New early dark energy (NEDE) is a component of vacuum energy at the electron volt scale, which decays in a first-order phase transition shortly before recombination F. Niedermann and M. S. Sloth, New ...early dark energy. The NEDE component has the potential to resolve the tension between recent local measurements of the expansion rate of the Universe using supernovae (SN) data and the expansion rate inferred from the early Universe through measurements of the cosmic microwave background (CMB) when assuming Λ CDM . We discuss in depth the two-scalar field model of the NEDE phase transition including the process of bubble percolation, collision, and coalescence. We also estimate the gravitational wave signal produced during the collision phase and argue that it can be searched for using pulsar timing arrays. In a second step, we construct an effective cosmological model, which describes the phase transition as an instantaneous process, and derive the covariant equations that match perturbations across the transition surface. Fitting the cosmological model to CMB, baryonic acoustic oscillations, and SN data, we report ... km s−1 Mpc−1 (68% C.L.) without the local measurement of the Hubble parameter, bringing the tension down to 2.5 σ . Including the local input, we find H0 = 71.4 ± 1.0 km s−1 Mpc−1 (68% C.L.) and strong evidence for a nonvanishing NEDE component with a ≃ 4σ significance.
The Macroeconomics of Epidemics Eichenbaum, Martin S; Rebelo, Sergio; Trabandt, Mathias
The Review of financial studies,
11/2021, Letnik:
34, Številka:
11
Journal Article
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Abstract
We extend the canonical epidemiology model to study the interaction between economic decisions and epidemics. Our model implies that people cut back on consumption and work to reduce the ...chances of being infected. These decisions reduce the severity of the epidemic but exacerbate the size of the associated recession. The competitive equilibrium is not socially optimal because infected people do not fully internalize the effect of their economic decisions on the spread of the virus. In our benchmark model, the best simple containment policy increases the severity of the recession but saves roughly half a million lives in the United States.
New early dark energy Niedermann, Florian; Sloth, Martin S.
Physical review. D,
02/2021, Letnik:
103, Številka:
4
Journal Article
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New measurements of the expansion rate of the Universe have plunged the standard model of cosmology into a severe crisis. In this paper, we propose a simple resolution to the problem that relies on a ...first order phase transition in a dark sector in the early Universe, before recombination. This will lead to a short phase of a new early dark energy (NEDE) component and can explain the observations. We model the false vacuum decay of the NEDE scalar field as a sudden transition from a cosmological constant source to a decaying fluid with constant equation of state. The corresponding fluid perturbations are covariantly matched to the adiabatic fluctuations of a subdominant scalar field that triggers the phase transition. Fitting our model to measurements of the cosmic microwave background (CMB), baryonic acoustic oscillations (BAO, and supernovae (SNe) yields a significant improvement of the best fit compared with the standard cosmological model without NEDE. We find the mean value of the present Hubble parameter in the NEDE model to be H0 = 71.4 ± 1.0 km s−1 Mpc−1 (68% C.L.).
The global spread of SARS-CoV-2/COVID-19 is devastating health systems and economies worldwide. Recombinant or vaccine-induced neutralizing antibodies are used to combat the COVID-19 pandemic. ...However, the recently emerged SARS-CoV-2 variants B.1.1.7 (UK), B.1.351 (South Africa), and P.1 (Brazil) harbor mutations in the viral spike (S) protein that may alter virus-host cell interactions and confer resistance to inhibitors and antibodies. Here, using pseudoparticles, we show that entry of all variants into human cells is susceptible to blockade by the entry inhibitors soluble ACE2, Camostat, EK-1, and EK-1-C4. In contrast, entry of the B.1.351 and P.1 variant was partially (Casirivimab) or fully (Bamlanivimab) resistant to antibodies used for COVID-19 treatment. Moreover, entry of these variants was less efficiently inhibited by plasma from convalescent COVID-19 patients and sera from BNT162b2-vaccinated individuals. These results suggest that SARS-CoV-2 may escape neutralizing antibody responses, which has important implications for efforts to contain the pandemic.
