Novel splice-affecting variants in CYP27A1 gene in two Chilean patients with Cerebrotendinous Xanthomatosis

Cerebrotendinous Xanthomatosis (CTX), a rare lipid storage disorder, is caused by recessive loss-of-function mutations of the 27-sterol hydroxylase (CYP27A1), producing an alteration of the synthesis of bile acids, with an accumulation of cholestanol. Clinical characteristics include juvenile cataracts, diarrhea, tendon xanthomas, cognitive impairment and other neurological manifestations. Early diagnosis is critical, because treatment with chenodeoxycholic acid may prevent neurological damage. We studied the CYP27A1 gene in two Chilean CTX patients by sequencing its nine exons, exon-intron boundaries, and cDNA from peripheral blood mononuclear cells. Patient 1 is a compound heterozygote for the novel substitution c.256-1G > T that causes exon 2 skipping, leading to a premature stop codon in exon 3, and for the previously-known pathogenic mutation c.1183C > T (p.Arg395Cys). Patient 2 is homozygous for the novel mutation c.1185-1G > A that causes exon 7 skipping and the generation of a premature stop codon in exon 8, leading to the loss of the crucial adrenoxin binding domain of CYP27A1

PPARGC1A gene promoter methylation as a biomarker of insulin secretion and sensitivity in response to glucose challenges

Methylation in CpG sites of the PPARGC1A gene (encoding PGC1-α) has been associated with adiposity, insulin secretion/sensitivity indexes and type 2 diabetes. We assessed the association between the methylation profile of the PPARGC1A gene promoter gene in leukocytes with insulin secretion/sensitivity indexes in normoglycemic women. A standard oral glucose tolerance test (OGTT) and an abbreviated version of the intravenous glucose tolerance test (IVGTT) were carried out in n = 57 Chilean nondiabetic women with measurements of plasma glucose, insulin, and C-peptide. Bisulfite-treated DNA from leukocytes was evaluated for methylation levels in six CpG sites of the proximal promoter of the PPARGC1A gene by pyrosequencing (positions -816, -783, -652, -617, -521 and -515). A strong correlation between the DNA methylation percentage of different CpG sites of the PPARGC1A promoter in leukocytes was found, suggesting an integrated epigenetic control of this region. We found a positive association between the methylation levels of the CpG site -783 with the insulin sensitivity Matsuda composite index (rho = 0.31; p = 0.02) derived from the OGTT. The CpG hypomethylation in the promoter position -783 of the PPARGC1A gene in leukocytes may represent a biomarker of reduced insulin sensitivity after the ingestion of glucose

Novel splice-affecting variants in CYP27A1 gene in two Chilean patients with Cerebrotendinous Xanthomatosis

Cerebrotendinous Xanthomatosis (CTX), a rare lipid storage disorder, is caused by recessive loss-of-function mutations of the 27-sterol hydroxylase (CYP27A1), producing an alteration of the synthesis of bile acids, with an accumulation of cholestanol. Clinical characteristics include juvenile cataracts, diarrhea, tendon xanthomas, cognitive impairment and other neurological manifestations. Early diagnosis is critical, because treatment with chenodeoxycholic acid may prevent neurological damage. We studied the CYP27A1 gene in two Chilean CTX patients by sequencing its nine exons, exon-intron boundaries, and cDNA from peripheral blood mononuclear cells. Patient 1 is a compound heterozygote for the novel substitution c.256-1G > T that causes exon 2 skipping, leading to a premature stop codon in exon 3, and for the previously-known pathogenic mutation c.1183C > T (p.Arg395Cys). Patient 2 is homozygous for the novel mutation c.1185-1G > A that causes exon 7 skipping and the generation of a premature stop codon in exon 8, leading to the loss of the crucial adrenoxin binding domain of CYP27A1

PPARGC1A gene promoter methylation as a biomarker of insulin secretion and sensitivity in response to glucose challenges

