38 research outputs found
A Functional Pipeline of Genome-Wide Association Data Leads to Midostaurin as a Repurposed Drug for Alzheimerâs Disease
Genome-wide association studies (GWAS) constitute a powerful tool to identify the different biochemical pathways associated with disease. This knowledge can be used to prioritize drugs targeting these routes, paving the road to clinical application. Here, we describe DAGGER (Drug Repositioning by Analysis of GWAS and Gene Expression in R), a straightforward pipeline to find currently approved drugs with repurposing potential. As a proof of concept, we analyzed a meta-GWAS of 1.6 Ă 107 single-nucleotide polymorphisms performed on Alzheimerâs disease (AD). Our pipeline uses the Genotype-Tissue Expression (GTEx) and Drug Gene Interaction (DGI) databases for a rational prioritization of 22 druggable targets. Next, we performed a two-stage in vivo functional assay. We used a C. elegans humanized model over-expressing the AÎČ1-42 peptide. We assayed the five top-scoring candidate drugs, finding midostaurin, a multitarget protein kinase inhibitor, to be a protective drug. Next, 3xTg AD transgenic mice were used for a final evaluation of midostaurinâs effect. Behavioral testing after three weeks of 20 mg/kg intraperitoneal treatment revealed a significant improvement in behavior, including locomotion, anxiety-like behavior, and new-place recognition. Altogether, we consider that our pipeline might be a useful tool for drug repurposing in complex diseases.This work was mainly financed by Programa Operativo FEDER funds from the European Union through grant UMA20-FEDERJA-133. We thank Fundacion SantĂngela for co-funding with grant 83/23.04.2021. P.G.-G. is supported by the CIBERNED employment plan CNV-304-PRF-866. CIBERNED is integrated into Instituto de Salud Carlos III. I.d.R is supported by a national grant from the Instituto de Salud Carlos III FI20/00215. A.R. is supported by national grants PI13/02434, PI16/01861, PI17/01474, PI19/01240, and PI19/01301. A.M.B.-L. and M.J.M. were funded by grant PID2020-120463RB-I00 funded by the Spanish Ministerio de Ciencia e InnovaciĂłn. A.C.-Z. holds a postdoctoral research contract from SecretarĂa General de Universidades, InvestigaciĂłn y TecnologĂaâJunta de AndalucĂa (POSTDOC21_00365). B.P.S (IFI21/00024) holds an âiPFISâ predoctoral contract from the National System of Health, EU-ERDF-ISCIII. M.d.C.M.-P. holds predoctoral grants from the Spanish Ministry of Science, Innovation and Universities (FPU17/00276). P.R. (CP19/00068) holds a âMiguel Servetâ research contract from the National System of Health, ISCIII co-funded by the European Social Fund, âInvesting in your future,â Gobierno de España. This research was funded by DelegaciĂłn del Gobierno para el Plan Nacional sobre Drogas, Ministerio de Salud, Gobierno de España (PND2020/048). Ethovision XT software v17 (Noldus, Wageningen, The Netherlands) funded by Plan Propio, Universidad de MĂĄlaga
Diseñando para la comunidad de costureras de La Mezquitera
El objetivo del PAP Diseñando para la comunidad de costureras de la Mezquitera es crear empresarios de la industria textil y de la moda con responsabilidad social.
