Human growth hormone (GH1) gene polymorphism map in a normal-statured adult population

OBJECTIVE: GH1 gene presents a complex map of single nucleotide polymorphisms (SNPs) in the entire promoter, coding and noncoding regions. The aim of the study was to establish the complete map of GH1 gene SNPs in our control normal population and to analyse its association with adult height. DESIGN, SUBJECTS AND MEASUREMENTS: A systematic GH1 gene analysis was designed in a control population of 307 adults of both sexes with height normally distributed within normal range for the same population: −2 standard deviation scores (SDS) to +2 SDS. An analysis was performed on individual and combined genotype associations with adult height. RESULTS: Twenty-five SNPs presented a frequency over 1%: 11 in the promoter (P1 to P11), three in the 5′UTR region (P12 to P14), one in exon 1 (P15), three in intron 1 (P16 to P18), two in intron 2 (P19 and P20), two in exon 4 (P21 and P22) and three in intron 4 (P23 to P25). Twenty-nine additional changes with frequencies under 1% were found in 29 subjects. P8, P19, P20 and P25 had not been previously described. P6, P12, P17 and P25 accounted for 6·2% of the variation in adult height (P = 0·0007) in this population with genotypes A/G at P6, G/G at P6 and A/G at P12 decreasing height SDS (−0·063 ± 0·031, −0·693 ± 0·350 and −0·489 ± 0·265, Mean ± SE) and genotypes A/T at P17 and T/G at P25 increasing height SDS (+1·094 ± 0·456 and +1·184 ± 0·432). CONCLUSIONS: This study established the GH1 gene sequence variation map in a normal adult height control population confirming the high density of SNPs in a relatively small gene. Our study shows that the more frequent SNPs did not significantly contribute to height determination, while only one promoter and two intronic SNPs contributed significantly to it. Studies in larger populations will have to confirm the associations and in vitro functional studies will elucidate the mechanisms involved. Systematic GH1 gene analysis in patients with growth delay and suspected GH deficiency/insufficiency will clarify whether different SNP frequencies and/or the presence of different sequence changes may be associated with phenotypes in them

La innovación incremental que permite a la artesanía ecuatoriana ser reconocida

El modelo teórico plantea una relación entre innovación incremental de manufactura del sombrero de paja toquilla con la orientación al mercado, autonomía, recompensa por innovación, transferencia del conocimiento y asociatividad. Estas relaciones se hallan en el rastreo de la literatura en contextos distintos al ecuatoriano y escasamente en las organizaciones artesanales del Ecuador. Se aplica el método científico con enfoque cuantitativo, de corte transversal y no probabilístico con el propósito de determinar los factores que impulsan la innovación incremental en el sector artesanal de manufactura del sombrero de paja toquilla. Se usa el Modelo de Regresión Lineal Múltiple por el Método de Mínimos Cuadrados. Los resultados del modelo empírico explican por arriba de 0.4 la varianza de la innovación incremental y prueban las hipótesis del constructo teórico con las variables independientes autonomía, recompensa por innovación y asociatividad. Un cambio en su calificación promedio explica un cambio en la calificación promedio de la innovación incremental. El estudio satisface a la pregunta central de investigación, objetivo general y objetivos metodológicos de la investigación. Las limitaciones se ubican en el contexto de la pandemia del Covid-19 que afectó la fase del estudio de campo y la naturaleza transversal de la recolección de datos. El estudio aporta a la Teoría de la Autodeterminación, Teoría Z, Teoría de Eficiencia Salarial, Teoría Relacionada y Teoría de Innovación Rural. Se generan nuevas líneas de investigación de producción sostenible y se impacta en la política pública municipal y provincial con cartas compromiso para legislar ordenanzas pro innovación incremental

Influence of the Surface Chemistry of Metal-Organic Polyhedra in Their Assembly into Ultrathin Films for Gas Separation

