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Antigenic and 3D structural characterization of soluble X4 and hybrid X4-R5 HIV-1 Env trimers
(2014)
Background: HIV-1 is decorated with trimeric glycoprotein spikes that enable infection by engaging CD4 and a chemokine coreceptor, either CCR5 or CXCR4. The variable loop 3 (V3) of the HIV-1 envelope protein (Env) is the main determinant for coreceptor usage. The predominant CCR5 using (R5) HIV-1 Env has been intensively studied in function and structure, whereas the trimeric architecture of the less frequent, but more cytopathic CXCR4 using (X4) HIV-1 Env is largely unknown, as are the consequences of sequence changes in and near V3 on antigenicity and trimeric Env structure.
Results: Soluble trimeric gp140 Env constructs were used as immunogenic mimics of the native spikes to analyze their antigenic properties in the context of their overall 3D structure. We generated soluble, uncleaved, gp140 trimers from a prototypic T-cell line-adapted (TCLA) X4 HIV-1 strain (NL4-3) and a hybrid (NL4-3/ADA), in which the V3 spanning region was substituted with that from the primary R5 isolate ADA. Compared to an ADA (R5) gp140, the NL4-3 (X4) construct revealed an overall higher antibody accessibility, which was most pronounced for the CD4 binding site (CD4bs), but also observed for mAbs against CD4 induced (CD4i) epitopes and gp41 mAbs. V3 mAbs showed significant binding differences to the three constructs, which were refined by SPR analysis. Of interest, the NL4-3/ADA construct with the hybrid NL4-3/ADA CD4bs showed impaired CD4 and CD4bs mAb reactivity despite the presence of the essential elements of the CD4bs epitope. We obtained 3D reconstructions of the NL4-3 and the NL4-3/ADA gp140 trimers via electron microscopy and single particle analysis, which indicates that both constructs inherit a propeller-like architecture. The first 3D reconstruction of an Env construct from an X4 TCLA HIV-1 strain reveals an open conformation, in contrast to recently published more closed structures from R5 Env. Exchanging the X4 V3 spanning region for that of R5 ADA did not alter the open Env architecture as deduced from its very similar 3D reconstruction.
Conclusions: 3D EM analysis showed an apparent open trimer configuration of X4 NL4-3 gp140 that is not modified by exchanging the V3 spanning region for R5 ADA.
Background: Mitochondrial acyl-CoA dehydrogenase family member 9 (ACAD9) is essential for the assembly of mitochondrial respiratory chain complex I. Disease causing biallelic variants in ACAD9 have been reported in individuals presenting with lactic acidosis and cardiomyopathy.
Results: We describe the genetic, clinical and biochemical findings in a cohort of 70 patients, of whom 29 previously unpublished. We found 34 known and 18 previously unreported variants in ACAD9. No patients harbored biallelic loss of function mutations, indicating that this combination is unlikely to be compatible with life. Causal pathogenic variants were distributed throughout the entire gene, and there was no obvious genotype-phenotype correlation.
Most of the patients presented in the first year of life. For this subgroup the survival was poor (50% not surviving the first 2 years) comparing to patients with a later presentation (more than 90% surviving 10 years). The most common clinical findings were cardiomyopathy (85%), muscular weakness (75%) and exercise intolerance (72%). Interestingly, severe intellectual deficits were only reported in one patient and severe developmental delays in four patients. More than 70% of the patients were able to perform the same activities of daily living when compared to peers.
Conclusions: Our data show that riboflavin treatment improves complex I activity in the majority of patient-derived fibroblasts tested. This effect was also reported for most of the treated patients and is mirrored in the survival data. In the patient group with disease-onset below 1 year of age, we observed a statistically-significant better survival for patients treated with riboflavin.
The production of K∗(892)0 and ϕ(1020) mesons has been measured in p–Pb collisions at √sNN = 5.02 TeV. K∗0 and ϕ are reconstructed via their decay into charged hadrons with the ALICE detector in the rapidity range - 0.5 < y < 0. The transverse momentum spectra, measured as a function of the multiplicity, have a pT range from 0 to 15 GeV/c for K∗0 and from 0.3 to 21 GeV/c for ϕ. Integrated yields, mean transverse momenta and particle ratios are reported and compared with results in pp collisions at √s = 7 TeV and Pb–Pb collisions at √sNN = 2.76 TeV. In Pb–Pb and p–Pb collisions, K∗0 and ϕ probe the hadronic phase of the system and contribute to the study of particle formation mechanisms by comparison with other identified hadrons. For this purpose, the mean transverse momenta and the differential proton-to-ϕ ratio are discussed as a function of the multiplicity of the event. The short-lived K∗0 is measured to investigate re-scattering effects, believed to be related to the size of the system and to the lifetime of the hadronic phase.