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•B.1.1.7, B.1.351, and P.1 do not show augmented host cell entry•Entry inhibitors under clinical evaluation block all variants•B.1.351 and P.1 can escape from therapeutic antibodies•B.1.351 and P.1 evade antibodies induced by infection and vaccination
Comparison of the SARS-CoV-2 variants B.1.1.7, B.1.351, and P.1 shows that inhibitors under clinical evaluation are still effective in blocking entry, though the B.1.351 and P.1 variants evade antibody responses induced upon infection as well as vaccination and evade certain therapeutic antibodies.
The rapid spread of the SARS-CoV-2 Omicron variant suggests that the virus might become globally dominant. Further, the high number of mutations in the viral spike protein raised concerns that the ...virus might evade antibodies induced by infection or vaccination. Here, we report that the Omicron spike was resistant against most therapeutic antibodies but remained susceptible to inhibition by sotrovimab. Similarly, the Omicron spike evaded neutralization by antibodies from convalescent patients or individuals vaccinated with the BioNTech-Pfizer vaccine (BNT162b2) with 12- to 44-fold higher efficiency than the spike of the Delta variant. Neutralization of the Omicron spike by antibodies induced upon heterologous ChAdOx1 (Astra Zeneca-Oxford)/BNT162b2 vaccination or vaccination with three doses of BNT162b2 was more efficient, but the Omicron spike still evaded neutralization more efficiently than the Delta spike. These findings indicate that most therapeutic antibodies will be ineffective against the Omicron variant and that double immunization with BNT162b2 might not adequately protect against severe disease induced by this variant.
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•Omicron uses human and animal ACE2 for host cell entry•Omicron is resistant against neutralization by several therapeutic antibodies•Omicron efficiently evades antibodies from infected or 2 × BNT-vaccinated patients•Omicron moderately evades antibodies induced by 3 × BNT or heterologous vaccination
The SARS-CoV-2 Omicron variant is rapidly spreading worldwide and a public health concern. Experiments show that this variant is resistant against several therapeutic antibodies for COVID-19 and efficiently evades antibodies induced upon infection or double BNT162b2 vaccination, but not triple BNT162b2 or ChAdOx1/BNT162b2 vaccination.
Treatment of relapsed or refractory acute myeloid leukemia (AML) has presented challenges for hematologists for decades. Despite numerous clinical studies, outcomes are consistently disappointing ...with 5-year overall survival rates of ∼10%. Allogeneic hematopoietic cell transplantation at the time of second complete remission remains the only reliable option with curative potential. However, recent approval of several new agents has transformed treatment paradigms that had been in place for almost half a century in AML. This new therapeutic landscape provides the opportunity to revisit the approach to relapsed or refractory AML. Through illustrative cases, we describe our approach, which increasingly relies on specific disease biology. We focus on treatment outside of the context of clinical trials because such trials are not available in most parts of the world. Primarily, we consider age, fitness to tolerate intensive chemotherapy, remission duration, and presence of a targetable mutation to guide treatment. The coming years will inevitably bring new targets and agents that may prove most effective when combined with each other and/or chemotherapy. Future studies are needed to determine how best to implement this evolving armamentarium of treatment options, to elucidate mechanisms of resistance, and to continue the pursuit of novel drug discovery.
