Automated Single-Particle Reconstruction of Heterogeneous Inorganic Nanoparticles

Single-particle reconstruction can be used to perform three-dimensional (3D) imaging of homogeneous populations of nano-sized objects, in particular viruses and proteins. Here, it is demonstrated that it can also be used to obtain 3D reconstructions of heterogeneous populations of inorganic nanoparticles. An automated acquisition scheme in a scanning transmission electron microscope is used to collect images of thousands of nanoparticles. Particle images are subsequently semi-automatically clustered in terms of their properties and separate 3D reconstructions are performed from selected particle image clusters. The result is a 3D dataset that is representative of the full population. The study demonstrates a methodology that allows 3D imaging and analysis of inorganic nanoparticles in a fully automated manner that is truly representative of large particle populations.Peer reviewe

Heterogeneity among Isolates Reveals that Fitness in Low Oxygen Correlates with Aspergillus fumigatus Virulence

Previous work has shown that environmental and clinical isolates of Aspergillus fumigatus represent a diverse population that occupies a variety of niches, has extensive genetic diversity, and exhibits virulence heterogeneity in a number of animal models of invasive pulmonary aspergillosis (IPA). However, mechanisms explaining differences in virulence among A. fumigatus isolates remain enigmatic. Here, we report a significant difference in virulence of two common lab strains, CEA10 and AF293, in the murine triamcinolone immunosuppression model of IPA, in which we previously identified severe low oxygen microenvironments surrounding fungal lesions. Therefore, we hypothesize that the ability to thrive within these lesions of low oxygen promotes virulence of A. fumigatus in this model. To test this hypothesis, we performed in vitro fitness and in vivo virulence analyses in the triamcinolone murine model of IPA with 14 environmental and clinical isolates of A. fumigatus Among these isolates, we observed a strong correlation between fitness in low oxygen in vitro and virulence. In further support of our hypothesis, experimental evolution of AF293, a strain that exhibits reduced fitness in low oxygen and reduced virulence in the triamcinolone model of IPA, results in a strain (EVOL20) that has increased hypoxia fitness and a corresponding increase in virulence. Thus, the ability to thrive in low oxygen correlates with virulence of A. fumigatus isolates in the context of steroid-mediated murin

Cosmology of the Tachyon in Brane Inflation

In certain implementations of the brane inflationary paradigm, the exit from inflation occurs when the branes annihilate through tachyon condensation. We investigate various cosmological effects produced by this tachyonic era. We find that only a very small region of the parameter space (corresponding to slow-roll with tiny inflaton mass) allows for the tachyon to contribute some e-folds to inflation. In addition, non-adiabatic density perturbations are generated at the end of inflation. When the brane is moving relativistically this contribution can be of the same order as fluctuations produced 55 e-folds before the end of inflation. The additional contribution is very nearly scale-invariant and enhances the tensor/scalar ratio. Additional non-gaussianities will also be generated, sharpening current constraints on DBI-type models which already predict a significantly non-gaussian signal.Comment: 30 pages, 2 figures; v3, minor revision, JCAP versio

Realizing the Nishimori transition across the error threshold for constant-depth quantum circuits

Preparing quantum states across many qubits is necessary to unlock the full potential of quantum computers. However, a key challenge is to realize efficient preparation protocols which are stable to noise and gate imperfections. Here, using a measurement-based protocol on a 127 superconducting qubit device, we study the generation of the simplest long-range order -- Ising order, familiar from Greenberger-Horne-Zeilinger (GHZ) states and the repetition code -- on 54 system qubits. Our efficient implementation of the constant-depth protocol and classical decoder shows higher fidelities for GHZ states compared to size-dependent, unitary protocols. By experimentally tuning coherent and incoherent error rates, we demonstrate stability of this decoded long-range order in two spatial dimensions, up to a critical point which corresponds to a transition belonging to the unusual Nishimori universality class. Although in classical systems Nishimori physics requires fine-tuning multiple parameters, here it arises as a direct result of the Born rule for measurement probabilities -- locking the effective temperature and disorder driving this transition. Our study exemplifies how measurement-based state preparation can be meaningfully explored on quantum processors beyond a hundred qubits.Comment: 16 pages, 18 figure

Missed visits and mortality among patients establishing initial outpatient HIV treatment

BACKGROUND: Dramatic increases in the number of patients requiring linkage to treatment for human immunodeficiency virus (HIV) infection are anticipated in response to updated Centers for Disease Control and Prevention HIV testing recommendations that advocate routine, opt-out HIV testing. METHODS: A retrospective analysis nested within a prospective HIV clinical cohort study evaluated patients who established initial outpatient treatment for HIV infection at the University of Alabama at Birmingham 1917 HIV/AIDS Clinic from 1 January 2000 through 31 December 2005. Survival methods were used to evaluate the impact of missed visits during the first year of care on subsequent mortality in the context of other baseline sociodemographic, psychosocial, and clinical factors. Mortality was ascertained by query of the Social Security Death Index as of 1 August 2007. RESULTS: Among 543 study participants initiating outpatient care for HIV infection, 60% missed a visit within the first year. The mortality rate was 2.3 deaths per 100 person-years for patients who missed visits, compared with 1.0 deaths per 100 person-years for those who attended all scheduled appointments during the first year after establishing outpatient treatment (P = .02). In Cox proportional hazards analysis, higher hazards of death were independently associated with missed visits (hazard ratio, 2.90; 95% confidence interval, 1.28-6.56), older age (hazard ratio, 1.58 per 10 years of age; 95% confidence interval, 1.12-2.22), and baseline CD4+ cell count \u3c 200 cells/mm(3) (hazard ratio, 2.70; 95% confidence interval, 1.00-7.30). CONCLUSIONS: Patients who missed visits within the first year after initiating outpatient treatment for HIV infection had more than twice the rate of long-term mortality, compared with those patients who attended all scheduled appointments. We posit that early missed visits are not causally responsible for the higher observed mortality but, rather, identify those patients who are more likely to exhibit health behaviors that portend increased subsequent mortality

