Prototipo de entrenador basado en realidad virtual inmersiva para la conducción de carretillas automotoras industriales

Trabajo de fin de Grado. Grado en Ingeniería Informática en Sistemas de Información. Curso académico 2019[ES] Through this Final Degree Project I intend to make an approach to a modern and unexplored technology, virtual reality, focused on a scientific field, such as the simulation of driving and operation of a work vehicle. The success of the project depends on the credibility of the simulator, and that what happens in the virtual world realistically reflects the behavior of the real truck and of the interactions carried out by the user. For this reason, I will begin the work by showing a brief history of how Forklifts appeared and how their evolution has been over time, showing as a final result the different types, components, physics, operation and areas of operation in which it has led to today. This information will allow me to recreate the entire virtual environment in a more close to reality, so that the joint interaction achieves total immersion of the user in the application, providing realistic driving experiences. Finally, I conclude with the sample of the software application, the steps made for its design and construction, the different training modes, the minimum requirements and a user manual.[EN] Through this Final Degree Project I intend to make an approach to a modern and unexplored technology, virtual reality, focused on a scientific field, such as the simulation of driving and operation of a work vehicle. The success of the project depends on the credibility of the simulator, and that what happens in the virtual world realistically reflects the behavior of the real truck and of the interactions carried out by the user. For this reason, I will begin the work by showing a brief history of how Forklifts appeared and how their evolution has been over time, showing as a final result the different types, components, physics, operation and areas of operation in which it has led to today. This information will allow me to recreate the entire virtual environment in a more close to reality, so that the joint interaction achieves total immersion of the user in the application, providing realistic driving experiences. Finally, I conclude with the sample of the software application, the steps made for its design and construction, the different training modes, the minimum requirements and a user manual

Differential Impact of Ad Libitum or Intermittent High-Fat Diets on Bingeing Ethanol-Mediated Behaviors

BACKGROUND: Dietary factors have significant effects on the brain, modulating mood, anxiety, motivation and cognition. To date, no attention has been paid to the consequences that the combination of ethanol (EtOH) and a high-fat diet (HFD) have on learning and mood disorders during adolescence. The aim of the present work was to evaluate the biochemical and behavioral consequences of ethanol binge drinking and an HFD consumption in adolescent mice. METHODS: Animals received either a standard diet or an HFD (ad libitum vs. binge pattern) in combination with ethanol binge drinking and were evaluated in anxiety and memory. The metabolic profile and gene expression of leptin receptors and clock genes were also evaluated. RESULTS: Excessive white adipose tissue and an increase in plasma insulin and leptin levels were mainly observed in ad libitum HFD + EtOH mice. An upregulation of the Lepr gene expression in the prefrontal cortex and the hippocampus was also observed in ad libitum HFD groups. EtOH-induced impairment on spatial memory retrieval was absent in mice exposed to an HFD, although the aversive memory deficits persisted. Mice bingeing on an HFD only showed an anxiolytic profile, without other alterations. We also observed a mismatch between Clock and Bmal1 expression in ad libitum HFD animals, which were mostly independent of EtOH bingeing. CONCLUSIONS: Our results confirm the bidirectional influence that occurs between the composition and intake pattern of a HFD and ethanol consumption during adolescence, even when the metabolic, behavioral and chronobiological effects of this interaction are dissociated

Critical requirement of SOS1 for tumor development and microenvironment modulation in KRASG12D-driven lung adenocarcinoma

