Phys. Rev. Lett. 126, 091301 (2021) We report on a search for nuclear recoil signals from solar $^8$B neutrinos
elastically scattering off xenon nuclei in XENON1T data, lowering the energy
threshold ...from 2.6 keV to 1.6 keV. We develop a variety of novel techniques to
limit the resulting increase in backgrounds near the threshold. No significant
$^8$B neutrino-like excess is found in an exposure of 0.6 t $\times$ y. For the
first time, we use the non-detection of solar neutrinos to constrain the light
yield from 1-2 keV nuclear recoils in liquid xenon, as well as non-standard
neutrino-quark interactions. Finally, we improve upon world-leading constraints
on dark matter-nucleus interactions for dark matter masses between 3 GeV/c$^2$
and 11 GeV/c$^2$ by as much as an order of magnitude.
We report constraints on light dark matter (DM) models using ionization signals in the XENON1T experiment. We mitigate backgrounds with strong event selections, rather than requiring a scintillation ...signal, leaving an effective exposure of \((22 \pm 3)\) tonne-days. Above \(\sim\!0.4\,\mathrm{keV}_\mathrm{ee}\), we observe \(<1 \, \text{event}/(\text{tonne} \times \text{day} \times \text{keV}_\text{ee})\), which is more than one thousand times lower than in similar searches with other detectors. Despite observing a higher rate at lower energies, no DM or CEvNS detection may be claimed because we cannot model all of our backgrounds. We thus exclude new regions in the parameter spaces for DM-nucleus scattering for DM masses \(m_\chi\) within \(3-6\,\mathrm{GeV}/\mathrm{c}^2\), DM-electron scattering for \(m_\chi > 30\,\mathrm{MeV}/\mathrm{c}^2\), and absorption of dark photons and axion-like particles for \(m_\chi\) within \(0.186 - 1 \, \mathrm{keV}/\mathrm{c}^2\).
The XENON1T liquid xenon time projection chamber is the most sensitive detector built to date for the measurement of direct interactions of weakly interacting massive particles with normal matter. ...The data acquisition system (DAQ) is constructed from commercial, open source, and custom components to digitize signals from the detector and store them for later analysis. The system achieves an extremely low signal threshold below a tenth of a photoelectron using a parallelized readout with the global trigger deferred to a later, software stage. The event identification is based on MongoDB database queries and has over 97% efficiency at recognizing interactions at the analysis energy threshold. A readout bandwidth over 300 MB/s is reached in calibration modes and is further expandable via parallelization. This DAQ system was successfully used during three years of operation of XENON1T.
Otoliths of eleven fish species have been identified in cores recovered from the trough Malangsdjupet (close to 70 degree N) on the Norwegian continental shelf. The codfish family (Gadidae) dominates ...with eight species. Three acme-zones belonging to the Merlangius merlangus Lineage-Zone are established: the Boreogadus sp. Acme-Zone (about 15,000 or 14,000 to 10,000 years B.P.), the Neocolliolus esmarki Acme-Zone (10,000 to 7,800 years B.P.) and the Micromesistius poutassou Acme-Zone (7,800 B.P. to present). The Boreogadus sp. Acme-Zone reflects and arctic environment while the two others reflect boreal conditions. The M. poutassou Acme-Zone represents a more oceanic environment than the early Holocene N. esmarki Acme-Zone.
We report on a search for nuclear recoil signals from solar \(^8\)B neutrinos elastically scattering off xenon nuclei in XENON1T data, lowering the energy threshold from 2.6 keV to 1.6 keV. We ...develop a variety of novel techniques to limit the resulting increase in backgrounds near the threshold. No significant \(^8\)B neutrino-like excess is found in an exposure of 0.6 t \(\times\) y. For the first time, we use the non-detection of solar neutrinos to constrain the light yield from 1-2 keV nuclear recoils in liquid xenon, as well as non-standard neutrino-quark interactions. Finally, we improve upon world-leading constraints on dark matter-nucleus interactions for dark matter masses between 3 GeV/c\(^2\) and 11 GeV/c\(^2\) by as much as an order of magnitude.