The formation of ultrathin films of Rh-based porous metal-organic polyhedra (Rh-MOPs) by the Langmuir-Blodgett method has been explored. Homogeneous and dense monolayer films were formed at the air-water interface either using two different coordinatively alkyl-functionalized Rh-MOPs (HRhMOP(diz)12 and HRhMOP(oiz)12) or by in situ incorporation of aliphatic chains to the axial sites of dirhodium paddlewheels of another Rh-MOP (OHRhMOP) at the air-liquid interface. All these Rh-MOP monolayers were successively deposited onto different substrates in order to obtain multilayer films with controllable thicknesses. Aliphatic chains were partially removed from HRhMOP(diz)12 films post-synthetically by a simple acid treatment, resulting in a relevant modification of the film hydrophobicity. Moreover, the CO2/N2 separation performance of Rh-MOP-supported membranes was also evaluated, proving that they can be used as selective layers for efficient CO2 separation. © 2022 The Authors. Published by American Chemical Society

Polyunsaturated Fatty Acid-Enriched Lipid Fingerprint of Glioblastoma Proliferative Regions Is Differentially Regulated According to Glioblastoma Molecular Subtype

Glioblastoma (GBM) represents one of the deadliest tumors owing to a lack of effective treatments. The adverse outcomes are worsened by high rates of treatment discontinuation, caused by the severe side effects of temozolomide (TMZ), the reference treatment. Therefore, understanding TMZ’s effects on GBM and healthy brain tissue could reveal new approaches to address chemotherapy side effects. In this context, we have previously demonstrated the membrane lipidome is highly cell type-specific and very sensitive to pathophysiological states. However, little remains known as to how membrane lipids participate in GBM onset and progression. Hence, we employed an ex vivo model to assess the impact of TMZ treatment on healthy and GBM lipidome, which was established through imaging mass spectrometry techniques. This approach revealed that bioactive lipid metabolic hubs (phosphatidylinositol and phosphatidylethanolamine plasmalogen species) were altered in healthy brain tissue treated with TMZ. To better understand these changes, we interrogated RNA expression and DNA methylation datasets of the Cancer Genome Atlas database. The results enabled GBM subtypes and patient survival to be linked with the expression of enzymes accounting for the observed lipidome, thus proving that exploring the lipid changes could reveal promising therapeutic approaches for GBM, and ways to ameliorate TMZ side effects.This study was supported in part by the Research Unit of the University Hospital Son Espases (“Ajuts a la Investigació de l’Hospital Son Espases 2017—Aplicación del lipidoma en el diagnóstico, pronóstico y tratamiento del glioma”), Basque Government (IT1162-19), the Institute of Health Carlos III (PI16/02200), and the EC (European Regional Development Fund, ERDF, CP12/03338). A.M.B. and J.B-E. hold predoctoral fellowships of the Govern Balear (Direcció General d’Innovació i Recerca, FPI/2160/2018 and FPI/1787/2015, respectively), co-funded by the ESF (European Social Fund). K.P.-R. contract was supported by the Govern Balear (Servei d’Ocupació de les IIles Balears and Garantia Juvenil, JQ-SP 18/17), co-funded by the ESF. G.B.-C.’s was supported by the Institute of Health Carlos III, co-funded by ERDF (Miguel Servet II program, CPII17/00005)

Applying reflective multicriteria decision analysis to understand the value of therapeutic alternatives in the management of gestational and peripartum anaemia in Spain

The objective of the FeminFER project was to assess the value of ferric carboxymaltose following a multicriteria decision analysis in obstetrics and gynaecology in Spain. Methods Ferric carboxymaltose (FCM) and ferrous sulphate were evaluated using the EVIDEM framework. Ten stakeholders participated to collect different perspectives. The framework was adapted considering evidence retrieved with a PICO-S search strategy and grey literature. Criteria/subcriteria were weighted by level of relevance and an evidence-based decision-making exercise was developed in each criterion; weights and scores were combined to obtain the value of intervention relative to each criterion/subcriterion, that were further combined into the Modulated Relative Benefit-Risk Balance (MRBRB). Results The most important criterion favouring FCM was Compared Efficacy/Effectiveness (0.183 +/- 0.07), followed by Patient Preferences (0.059 +/- 0.10). Only Direct medical costs criterion favoured FS (-0.003 +/- 0.03). MRBRB favoured FCM; 0.45 +/- 0.19; in a scale from -1 to + 1. Conclusions In conclusion, considering the several criteria involved in the decision-making process, participants agreed with the use of FCM according to its MRBRB

