23 research outputs found
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
RICORS2040 : The need for collaborative research in chronic kidney disease
Chronic kidney disease (CKD) is a silent and poorly known killer. The current concept of CKD is relatively young and uptake by the public, physicians and health authorities is not widespread. Physicians still confuse CKD with chronic kidney insufficiency or failure. For the wider public and health authorities, CKD evokes kidney replacement therapy (KRT). In Spain, the prevalence of KRT is 0.13%. Thus health authorities may consider CKD a non-issue: very few persons eventually need KRT and, for those in whom kidneys fail, the problem is 'solved' by dialysis or kidney transplantation. However, KRT is the tip of the iceberg in the burden of CKD. The main burden of CKD is accelerated ageing and premature death. The cut-off points for kidney function and kidney damage indexes that define CKD also mark an increased risk for all-cause premature death. CKD is the most prevalent risk factor for lethal coronavirus disease 2019 (COVID-19) and the factor that most increases the risk of death in COVID-19, after old age. Men and women undergoing KRT still have an annual mortality that is 10- to 100-fold higher than similar-age peers, and life expectancy is shortened by ~40 years for young persons on dialysis and by 15 years for young persons with a functioning kidney graft. CKD is expected to become the fifth greatest global cause of death by 2040 and the second greatest cause of death in Spain before the end of the century, a time when one in four Spaniards will have CKD. However, by 2022, CKD will become the only top-15 global predicted cause of death that is not supported by a dedicated well-funded Centres for Biomedical Research (CIBER) network structure in Spain. Realizing the underestimation of the CKD burden of disease by health authorities, the Decade of the Kidney initiative for 2020-2030 was launched by the American Association of Kidney Patients and the European Kidney Health Alliance. Leading Spanish kidney researchers grouped in the kidney collaborative research network Red de Investigación Renal have now applied for the Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS) call for collaborative research in Spain with the support of the Spanish Society of Nephrology, Federación Nacional de Asociaciones para la Lucha Contra las Enfermedades del Riñón and ONT: RICORS2040 aims to prevent the dire predictions for the global 2040 burden of CKD from becoming true
Mitochondrial genetic diversity, selection and recombination in a canine transmissible cancer.
Canine transmissible venereal tumour (CTVT) is a clonally transmissible cancer that originated approximately 11,000 years ago and affects dogs worldwide. Despite the clonal origin of the CTVT nuclear genome, CTVT mitochondrial genomes (mtDNAs) have been acquired by periodic capture from transient hosts. We sequenced 449 complete mtDNAs from a global population of CTVTs, and show that mtDNA horizontal transfer has occurred at least five times, delineating five tumour clades whose distributions track two millennia of dog global migration. Negative selection has operated to prevent accumulation of deleterious mutations in captured mtDNA, and recombination has caused occasional mtDNA re-assortment. These findings implicate functional mtDNA as a driver of CTVT global metastatic spread, further highlighting the important role of mtDNA in cancer evolution.Wellcome Trust Investigator Award, 102942/Z/13/A
Elizabeth P Murchison
Leverhulme Trust Philip Leverhulme Prize Elizabeth P Murchison
Royal Society Research Grant, RG130615 Elizabeth P Murchiso
Somatic evolution and global expansion of an ancient transmissible cancer lineage
Made available in DSpace on 2019-10-06T15:53:36Z (GMT). No. of bitstreams: 0