Measurement of electrons from heavy-flavour hadron decays in p–Pb collisions at √sNN = 5.02 TeV
(2015)
The production of electrons from heavy-flavour hadron decays was measured as a function of transverse momentum (pT) in minimum-bias p–Pb collisions at √sNN = 5.02 TeV using the ALICE detector at the LHC. The measurement covers the pT interval 0.5 < pT < 12 GeV/c and the rapidity range −1.065 < ycms < 0.135 in the centre-of-mass reference frame. The contribution of electrons from background sources was subtracted using an invariant mass approach. The nuclear modification factor RpPb was calculated by comparing the pT-differential invariant cross section in p–Pb collisions to a pp reference at the same centre-of-mass energy, which was obtained by interpolating measurements at √s = 2.76 TeV and √s = 7 TeV. The RpPb is consistent with unity within uncertainties of about 25%, which become larger for pT below 1 GeV/c. The measurement shows that heavy-flavour production is consistent with binary scaling, so that a suppression in the high-pT yield in Pb–Pb collisions has to be attributed to effects induced by the hot medium produced in the final state. The data in p–Pb collisions are described by recent model calculations that include cold nuclear matter effects.
National greenhouse gas inventories (GHGIs) are submitted annually to the United Nations Framework Convention on Climate Change (UNFCCC). They are estimated in compliance with Intergovernmental Panel on Climate Change (IPCC) methodological guidance using activity data, emission factors and facility-level measurements. For some sources, the outputs from these calculations are very uncertain. Inverse modelling techniques that use high-quality, long-term measurements of atmospheric gases have been developed to provide independent verification of national GHGIs. This is considered good practice by the IPCC as it helps national inventory compilers to verify reported emissions and to reduce emission uncertainty. Emission estimates from the InTEM (Inversion Technique for Emission Modelling) model are presented for the UK for the hydrofluorocarbons (HFCs) reported to the UNFCCC (HFC-125, HFC-134a, HFC-143a, HFC-152a, HFC-23, HFC-32, HFC-227ea, HFC-245fa, HFC-43-10mee and HFC-365mfc). These HFCs have high global warming potentials (GWPs), and the global background mole fractions of all but two are increasing, thus highlighting their relevance to the climate and a need for increasing the accuracy of emission estimation for regulatory purposes. This study presents evidence that the long-term annual increase in growth of HFC-134a has stopped and is now decreasing. For HFC-32 there is an early indication, its rapid global growth period has ended, and there is evidence that the annual increase in global growth for HFC-125 has slowed from 2018. The inverse modelling results indicate that the UK implementation of European Union regulation of HFC emissions has been successful in initiating a decline in UK emissions from 2018. Comparison of the total InTEM UK HFC emissions in 2020 with the average from 2009–2012 shows a drop of 35 %, indicating progress toward the target of a 79 % decrease in sales by 2030. The total InTEM HFC emission estimates (2008–2018) are on average 73 (62–83) % of, or 4.3 (2.7–5.9) Tg CO2-eq yr−1 lower than, the total HFC emission estimates from the UK GHGI. There are also significant discrepancies between the two estimates for the individual HFCs.
National Greenhouse Gas Inventories (GHGI) are submitted annually to the United Nations Framework Convention on Climate Change (UNFCCC). They are estimated in compliance with Intergovernmental Panel on Climate Change (IPCC) methodological guidance using activity data, emission factors and facility-level measurements. For some sources, the outputs from these calculations are very uncertain. Inverse modelling techniques that use high-quality, long-term measurements of atmospheric gases have been developed to provide independent verification of national GHGI. This is considered good practice by the IPCC as it helps national inventory compilers to verify reported emissions and to reduce emission uncertainty. Emission estimates from the InTEM (Inversion Technique for Emissions Modelling) model are presented for the UK for the hydrofluorocarbons (HFCs) reported to the UNFCCC (HFC-125, HFC-134a, HFC-143a, HFC-152a, HFC-23, HFC-32, HFC-227ea, HFC-245fa, HFC-43-10mee and HFC-365mfc). These HFCs have high Global Warming Potentials (GWPs) and the global background mole fractions of all but two are increasing, thus highlighting their relevance to the climate and a need for increasing the accuracy of emission estimation for regulatory purposes. This study presents evidence that the long-term annual increase in growth of HFC-134a has stopped and is now decreasing. For HFC-32 there is an early indication its rapid global growth period has ended, and there is evidence that the annual increase in global growth for HFC-125 has slowed from 2018. The inverse modelling results indicate that the UK implementation of European Union regulation of HFC emissions has been successful in initiating a decline in UK emissions in the since 2018. Comparison of the total InTEM UK HFC emissions in 2020 with the average from 2009–2012 shows a drop of 35%, indicating progress toward the target of a 79% decrease in sales by 2030. The total InTEM HFC emission estimates (2008–2018) are on average 73 (62–83)% of, or 4.3 (2.7–5.9) Tg CO2-eq yr−1 lower than, the total HFC emission estimates from the UK GHGI inventory. There are also significant discrepancies between the two estimates for the individual HFCs.