Se trabajĂł con un equipo multidisciplinario de alumnos, asĂ como con la comunidad de costureras de la Mezquitera. Una comunidad organizada años atrĂĄs por un PAP del Iteso. Una vez entendido el contexto y entorno actual que rodea a la comunidad se procediĂł a dar soluciĂłn a la problemĂĄtica. Se propusieron 9 marcas de diseño, de prendas de vestir y accesorios para hogar, hechas de materiales textiles. Se hicieron estudios de factibilidad de acuerdo con las tendencias de consumo actuales, se diseñaron prendas con elementos diferenciadores para reducir al mĂĄximo la posibilidad de fracaso y se sacaron producciones pequeñas para evitar la sobreproducciĂłn de prendas y el fast fashion. Para llevar a cabo dichas producciones se pasĂł por la etapa de prototipado, optimizando recursos y minimizando riesgos, y se pasĂł a producciĂłn en volumen. Se procediĂł a hacer la identidad de cada marca, de acuerdo con el nicho de mercado de cada una, redes sociales individuales para publicidad y venta y fotografĂa de producto. TambiĂ©n se hicieron redes comunitarias para mostrar el trabajo del PAP e impulsar las marcas, ademĂĄs de un sitio web comunitario del colectivo. Se logrĂł un equilibrio entre diseño, emprendimiento y generaciĂłn de empleos con trabajo Ă©tico y salario justo, cuidando la optimizaciĂłn de recursos y la reducciĂłn de desperdicios.ITESO, A.C
Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2
The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality
Newly discovered seed dispersal system of Juniperus cedrus questions the pristine nature of the high elevation scrub of El Teide (Tenerife, Canary Islands)
As a working hypothesis, we examined evidence for the former presence of a climacic
woodland of Juniperus cedrus above the pine forest in the high elevation area of Tenerife
(Canary Islands), which would indicate that the current dominant vegetation (endemic
Spartocytisus supranubius scrub) may not be pristine. The main causes of the great regression
of this woodland were caused by human activities (timber harvesting, herbivory
by goats, and fires). The main support for this hypothesis is the survival of a presumably
relict seed dispersal system of the endangered endemic J. cedrus, which relies mainly on
the wintering thrush Turdus torquatus. The fact that genetic factors are directly involved in
the control of bird migration routes strongly supports the idea that this interaction could be
remnant of an older system, probably more widespread in the past. To test this hypothesis,
we propose that a paleoecological approach could reconstruct the vegetation dynamics in
the Teide National Park (Tenerife) and the past presence of this seed disperser migratory
thrush. The analysis of plant microfossils in sediments (e.g., pollen, spores, phytoliths,
coprolites, and charcoal) would allow us to evaluate whether the current vegetation is
the same as that which naturally existed in the past, and assess the impact of the anthropogenic
and natural factors to which it has been subjected during history. The results
of these analyses will be useful for future management policies and practices aimed at
restoring the pristine landscape and biotic interactions of the Teide National Park. To our
knowledge, the case presented in this contribution, based on the high dependence of the
seed dispersal of an endemic tree (J. cedrus) on a migratory bird, is the only reported in
the context of oceanic islands.Ministerio de Ciencia e InnovaciĂłnGobierno de las Islas CanariasOrganismo AutĂłnomo de Parques Nacionale
A vida infantil e sua intimidade pĂșblica: o trabalho social como novidade na atenção Ă infĂąncia na AmĂ©rica Latina, 1928-1948
Autoantibodies against type I IFNs in patients with critical influenza pneumonia
In an international cohort of 279 patients with hypoxemic influenza pneumonia, we identified 13 patients (4.6%) with autoantibodies neutralizing IFN-alpha and/or -omega, which were previously reported to underlie 15% cases of life-threatening COVID-19 pneumonia and one third of severe adverse reactions to live-attenuated yellow fever vaccine. Autoantibodies neutralizing type I interferons (IFNs) can underlie critical COVID-19 pneumonia and yellow fever vaccine disease. We report here on 13 patients harboring autoantibodies neutralizing IFN-alpha 2 alone (five patients) or with IFN-omega (eight patients) from a cohort of 279 patients (4.7%) aged 6-73 yr with critical influenza pneumonia. Nine and four patients had antibodies neutralizing high and low concentrations, respectively, of IFN-alpha 2, and six and two patients had antibodies neutralizing high and low concentrations, respectively, of IFN-omega. The patients' autoantibodies increased influenza A virus replication in both A549 cells and reconstituted human airway epithelia. The prevalence of these antibodies was significantly higher than that in the general population for patients 70 yr of age (3.1 vs. 4.4%, P = 0.68). The risk of critical influenza was highest in patients with antibodies neutralizing high concentrations of both IFN-alpha 2 and IFN-omega (OR = 11.7, P = 1.3 x 10(-5)), especially those <70 yr old (OR = 139.9, P = 3.1 x 10(-10)). We also identified 10 patients in additional influenza patient cohorts. Autoantibodies neutralizing type I IFNs account for similar to 5% of cases of life-threatening influenza pneumonia in patients <70 yr old
Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study
Background: Approximately 450â000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods: For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings: Of 63â093 individuals in the FHSC registry, 11â848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11â476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11â848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10â099 (89·9%) of 11â235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11â848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10â202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10â804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10â428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation: Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life
XVI International Congress of Control Electronics and Telecommunications: "Techno-scientific considerations for a post-pandemic world intensive in knowledge, innovation and sustainable local development"
Este tĂtulo, sugestivo por los impactos durante la situaciĂłn de la Covid 19 en el mundo, y que en Colombia lastimosamente han sido muy crĂticos, permiten asumir la obligada superaciĂłn de tensiones sociales, polĂticas, y econĂłmicas; pero sobre todo cientĂficas y tecnolĂłgicas.
