Superconductivity and ferromagnetism are antagonistic forms of order, and rarely coexist. Many interesting new phenomena occur, however, in hybrid superconducting/ferromagnetic systems. For example, ...a Josephson junction containing a ferromagnetic material can exhibit an intrinsic phase shift of pi in its ground state for certain thicknesses of the material. Such ' pi -junctions' were first realized experimentally in 2001 (refs ,), and have been proposed as circuit elements for both high-speed classical superconducting computing and for quantum computing. Here we demonstrate experimentally that the phase state of a Josephson junction containing two ferromagnetic layers can be toggled between 0 and pi by changing the relative orientation of the two magnetizations. These controllable 0- pi junctions have immediate applications in cryogenic memory, where they serve as a necessary component to an ultralow power superconducting computer. Such a fully superconducting computer is estimated to be orders of magnitude more energy-efficient than current semiconductor-based supercomputers. Phase-controllable junctions also open up new possibilities for superconducting circuit elements such as superconducting 'programmable logic', where they could function in superconducting analogues to field-programmable gate arrays.
Purpose
The increasing interest and availability of non-standard positron-emitting radionuclides has heightened the relevance of radionuclide choice in the development and optimization of new ...positron emission tomography (PET) imaging procedures, both in preclinical research and clinical practice. Differences in achievable resolution arising from positron range can largely influence application suitability of each radionuclide, especially in small-ring preclinical PET where system blurring factors due to annihilation photon acollinearity and detector geometry are less significant. Some resolution degradation can be mitigated with appropriate range corrections implemented during image reconstruction, the quality of which is contingent on an accurate characterization of positron range.
Procedures
To address this need, we have characterized the positron range of several standard and non-standard PET radionuclides (As-72, F-18, Ga-68, Mn-52, Y-86, and Zr-89) through imaging of small-animal quality control phantoms on a benchmark preclinical PET scanner. Further, the Particle and Heavy Ion Transport code System (PHITS v3.02) code was utilized for Monte Carlo modeling of positron range-dependent blurring effects.
Results
Positron range kernels for each radionuclide were derived from simulation of point sources in ICRP reference tissues. PET resolution and quantitative accuracy afforded by various radionuclides in practicable imaging scenarios were characterized using a convolution-based method based on positron annihilation distributions obtained from PHITS. Our imaging and simulation results demonstrate the degradation of small animal PET resolution, and quantitative accuracy correlates with increasing positron energy; however, for a specific “benchmark” preclinical PET scanner and reconstruction workflow, these differences were observed to be minimal given radionuclides with average positron energies below ~ 400 keV.
Conclusion
Our measurements and simulations of the influence of positron range on PET resolution compare well with previous efforts documented in the literature and provide new data for several radionuclides in increasing clinical and preclinical use. The results will support current and future improvements in methods for positron range corrections in PET imaging.
The complete characterization of the pressure profile of high-redshift galaxy clusters, from their core to their outskirts, is a major issue for the study of the formation of large-scale structures. ...It is essential to constrain a potential redshift evolution of both the slope and scatter of the mass-observable scaling relations used in cosmology studies based on cluster statistics. In this paper, we present the first thermal Sunyaev–Zel’dovich (tSZ) mapping of a cluster from the sample of the New IRAM Kids Arrays (NIKA2) SZ large program that aims at constraining the redshift evolution of cluster pressure profiles and the tSZ-mass scaling relation. We observed the galaxy cluster PSZ2 G144.83+25.11 at redshift z = 0.58 with the NIKA2 camera, a dual-band (150 and 260 GHz) instrument operated at the Institut de Radioastronomie Millimtrique (IRAM) 30-m telescope. We identify a thermal pressure excess in the south-west region of PSZ2 G144.83+25.11 and a high-redshift sub-millimeter point source that affect the intracluster medium (ICM) morphology of the cluster. The NIKA2 data are used jointly with tSZ data acquired by the Multiplexed SQUID/TES Array at Ninety Gigahertz (MUSTANG), Bolocam, and Planck experiments in order to non-parametrically set the best constraints on the electronic pressure distribution from the cluster core (R ~ 0.02R500) to its outskirts (R ~ 3R500). We investigate the impact of the over-pressure region on the shape of the pressure profile and on the constraints on the integrated Compton parameter Y500. A hydrostatic mass analysis is also performed by combining the tSZ-constrained pressure profile with the deprojected electronic density profile from XMM-Newton. This allows us to conclude that the estimates of Y500 and M500 obtained from the analysis with and without masking the disturbed ICM region differ by 65% and 79%, respectively. This work highlights that NIKA2 will have a crucial impact on the characterization of the scatter of the Y500−M500 scaling relation due to its high potential to constrain the thermodynamic and morphological properties of the ICM when used in synergy with X-ray observations of similar angular resolution. This study also presents the typical products that will be delivered to the community for all clusters included in the NIKA2 tSZ Large Program.
