Liver cirrhosis is a major cause of death worldwide and is characterized by extensive fibrosis. There are currently no effective antifibrotic therapies available. To obtain a better understanding of ...the cellular and molecular mechanisms involved in disease pathogenesis and enable the discovery of therapeutic targets, here we profile the transcriptomes of more than 100,000 single human cells, yielding molecular definitions for non-parenchymal cell types that are found in healthy and cirrhotic human liver. We identify a scar-associated TREM2
CD9
subpopulation of macrophages, which expands in liver fibrosis, differentiates from circulating monocytes and is pro-fibrogenic. We also define ACKR1
and PLVAP
endothelial cells that expand in cirrhosis, are topographically restricted to the fibrotic niche and enhance the transmigration of leucocytes. Multi-lineage modelling of ligand and receptor interactions between the scar-associated macrophages, endothelial cells and PDGFRα
collagen-producing mesenchymal cells reveals intra-scar activity of several pro-fibrogenic pathways including TNFRSF12A, PDGFR and NOTCH signalling. Our work dissects unanticipated aspects of the cellular and molecular basis of human organ fibrosis at a single-cell level, and provides a conceptual framework for the discovery of rational therapeutic targets in liver cirrhosis.
We report constraints on spin-independent weakly interacting massive particle (WIMP)-nucleon scattering using a 3.35×10^{4} kg day exposure of the Large Underground Xenon (LUX) experiment. A ...dual-phase xenon time projection chamber with 250 kg of active mass is operated at the Sanford Underground Research Facility under Lead, South Dakota (USA). With roughly fourfold improvement in sensitivity for high WIMP masses relative to our previous results, this search yields no evidence of WIMP nuclear recoils. At a WIMP mass of 50 GeV c^{-2}, WIMP-nucleon spin-independent cross sections above 2.2×10^{-46} cm^{2} are excluded at the 90% confidence level. When combined with the previously reported LUX exposure, this exclusion strengthens to 1.1×10^{-46} cm^{2} at 50 GeV c^{-2}.
We present constraints on weakly interacting massive particles (WIMP)-nucleus scattering from the 2013 data of the Large Underground Xenon dark matter experiment, including 1.4×10^{4} kg day of ...search exposure. This new analysis incorporates several advances: single-photon calibration at the scintillation wavelength, improved event-reconstruction algorithms, a revised background model including events originating on the detector walls in an enlarged fiducial volume, and new calibrations from decays of an injected tritium β source and from kinematically constrained nuclear recoils down to 1.1 keV. Sensitivity, especially to low-mass WIMPs, is enhanced compared to our previous results which modeled the signal only above a 3 keV minimum energy. Under standard dark matter halo assumptions and in the mass range above 4 GeV c^{-2}, these new results give the most stringent direct limits on the spin-independent WIMP-nucleon cross section. The 90% C.L. upper limit has a minimum of 0.6 zb at 33 GeV c^{-2} WIMP mass.
We determine the low-redshift field galaxy stellar mass function (GSMF) using an area of 143 deg2 from the first three years of the Galaxy And Mass Assembly (GAMA) survey. The magnitude limits of ...this redshift survey are r < 19.4 mag over two-thirds and 19.8 mag over one-third of the area. The GSMF is determined from a sample of 5210 galaxies using a density-corrected maximum volume method. This efficiently overcomes the issue of fluctuations in the number density versus redshift. With H
0= 70 km s−1 Mpc−1, the GSMF is well described between 108 and 1011.5 M⊙ using a double Schechter function with
,
, α1=−0.35,
and α2=−1.47. This result is more robust to uncertainties in the flow-model corrected redshifts than from the shallower Sloan Digital Sky Survey main sample (r < 17.8 mag). The upturn in the GSMF is also seen directly in the i-band and K-band galaxy luminosity functions. Accurately measuring the GSMF below 108 M⊙ is possible within the GAMA survey volume but as expected requires deeper imaging data to address the contribution from low surface-brightness galaxies.