The impact of genetic ablation of SOS1 or SOS2 is evaluated in a murine model of KRASG12D-driven lung adenocarcinoma (LUAD). SOS2 ablation shows some protection during early stages but only SOS1 ablation causes significant, specific long term increase of survival/lifespan of the KRASG12D mice associated to markedly reduced tumor burden and reduced populations of cancer-associated fibroblasts, macrophages and T-lymphocytes in the lung tumor microenvironment (TME). SOS1 ablation also causes specific shrinkage and regression of LUAD tumoral masses and components of the TME in pre-established KRASG12D LUAD tumors. The critical requirement of SOS1 for KRASG12D-driven LUAD is further confirmed by means of intravenous tail injection of KRASG12D tumor cells into SOS1KO/KRASWT mice, or of SOS1-less, KRASG12D tumor cells into wildtype mice. In silico analyses of human lung cancer databases support also the dominant role of SOS1 regarding tumor development and survival in LUAD patients. Our data indicate that SOS1 is critically required for development of KRASG12D-driven LUAD and confirm the validity of this RAS-GEF activator as an actionable therapeutic target in KRAS mutant LUAD.Work supported by grants ISCIII-MCUI (FIS PI19/00934), JCyL (SA264P18-UIC 076), Areces Foundation (CIVP19A5942), and ISCIII-CIBERONC (group CB16/12/00352) to E.S.; Solorzano-Barruso Foundation (FS/32-2020) and Eugenio Rodriguez Pascual Foundation to F.C.B.; MCI (RTI2018-099161-A-I00) to E.C. This research was co-financed by FEDER funds. These CIC groups are supported by the Programa de Apoyo a Planes Estratégicos de Investigación de Estructuras de Investigación de Excelencia of Castilla y León autonomous government (CLC-2017-01) and AECC Excellence program Stop Ras Cancers (EPAEC222641CICS)

Functional specificity of the members of the Sos family of Ras-GEF Activators: Novel role of Sos2 in control of epidermal stem cell homeostasis

© 2021 by the authors.Prior reports showed the critical requirement of Sos1 for epithelial carcinogenesis, but the specific functionalities of the homologous Sos1 and Sos2 GEFs in skin homeostasis and tumorigenesis remain unclear. Here, we characterize specific mechanistic roles played by Sos1 or Sos2 in primary mouse keratinocytes (a prevalent skin cell lineage) under different experimental conditions. Functional analyses of actively growing primary keratinocytes of relevant genotypes—WT, Sos1-KO, Sos2-KO, and Sos1/2-DKO—revealed a prevalent role of Sos1 regarding transcriptional regulation and control of RAS activation and mechanistic overlapping of Sos1 and Sos2 regarding cell proliferation and survival, with dominant contribution of Sos1 to the RAS-ERK axis and Sos2 to the RAS-PI3K/AKT axis. Sos1/2-DKO keratinocytes could not grow under 3D culture conditions, but single Sos1-KO and Sos2-KO keratinocytes were able to form pseudoepidermis structures that showed disorganized layer structure, reduced proliferation, and increased apoptosis in comparison with WT 3D cultures. Remarkably, analysis of the skin of both newborn and adult Sos2-KO mice uncovered a significant reduction of the population of stem cells located in hair follicles. These data confirm that Sos1 and Sos2 play specific, cell-autonomous functions in primary keratinocytes and reveal a novel, essential role of Sos2 in control of epidermal stem cell homeostasis.The E.S. group was supported by grants from ISCIII-MCUI (FIS PI19/00934), JCyL (SA264P18-UIC 076), Areces Foundation (CIVP19A5942), Solorzano-Barruso Foundation (FS/32-2020), and by ISCIII-CIBERONC (group CB16/12/00352). Research was co-financed by FEDER funds. The J.M.P. lab is co-funded by European Regional Development Fund (FEDER) grants from Science and Innovation (SAF2015-66015-R and PID2019-110758RB-I00 to J.M.P.) and Instituto de Salud Carlos III (CIBERONC no. CB16/12/00228 to J.M.P.). The XRB lab is funded by “la Caixa” Banking Foundation (HR20-00164), the Castilla-León autonomous government (CSI252P18, CSI145P20, CLC-2017-01), the Spanish Ministry of Science and Innovation (MSI) (RTI2018-096481-B-100), and the Spanish Association against Cancer (GC16173472GARC). The CIC is supported by the Programa de Apoyo a Planes Estratégicos de Investigación de Estructuras de Investigación de Excelencia of the Castilla-León autonomous government (CLC-2017-01). L.F.L.-M. and N.F.-P. contracts have been supported by funding from the Spanish Ministry of Universities (FPU13/02923, FPU17/03912) and, in the case of L.F.L.M., by CLC-2017-01 grant