Methylation in CpG sites of the PPARGC1A gene (encoding PGC1-α) has been associated with adiposity, insulin secretion/sensitivity indexes and type 2 diabetes. We assessed the association between the methylation profile of the PPARGC1A gene promoter gene in leukocytes with insulin secretion/sensitivity indexes in normoglycemic women. A standard oral glucose tolerance test (OGTT) and an abbreviated version of the intravenous glucose tolerance test (IVGTT) were carried out in n = 57 Chilean nondiabetic women with measurements of plasma glucose, insulin, and C-peptide. Bisulfite-treated DNA from leukocytes was evaluated for methylation levels in six CpG sites of the proximal promoter of the PPARGC1A gene by pyrosequencing (positions -816, -783, -652, -617, -521 and -515). A strong correlation between the DNA methylation percentage of different CpG sites of the PPARGC1A promoter in leukocytes was found, suggesting an integrated epigenetic control of this region. We found a positive association between the methylation levels of the CpG site -783 with the insulin sensitivity Matsuda composite index (rho = 0.31; p = 0.02) derived from the OGTT. The CpG hypomethylation in the promoter position -783 of the PPARGC1A gene in leukocytes may represent a biomarker of reduced insulin sensitivity after the ingestion of glucose

Overview of recent TJ-II stellarator results

The main results obtained in the TJ-II stellarator in the last two years are reported. The most important topics investigated have been modelling and validation of impurity transport, validation of gyrokinetic simulations, turbulence characterisation, effect of magnetic configuration on transport, fuelling with pellet injection, fast particles and liquid metal plasma facing components. As regards impurity transport research, a number of working lines exploring several recently discovered effects have been developed: the effect of tangential drifts on stellarator neoclassical transport, the impurity flux driven by electric fields tangent to magnetic surfaces and attempts of experimental validation with Doppler reflectometry of the variation of the radial electric field on the flux surface. Concerning gyrokinetic simulations, two validation activities have been performed, the comparison with measurements of zonal flow relaxation in pellet-induced fast transients and the comparison with experimental poloidal variation of fluctuations amplitude. The impact of radial electric fields on turbulence spreading in the edge and scrape-off layer has been also experimentally characterized using a 2D Langmuir probe array. Another remarkable piece of work has been the investigation of the radial propagation of small temperature perturbations using transfer entropy. Research on the physics and modelling of plasma core fuelling with pellet and tracer-encapsulated solid-pellet injection has produced also relevant results. Neutral beam injection driven Alfvénic activity and its possible control by electron cyclotron current drive has been examined as well in TJ-II. Finally, recent results on alternative plasma facing components based on liquid metals are also presented.ISSN:0029-5515ISSN:1741-432

Search for CPCP violation in D0^0→\to KS0^0_\mathrm{S}KS0^0_\mathrm{S} decays in proton-proton collisions at s\sqrt{s} = 13 TeV

International audienceA search is reported for charge-parity D$^0$$\to$ K$^0_\mathrm{S}$K$^0_\mathrm{S}$$CP$ violation in D$^0$$\to$ K$^0_\mathrm{S}$K$^0_\mathrm{S}$ decays, using data collected in proton-proton collisions at $\sqrt{s}$ = 13 TeV recorded by the CMS experiment in 2018. The analysis uses a dedicated data set that corresponds to an integrated luminosity of 41.6 fb$^{-1}$, which consists of about 10 billion events containing a pair of ẖadrons, nearly all of which decay to charm hadrons. The flavor of the neutral D meson is determined by the pion charge in the reconstructed decays D$^{*+}$$\to$ D$^0\pi^+$ and D$^{*-}$$\to$ D$^0\pi^-$. The D$^0$$\to$ K$^0_\mathrm{S}$K$^0_\mathrm{S}$$CP$ asymmetry in D$^0$$\to$ K$^0_\mathrm{S}$K$^0_\mathrm{S}$ is measured to be $A_{CP}$( K$^0_\mathrm{S}$K$^0_\mathrm{S}$) = (6.2 $\pm$ 3.0 $\pm$ 0.2 $\pm$ 0.8)%, where the three uncertainties represent the statistical uncertainty, the systematic uncertainty, and the uncertainty in the measurement of the D$^0$ $\to$ K$^0_\mathrm{S}$K$^0_\mathrm{S}$ $CP$ asymmetry in the D$^0$ $\to$ K$^0_\mathrm{S}\pi^+\pi^-$ decay. This is the first D$^0$ $\to$ K$^0_\mathrm{S}$K$^0_\mathrm{S}$ $CP$ asymmetry measurement by CMS in the charm sector as well as the first to utilize a fully hadronic final state