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A genome-wide association study (GWAS) seeks to identify genetic variants that contribute to the development and progression of a specific disease. Over the past 10 years, new approaches using mixed ...models have emerged to mitigate the deleterious effects of population structure and relatedness in association studies. However, developing GWAS techniques to accurately test for association while correcting for population structure is a computational and statistical challenge. Using laboratory mouse strains as an example, our review characterizes the problem of population structure in association studies and describes how it can cause false positive associations. We then motivate mixed models in the context of unmodeled factors.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Hypertrophic cardiomyopathy (HCM) is characterized by substantial genetic and phenotypic heterogeneity, leading to considerable diversity in clinical course including the most common cause of sudden ...death in young people and a determinant of heart failure symptoms in patients of any age. Traditionally, two-dimensional echocardiography has been the most reliable method for establishing a clinical diagnosis of HCM. However, cardiovascular magnetic resonance (CMR), with its high spatial resolution and tomographic imaging capability, has emerged as a technique particularly well suited to characterize the diverse phenotypic expression of this complex disease. For example, CMR is often superior to echocardiography for HCM diagnosis, by identifying areas of segmental hypertrophy (ie., anterolateral wall or apex) not reliably visualized by echocardiography (or underestimated in terms of extent). High-risk HCM patient subgroups identified with CMR include those with thin-walled scarred LV apical aneurysms (which prior to CMR imaging in HCM remained largely undetected), end-stage systolic dysfunction, and massive LV hypertrophy. CMR observations also suggest that the cardiomyopathic process in HCM is more diffuse than previously regarded, extending beyond the LV myocardium to include thickening of the right ventricular wall as well as substantial morphologic diversity with regard to papillary muscles and mitral valve. These findings have implications for management strategies in patients undergoing invasive septal reduction therapy. Among HCM family members, CMR has identified unique phenotypic markers of affected genetic status in the absence of LV hypertrophy including: myocardial crypts, elongated mitral valve leaflets and late gadolinium enhancement. The unique capability of contrast-enhanced CMR with late gadolinium enhancement to identify myocardial fibrosis has raised the expectation that this may represent a novel marker, which may enhance risk stratification. At this time, late gadolinium enhancement appears to be an important determinant of adverse LV remodeling associated with systolic dysfunction. However, the predictive significance of LGE for sudden death is incompletely resolved and ultimately future large prospective studies may provide greater insights into this issue. These observations underscore an important role for CMR in the contemporary assessment of patients with HCM, providing important information impacting diagnosis and clinical management strategies.
The use of transaminases to access pharmaceutically relevant chiral amines is an attractive alternative to transition-metal-catalysed asymmetric chemical synthesis. However, one major challenge is ...their limited substrate scope. Here we report the creation of highly active and stereoselective transaminases starting from fold class I. The transaminases were developed by extensive protein engineering followed by optimization of the identified motif. The resulting enzymes exhibited up to 8,900-fold higher activity than the starting scaffold and are highly stereoselective (up to >99.9% enantiomeric excess) in the asymmetric synthesis of a set of chiral amines bearing bulky substituents. These enzymes should therefore be suitable for use in the synthesis of a wide array of potential intermediates for pharmaceuticals. We also show that the motif can be engineered into other protein scaffolds with sequence identities as low as 70%, and as such should have a broad impact in the field of biocatalytic synthesis and enzyme engineering.
Recently, a full-shape analysis of large-scale structure (LSS) data was employed to provide new constraints on a class of early dark energy models. In this paper, we derive similar constraints on new ...early dark energy (NEDE) using the publicly available pybird code, which makes use of the effective field theory of LSS. We study the NEDE base model with the fraction of NEDE and the trigger field mass as two additional parameters allowed to vary freely, while making simplifying assumptions about the decaying fluid sector. Including the full-shape analysis of LSS together with measurements of the cosmic microwave background, baryonic acoustic oscillations, and supernovae data, we report H 0 = 71.2 ± 1.0 km s−1 Mpc−1 (68% C.L.) together with an approximate 4 σ evidence for a nonvanishing fraction of NEDE. This is an insignificant change to the value previously found without full-shape LSS data, H 0 = 71.4 ± 1.0 km s−1 Mpc−1 (68% C.L.). As a result, while the NEDE fit cannot be improved upon the inclusion of additional LSS data, it is also not adversely affected by it, making it compatible with current constraints from LSS data. In fact, we find evidence that the effective field theory of LSS acts in favor of NEDE.
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