Nuclear spins were among the first physical platforms to be considered for quantum information processing
, because of their exceptional quantum coherence
and atomic-scale footprint. However, their ...full potential for quantum computing has not yet been realized, owing to the lack of methods with which to link nuclear qubits within a scalable device combined with multi-qubit operations with sufficient fidelity to sustain fault-tolerant quantum computation. Here we demonstrate universal quantum logic operations using a pair of ion-implanted
P donor nuclei in a silicon nanoelectronic device. A nuclear two-qubit controlled-Z gate is obtained by imparting a geometric phase to a shared electron spin
, and used to prepare entangled Bell states with fidelities up to 94.2(2.7)%. The quantum operations are precisely characterized using gate set tomography (GST)
, yielding one-qubit average gate fidelities up to 99.95(2)%, two-qubit average gate fidelity of 99.37(11)% and two-qubit preparation/measurement fidelities of 98.95(4)%. These three metrics indicate that nuclear spins in silicon are approaching the performance demanded in fault-tolerant quantum processors
. We then demonstrate entanglement between the two nuclei and the shared electron by producing a Greenberger-Horne-Zeilinger three-qubit state with 92.5(1.0)% fidelity. Because electron spin qubits in semiconductors can be further coupled to other electrons
or physically shuttled across different locations
, these results establish a viable route for scalable quantum information processing using donor nuclear and electron spins.
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019 has triggered an ongoing global pandemic of the severe pneumonia-like disease coronavirus disease 2019 (COVID-19)
.... The development of a vaccine is likely to take at least 12-18 months, and the typical timeline for approval of a new antiviral therapeutic agent can exceed 10 years. Thus, repurposing of known drugs could substantially accelerate the deployment of new therapies for COVID-19. Here we profiled a library of drugs encompassing approximately 12,000 clinical-stage or Food and Drug Administration (FDA)-approved small molecules to identify candidate therapeutic drugs for COVID-19. We report the identification of 100 molecules that inhibit viral replication of SARS-CoV-2, including 21 drugs that exhibit dose-response relationships. Of these, thirteen were found to harbour effective concentrations commensurate with probable achievable therapeutic doses in patients, including the PIKfyve kinase inhibitor apilimod
and the cysteine protease inhibitors MDL-28170, Z LVG CHN2, VBY-825 and ONO 5334. Notably, MDL-28170, ONO 5334 and apilimod were found to antagonize viral replication in human pneumocyte-like cells derived from induced pluripotent stem cells, and apilimod also demonstrated antiviral efficacy in a primary human lung explant model. Since most of the molecules identified in this study have already advanced into the clinic, their known pharmacological and human safety profiles will enable accelerated preclinical and clinical evaluation of these drugs for the treatment of COVID-19.
70-year legacy of the Framingham Heart Study Andersson, Charlotte; Johnson, Andrew D; Benjamin, Emelia J ...
Nature reviews cardiology,
11/2019, Letnik:
16, Številka:
11
Journal Article
Recenzirano
The Framingham Heart Study (FHS) was established in 1948 to improve understanding of the epidemiology of coronary heart disease (CHD) in the USA. In 1961, seminal work identified major risk factors ...for CHD (high blood pressure, high cholesterol levels and evidence on the electrocardiogram of left ventricular hypertrophy), which later formed the basis for multivariable 10-year and 30-year risk-prediction algorithms. The FHS cohorts now comprise three generations of participants (n ≈ 15,000) and two minority cohorts. The FHS cohorts are densely phenotyped, with recurring follow-up examinations and surveillance for cardiovascular and non-cardiovascular end points. Assessment of subclinical disease and physiological profiling of these cohorts (with the use of echocardiography, ambulatory electrocardiographic monitoring, exercise stress testing, cardiac CT, heart and brain MRI, serial vascular tonometry and accelerometry) have been performed repeatedly. Over the past decade, the FHS cohorts have undergone deep 'omics' profiling (including whole-genome sequencing, DNA methylation analysis, transcriptomics, high-throughput proteomics and metabolomics, and microbiome studies). The FHS is a rich, longitudinal, transgenerational and deeply phenotyped cohort study with a sustained focus on state-of-the-art epidemiological methods and technological advances to facilitate scientific discoveries.