Measurement of inclusive and differential cross sections for W+^{+}W−^{-} production in proton-proton collisions at s= \sqrt{s} = 13.6 TeV

Measurements at $\sqrt{s}=$ 13.6 TeV of the opposite-sign W boson pair production cross section in proton-proton collisions are presented. The data used in this study were collected with the CMS detector at the CERN LHC in 2022, and correspond to an integrated luminosity of 34.8 fb$^{-1}$. Events are selected by requiring one electron and one muon of opposite charge. A maximum likelihood fit is performed on signal- and background-enriched data categories defined by the flavour and charge of the leptons, the number of jets, and number of jets originating from b quarks. An inclusive W$^{+}$W$^{-}$ production cross section of 125.7 $\pm$ 5.6 pb is measured, in agreement with standard model predictions. Cross sections are also reported in a fiducial region close to that of the detector acceptance, both inclusively and differentially, as a function of the jet multiplicity in the event. For first time in proton-proton collisions, WW events with at least two reconstructed jets are studied and compared with recent theoretical predictions.Measurements at $\sqrt{s}$ = 13.6 TeV of the opposite-sign W boson pair production cross section in proton-proton collisions are presented. The data used in this study were collected with the CMS detector at the CERN LHC in 2022, and correspond to an integrated luminosity of 34.8 fb$^{-1}$. Events are selected by requiring one electron and one muon of opposite charge. A maximum likelihood fit is performed on signal- and background-enriched data categories defined by the flavour and charge of the leptons, the number of jets, and number of jets originating from b quarks. An inclusive W$^+$W$^-$ production cross section of 125.7 $\pm$ 5.6 pb is measured, in agreement with standard model predictions. Cross sections are also reported in a fiducial region close to that of the detector acceptance, both inclusively and differentially, as a function of the jet multiplicity in the event. For first time in proton-proton collisions, WW events with at least two reconstructed jets are studied and compared with recent theoretical predictions

Search for a resonance decaying to a W boson and a photon in proton-proton collisions at s= \sqrt{s} = 13 TeV using leptonic W boson decays

A search for a new charged particle X with mass between 0.3 and 2.0 TeV decaying to a W boson and a photon is presented, using proton-proton collision data at a center-of-mass energy of 13 TeV, collected by the CMS experiment and corresponding to an integrated luminosity of 138 fb$^{-1}$. Particle X has electric charge $\pm$1 and is assumed to have spin 0. The search is performed using the electron and muon decays of the W boson. No significant excess above the predicted background is observed. The upper limit at 95% confidence level on the product of the production cross section of the X and its branching fraction to a W boson and a photon is found to be 94 (137) fb for a 0.3 TeV resonance and 0.75 (0.81) fb for a 2.0 TeV resonance, for an X width-to-mass ratio of 0.01% (5%). This search presents the most stringent constraints to date on the existence of such resonances across the probed mass range. A statistical combination with an earlier study based on the hadronic decay mode of the W boson is also performed, and the upper limit at 95% confidence level for a 2.0 TeV resonance is reduced to 0.50 (0.63) fb for an X width-to-mass ratio of 0.01% (5%).A search for a new charged particle X with mass between 0.3 and 2.0 TeV decaying to a W boson and a photon is presented, using proton-proton collision data at a center-of-mass energy of 13 TeV, collected by the CMS experiment and corresponding to an integrated luminosity of 138 fb$^{-1}$. Particle X has electric charge $\pm$1 and is assumed to have spin 0. The search is performed using the electron and muon decays of the W boson. No significant excess above the predicted background is observed. The upper limit at 95% confidence level on the product of the production cross section of the X and its branching fraction to a W boson and a photon is found to be 94 (137) fb for a 0.3 TeV resonance and 0.75 (0.81) fb for a 2.0 TeV resonance, for an X width-to-mass ratio of 0.01% (5%). This search presents the most stringent constraints to date on the existence of such resonances across the probed mass range. A statistical combination with an earlier study based on the hadronic decay mode of the W boson is also performed, and the upper limit at 95% confidence level for a 2.0 TeV resonance is reduced to 0.50 (0.63) fb for an X width-to-mass ratio of 0.01% (5%)