Previous issue date: 2019-08-02GPD Charitable TrustLeverhulme TrustThe canine transmissible venereal tumor (CTVT) is a cancer lineage that arose several millennia ago and survives by âmetastasizingâ between hosts through cell transfer. The somatic mutations in this cancer record its phylogeography and evolutionary history. We constructed a time-resolved phylogeny from 546 CTVT exomes and describe the lineage's worldwide expansion. Examining variation in mutational exposure, we identify a highly context-specific mutational process that operated early in the cancer's evolution but subsequently vanished, correlate ultraviolet-light mutagenesis with tumor latitude, and describe tumors with heritable hyperactivity of an endogenous mutational process. CTVT displays little evidence of ongoing positive selection, and negative selection is detectable only in essential genes. We illustrate how long-lived clonal organisms capture changing mutagenic environments, and reveal that neutral genetic drift is the dominant feature of long-term cancer evolution.Transmissible Cancer Group Department of Veterinary Medicine University of CambridgeAnimal Management in Rural and Remote Indigenous Communities (AMRRIC)World VetsAnimal Shelter Stichting Dierenbescherming SurinameSikkim Anti-Rabies and Animal Health Programme Department of Animal Husbandry Livestock Fisheries and Veterinary Services Government of SikkimRoyal (Dick) School of Veterinary Studies Roslin Institute University of Edinburgh Easter Bush CampusConserLab Animal Preventive Medicine Department Faculty of Animal and Veterinary Sciences University of ChileCorozal Veterinary Hospital University of PanamĂĄSt. George's UniversityNakuru District Veterinary Scheme LtdAnimal Medical CentreInternational Animal Welfare Training Institute UC Davis School of Veterinary MedicineCentro UniversitĂĄrio de Rio Preto (UNIRP)Department of Clinical and Veterinary Surgery SĂŁo Paulo State University (UNESP)Ladybrand Animal ClinicVeterinary Clinic Sr. Dog'sWorld Vets Latin America Veterinary Training CenterNational Veterinary Research InstituteAnimal ClinicIntermunicipal Stray Animals Care Centre (DIKEPAZ)Animal Protection Society of SamoaFaculty of Veterinary Science University of ZuliaVeterinary Clinic BIOCONTROLFaculty of Veterinary Medicine School of Health Sciences University of ThessalyVeterinary Clinic El Roble Animal Healthcare Network Faculty of Animal and Veterinary Sciences University of ChileOnevetGroup Hospital VeterinĂĄrio BernaUniversidade Vila VelhaVeterinary Clinic ZoovetservisĂcole Inter-Ă©tats des Sciences et MĂ©decine VĂ©tĂ©rinaires de DakarDepartment of Small Animal Medicine Faculty of Veterinary Medicine Utrecht UniversityVetexpert Veterinary GroupVeterinary Clinic Lopez QuintanaClinique Veterinaire de Grand Fond Saint Gilles les BainsDepartment of Veterinary Sciences University of MessinaFacultad de Medicina Veterinaria y Zootecnia Universidad AutĂłnoma del Estado de MĂ©xicoSchool of Veterinary Medicine Universidad de las AmĂ©ricasCancer Development and Innate Immune Evasion Lab Champalimaud Center for the UnknownTouray and Meyer Vet ClinicHillside Animal HospitalKampala Veterinary SurgeryAsavet Veterinary CharitiesVets Beyond BordersFaculty of Veterinary Medicine Autonomous University of YucatanLaboratorio de PatologĂa Veterinaria Universidad de CaldasInterdisciplinary Centre of Research in Animal Health (CIISA) Faculty of Veterinary Medicine University of LisbonFour Paws InternationalHelp in SufferingVeterinary Clinic Dr JosĂ© RojasDepartment of Biotechnology Balochistan University of Information Technology Engineering and Management SciencesCorozal Veterinary ClinicVeterinary Clinic VetmasterState Hospital of Veterinary MedicineJomo Kenyatta University of Agriculture and TechnologyLaboratory of Biomedicine and Regenerative Medicine Department of Clinical Sciences Faculty of Animal and Veterinary Sciences University of ChileFaculty of Veterinary and Agricultural Sciences University of MelbourneAnimal Anti Cruelty LeagueClinical Sciences Department Faculty of Veterinary Medicine BucharestDepartment of Pathology Faculty of Veterinary Medicine Ankara UniversityFaculty of Veterinary Sciences National University of AsuncionLilongwe Society for Protection and Care of Animals (LSPCA)Wellcome Sanger InstituteDepartment of Cellular and Molecular Medicine University of California San DiegoDepartment of Clinical and Veterinary Surgery SĂŁo Paulo State University (UNESP)Leverhulme Trust: 102942/Z/13/
Actualidad y prospectiva de la investigaciĂłn cientĂfica en el Centro Universitario Amecameca de la Universidad AutĂłnoma del Estado de MĂ©xico
Con responsabilidad, se organizó un programa cuya finalidad fuera publicitar con transparencia dichos avances, a través de un esfuerzo de rendición de cuentas a la comunidad inmediata, la universitaria, y a la comunidad abierta, la sociedad que la principal referencia para tal efecto.