The Middle East respiratory syndrome coronavirus (MERS-CoV), an emerging human coronavirus, causes severe acute respiratory illness with a 35% mortality rate. In light of the recent surge in reported ...infections we have developed asymmetric five-primer reverse transcription loop-mediated isothermal amplification (RT-LAMP) assays for detection of MERS-CoV. Isothermal amplification assays will facilitate the development of portable point-of-care diagnostics that are crucial for management of emerging infections. The RT-LAMP assays are designed to amplify MERS-CoV genomic loci located within the open reading frame (ORF)1a and ORF1b genes and upstream of the E gene. Additionally we applied one-step strand displacement probes (OSD) for real-time sequence-specific verification of LAMP amplicons. Asymmetric amplification effected by incorporating a single loop primer in each assay accelerated the time-to-result of the OSD-RT-LAMP assays. The resulting assays could detect 0.02 to 0.2 plaque forming units (PFU) (5 to 50 PFU/ml) of MERS-CoV in infected cell culture supernatants within 30 to 50 min and did not cross-react with common human respiratory pathogens.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We created a deeply extracted and annotated database of genome-wide association studies (GWAS) results. GRASP v1.0 contains >6.2 million SNP-phenotype association from among 1390 GWAS studies. We ...re-annotated GWAS results with 16 annotation sources including some rarely compared to GWAS results (e.g. RNAediting sites, lincRNAs, PTMs).
To create a high-quality resource to facilitate further use and interpretation of human GWAS results in order to address important scientific questions.
GWAS have grown exponentially, with increases in sample sizes and markers tested, and continuing bias toward European ancestry samples. GRASP contains >100 000 phenotypes, roughly: eQTLs (71.5%), metabolite QTLs (21.2%), methylation QTLs (4.4%) and diseases, biomarkers and other traits (2.8%). cis-eQTLs, meQTLs, mQTLs and MHC region SNPs are highly enriched among significant results. After removing these categories, GRASP still contains a greater proportion of studies and results than comparable GWAS catalogs. Cardiovascular disease and related risk factors pre-dominate remaining GWAS results, followed by immunological, neurological and cancer traits. Significant results in GWAS display a highly gene-centric tendency. Sex chromosome X (OR = 0.180.16-0.20) and Y (OR = 0.0030.001-0.01) genes are depleted for GWAS results. Gene length is correlated with GWAS results at nominal significance (P ≤ 0.05) levels. We show this gene-length correlation decays at increasingly more stringent P-value thresholds. Potential pleotropic genes and SNPs enriched for multi-phenotype association in GWAS are identified. However, we note possible population stratification at some of these loci. Finally, via re-annotation we identify compelling functional hypotheses at GWAS loci, in some cases unrealized in studies to date.
Pooling summary-level GWAS results and re-annotating with bioinformatics predictions and molecular features provides a good platform for new insights.
The GRASP database is available at http://apps.nhlbi.nih.gov/grasp.
The work of Berezinskii, Kosterlitz and Thouless in the 1970s
revealed exotic phases of matter governed by the topological properties of low-dimensional materials such as thin films of superfluids ...and superconductors. A hallmark of this phenomenon is the appearance and interaction of vortices and antivortices in an angular degree of freedom-typified by the classical XY model-owing to thermal fluctuations. In the two-dimensional Ising model this angular degree of freedom is absent in the classical case, but with the addition of a transverse field it can emerge from the interplay between frustration and quantum fluctuations. Consequently, a Kosterlitz-Thouless phase transition has been predicted in the quantum system-the two-dimensional transverse-field Ising model-by theory and simulation
. Here we demonstrate a large-scale quantum simulation of this phenomenon in a network of 1,800 in situ programmable superconducting niobium flux qubits whose pairwise couplings are arranged in a fully frustrated square-octagonal lattice. Essential to the critical behaviour, we observe the emergence of a complex order parameter with continuous rotational symmetry, and the onset of quasi-long-range order as the system approaches a critical temperature. We describe and use a simple approach to statistical estimation with an annealing-based quantum processor that performs Monte Carlo sampling in a chain of reverse quantum annealing protocols. Observations are consistent with classical simulations across a range of Hamiltonian parameters. We anticipate that our approach of using a quantum processor as a programmable magnetic lattice will find widespread use in the simulation and development of exotic materials.