Influence of the surface chemistry of metal-organic polyhedra in their assembly into ultrathin films for gas separation

The formation of ultrathin films of Rh-based porous metal–organic polyhedra (Rh-MOPs) by the Langmuir–Blodgett method has been explored. Homogeneous and dense monolayer films were formed at the air–water interface either using two different coordinatively alkyl-functionalized Rh-MOPs (HRhMOP(diz)12 and HRhMOP(oiz)12) or by in situ incorporation of aliphatic chains to the axial sites of dirhodium paddlewheels of another Rh-MOP (OHRhMOP) at the air–liquid interface. All these Rh-MOP monolayers were successively deposited onto different substrates in order to obtain multilayer films with controllable thicknesses. Aliphatic chains were partially removed from HRhMOP(diz)12 films post-synthetically by a simple acid treatment, resulting in a relevant modification of the film hydrophobicity. Moreover, the CO2/N2 separation performance of Rh-MOP-supported membranes was also evaluated, proving that they can be used as selective layers for efficient CO2 separation.This work was funded by MCIN/AEI/10.13039/501100011033 and ERDF “A way of making Europe” (grant PID2019-105881RB-I00). The authors also acknowledge the support from the Spanish MINECO (project RTI2018-095622-B-I00) and the Catalan AGAUR (project 2017 SGR 238). It was also funded by the CERCA Programme/Generalitat de Catalunya and through a fellowship (LCF/BQ/PR20/11770011) from “la Caixa” Foundation (ID 100010434). ICN2 is supported by the Severo Ochoa programme from the Spanish MINECO (grant no. SEV-2017-0706). I.T. and M.P.-M. gratefully acknowledge their DGA PhD fellowship from Government of Aragon. The microscopy work was carried out in the Laboratorio de Microscopias Avanzadas at the Instituto de Nanociencia y Materiales de Aragon (LMA-INMA). This work benefited from the use of the SasView application, originally developed under NSF award DMR-0520547. SasView contains code developed with funding from the European Union’s Horizon 2020 research and innovation programme under the SINE2020 project, grant agreement no. 654000. The authors thank the synchrotron SOLEIL for beamtime provision under projects 20190435 and 20191874.Peer reviewe

Supporting information for the manuscript Influence of the Surface Chemistry of Metal–Organic Polyhedra in Their Assembly into Ultrathin Films for Gas Separation