Western Cambodia is recognized as the epicenter of Plasmodium falciparum multidrug resistance. Recent reports of the efficacy of dihydroartemisinin (DHA)-piperaquine (PP), the latest of the ...artemisinin-based combination therapies (ACTs) recommended by the WHO, have prompted further investigations. The clinical efficacy of dihydroartemisinin-piperaquine in uncomplicated falciparum malaria was assessed in western and eastern Cambodia over 42 days. Day 7 plasma piperaquine concentrations were measured and day 0 isolates tested for in vitro susceptibilities to piperaquine and mefloquine, polymorphisms in the K13 gene, and the copy number of the Pfmdr-1 gene. A total of 425 patients were recruited in 2011 to 2013. The proportion of patients with recrudescent infections was significantly higher in western (15.4%) than in eastern (2.5%) Cambodia (P <10(-3)). Day 7 plasma PP concentrations and median 50% inhibitory concentrations (IC50) of PP were independent of treatment outcomes, in contrast to median mefloquine IC50, which were found to be lower for isolates from patients with recrudescent infections (18.7 versus 39.7 nM; P = 0.005). The most significant risk factor associated with DHA-PP treatment failure was infection by parasites carrying the K13 mutant allele (odds ratio OR, 17.5; 95% confidence interval CI, 1 to 308; P = 0.04). Our data show evidence of P. falciparum resistance to PP in western Cambodia, an area of widespread artemisinin resistance. New therapeutic strategies, such as the use of triple ACTs, are urgently needed and must be tested. (This study has been registered at the Australian New Zealand Clinical Trials Registry under registration no. ACTRN12614000344695.).
We present experimental constraints on the spin-dependent WIMP (weakly interacting massive particle)-nucleon elastic cross sections from LUX data acquired in 2013. LUX is a dual-phase xenon time ...projection chamber operating at the Sanford Underground Research Facility (Lead, South Dakota), which is designed to observe the recoil signature of galactic WIMPs scattering from xenon nuclei. A profile likelihood ratio analysis of 1.4×10^{4} kg day of fiducial exposure allows 90% C.L. upper limits to be set on the WIMP-neutron (WIMP-proton) cross section of σ_{n}=9.4×10^{-41} cm^{2} (σ_{p}=2.9×10^{-39} cm^{2}) at 33 GeV/c^{2}. The spin-dependent WIMP-neutron limit is the most sensitive constraint to date.
Resonantly driven CNOT gate for electron spins Zajac, D M; Sigillito, A J; Russ, M ...
Science (American Association for the Advancement of Science),
01/2018, Letnik:
359, Številka:
6374
Journal Article
Recenzirano
Odprti dostop
Single-qubit rotations and two-qubit CNOT operations are crucial ingredients for universal quantum computing. Although high-fidelity single-qubit operations have been achieved using the electron spin ...degree of freedom, realizing a robust CNOT gate has been challenging because of rapid nuclear spin dephasing and charge noise. We demonstrate an efficient resonantly driven CNOT gate for electron spins in silicon. Our platform achieves single-qubit rotations with fidelities greater than 99%, as verified by randomized benchmarking. Gate control of the exchange coupling allows a quantum CNOT gate to be implemented with resonant driving in ~200 nanoseconds. We used the CNOT gate to generate a Bell state with 78% fidelity (corrected for errors in state preparation and measurement). Our quantum dot device architecture enables multi-qubit algorithms in silicon.