El programa se concretiza a travĂ©s del presente libro, conformado con una inspiraciĂłn de investigaciĂłn multidisciplinaria; sin embargo, para llegar a tal fin, el reto es realizar el proceso de bĂșsqueda y generaciĂłn de conocimiento transitando hacia la colaboraciĂłn de los cuerpos acadĂ©micos, que puedan construir nuevos conocimientos fortalecidos por la convergencia de diferentes campos del saber. En consecuencia, la primera etapa de esta estrategia es la publicidad de los trabajos investigativos ejercidos, para hacer un balance al dĂa, pero tambiĂ©n proyectar el futuro de cada campo y ĂĄrea del conocimiento.
La organizaciĂłn explicativa estĂĄ organizada por tres bloques representativos del quehacer en la generaciĂłn de conocimiento del Centro Universitario, un primer bloque centra el interĂ©s en las humanidades, educaciĂłn y sustentabilidad; el segundo bloque lo integra la reflexiĂłn cientĂfica sobre la construcciĂłn democrĂĄtica, derechos humanos y equidad de gĂ©nero; en el tercer segmento se destina a la seguridad alimentaria, salud pĂșblica y sistemas agropecuarios.
La actualidad de la investigaciĂłn eleva la producciĂłn lograda y lo que en el momento se encuentra en construcciĂłn y los alcances que produce para la docencia, la investigaciĂłn misma, y para la sociedad en general. La prospectiva es un ĂĄrea que todos los capĂtulos desarrollan con el propĂłsito de delinear los alcances innovadores por andar en teorĂa, metodologĂa e incluso en los saberes mismo
Recurrent horizontal transfer identifies mitochondrial positive selection in a transmissible cancer
Abstract: Autonomous replication and segregation of mitochondrial DNA (mtDNA) creates the potential for evolutionary conflict driven by emergence of haplotypes under positive selection for âselfishâ traits, such as replicative advantage. However, few cases of this phenomenon arising within natural populations have been described. Here, we survey the frequency of mtDNA horizontal transfer within the canine transmissible venereal tumour (CTVT), a contagious cancer clone that occasionally acquires mtDNA from its hosts. Remarkably, one canine mtDNA haplotype, A1d1a, has repeatedly and recently colonised CTVT cells, recurrently replacing incumbent CTVT haplotypes. An A1d1a control region polymorphism predicted to influence transcription is fixed in the products of an A1d1a recombination event and occurs somatically on other CTVT mtDNA backgrounds. We present a model whereby âselfishâ positive selection acting on a regulatory variant drives repeated fixation of A1d1a within CTVT cells
A Large-Scale Genetic Analysis Reveals a Strong Contribution of the HLA Class II Region to Giant Cell Arteritis Susceptibility
We conducted a large-scale genetic analysis on giant cell arteritis (GCA), a polygenic immune-mediated vasculitis. A case-control cohort, comprising 1,651 case subjects with GCA and 15,306 unrelated control subjects from six different countries of European ancestry, was genotyped by the Immunochip array. We also imputed HLA data with a previously validated imputation method to perform a more comprehensive analysis of this genomic region. The strongest association signals were observed in the HLA region, with rs477515 representing the highest peak (p = 4.05 Ă 10â40, OR = 1.73). A multivariate model including class II amino acids of HLA-DRÎČ1 and HLA-DQα1 and one class I amino acid of HLA-B explained most of the HLA association with GCA, consistent with previously reported associations of classical HLA alleles like HLA-DRB1â04. An omnibus test on polymorphic amino acid positions highlighted DRÎČ1 13 (p = 4.08 Ă 10â43) and HLA-DQα1 47 (p = 4.02 Ă 10â46), 56, and 76 (both p = 1.84 Ă 10â45) as relevant positions for disease susceptibility. Outside the HLA region, the most significant loci included PTPN22 (rs2476601, p = 1.73 Ă 10â6, OR = 1.38), LRRC32 (rs10160518, p = 4.39 Ă 10â6, OR = 1.20), and REL (rs115674477, p = 1.10 Ă 10â5, OR = 1.63). Our study provides evidence of a strong contribution of HLA class I and II molecules to susceptibility to GCA. In the non-HLA region, we confirmed a key role for the functional PTPN22 rs2476601 variant and proposed other putative risk loci for GCA involved in Th1, Th17, and Treg cell function
