477 research outputs found
Genetic comparison of sickle cell anaemia cohorts from Brazil and the United States reveals high levels of divergence
Genetic analysis of admixed populations raises special concerns with regard to study design and data processing, particularly to avoid population stratification biases. The point mutation responsible for sickle cell anaemia codes for a variant hemoglobin, sickle hemoglobin or HbS, whose presence drives the pathophysiology of disease. Here we propose to explore ancestry and population structure in a genome-wide study with particular emphasis on chromosome 11 in two SCA admixed cohorts obtained from urban populations of Brazil (Pernambuco and Sao Paulo) and the United States (Pennsylvania). Ancestry inference showed different proportions of European, African and American backgrounds in the composition of our samples. Brazilians were more admixed, had a lower African background (43% vs. 78% on the genomic level and 44% vs. 76% on chromosome 11) and presented a signature of positive selection and Iberian introgression in the HbS region, driving a high differentiation of this locus between the two cohorts. The genetic structures of the SCA cohorts from Brazil and US differ considerably on the genome-wide, chromosome 11 and HbS mutation locus levels9CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQCOORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP8367/2011-1; 150398/2013-1; 304455/2012-1; 310938/2014-7; 305218/2017-48367/2011-1; 150398/2013-1; 304455/2012-1; 310938/2014-7; 305218/2017-42008/57441-0; 2014/00984-3; 2012/06438-5; 2015/13152-9; 2008/10596-
Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice
Pathogenic variants in KMT5B, a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM# 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest (n = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and Kmt5b haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in KMT5B-related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems
Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice.
Pathogenic variants in KMT5B, a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM# 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest (n = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and Kmt5b haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in KMT5B-related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems
Physics case for an LHCb Upgrade II - Opportunities in flavour physics, and beyond, in the HL-LHC era
The LHCb Upgrade II will fully exploit the flavour-physics opportunities of the HL-LHC, and study additional physics topics that take advantage of the forward acceptance of the LHCb spectrometer. The LHCb Upgrade I will begin operation in 2020. Consolidation will occur, and modest enhancements of the Upgrade I detector will be installed, in Long Shutdown 3 of the LHC (2025) and these are discussed here. The main Upgrade II detector will be installed in long shutdown 4 of the LHC (2030) and will build on the strengths of the current LHCb experiment and the Upgrade I. It will operate at a luminosity up to 2×1034
cm−2s−1, ten times that of the Upgrade I detector. New detector components will improve the intrinsic performance of the experiment in certain key areas. An Expression Of Interest proposing Upgrade II was submitted in February 2017. The physics case for the Upgrade II is presented here in more depth. CP-violating phases will be measured with precisions unattainable at any other envisaged facility. The experiment will probe b → sl+l−and b → dl+l− transitions in both muon and electron decays in modes not accessible at Upgrade I. Minimal flavour violation will be tested with a precision measurement of the ratio of B(B0 → μ+μ−)/B(Bs → μ+μ−). Probing charm CP violation at the 10−5 level may result in its long sought discovery. Major advances in hadron spectroscopy will be possible, which will be powerful probes of low energy QCD. Upgrade II potentially will have the highest sensitivity of all the LHC experiments on the Higgs to charm-quark couplings. Generically, the new physics mass scale probed, for fixed couplings, will almost double compared with the pre-HL-LHC era; this extended reach for flavour physics is similar to that which would be achieved by the HE-LHC proposal for the energy frontier
LHCb upgrade software and computing : technical design report
This document reports the Research and Development activities that are carried out in the software and computing domains in view of the upgrade of the LHCb experiment. The implementation of a full software trigger implies major changes in the core software framework, in the event data model, and in the reconstruction algorithms. The increase of the data volumes for both real and simulated datasets requires a corresponding scaling of the distributed computing infrastructure. An implementation plan in both domains is presented, together with a risk assessment analysis
Multidifferential study of identified charged hadron distributions in -tagged jets in proton-proton collisions at 13 TeV
Jet fragmentation functions are measured for the first time in proton-proton
collisions for charged pions, kaons, and protons within jets recoiling against
a boson. The charged-hadron distributions are studied longitudinally and
transversely to the jet direction for jets with transverse momentum 20 GeV and in the pseudorapidity range . The
data sample was collected with the LHCb experiment at a center-of-mass energy
of 13 TeV, corresponding to an integrated luminosity of 1.64 fb. Triple
differential distributions as a function of the hadron longitudinal momentum
fraction, hadron transverse momentum, and jet transverse momentum are also
measured for the first time. This helps constrain transverse-momentum-dependent
fragmentation functions. Differences in the shapes and magnitudes of the