19 pages. -- Figure S1. Absorption spectra (450-650 nm range) of OHRhMOP dissolved in methanol/chloroform (1:5) and the product formed after the addition of ca. 3.8×10- 3 mmol of diz to a dispersion of ca. 1.5×10-4 mmol OHRhMOP in 2 mL of THF. The maximum absorption at ca. 552 nm after diz addition indicates that all the dirhodium paddlewheels of OHRhMOP are coordinated to one diz, obtaining OHRhMOP(diz)12. -- Figure S2. Raw GIXD data for C12RhMOP (left), HRhMOP(diz)12 (middle) and OHRhMOP (right), at the indicated pressures. The water subphase data are shown as grey lines. Insets highlight the q range exhibiting the Bragg peak of alkyl chains ordering, in the case of C12RhMOP and HRhMOP(diz)12. -- Figure S3. Top: high q portion of GIXD data for C12RhMOP (left, collapsed) and HRhMOP(diz)12 (right, 10 mN/m), integrated over only the bottom half, top half, bottom first quarter or the whole detector, as indicated. The Bragg peak at ca. 1.51 Å-1 characteristic of alkyl chain interdigitation/order is not present in the data at higher qz. Bottom: intensity of the alkyl chains Bragg rod vs. qz, C12RhMOP. -- Figure S4. GIXD data for OHRhMOP at the gas-water interface at 10 mN/m, after correction for the water subphase. The red line is the diffusion form factor of coreshell spheres with an empty (SLD = 0) core of 5 Å radius and a dense shell of 11.5 Å thickness (SLD = 2x10-6 Å-2), considering a pinhole instrumental smearing dQ/Q of 5 %, that can only account for the two stronger peaks at 0.63 and 0.87 Å–1. (left), HRhMOP(diz)12 (right) at 10 mN/m. -- Scheme S1. LS sequential deposition of MOP monolayers onto PTMSP supports. One MOP monolayer is deposited each time that the support contacts the film formed at the air-liquid interface. After each transfer, the film is dried with N2 at ambient temperature and the transference is repeated as many times as necessary to obtain films with the desired number of Rh-MOP monolayers. -- Figure S5. UV-Vis spectra for the three Rh-MOPs studied. Solution spectra and LS films deposited onto quartz substrates are compared for each Rh-MOP. -- Figure S6. Representative AFM topography images from HRhMOP(oiz)12 and HRhMOP(diz)12 LS films transferred onto quartz substrates at 20 mN/m used to evaluate the film thickness. -- Figure S7. Representative AFM topography image of quartz, left, and a Si(100), right, substrates before MOP film deposition. -- Figure S8. Representative AFM topography and phase images from a OHRhMOP LS film transferred at 2 mN/m and evaluation of film thickness and defects dimensions. -- Figure S9. Linear increase of the absorbance at 214 nm vs. the number of Rh- MOP LS layers transferred at 20 mN/m onto quartz substrates (● HRhMOP(oiz)12;■: HRhMOP(diz)12). -- Figure S10. Rh-MOP mass deposited onto QCM disks at 20 mN/m versus the number of LS layers transferred (■: C12RhMOP;▲: HRhMOP(oiz)12, ●: HRhMOP(diz)12). -- Figure S11. Brewster Angle Microscope (BAM) images obtained during OHRhMOP + diz film compression at indicated surface pressures and the corresponding areas per molecule. OHRhMOP + diz different ratios were used in the experiments (1:25 in top images, and 1:50 in bottom images, respectively). -- Figure S12. Characterization of the films obtained from OHRhMOP + diz (1:25) reaction at the air-liquid interface: a) UV-Vis spectra from sequential deposition of LS films transferred onto quartz at 20 mN/m. Inset: Linear increase of the absorbance at 221nm vs. the number of LS layers transferred. b) Mass deposited onto QCM disks vs. the number of LS layers transferred (red line: OHRhMOP +diz; blue line: HRhMOP(diz)12, green line: C12RhMOP). -- Figure S13: UV-Vis spectra from HRhMOP(diz)12 LS films deposited onto quartz at 20 mN/m before and after the acid treatment: 1 layer (continuous line) and 3 layers (dashed line). -- Figure S14. Representative AFM topography and phase images from a HRhMOP(diz)12 LS film (1 layer) deposited onto Si (100) before and after acid treatment with HCl vapors. -- Table S1: Parameters of the components used to simulate the Rh 3d high resolution XPS spectra (see Figure 9) of OHRhMOP (powder), 1 LS film deposited at 20 mN/m after OHRhMOP + diz (1:25) reaction at the air-liquid interface and drop-cast film obtained after OHRhMOP + diz (1:25) reaction in THF. -- Table S2: Comparison of the performance of MOP and PIM ultrathin films (30 LS monolayers deposited onto PTMSP membranes) in CO2/N2 (10/90 in volume) separation at 35 ºC. At least 2 different samples were fabricated and measured to provide the corresponding error estimations.The formation of ultrathin films of Rh-based porous metal–organic polyhedra (Rh-MOPs) by the Langmuir–Blodgett method has been explored. Homogeneous and dense monolayer films were formed at the air–water interface either using two different coordinatively alkyl-functionalized Rh-MOPs (HRhMOP­(diz)12 and HRhMOP­(oiz)12) or by in situ incorporation of aliphatic chains to the axial sites of dirhodium paddlewheels of another Rh-MOP (OHRhMOP) at the air–liquid interface. All these Rh-MOP monolayers were successively deposited onto different substrates in order to obtain multilayer films with controllable thicknesses. Aliphatic chains were partially removed from HRhMOP­(diz)12 films post-synthetically by a simple acid treatment, resulting in a relevant modification of the film hydrophobicity. Moreover, the CO2/N2 separation performance of Rh-MOP-supported membranes was also evaluated, proving that they can be used as selective layers for efficient CO2 separation.Peer reviewe