A Randomized Ph2 Study of MEDI0680 in Combination With Durvalumab vs. Nivolumab Monotherapy in Patients With Advanced or Metastatic Clear Cell Renal Cell Carcinoma

BACKGROUND: MEDI0680 is a humanized anti-programmed cell death-1 (PD-1) antibody and durvalumab is an anti-PD-L1 antibody. Combining treatment using these antibodies may improve efficacy versus blockade of PD-1 alone. This phase 2 study evaluated antitumor activity and safety of MEDI0680 plus durvalumab versus nivolumab monotherapy in immunotherapy naïve patients with advanced clear cell renal cell carcinoma who received at least one prior line of anti-angiogenic therapy. METHODS: Patients received either MEDI0680 (20 mg/kg) with durvalumab (750 mg) or nivolumab (240 mg), all IV Q2W. The primary endpoint was investigator-assessed objective response rate (ORR). Secondary endpoints included best overall response, progression-free survival (PFS), safety, overall survival (OS), and immunogenicity. Exploratory endpoints included changes in circulating tumor DNA (ctDNA), baseline tumor mutational burden (TMB), and tumor-infiltrated immune cell profiles. RESULTS: Sixty-three patients were randomized (combination, n = 42; nivolumab, n = 21). ORR was 16.7% (7/42; 95% CI, 7.0-31.4) with combination treatment and 23.8% (5/21; 95% CI, 8.2- 47.2) with nivolumab. Median PFS was 3.6 months in both arms; median OS was not reached in either arm. Due to AEs, 23.8% of patients discontinued MEDI0680 and durvalumab and 14.3% of patients discontinued nivolumab. In the combination arm, reduction in ctDNA fraction was associated with longer PFS. ctDNA mutational analysis did not demonstrate an association with response in either arm. Tumor-infiltrated immune profiles showed an association between immune cell activation and response in the combination arm. CONCLUSIONS: MEDI0680 combined with durvalumab was safe and tolerable; however, it did not improve efficacy versus nivolumab monotherapy

Comparison of Pittsburgh compound B and florbetapir in cross-sectional and longitudinal studies.

IntroductionQuantitative in vivo measurement of brain amyloid burden is important for both research and clinical purposes. However, the existence of multiple imaging tracers presents challenges to the interpretation of such measurements. This study presents a direct comparison of Pittsburgh compound B-based and florbetapir-based amyloid imaging in the same participants from two independent cohorts using a crossover design.MethodsPittsburgh compound B and florbetapir amyloid PET imaging data from three different cohorts were analyzed using previously established pipelines to obtain global amyloid burden measurements. These measurements were converted to the Centiloid scale to allow fair comparison between the two tracers. The mean and inter-individual variability of the two tracers were compared using multivariate linear models both cross-sectionally and longitudinally.ResultsGlobal amyloid burden measured using the two tracers were strongly correlated in both cohorts. However, higher variability was observed when florbetapir was used as the imaging tracer. The variability may be partially caused by white matter signal as partial volume correction reduces the variability and improves the correlations between the two tracers. Amyloid burden measured using both tracers was found to be in association with clinical and psychometric measurements. Longitudinal comparison of the two tracers was also performed in similar but separate cohorts whose baseline amyloid load was considered elevated (i.e., amyloid positive). No significant difference was detected in the average annualized rate of change measurements made with these two tracers.DiscussionAlthough the amyloid burden measurements were quite similar using these two tracers as expected, difference was observable even after conversion into the Centiloid scale. Further investigation is warranted to identify optimal strategies to harmonize amyloid imaging data acquired using different tracers

Design-controlled synthesis of IrO2 sub-monolayers on Au nanoflowers : marrying plasmonic and electrocatalytic properties

We develop herein plasmonic-catalytic Au-IrO2 nanostructures with a morphology optimized for efficient light harvesting and catalytic surface area; the nanoparticles have a nanoflower morphology, with closely spaced Au branches all partially covered by an ultrathin (1 nm) IrO2 shell. This nanoparticle architecture optimizes optical features due to the interactions of closely spaced plasmonic branches forming electromagnetic hot spots, and the ultra-thin IrO2 layer maximizes efficient use of this expensive catalyst. This concept was evaluated towards the enhancement of the electrocatalytic performances towards the oxygen evolution reaction (OER) as a model transformation. The OER can play a central role in meeting future energy demands but the performance of conventional electrocatalysts in this reaction is limited by the sluggish OER kinetics. We demonstrate an improvement of the OER performance for one of the most active OER catalysts, IrO2, by harvesting plasmonic effects from visible light illumination in multimetallic nanoparticles. We find that the OER activity for the Au-IrO2 nanoflowers can be improved under LSPR excitation, matching best properties reported in the literature. Our simulations and electrocatalytic data demonstrate that the enhancement in OER activities can be attributed to an electronic interaction between Au and IrO2 and to the activation of Ir-O bonds by LSPR excited hot holes, leading to a change in the reaction mechanism (rate-determinant step) under visible light illumination.Peer reviewe