PharmVar GeneFocus: CYP3A5 Rodriguez‐Antona, Cristina; Savieo, Jessica L.; Lauschke, Volker M. ...
Clinical pharmacology and therapeutics,
December 2022, Letnik:
112, Številka:
6
Journal Article
Recenzirano
Odprti dostop
The Pharmacogene Variation Consortium (PharmVar) catalogs star (*) allele nomenclature for the polymorphic human CYP3A5 gene. Genetic variation within the CYP3A5 gene locus impacts the metabolism of ...several clinically important drugs, including the immunosuppressants tacrolimus, sirolimus, cyclosporine, and the benzodiazepine midazolam. Variable CYP3A5 activity is of clinical importance regarding tacrolimus metabolism. This GeneFocus provides a CYP3A5 gene summary with a focus on aspects regarding standardized nomenclature. In addition, this review also summarizes recent changes and updates, including the retirement of several allelic variants and provides an overview of how PharmVar CYP3A5 star allele nomenclature is utilized by the Pharmacogenomics Knowledgebase (PharmGKB) and the Clinical Pharmacogenetics Implementation Consortium (CPIC).
Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have been postulated to affect susceptibility to COVID-19. Observational studies so far have lacked rigorous ...ascertainment adjustment and international generalisability. We aimed to determine whether use of ACEIs or ARBs is associated with an increased susceptibility to COVID-19 in patients with hypertension.
In this international, open science, cohort analysis, we used electronic health records from Spain (Information Systems for Research in Primary Care SIDIAP) and the USA (Columbia University Irving Medical Center data warehouse CUIMC and Department of Veterans Affairs Observational Medical Outcomes Partnership VA-OMOP) to identify patients aged 18 years or older with at least one prescription for ACEIs and ARBs (target cohort) or calcium channel blockers (CCBs) and thiazide or thiazide-like diuretics (THZs; comparator cohort) between Nov 1, 2019, and Jan 31, 2020. Users were defined separately as receiving either monotherapy with these four drug classes, or monotherapy or combination therapy (combination use) with other antihypertensive medications. We assessed four outcomes: COVID-19 diagnosis; hospital admission with COVID-19; hospital admission with pneumonia; and hospital admission with pneumonia, acute respiratory distress syndrome, acute kidney injury, or sepsis. We built large-scale propensity score methods derived through a data-driven approach and negative control experiments across ten pairwise comparisons, with results meta-analysed to generate 1280 study effects. For each study effect, we did negative control outcome experiments using a possible 123 controls identified through a data-rich algorithm. This process used a set of predefined baseline patient characteristics to provide the most accurate prediction of treatment and balance among patient cohorts across characteristics. The study is registered with the EU Post-Authorisation Studies register, EUPAS35296.
Among 1 355 349 antihypertensive users (363 785 ACEI or ARB monotherapy users, 248 915 CCB or THZ monotherapy users, 711 799 ACEI or ARB combination users, and 473 076 CCB or THZ combination users) included in analyses, no association was observed between COVID-19 diagnosis and exposure to ACEI or ARB monotherapy versus CCB or THZ monotherapy (calibrated hazard ratio HR 0·98, 95% CI 0·84–1·14) or combination use exposure (1·01, 0·90–1·15). ACEIs alone similarly showed no relative risk difference when compared with CCB or THZ monotherapy (HR 0·91, 95% CI 0·68–1·21; with heterogeneity of >40%) or combination use (0·95, 0·83–1·07). Directly comparing ACEIs with ARBs demonstrated a moderately lower risk with ACEIs, which was significant with combination use (HR 0·88, 95% CI 0·79–0·99) and non-significant for monotherapy (0·85, 0·69–1·05). We observed no significant difference between drug classes for risk of hospital admission with COVID-19, hospital admission with pneumonia, or hospital admission with pneumonia, acute respiratory distress syndrome, acute kidney injury, or sepsis across all comparisons.
No clinically significant increased risk of COVID-19 diagnosis or hospital admission-related outcomes associated with ACEI or ARB use was observed, suggesting users should not discontinue or change their treatment to decrease their risk of COVID-19.
Wellcome Trust, UK National Institute for Health Research, US National Institutes of Health, US Department of Veterans Affairs, Janssen Research & Development, IQVIA, South Korean Ministry of Health and Welfare Republic, Australian National Health and Medical Research Council, and European Health Data and Evidence Network.