Excitotoxic inactivation of constitutive oxidative stress detoxification pathway in neurons can be rescued by PKD1

Excitotoxicity, a critical process in neurodegeneration, induces oxidative stress and neuronal death through mechanisms largely unknown. Since oxidative stress activates protein kinase D1 (PKD1) in tumor cells, we investigated the effect of excitotoxicity on neuronal PKD1 activity. Unexpectedly, we find that excitotoxicity provokes an early inactivation of PKD1 through a dephosphorylation-dependent mechanism mediated by protein phosphatase-1 (PP1) and dual specificity phosphatase-1 (DUSP1). This step turns off the IKK/NF-kappa B/SOD2 antioxidant pathway. Neuronal PKD1 inactivation by pharmacological inhibition or lentiviral silencing in vitro, or by genetic inactivation in neurons in vivo, strongly enhances excitotoxic neuronal death. In contrast, expression of an active dephosphorylation-resistant PKD1 mutant potentiates the IKK/NF-kappa B/SOD2 oxidative stress detoxification pathway and confers neuroprotection from in vitro and in vivo excitotoxicity. Our results indicate that PKD1 inactivation underlies excitotoxicity-induced neuronal death and suggest that PKD1 inactivation may be critical for the accumulation of oxidation-induced neuronal damage during aging and in neurodegenerative disorders

Genomic Characterization of Host Factors Related to SARS-CoV-2 Infection in People with Dementia and Control Populations: The GR@ACE/DEGESCO Study

Emerging studies have suggested several chromosomal regions as potential host genetic factors involved in the susceptibility to SARS-CoV-2 infection and disease outcome. We nested a COVID-19 genome-wide association study using the GR@ACE/DEGESCO study, searching for susceptibility factors associated with COVID-19 disease. To this end, we compared 221 COVID-19 confirmed cases with 17,035 individuals in whom the COVID-19 disease status was unknown. Then, we performed a meta-analysis with the publicly available data from the COVID-19 Host Genetics Initiative. Because the APOE locus has been suggested as a potential modifier of COVID-19 disease, we added sensitivity analyses stratifying by dementia status or by disease severity. We confirmed the existence of the 3p21.31 region (LZTFL1, SLC6A20) implicated in the susceptibility to SARS-CoV-2 infection and TYK2 gene might be involved in COVID-19 severity. Nevertheless, no statistically significant association was observed in the COVID-19 fatal outcome or in the stratified analyses (dementia-only and non-dementia strata) for the APOE locus not supporting its involvement in SARS-CoV-2 pathobiology or COVID-19 prognosis

Towards precision medicine: defining and characterizing adipose tissue dysfunction to identify early immunometabolic risk in symptom-free adults from the GEMM family study

Interactions between macrophages and adipocytes are early molecular factors influencing adipose tissue (AT) dysfunction, resulting in high leptin, low adiponectin circulating levels and low-grade metaflammation, leading to insulin resistance (IR) with increased cardiovascular risk. We report the characterization of AT dysfunction through measurements of the adiponectin/leptin ratio (ALR), the adipo-insulin resistance index (Adipo-IRi), fasting/postprandial (F/P) immunometabolic phenotyping and direct F/P differential gene expression in AT biopsies obtained from symptom-free adults from the GEMM family study. AT dysfunction was evaluated through associations of the ALR with F/P insulin-glucose axis, lipid-lipoprotein metabolism, and inflammatory markers. A relevant pattern of negative associations between decreased ALR and markers of systemic low-grade metaflammation, HOMA, and postprandial cardiovascular risk hyperinsulinemic, triglyceride and GLP-1 curves was found. We also analysed their plasma non-coding microRNAs and shotgun lipidomics profiles finding trends that may reflect a pattern of adipose tissue dysfunction in the fed and fasted state. Direct gene differential expression data showed initial patterns of AT molecular signatures of key immunometabolic genes involved in AT expansion, angiogenic remodelling and immune cell migration. These data reinforce the central, early role of AT dysfunction at the molecular and systemic level in the pathogenesis of IR and immunometabolic disorders