Activated T cells differentiate into functional subsets with distinct metabolic programs. Glutaminase (GLS) converts glutamine to glutamate to support the tricarboxylic acid cycle and redox and ...epigenetic reactions. Here, we identify a key role for GLS in T cell activation and specification. Though GLS deficiency diminished initial T cell activation and proliferation and impaired differentiation of Th17 cells, loss of GLS also increased Tbet to promote differentiation and effector function of CD4 Th1 and CD8 CTL cells. This was associated with altered chromatin accessibility and gene expression, including decreased PIK3IP1 in Th1 cells that sensitized to IL-2-mediated mTORC1 signaling. In vivo, GLS null T cells failed to drive Th17-inflammatory diseases, and Th1 cells had initially elevated function but exhausted over time. Transient GLS inhibition, however, led to increased Th1 and CTL T cell numbers. Glutamine metabolism thus has distinct roles to promote Th17 but constrain Th1 and CTL effector cell differentiation.
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•T cells utilize GLS to support glutaminolysis that integrates with glycolysis•GLS promotes differentiation and function of Th17 cells yet restrains Th1 cells•GLS alters chromatin and gene expression to enhance IL2 and mTORC1 signaling•Targeting GLS protects from Th17 and enhances Th1 cells but can lead to exhaustion
Glutamine metabolism, and its effects on chromatin, promotes Th17 but constrains Th1 and CTL effector cell differentiation.
Prominent cognitive deficits have been documented in bipolar disorder, and multiple studies suggest that these deficits can be observed among non-affected first-degree relatives of those with bipolar ...disorder. Although there is variability in the degree of cognitive deficits, these deficits are robustly relevant for functional outcomes. A separate literature documents clear difficulties in emotionality, emotion regulation, and emotion-relevant impulsivity within bipolar disorder, and demonstrates that these emotion-relevant variables are also central to outcome. Although cognitive and emotion domains are typically studied independently, basic research and emergent findings in bipolar disorder suggest that there are important ties between cognitive deficits and the emotion disturbances observed in bipolar disorder. Understanding these relationships has relevance for fostering more integrative research, for clarifying relevant aspects related to functionality and vulnerability within bipolar disorder, and for the development of novel treatment interventions.
Bipolar disorder (BD) is a severe psychiatric illness that has been ranked as one of the 20 leading medical causes of disability (WHO, 2011). BD has been shown to be the psychiatric disorder with the highest rates of completed suicide across two major cohort studies (Ilgen et al., 2010; Nordentoft, Mortensen, & Pedersen, 2011). In a cross-national representative sample, one in four persons diagnosed with bipolar I disorder reported a suicide attempt (Merikangas et al., 2011). Rates of relapse remain high despite available treatments (Gitlin, Swendsen, Heller, & Hammen, 1995), and in the year after hospitalization for manic episode, two-thirds of patients do not return to work (Strakowski et al., 1998). Poverty, homelessness, and incarceration are all too common (Copeland et al., 2009).
Despite the often poor outcomes, there is also evidence for outstanding accomplishments and creativity among those with milder forms of the disorder and their family members (Coryell et al., 1989; Jamison, 1993; Murray & Johnson, 2010). Some individuals appear to achieve more than the general population, suggesting the importance of understanding the variables that predict differential outcome within bipolar disorder.
Within this paper, we focus on two key predictors of outcomes within bipolar disorder: cognition and emotionality. We review evidence that problems in cognition and emotionality are prominent among those diagnosed with the disorder, are not artifacts of symptom state, and relate substantively to poorer outcomes. Although traditionally studied separately, new work points toward the idea that cognition and emotionality are intricately linked within bipolar disorder. Drawing from research within bipolar disorder as well as outside of bipolar disorder, we build a model of how cognition and emotionality might be tied within bipolar disorder. We then provide suggestions for future research.