SCL/Tal-1 is a transcription factor necessary for hematopoietic stem cell differentiation. Although SCL is also expressed in endothelial and neural progenitors, SCL function in these cells remains ...unknown. In the zebrafish mutant cloche (clo), SCL expression is nearly abolished in hematopoietic and vascular tissues. Correspondingly, it was shown previously that clo fails to differentiate blood and angioblasts. Genetic analysis demonstrates that the clo mutation is not linked to the SCL locus. Forced expression of SCL in clo embryos rescues the blood and vascular defects, suggesting that SCL acts downstream of clo to specify hematopoietic and vascular differentiation.
We describe a collection of expressed sequence tags (ESTs) for Saccoglossus kowalevskii, a direct-developing hemichordate valuable for evolutionary comparisons with chordates. The 202,175 ESTs ...represent 163,633 arrayed clones carrying cDNAs prepared from embryonic libraries, and they assemble into 13,677 continuous sequences (contigs), leaving 10,896 singletons (excluding mitochondrial sequences). Of the contigs, 53% had significant matches when BLAST was used to query the NCBI databases (≤10⁻¹⁰), as did 51% of the singletons. Contigs most frequently matched sequences from amphioxus (29%), chordates (67%), and deuterostomes (87%). From the clone array, we isolated 400 full-length sequences for transcription factors and signaling proteins of use for evolutionary and developmental studies. The set includes sequences for fox, pax, tbx, hox, and other homeobox-containing factors, and for ligands and receptors of the TGFβ, Wnt, Hh, Delta/Notch, and RTK pathways. At least 80% of key sequences have been obtained, when judged against gene lists of model organisms. The median length of these cDNAs is 2.3 kb, including 1.05 kb of 3' untranslated region (UTR). Only 30% are entirely matched by single contigs assembled from ESTs. We conclude that an EST collection based on 150,000 clones is a rich source of sequences for molecular developmental work, and that the EST approach is an efficient way to initiate comparative studies of a new organism.
Quinoa (Chenopodium quinoa Willd.) is a staple food crop for millions of impoverished rural inhabitants of Andean South America where it has been cultivated for millennia. Interest in quinoa, due ...largely to its superior nutritional characteristics, is fuelling a growing export market and has led to an increased focus on genetic research and the development of quinoa breeding programmes throughout South America. The success of these breeding programmes will rely heavily on the development of core germplasm collections and germplasm conservation. We report the development of a set of fluorescence-tagged microsatellite molecular markers that can be used to characterize genetic diversity within quinoa germplasm and we use this set of 36 microsatellites markers to genetically characterize the diversity of 121 accessions of C. quinoa held in the USDA germplasm bank, 22 accessions from the CIP-FAO international nursery collection and eight accessions representing parents from genetic mapping populations. A total of 420 alleles were detected among the quinoa accessions with an average of 11 alleles detected per microsatellite locus. Genetic heterogeneity was observed in 32% of the quinoa accessions at a given locus and suggests that many of these accessions represent heterogeneous seed lots or landraces. Both unweighted pair-group method with arithmetic averages (UPGMA) and principle components analysis (PCA) analyses partitioned the quinoa accessions into two main clusters. The first major cluster consisted of accessions from the Andean highlands of Peru, Bolivia, Ecuador, Argentina and extreme northeastern Chile. The other main cluster contained accessions from both the lowlands of Chile and a set of USDA accessions with no known passport data, collected by Emigdio Ballón. Using the patterns of genetic diversity detected within the C. quinoa accessions we discuss hypotheses regarding quinoa's centre of diversity, including highland and lowland ecotype clustering patterns, origin of lowland varieties, origin of domestication, and diversity levels in the USDA and CIP-FAO collections. PUBLICATION ABSTRACT
Plasma-derived antithrombin III (ATIII) prevents the lethal effects of Escherichia coli infusion in baboons, but the mechanisms behind this effect are not clear. In the present study, we evaluated ...the effects of recombinant human ATIII (rhATIII) on the clinical course and the inflammatory cytokine and coagulation responses in baboons challenged with lethal dose of E coli. Animals in the treatment group (n = 5) received high doses of rhATIII starting 1 hour before an E colichallenge. Those in the control group were administered saline. Survival was significantly improved in the treatment group (P = .002). Both groups had similar hemodynamic responses to E coli challenge but different coagulation and inflammatory responses. The rhATIII group had an accelerated increase of thrombin-ATIII complexes and significantly less fibrinogen consumption compared to controls. In addition, the rhATIII group had much less severe thrombotic pathology on autopsy and virtually no fibrinolytic response to E coli challenge. Furthermore, the rhATIII group had a significantly attenuated inflammatory response as evidenced by marked reduction of the release of various cytokines. We conclude that the early administration of high doses of rhATIII improves the outcome in baboons lethally challenged with E coli, probably due to the combined anticoagulation and anti-inflammatory effects of this therapy.
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