Eliglustat, an oral substrate reduction therapy, is a first‐line treatment for adults with Gaucher disease type 1 (GD1) who are poor, intermediate, or extensive CYP2D6 metabolizers (>90% of ...patients). In the primary analysis of the Phase 3 ENGAGE trial (NCT00891202), eliglustat treatment for 9 months resulted in significant reductions in spleen and liver volumes and increases in hemoglobin concentration and platelet count compared with placebo. We report 18‐month outcomes of patients who entered the trial extension period, in which all patients received eliglustat. Of 40 trial patients, 39 entered the extension period, and 38 completed 18 months. Absolute values and percent change over time were determined for spleen and liver volume, hemoglobin concentration, platelet count, bone mineral density, bone marrow burden, and Gaucher disease biomarkers. For patients randomized to eliglustat in the double‐blind period, continuing treatment with eliglustat for 9 more months resulted in incremental improvement of all disease parameters. For patients randomized to placebo in the double‐blind period, eliglustat treatment during the 9‐month, open‐label period resulted in significant decrease of spleen and liver volumes and significant increase of hemoglobin and platelets, with a similar rate of change to patients who had received eliglustat in the double‐blind period. Eliglustat treatment was also associated with improvement in bone marrow burden score, bone mineral density, and established biomarkers of Gaucher disease, including reduction of the bioactive lipid, glucosylsphingosine. These findings underscore the efficacy of eliglustat in treatment‐naïve patients. Eliglustat was well‐tolerated, and there were no new safety concerns with longer‐term exposure.
Venglustat inhibits the enzymatic conversion of ceramide to glucosylceramide, reducing available substrate for the synthesis of more complex glycosphingolipids. It offers a potential new approach to ...the treatment of patients with Fabry disease (α-Gal A deficiency), in whom progressive accumulation of such glycosphingolipids, including globotriaosylceramide (GL-3), in the lysosomes of a wide range of cell types often leads to vital organ complications in adulthood. An international, open-label, single-arm, Phase 2a uncontrolled 26-week clinical study (NCT02228460) and a 130-week extension study (NCT02489344) were conducted to assess the safety, pharmacodynamics, pharmacokinetics, and exploratory efficacy of 15 mg once daily oral venglustat in treatment-naïve adult male patients with classic Fabry disease. Of 11 patients (18–37 years old) who initially enrolled, nine completed the 26-week study and seven completed the extension study. A total of 169 treatment-emergent adverse events (TEAEs) were reported by nine patients, the majority being mild (73%) and unrelated to the study drug (70%). Nine serious TEAEs (serious adverse events) and 11 severe TEAEs, including a self-harm event, were reported. No deaths or treatment-related life-threatening adverse events were reported. Skin GL-3 scores in superficial skin capillary endothelium (SSCE), estimated by light microscopy, were unchanged from baseline at Week 26 in five patients, decreased in three patients, and increased in one patient. There was no significant change in GL-3 scores or significant shift in grouped GL-3 scores. Five of six patients had reductions from baseline in GL-3 score at the end of the extension study. At Weeks 26 and 156 the mean (standard deviation) changes from baseline in the fraction of the volume of SSCE cytoplasm occupied by GL-3 inclusions, measured by electron microscopy unbiased stereology, were − 0.06 (0.03) (p = 0.0010) and − 0.12 (0.04) (p = 0.0008), respectively. Venglustat treatment reduced markers in the synthetic and degradative pathway of major glycosphingolipids; proximal markers reduced rapidly and more distal markers (plasma GL-3 and globotriaosylsphingosine) reduced progressively. There were no biochemical or histological indications of progression of Fabry disease over 3 years of follow-up. These findings confirm target engagement and the pharmacodynamic effects of venglustat in adult males with classic Fabry disease. However, further clinical evaluation in larger studies is needed to determine efficacy and safety.
•Substantial pharmacodynamic effects of venglustat in adult males with Fabry disease.•Adverse events were mostly mild (73%) and unrelated to study drug (70%).•No deaths or treatment-related life-threatening adverse events.•Nine serious and 11 severe treatment-emergent adverse events.•Exploratory efficacy justifies further clinical evaluation in patients with Fabry disease.
Eliglustat, an oral substrate reduction therapy, is approved for eligible adults with Gaucher disease type 1. In the Phase 3 ENGAGE trial of previously untreated adults with Gaucher disease type 1, ...eliglustat‐treated patients had statistically significant improvements in organ volumes and hematologic parameters compared with placebo in the 9‐month primary analysis. We report final outcomes by time on eliglustat among all patients who participated in the ENGAGE trial and extension. No patient deteriorated clinically or withdrew due to adverse events; 39/40 patients entered the open‐label extension period and 34/40 (85%) remained in the trial until completion or switching to commercial eliglustat after its approval (2.3–6 years). Clinically meaningful improvements in Gaucher disease manifestations were seen in all patients concomitant with reductions in pathological lipid substrate levels (glucosylceramide and glucosylsphingosine). Among patients with 4.5 years of eliglustat exposure, mean spleen volume decreased by 66% (from 17.1 to 5.8 multiples of normal MN, n = 13), mean liver volume decreased by 23% (from 1.5 to 1.1 MN, n = 13), mean hemoglobin increased 1.4 g/dl (from 11.9 to 13.4 g/dl, n = 12), mean platelet count increased by 87% (from 67.6 to 122.6 × 109/L, n = 12), median chitotriosidase decreased by 82% (from 13 394 to 2312 nmol/h/ml, n = 11), median glucosylceramide decreased by 79% (from 11.5 to 2.4 μg/ml, n = 11), median glucosylsphingosine decreased by 84% (from 518.5 to 72.1 ng/ml, n = 10), and mean spine T‐score increased from −1.07 (osteopenia) to −0.53 (normal) (n = 9). The magnitude of improvement in Gaucher disease manifestations and biomarkers over time was similar among the full trial cohort. Eliglustat was well‐tolerated and led to clinically significant improvements in previously untreated patients with Gaucher disease type 1 during 4.5 years of treatment.