Differential role of the RasGEFs Sos1 and Sos2 in mouse skin homeostasis and carcinogenesis

Using Sos1 knockout (Sos1-KO), Sos2-KO, and Sos1/2 double-knockout (Sos1/2-DKO) mice, we assessed the functional role of Sos1 and Sos2 in skin homeostasis under physiological and/or pathological conditions. Sos1 depletion resulted in significant alterations of skin homeostasis, including reduced keratinocyte proliferation, altered hair follicle and blood vessel integrity in dermis, and reduced adipose tissue in hypodermis. These defects worsened significantly when both Sos1 and Sos2 were absent. Simultaneous Sos1/2 disruption led to severe impairment of the ability to repair skin wounds, as well as to almost complete ablation of the neutrophil-mediated inflammatory response in the injury site. Furthermore, Sos1 disruption delayed the onset of tumor initiation, decreased tumor growth, and prevented malignant progression of papillomas in a DMBA (7,12-dimethylbenz[α]anthracene)/TPA (12-O-tetradecanoylphorbol-13-acetate)-induced skin carcinogenesis model. Finally, Sos1 depletion in preexisting chemically induced papillomas resulted also in decreased tumor growth, probably linked to significantly reduced underlying keratinocyte proliferation. Our data unveil novel, distinctive mechanistic roles of Sos 1 and Sos2 in physiological control of skin homeostasis and wound repair, as well as in pathological development of chemically induced skin tumors. These observations underscore the essential role of Sos proteins in cellular proliferation and migration and support the consideration of these RasGEFs as potential biomarkers/therapy targets in Ras-driven epidermal tumors.This study was supported by grants FIS PI16/02137 from ISCIII (MINECO), SA043U16 (UIC 076) from JCyL, and AECC Spain (to E.S.); by MINECO grant SAF2015-66015-R; and by MSyC grants ISCIII-RETIC RD12/0036/0009, PIE 15/00076, and CB/16/00228 (to J.M.P.). This research was cofinanced by FEDER fund

PPAR-γ Gene Expression in Human Adipose Tissue Is Associated with Weight Loss After Sleeve Gastrectomy

[EN] Background The peroxisome proliferator-activated receptor (PPAR)-γ plays a key role in adipose tissue differentiation and fat metabolism. However, it is unclear which factors may regulate its expression and whether obese patients have changes in adipose tissue expression of PPAR-γor potential regulators such as miR-27. Thus, our aims were to analyze PPAR-γ and miR-27 expression in adipose tissue of obese patients, and to correlate their levels with clinical variables. Subjects and Methods. We included 43 morbidly obese subjects who underwent sleeve gastrectomy (31 of them completed 1-year follow-up) and 19 non-obese subjects. mRNA expression of PPAR-γ1 and PPAR-γ2, miR-27a, and miR-27b was measured by qPCR in visceral and subcutaneous adipose tissue. Clinical variables and serum adipokine and hormone levels were correlated with PPAR-γ and miR-27 expression. In addition, a systematic review of the literature regarding PPAR-γ expression in adipose tissue of obese patients was performed. Results We found no differences in the expression of PPAR-γ and miR-27 in adipose tissue of obese patients vs. controls. The literature review revealed discrepant results regarding PPAR-γ expression in adipose tissue of obese patients. Of note, we described a significant negative correlation between pre-operative PPAR-γ1 expression in adipose tissue of obese patients and post-operative weight loss, potentially linked with insulin resistance markers. Conclusion PPAR-γ1 expression in adipose tissue is associated with weight loss after sleeve gastrectomy and may be used as a biomarker for response to surgery.Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This work was funded by the following grants to M.M.: ISCIII and FEDER, PI10/01692, PI16/01548, RD16/0017/0023, and I3SNS-INT12/049, L.H.C.: Junta de Castilla y León GRS 681/A/11, J.-L. T.: GRS 1587/A/17 and GRS1356/A/16, G.S.: ERC 260464, EFSD 2030, MICINNSAF2013-43506-R, and Comunidad de Madrid S2010/BMD-2326. G.S. is an investigator of the Ramón y Cajal Program.Publicación en abierto financiada por el Consorcio de Bibliotecas Universitarias de Castilla y León (BUCLE), con cargo al Programa Operativo 2014ES16RFOP009 FEDER 2014-2020 DE CASTILLA Y LEÓN, Actuación:20007-CL - Apoyo Consorcio BUCL