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
Direct-fed microbes: A tool for improving the utilization of low quality roughages in ruminants
Due to probable toxicity
problems to the host animals, these feed additives are not
routinely used (Salem et al. 2014a, b). Recently, a great
awareness from public health aspects such as residues of
these chemicals in milk and meat, and bacterial resistance
to antibiotics as a result of increased use in the food chains
prohibits their use as feed additives (Barton 2000). These
supplements have been criticized by the consumersâ organizations
on the ground of product safety and quality. The
consumersâ demands have stimulated to search for natural
alternatives to chemical feed additives. Supplementation
with probiotics that can survive in the rumen has become a
suitable alternative (Fon and Nsahlai 2013).For many years, ruminant nutritionists and microbiologists have been interested in manipulating the microbial ecosystem
of the rumen to improve production efficiency of different ruminant species. Removal and restriction of antibiotics subtherapeutic
uses from ruminant diets has amplified interest in improving nutrient utilization and animal performance and
search for more safe alternatives. Some bacterial and fungal microorganisms as a direct-fed microbial (DFM) can be the
most suitable solutions. Microorganisms that are commonly used in DFM for ruminants may be classified mainly as lactic
acid producing bacteria (LAB), lactic acid utilizing bacteria (LUB), or other microorganismâs species like Lactobacillus, Bifidobacterium,
Enterococcus, Streptococcus, Bacillus, Propionibacterium, Megasphaera elsdenii and Prevotellabryantii, in
addition to some fungal species of yeast such as Saccharomyces and Aspergillus. A definitive mode of action for bacterial
or fungal DFM has not been established; although a variety of mechanisms have been suggested. Bacterial DFM potentially
moderate rumen conditions, and improve weight gain and feed efficiency. Fungal DFM may reduce harmful oxygen from
the rumen, prevent excess lactate production, increase feed digestibility, and alter rumen fermentation patterns. DFM may
also compete with and inhibit the growth of pathogens, immune system modulation, and modulate microbial balance in the
gastrointestinal tract. Improved dry matter intake, milk yield, fat corrected milk yield and milk fat content were obtained with
DFM administration. However, the response to DFM is not constant; depending on dosages, feeding times and frequencies,
and strains of DFM. Nonetheless, recent studies have supported the positive effects of DFM on ruminant performance
Effects of Saccharomyces cerevisiae at direct addition or pre-incubation on in vitro gas production kinetics and degradability of four fibrous feeds
The aim of this study was to determine
effects of increasing doses of the yeast
(Saccharomyces cerevisiae) in two methods of
applications (direct or 72 h of pre-incubation)
on in vitro GP, degradability and some ruminal
fermentation parameters of the fibrous feedstuffs
of corn stover, oat straw, sugarcane
bagasse, and sorghum straw.The objective of this study was to evaluate
the effects of Saccharomyces cerevisiae on in
vitro gas production (GP) kinetics and degradability
of corn stover, oat straw, sugarcane
bagasse and sorghum straw. Feedstuffs were
incubated with different doses of yeast [0, 4, 8
and 12 mg/g dry matter (DM)] at direct addition
or 72 h pre-incubation. Rumen GP was
recorded at 2, 4, 6, 8, 10, 12, 14, 24, 30, 48, 54
and 72 h of incubation. After 72 h, rumen pH
and methane were determined and contents
were filtrated for DM, neutral (NDF) and acid
detergent fibre (ADF) degradability. Fibrous
speciesĂmethod of applicationĂyeast interactions
occurred (P<0.001) for all measured
ruminal GP parameters and degradability. The
direct addition or 72 h pre-incubation of S.
cerevisiae with corn stover improved (P<0.05)
GP and methane and decreased (P<0.05) the
lag time (L) and NDF degradability (NDFD).
The direct addition of S. cerevisiae to oat straw
increased (P<0.05) rate of GP (c) and
decreased (P<0.05) asymptotic GP (b).
However, 72 h pre-incubation increased
(P<0.05) c with linearly decreased b, DM
degradability (DMD) and NDFD. Applying S