Venglustat is a small‐molecule glucosylceramide synthase (GCS) inhibitor designed to reduce the production of glucosylceramide (GL‐1) and thus is expected to substantially reduce formation of ...glucosylceramide‐based glycosphingolipids. Because of its effect on glycosphingolipid formation, GCS inhibition has therapeutic potential across many disorders affecting glycosphingolipid metabolism. Therefore, venglustat is under development for substrate reduction therapy in multiple diseases, including Gaucher disease type 3, Parkinson's disease associated with GBA mutations, Fabry disease, GM2 gangliosidosis, and autosomal dominant polycystic kidney disease. Phase 1 studies were conducted in healthy volunteers to determine venglustat pharmacokinetics, pharmacodynamics, safety, and tolerability and to assess food effects on pharmacokinetics (single‐dose and food‐effect studies: NCT01674036; repeated‐dose study: NCT01710826). Following a single oral dose of venglustat l‐malate (2, 5, 15, 25, 50, 100, or 150 mg), venglustat demonstrated linear pharmacokinetics, rapid absorption (median tmax, 3.00–5.50 hours), systemic exposure unaffected by food, low apparent total body clearance (mean CL/F, 5.18–6.43 L/h), and pooled geometric mean t1/2z of 28.9 hours. Following repeated once‐daily oral doses of venglustat l‐malate (5, 10, or 20 mg) for 14 days, apparent steady state occurred within 5 days of repeated dosing, with pooled accumulation ratios of 2.10 for Cmax and 2.22 for AUC0–24, and no statistically significant effect of dose or sex on accumulation. The mean fraction of dose excreted unchanged in urine (fe0–24) was 26.3% to 33.1%. Plasma GL‐1 and GM3 decreased time‐ and dose‐dependently. Venglustat demonstrated a favorable safety and tolerability profile.
Menopause is often followed by obesity and, related to this, non-alcoholic fatty liver disease (NAFLD). Two bile acid (BA) receptors, farnesoid X receptor (FXR) and G-protein-coupled receptor TGR5, ...have emerged as putative therapeutic targets for obesity and NAFLD.
Aim of this study: to evaluate the efficacy of selective agonists INT747/obeticholic acid (FXR) and INT777 (TGR5) as novel treatments for the metabolic effects of oestrogen deficiency.
Ovariectomized (OVX) or sham-operated (SHAM) mice were fed a high-fat diet (HFD) for 5weeks. During the last 4weeks two groups of OVX and SHAM mice received either INT747- or INT777-supplemented HFD.
OVX mice had significantly higher bodyweight gain than SHAM mice, which was attenuated by INT747- or INT777-treatment. No significant changes in food intake or physical activity were found. OVX mice had significantly lower energy expenditure than SHAM mice; INT747- and INT777-treated OVX mice had intermediate energy expenditure. Liver triglyceride and cholesterol content was significantly increased in OVX compared to SHAM mice, which was normalized by INT747- or INT777-treatment. Significant changes in metabolic gene expression were found in liver (Cpt1, Acox1), muscle (Ucp3, Pdk4, Cpt1, Acox1, Fasn, Fgf21), brown adipocytes (Dio2) and white adipocytes (c/EBPα, Pparγ, Adipoq). For the first time, expression of FXR and induction of its target gene Pltp1 was shown in skeletal muscle.
BA receptor agonists are suitable therapeutics to correct postmenopausal metabolic changes in an OVX mouse model. Potential mechanisms include increased energy expenditure and changes in expression patterns of key metabolic genes in liver, muscle and adipose tissues.
•OVX mice become obese due to decreased energy expenditure.•BA receptor agonists INT-747 and INT-777 increase energy expenditure in OVX mice.•INT-747 and INT-777 correct liver steatosis in OVX mice by increasing FA oxidation.•INT-747 and INT-777 change the expression of key metabolic genes in multiple organs.•INT-747 and INT-777 correct postmenopausal metabolic changes in an OVX mouse model.
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