Inicialmente, esto supone la existencia de una capacidad de la sociedad colombiana por recuperar su estado inicial despuĂ©s de que haya cesado la perturbaciĂłn a la que fue sometida por la catastrĂłfica pandemia, y superar ese anterior estado de cosas ya que se encontraban -y aĂșn se encuentran- muchos problemas locales mal resueltos, medianamente resueltos, y muchos sin resolver: es decir, habrĂĄ que rediseñar y fortalecer una probada resiliencia social existente - producto del prolongado conflicto social colombiano superado parcialmente por un proceso de paz exitoso - desde la tecnociencia local; como lo indicaba Markus Brunnermeier - economista alemĂĄn y catedrĂĄtico de economĂa de la Universidad de Princeton- en su libro The Resilient SocietyâŠLa cuestiĂłn no es preveerlo todo sino poder reaccionarâŠaprender a recuperarse rĂĄpido.This title, suggestive of the impacts during the Covid 19 situation in the world, and which have unfortunately been very critical in Colombia, allows us to assume the obligatory overcoming of social, political, and economic tensions; but above all scientific and technological.
Initially, this supposes the existence of a capacity of Colombian society to recover its initial state after the disturbance to which it was subjected by the catastrophic pandemic has ceased, and to overcome that previous state of affairs since it was found -and still is find - many local problems poorly resolved, moderately resolved, and many unresolved: that is, an existing social resilience test will have to be redesigned and strengthened - product of the prolonged Colombian social conflict partially overcome by a successful peace process - from local technoscience; As Markus Brunnermeier - German economist and professor of economics at Princeton University - indicates in his book The Resilient Society...The question is not to foresee everything but to be able to react...learn to recover quickly.Bogot
Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study
Summary
Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally.
Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies
have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of
the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income
countries globally, and identified factors associated with mortality.
Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to
hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis,
exomphalos, anorectal malformation, and Hirschsprungâs disease. Recruitment was of consecutive patients for a
minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical
status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary
intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause,
in-hospital mortality for all conditions combined and each condition individually, stratified by country income status.
We did a complete case analysis.
Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital
diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal
malformation, and 517 with Hirschsprungâs disease) from 264 hospitals (89 in high-income countries, 166 in middleincome
countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male.
Median gestational age at birth was 38 weeks (IQR 36â39) and median bodyweight at presentation was 2·8 kg (2·3â3·3).
Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income
countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups).
Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome
countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries;
pâ€0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients
combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88â4·11],
p<0·0001; middle-income vs high-income countries, 2·11 [1·59â2·79], p<0·0001), sepsis at presentation (1·20
[1·04â1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention
(ASA 4â5 vs ASA 1â2, 1·82 [1·40â2·35], p<0·0001; ASA 3 vs ASA 1â2, 1·58, [1·30â1·92], p<0·0001]), surgical safety
checklist not used (1·39 [1·02â1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed
(ventilation 1·96, [1·41â2·71], p=0·0001; parenteral nutrition 1·35, [1·05â1·74], p=0·018). Administration of
parenteral nutrition (0·61, [0·47â0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65
[0·50â0·86], p=0·0024) or percutaneous central line (0·69 [0·48â1·00], p=0·049) were associated with lower mortality.
Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome,
middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will
be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger
than 5 years by 2030