The multi-strange baryon yields in PbPb collisions have been shown to exhibit an enhancement relative to pp reactions. In this work, Ξ and Ω production rates have been measured with the ALICE experiment as a function of transverse momentum, pT, in pPb collisions at a centre-of-mass energy of sNN=5.02 TeV. The results cover the kinematic ranges 0.6 GeV/c<pT<7.2 GeV/c and 0.8 GeV/c<pT<5 GeV/c, for Ξ and Ω respectively, in the common rapidity interval −0.5<yCMS<0. Multi-strange baryons have been identified by reconstructing their weak decays into charged particles. The pT spectra are analysed as a function of event charged-particle multiplicity, which in pPb collisions ranges over one order of magnitude and lies between those observed in pp and PbPb collisions. The measured pT distributions are compared to the expectations from a Blast-Wave model. The parameters which describe the production of lighter hadron species also describe the hyperon spectra in high multiplicity pPb collisions. The yield of hyperons relative to charged pions is studied and compared with results from pp and PbPb collisions. A continuous increase in the yield ratios as a function of multiplicity is observed in pPb data, the values of which range from those measured in minimum bias pp to the ones in PbPb collisions. A statistical model qualitatively describes this multiplicity dependence using a canonical suppression mechanism, in which the small volume causes a relative reduction of hadron production dependent on the strangeness content of the hyperon.
The multi-strange baryon yields in Pb--Pb collisions have been shown to exhibit an enhancement relative to pp reactions. In this work, Ξ and Ω production rates have been measured with the ALICE experiment as a function of transverse momentum, pT, in p-Pb collisions at a centre-of-mass energy of sNN−−−√ = 5.02 TeV. The results cover the kinematic ranges 0.6 GeV/c<pT<7.2 GeV/c and 0.8 GeV/c<pT< 5 GeV/c, for Ξ and Ω respectively, in the common rapidity interval -0.5 <yCMS< 0. Multi-strange baryons have been identified by reconstructing their weak decays into charged particles. The pT spectra are analysed as a function of event charged-particle multiplicity, which in p-Pb collisions ranges over one order of magnitude and lies between those observed in pp and Pb-Pb collisions. The measured pT distributions are compared to the expectations from a Blast-Wave model. The parameters which describe the production of lighter hadron species also describe the hyperon spectra in high multiplicity p-Pb. The yield of hyperons relative to charged pions is studied and compared with results from pp and Pb-Pb collisions. A statistical model is employed, which describes the change in the ratios with volume using a canonical suppression mechanism, in which the small volume causes a species-dependent relative reduction of hadron production. The calculations, in which the magnitude of the effect depends on the strangeness content, show good qualitative agreement with the data.
The production of K∗(892)0 and ϕ(1020) mesons has been measured in p-Pb collisions at sNN−−−√ = 5.02 TeV. K∗0 and ϕ are reconstructed via their decay into charged hadrons with the ALICE detector in the rapidity range −0.5<y<0. The transverse momentum spectra, measured as a function of the multiplicity, have pT range from 0 to 15 GeV/c for K∗0 and from 0.3 to 21 GeV/c for ϕ. Integrated yields, mean transverse momenta and particle ratios are reported and compared with results in pp collisions at s√ = 7 TeV and Pb-Pb collisions at sNN−−−√ = 2.76 TeV. In Pb-Pb and p-Pb collisions, K∗0 and ϕ probe the hadronic phase of the system and contribute to the study of particle formation mechanisms by comparison with other identified hadrons. For this purpose, the mean transverse momenta and the differential proton-to-ϕ ratio are discussed as a function of the multiplicity of the event. The short-lived K∗0 is measured to investigate re-scattering effects, believed to be related to the size of the system and to the lifetime of the hadronic phase.
The production of K∗(892)0 and ϕ(1020) mesons has been measured in p-Pb collisions at sNN−−−√ = 5.02 TeV. K∗0 and ϕ are reconstructed via their decay into charged hadrons with the ALICE detector in the rapidity range −0.5<y<0. The transverse momentum spectra, measured as a function of the multiplicity, have pT range from 0 to 15 GeV/c for K∗0 and from 0.3 to 21 GeV/c for ϕ. Integrated yields, mean transverse momenta and particle ratios are reported and compared with results in pp collisions at s√ = 7 TeV and Pb-Pb collisions at sNN−−−√ = 2.76 TeV. In Pb-Pb and p-Pb collisions, K∗0 and ϕ probe the hadronic phase of the system and contribute to the study of particle formation mechanisms by comparison with other identified hadrons. For this purpose, the mean transverse momenta and the differential proton-to-ϕ ratio are discussed as a function of the multiplicity of the event. The short-lived K∗0 is measured to investigate re-scattering effects, believed to be related to the size of the system and to the lifetime of the hadronic phase.