measured distributions for the different hadron species provide insights into
the hadronization process for jets predominantly initiated by light quarks.Comment: All figures and tables, along with machine-readable versions and any
supplementary material and additional information, are available at
https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-013.html (LHCb
public pages
Study of the decay
The decay is studied
in proton-proton collisions at a center-of-mass energy of TeV
using data corresponding to an integrated luminosity of 5
collected by the LHCb experiment. In the system, the
state observed at the BaBar and Belle experiments is
resolved into two narrower states, and ,
whose masses and widths are measured to be where the first uncertainties are statistical and the second
systematic. The results are consistent with a previous LHCb measurement using a
prompt sample. Evidence of a new
state is found with a local significance of , whose mass and width
are measured to be and , respectively. In addition, evidence of a new decay mode
is found with a significance of
. The relative branching fraction of with respect to the
decay is measured to be , where the first
uncertainty is statistical, the second systematic and the third originates from
the branching fractions of charm hadron decays.Comment: All figures and tables, along with any supplementary material and
additional information, are available at
https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-028.html (LHCb
public pages
Measurement of the ratios of branching fractions and
The ratios of branching fractions
and are measured, assuming isospin symmetry, using a
sample of proton-proton collision data corresponding to 3.0 fb of
integrated luminosity recorded by the LHCb experiment during 2011 and 2012. The
tau lepton is identified in the decay mode
. The measured values are
and
, where the first uncertainty is
statistical and the second is systematic. The correlation between these
measurements is . Results are consistent with the current average
of these quantities and are at a combined 1.9 standard deviations from the
predictions based on lepton flavor universality in the Standard Model.Comment: All figures and tables, along with any supplementary material and
additional information, are available at
https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-039.html (LHCb
public pages
Genetics and molecular effects of sleep and sleep deprivation in humans and mice
A privacao de sono (PS) e um problema cada vez mais comum na sociedade moderna e esta diretamente relacionada a diversas alteracoes metabolicas, hormonais, neuroquimicas e comportamentais. Tem sido proposto que a falta de sono promove efeitos significativos nos padroes de expressao genica em cerebro em modelos animais. Entretanto, dados de expressao genica em humanos sao ainda incipientes, e o mesmo e valido para estudos em tecidos perifericos de roedores. Nesse sentido, a robusta tecnologia de microarray abriu uma nova janela para os estudos dos processos moleculares envolvidos no ciclo vigilia-sono. Os objetivos principais sao observacao da expressao genica global em tecidos perifericos de humanos (sangue) e camundongos (pulmao e coracao). Parte 1. Humanos: Avaliamos a expressao genica de 9 voluntarios submetidos a privacao de sono total, os quais permaneceram em alerta e ativos durante 60 horas consecutivas. As coletas de sangue para os experimentos de microarray foram realizadas na manha seguinte a noite de sono basal, na manha seguinte apos 48 horas de privacao de sono e, finalmente, na manha seguinte apos uma noite de sono rebote. Os resultados demonstraram a diminuicao da expressao de genes ligados ao sistema imune na PS, como por exemplo, os receptores de Natural killers, as granzimas A e B e os receptores de celulas T, os quais tem um importante papel na defesa do organismo. Um resultado interessante e que corrobora a literatura foi a alteracao da expressao de genes ligados ao reticulo endoplasmatico (RE), como genes codificadores de proteinas chaperonas. Parte 2. Camundongos: Os experimentos foram realizados em camundongos machos (C57BL/6J) com 10 semanas de idade pelo metodo de gentle-handling. Os animais foram eutanasiados por deslocamento cervical e decaptacao seguindo 3, 6, 9, e 12 horas de privacao de sono total (N = 8 ou 9 em cada ponto de tempo). Em paralelo, um grupo de animais em que nao foram realizadas perturbacoes (grupo de animais de sono espontaneo, tambem foi eutanasiado nos mesmos pontos de tempo que os animais privados de sono (N=8 para cada tempo respectivamente). Um grupo de controle adicional (tempo basal 0) (N=10), que estava acordado espontaneamente, foi eutanasiado no tempo zero, isto e, no momento em que as luzes foram acesas, as 7 horas da manha. Os resultados em pulmao e coracao demonstraram que houve alteracao da expressao em genes de chaperonas e do RE endoplasmatico, estresse oxidativo e enxofre no pulmao, e degradacao de proteinas no coracao. Os dados dao suporte a hipotese de que a falta de sono pode levar a alteracoes moleculares que resultam em perturbacoes da imunidade celular, assim como na inducao de inflamacao e equilibrio homeostatico. Assim, o intuito deste estudo foi de contribuir para a identificacao de possiveis marcadores biologicos representativos das alteracoes moleculares ocorridas em tecidos perifericos como: sangue, coracao e pulmao, no sono e na privacao de sono em humanos e camundongos, a partir da caracterizacao dos eventos moleculares envolvidos nos processos homeostaticos do sono nao restritos ao Sistema Nervoso CentralAssociação Fundo de Incentivo à Psicofarmacologia (AFIP)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)FAPESP: 98/14303-3BV UNIFESP: Teses e dissertaçõe
The expression and polymorfism of genes H19 e IGF2 in kidney tissue
BV UNIFESP: Teses e dissertaçõe
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