for molecular causes of NAGSD

Sin / Sense

Sexto desafío por la erradicación de la violencia contra las mujeres del Institut Universitari d’Estudis Feministes i de Gènere «Purificación Escribano» de la Universitat Jaume