PPAR-γ Gene Expression in Human Adipose Tissue Is Associated with Weight Loss After Sleeve Gastrectomy

Background: The peroxisome proliferator-activated receptor (PPAR)-γ plays a key role in adipose tissue differentiation and fat metabolism. However, it is unclear which factors may regulate its expression and whether obese patients have changes in adipose tissue expression of PPAR-γor potential regulators such as miR-27. Thus, our aims were to analyze PPAR-γ and miR-27 expression in adipose tissue of obese patients, and to correlate their levels with clinical variables. Subjects and methods: We included 43 morbidly obese subjects who underwent sleeve gastrectomy (31 of them completed 1-year follow-up) and 19 non-obese subjects. mRNA expression of PPAR-γ1 and PPAR-γ2, miR-27a, and miR-27b was measured by qPCR in visceral and subcutaneous adipose tissue. Clinical variables and serum adipokine and hormone levels were correlated with PPAR-γ and miR-27 expression. In addition, a systematic review of the literature regarding PPAR-γ expression in adipose tissue of obese patients was performed. Results: We found no differences in the expression of PPAR-γ and miR-27 in adipose tissue of obese patients vs. controls. The literature review revealed discrepant results regarding PPAR-γ expression in adipose tissue of obese patients. Of note, we described a significant negative correlation between pre-operative PPAR-γ1 expression in adipose tissue of obese patients and post-operative weight loss, potentially linked with insulin resistance markers. Conclusion: PPAR-γ1 expression in adipose tissue is associated with weight loss after sleeve gastrectomy and may be used as a biomarker for response to surgeryThis work was funded by the following grants to M.M.: ISCIII and FEDER, PI10/01692, PI16/01548, RD16/0017/0023, and I3SNS-INT12/049, L.H.C.: Junta de Castilla y León GRS 681/A/11, J.-L. T.: GRS 1587/A/17 and GRS1356/A/16, G.S.: ERC 260464, EFSD 2030, MICINNSAF2013-43506-R, and Comunidad de Madrid S2010/BMD-2326. G.S. is an investigator of the Ramón y Cajal Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. ISCIII,PI10/01692,Miguel Marcos,PI16/01548,Miguel Marcos,Gerencia regional de salud,junta de castilla y león,GRS 681/A/11,Lourdes Hernández-Cosido,J.-L. T,Lourdes Hernández-Cosido,Gerencia Regional de Salud,Junta de Castilla y León,GRS 1587/A/17,Jorge-Luis Torres,GRS1356/A/16,Jorge-Luis Torre