Before considering findings, it is worth noting that there are several forms of the disorder, defined by varying degrees and duration of manic symptoms (APA, 2013; WHO, 1993). Manic episodes are defined by abnormally elevated or irritable mood, accompanied by increased activity and at least three symptoms (four if mood is only irritable) such as decreased need for sleep, increased self-confidence, racing thoughts or flight of ideas, rapid speech, distractibility, goal-directed activity, and engagement in pleasurable activities without regard to potential negative consequences. To meet criteria for mania, these symptoms must persist for at least one week or require hospitalization, and must lead to difficulties with functioning. If functional impairment is not more than mild and duration is between 4 and 6 days, the episode is considered a hypomanic episode. Bipolar I disorder (BD I) is diagnosed on the basis of at least one lifetime manic episode within the DSM-5 and by at least two episodes within the ICD, whereas bipolar II disorder is diagnosed on the basis of at least one hypomanic episode (and no manic episodes) as well as major depressive episodes. Cyclothymic disorder is defined by chronic but milder fluctuations between manic and depressive symptoms. Most research focuses on BD I.
In addition to diagnosed samples, research has focused on those at high risk for bipolar disorder, including first-degree relatives of those with BD. This work draws on the evidence for extremely high heritability of BD I, with estimates from community-based twin studies of 0.85 (Kieseppä, Partonen, Haukka, Kaprio, & Lönnqvist, 2014). Other research has considered high risk for BD by virtue of lifetime subsyndromal symptoms, as measured by scales such as the Hypomanic Personality Scale (Eckblad & Chapman, 1986) or the General Behavior Inventory (Depue, Krauss, Spoont, & Arbisi, 1989). The study of high-risk individuals provides a way to decipher whether deficits are present before the onset of the disorder, of importance given models suggesting that episodes of the disorder may change brain function (Chang, Steiner, & Ketter, 2000; Strakowski, 2012) as well as individuals' perceptions of their emotion regulation.
Beyond defining BD, it is worth defining some of the many different neuropsychological tasks that have been widely studied in BD. Perhaps no area has received more attention than executive function. Executive function is related to three core functions: 1) inhibition, the ability to suppress irrelevant information in working memory in order to accomplish an established goal; 2) working memory, the ability to hold and manipulate information in mind; and 3) cognitive flexibility, the ability to shift strategies in response to feedback (Diamond, 2013; Miyake et al., 2000). Attention (defined as the process of selecting information reception from internal or external cues) is implicated in all three of these aspects of executive function. Much of the literature we will discuss focuses on response inhibition, or the ability to suppress a prepotent response, which is considered a subtype of inhibition. Some tests measure multiple facets of executive function; for example the Trails B test likely requires working memory and cognitive flexibility (Sánchez-Cubillo et al., 2009).
Aside from executive function, multiple other facets of cognition have been widely studied in bipolar disorder. Verbal and non-verbal memory are related to the ability to register, store and retrieve verbal or visual information (Lezak, 1995). Verbal fluency is measured as the number of verbal responses a person can generate to a given target, such as a specific semantic category (e.g., animals, furniture) or phonetic category (e.g., words that begin with letter F) (Diamond, 2013). Although cognitive tasks have been designed to evaluate these specific functions, it is important to note that most measures are highly inter-correlated and may assess multiple overlapping functions to some extent (for example, the Trails B test is often described as an “executive function” task, although this task likely involves both working memory and cognitive flexibility. Not surprisingly, then, some authors label the function of certain tests differently, and this is particularly evident in meta-analyses of cognition. As we describe findings in this paper, we will use the terms proposed by the authors but will also identify key tests used to define a cognitive construct.
With this background in mind, we turn to a discussion of cognitive deficits, then of emotion-related traits. Our hope is that those concise summaries provide evidence for the importance of both domains, but also specificity regarding the facets of emotion and cognition that are most impaired in BD. This specificity then guides our consideration of models that integrate cognition and emotion.
•People with bipolar disorder and their relatives often show neurocognitive deficits.•Emotion concerns are observed in bipolar disorder and those vulnerable to the disorder.•New models outside of bipolar disorder suggest these domains are linked.•It is important to integrate neurocognition and emotion research within bipolar disorder.
Embryos of many animal models express germ line determinants that suppress transcription and mediate early germ line commitment, which occurs before the somatic cell lineages are established. ...However, not all animals segregate their germ line in this manner. The 'last cell standing' model describes primordial germ cell (PGC) development in axolotls, in which PGCs are maintained by an extracellular signalling niche, and germ line commitment occurs after gastrulation. Here, we propose that this 'stochastic' mode of PGC specification is conserved in vertebrates, including non-rodent mammals. We postulate that early germ line segregation liberates genetic regulatory networks for somatic development to evolve, and that it therefore emerged repeatedly in the animal kingdom in response to natural selection.
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