Search for CP violation in D0→KS0KS0 \mathrm{D^0}\to\mathrm{K^0_S}\mathrm{K^0_S} decays in proton-proton collisions at s= \sqrt{s} = 13 TeV

A search is reported for charge-parity CP violation in $\mathrm{D^0}\to\mathrm{K^0_S}\mathrm{K^0_S}$ decays, using data collected in proton-proton collisions at $\sqrt{s} =$ 13 TeV recorded by the CMS experiment in 2018. The analysis uses a dedicated data set that corresponds to an integrated luminosity of 41.6 fb$^{-1}$, which consists of about 10 billion events containing a pair of b hadrons, nearly all of which decay to charm hadrons. The flavor of the neutral $\mathrm{D}$ meson is determined by the pion charge in the reconstructed decays $\mathrm{D}^{*+}\to\mathrm{D^0}\pi^{+}$ and $\mathrm{D}^{*-}\to\overline{\mathrm{D}}^{0}\pi^{-}$. The CP asymmetry in $\mathrm{D^0}\to\mathrm{K^0_S}\mathrm{K^0_S}$ is measured to be $A_{CP}(\mathrm{K^0_S}\mathrm{K^0_S}) =$ (6.2 $\pm$ 3.0 $\pm$ 0.2 $\pm$ 0.8)%, where the three uncertainties represent the statistical uncertainty, the systematic uncertainty, and the uncertainty in the measurement of the CP asymmetry in the $\mathrm{D^0}\to\mathrm{K^0_S}\pi^{+}\pi^{-}$ decay. This is the first CP asymmetry measurement by CMS in the charm sector as well as the first to utilize a fully hadronic final state.A search is reported for charge-parity D$^0$$\to$ K$^0_\mathrm{S}$K$^0_\mathrm{S}$$CP$ violation in D$^0$$\to$ K$^0_\mathrm{S}$K$^0_\mathrm{S}$ decays, using data collected in proton-proton collisions at $\sqrt{s}$ = 13 TeV recorded by the CMS experiment in 2018. The analysis uses a dedicated data set that corresponds to an integrated luminosity of 41.6 fb$^{-1}$, which consists of about 10 billion events containing a pair of ẖadrons, nearly all of which decay to charm hadrons. The flavor of the neutral D meson is determined by the pion charge in the reconstructed decays D$^{*+}$$\to$ D$^0\pi^+$ and D$^{*-}$$\to$ D$^0\pi^-$. The D$^0$$\to$ K$^0_\mathrm{S}$K$^0_\mathrm{S}$$CP$ asymmetry in D$^0$$\to$ K$^0_\mathrm{S}$K$^0_\mathrm{S}$ is measured to be $A_{CP}$( K$^0_\mathrm{S}$K$^0_\mathrm{S}$) = (6.2 $\pm$ 3.0 $\pm$ 0.2 $\pm$ 0.8)%, where the three uncertainties represent the statistical uncertainty, the systematic uncertainty, and the uncertainty in the measurement of the D$^0$ $\to$ K$^0_\mathrm{S}$K$^0_\mathrm{S}$ $CP$ asymmetry in the D$^0$ $\to$ K$^0_\mathrm{S}\pi^+\pi^-$ decay. This is the first D$^0$ $\to$ K$^0_\mathrm{S}$K$^0_\mathrm{S}$ $CP$ asymmetry measurement by CMS in the charm sector as well as the first to utilize a fully hadronic final state