Uncovering genetic causes of hypophosphatemia

Background Chronic hypophosphatemia can result from a variety of acquired disorders, such as malnutrition, intestinal malabsorption, hyperparathyroidism, vitamin D deficiency, excess alcohol intake, some drugs, or organ transplantation. Genetic disorders can be a cause of persistent hypophosphatemia, although they are less recognized. We aimed to better understand the prevalence of genetic hypophosphatemia in the population. Methods By combining retrospective and prospective strategies, we searched the laboratory database of 815,828 phosphorus analyses and included patients 17?55 years old with low serum phosphorus. We reviewed the charts of 1287 outpatients with at least 1 phosphorus result ?2.2 mg/dL. After ruling out clear secondary causes, 109 patients underwent further clinical and analytical studies. Among them, we confirmed hypophosphatemia in 39 patients. After excluding other evident secondary causes, such as primary hyperparathyroidism and vitamin D deficiency, we performed a molecular analysis in 42 patients by sequencing the exonic and flanking intronic regions of a panel of genes related to rickets or hypophosphatemia (CLCN5, CYP27B1, dentin matrix acidic phosphoprotein 1, ENPP1, FAM20C, FGFR1, FGF23, GNAS, PHEX, SLC34A3, and VDR). Results We identified 14 index patients with hypophosphatemia and variants in genes related to phosphate metabolism. The phenotype of most patients was mild, but two patients with X-linked hypophosphatemia (XLH) due to novel PHEX mutations had marked skeletal abnormalities. Conclusion Genetic causes should be considered in children, but also in adult patients with hypophosphatemia of unknown origin. Our data are consistent with the conception that XLH is the most common cause of genetic hypophosphatemia with an overt musculoskeletal phenotype

Cytotoxic cell populations developed during treatment with tyrosine kinase inhibitors protect autologous CD4+ T cells from HIV-1 infection

Factor de impacto: 5,858 Q1Tyrosine kinase inhibitors (TKIs) are successfully used in clinic to treat chronic myeloid leukemia (CML). Our group previously described that CD4+ T cells from patients with CML on treatment with TKIs such as dasatinib were resistant to HIV-1 infection ex vivo. The main mechanism for this antiviral activity was primarily based on the inhibition of SAMHD1 phosphorylation, which preserves the activity against HIV-1 of this innate immune factor. Approximately 50% CML patients who achieved a deep molecular response (DMR) may safely withdraw TKI treatment without molecular recurrence. Therefore, it has been speculated that TKIs may induce a potent antileukemic response that is maintained in most patients even one year after treatment interruption (TI). Subsequent to in vitro T-cell activation, we observed that SAMHD1 was phosphorylated in CD4+ T cells from CML patients who withdrew TKI treatment more than one year earlier, which indicated that these cells were now susceptible to HIV-1 infection. Importantly, these patients were seronegative for HIV-1 and seropositive for cytomegalovirus (CMV), but without CMV viremia. Although activated CD4+ T cells from CML patients on TI were apparently permissive to HIV-1 infection ex vivo, the frequency of proviral integration was reduced more than 12-fold on average when these cells were infected ex vivo in comparison with cells isolated from untreated, healthy donors. This reduced susceptibility to infection could be related to an enhanced NK-dependent cytotoxic activity, which was increased 8-fold on average when CD4+ T cells were infected ex vivo with HIV-1 in the presence of autologous NK cells. Enhanced cytotoxic activity was also observed in CD8 + T cells from these patients, which showed 8-fold increased expression of TCRγδ and more than 18-fold increased production of IFNγ upon activation with CMV peptides. In conclusion, treatment with TKIs induced a potent antileukemic response that may also have antiviral effects against HIV-1 and CMV, suggesting that transient use of TKIs in HIV-infected patients could develop a sustained antiviral response that would potentially interfere with HIV-1 reservoir dynamics.This work was supported by NIH grant R01AI143567; the Spanish Ministry of Economy and Competitiveness (SAF2016-78480-R); the Spanish AIDS Research Network RD16CIII/0002/0001 that is included in Acción Estratégica en Salud, Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica 2016-2020, Instituto de Salud Carlos III, European Region Development Fund (ERDF). The work of María Rosa López-Huertas and Sara Rodríguez-Mora is financed by NIH grant R01AI143567. The work of Lorena Vigón is supported by a pre-doctoral grant from Instituto de Salud Carlos III (FIS PI16CIII/00034-ISCIII-FEDER). The work of Elena Mateos is supported by the Spanish Ministry of Economy and Competitiveness SAF2016-78480-R.S