Biomass burning (BB) is a major global source of trace gases and particles. Accurately representing the production and evolution of these emissions is an important goal for atmospheric chemical ...transport models. We measured a suite of gases and aerosols emitted from an 81 hectare prescribed fire in chaparral fuels on the central coast of California, US on 17 November 2009. We also measured physical and chemical changes that occurred in the isolated downwind plume in the first ~4 h after emission. The measurements were carried out onboard a Twin Otter aircraft outfitted with an airborne Fourier transform infrared spectrometer (AFTIR), aerosol mass spectrometer (AMS), single particle soot photometer (SP2), nephelometer, LiCor CO2 analyzer, a chemiluminescence ozone instrument, and a wing-mounted meteorological probe. Our measurements included: CO2; CO; NOx; NH3; non-methane organic compounds; organic aerosol (OA); inorganic aerosol (nitrate, ammonium, sulfate, and chloride); aerosol light scattering; refractory black carbon (rBC); and ambient temperature, relative humidity, barometric pressure, and three-dimensional wind velocity. The molar ratio of excess O3 to excess CO in the plume (ΔO3/ΔCO) increased from −5.13 (±1.13) × 10−3 to 10.2 (±2.16) × 10−2 in ~4.5 h following smoke emission. Excess acetic and formic acid (normalized to excess CO) increased by factors of 1.73 ± 0.43 and 7.34 ± 3.03 (respectively) over the same time since emission. Based on the rapid decay of C2H4 we infer an in-plume average OH concentration of 5.27 (±0.97) × 106 molec cm−3, consistent with previous studies showing elevated OH concentrations in biomass burning plumes. Ammonium, nitrate, and sulfate all increased over the course of 4 h. The observed ammonium increase was a factor of 3.90 ± 2.93 in about 4 h, but accounted for just ~36% of the gaseous ammonia lost on a molar basis. Some of the gas phase NH3 loss may have been due to condensation on, or formation of, particles below the AMS detection range. NOx was converted to PAN and particle nitrate with PAN production being about two times greater than production of observable nitrate in the first ~4 h following emission. The excess aerosol light scattering in the plume (normalized to excess CO2) increased by a factor of 2.50 ± 0.74 over 4 h. The increase in light scattering was similar to that observed in an earlier study of a biomass burning plume in Mexico where significant secondary formation of OA closely tracked the increase in scattering. In the California plume, however, ΔOA/ΔCO2 decreased sharply for the first hour and then increased slowly with a net decrease of ~20% over 4 h. The fraction of thickly coated rBC particles increased up to ~85% over the 4 h aging period. Decreasing OA accompanied by increased scattering/particle coating in initial aging may be due to a combination of particle coagulation and evaporation processes. Recondensation of species initially evaporated from the particles may have contributed to the subsequent slow rise in OA. We compare our results to observations from other plume aging studies and suggest that differences in environmental factors such as smoke concentration, oxidant concentration, actinic flux, and RH contribute significantly to the variation in plume evolution observations.
This is a cross-sectional, observational study to determine the frequency and associated features of HIV-associated neurocognitive disorders (HAND) in a large, diverse sample of infected individuals ...in the era of combination antiretroviral therapy (CART).
A total of 1,555 HIV-infected adults were recruited from 6 university clinics across the United States, with minimal exclusions. We used standardized neuromedical, psychiatric, and neuropsychological (NP) examinations, and recently published criteria for diagnosing HAND and classifying 3 levels of comorbidity (minimal to severe non-HIV risks for NP impairment).
Fifty-two percent of the total sample had NP impairment, with higher rates in groups with greater comorbidity burden (40%, 59%, and 83%). Prevalence estimates for specific HAND diagnoses (excluding severely confounded cases) were 33% for asymptomatic neurocognitive impairment, 12% for mild neurocognitive disorder, and only 2% for HIV-associated dementia (HAD). Among participants with minimal comorbidities (n = 843), history of low nadir CD4 was a strong predictor of impairment, and the lowest impairment rate on CART occurred in the subset with suppressed plasma viral loads and nadir CD4 ≥200 cells/mm(3) (30% vs 47% in remaining subgroups).
The most severe HAND diagnosis (HAD) was rare, but milder forms of impairment remained common, even among those receiving CART who had minimal comorbidities. Future studies should clarify whether early disease events (e.g., profound CD4 decline) may trigger chronic CNS changes, and whether early CART prevents or reverses these changes.
Opioids have been used to manage pain for thousands of years, but they have significant potential for abuse. Prescription opioids, like oxycodone, are associated with 32% of overdoses, that have ...reached a total of 75,673 deaths in 2021. A major challenge is maximizing their therapeutic potential while minimizing the negative side effects including opioid use disorder (OUD). The Ketogenic Diet (KD) has been reported to reduce pain and decrease the severity of alcohol use disorder, yet its effects on oxycodone responses remain unknown. KD mice displayed increased oxycodone-induced locomotor activity and enhanced antinociceptive effects of oxycodone, suggesting a dietary effect on opiate sensitivity. Male KD mice exposed to chronic oxycodone exhibited increased naloxone-induced jumps, suggesting a sex-specific effect of diet on opioid withdrawal. Consistent with this, male KD mice self-administered less oxycodone while female KD mice did not differ from controls. Finally, no effect of KD on motivation to obtain oxycodone was observed during a progressive ratio schedule. These data suggest sex-biased effects of KD on responses to opioids that should be considered and potentially leveraged in both clinical pain management and treatment of OUD.
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