SARS-CoV-2 enters host cells through an interaction between the spike glycoprotein and the angiotensin converting enzyme 2 (ACE2) receptor. Directly preventing this interaction presents an attractive ...possibility for suppressing SARS-CoV-2 replication. Here, we report the isolation and characterization of an alpaca-derived single domain antibody fragment, Ty1, that specifically targets the receptor binding domain (RBD) of the SARS-CoV-2 spike, directly preventing ACE2 engagement. Ty1 binds the RBD with high affinity, occluding ACE2. A cryo-electron microscopy structure of the bound complex at 2.9 Å resolution reveals that Ty1 binds to an epitope on the RBD accessible in both the 'up' and 'down' conformations, sterically hindering RBD-ACE2 binding. While fusion to an Fc domain renders Ty1 extremely potent, Ty1 neutralizes SARS-CoV-2 spike pseudovirus as a 12.8 kDa nanobody, which can be expressed in high quantities in bacteria, presenting opportunities for manufacturing at scale. Ty1 is therefore an excellent candidate as an intervention against COVID-19.
Colloquium : Quantum coherence as a resource Streltsov, Alexander; Adesso, Gerardo; Plenio, Martin B
Reviews of modern physics,
10/2017, Letnik:
89, Številka:
4
Journal Article
Recenzirano
Odprti dostop
The coherent superposition of states, in combination with the quantization of observables, represents one of the most fundamental features that mark the departure of quantum mechanics from the ...classical realm. Quantum coherence in many-body systems embodies the essence of entanglement and is an essential ingredient for a plethora of physical phenomena in quantum optics, quantum information, solid state physics, and nanoscale thermodynamics. In recent years, research on the presence and functional role of quantum coherence in biological systems has also attracted considerable interest. Despite the fundamental importance of quantum coherence, the development of a rigorous theory of quantum coherence as a physical resource has been initiated only recently. This Colloquium discusses and reviews the development of this rapidly growing research field that encompasses the characterization, quantification, manipulation, dynamical evolution, and operational application of quantum coherence.
This paper develops a model of the nursing home industry to investigate the quality effects of policies that either raise regulated reimbursement rates or increase local competition. Using data from ...Pennsylvania, I estimate the parameters of the model. The findings indicate that nursing homes increase the quality of care, measured by the number of skilled nurses per resident, by 8.7 percent following a universal 10 percent increase in Medicaid reimbursement rates. In contrast, I find that pro-competitive policies lead to only small increases in skilled nurse staffing ratios, suggesting that Medicaid increases are more cost effective in raising the quality of care.
In response to major changes in diagnostic algorithms and the publication of mature results from various large clinical trials, the European Association of Neuro-Oncology (EANO) recognized the need ...to provide updated guidelines for the diagnosis and management of adult patients with diffuse gliomas. Through these evidence-based guidelines, a task force of EANO provides recommendations for the diagnosis, treatment and follow-up of adult patients with diffuse gliomas. The diagnostic component is based on the 2016 update of the WHO Classification of Tumors of the Central Nervous System and the subsequent recommendations of the Consortium to Inform Molecular and Practical Approaches to CNS Tumour Taxonomy - Not Officially WHO (cIMPACT-NOW). With regard to therapy, we formulated recommendations based on the results from the latest practice-changing clinical trials and also provide guidance for neuropathological and neuroradiological assessment. In these guidelines, we define the role of the major treatment modalities of surgery, radiotherapy and systemic pharmacotherapy, covering current advances and cognizant that unnecessary interventions and expenses should be avoided. This document is intended to be a source of reference for professionals involved in the management of adult patients with diffuse gliomas, for patients and caregivers, and for health-care providers.
The coronavirus disease 2019 (COVID-19) pandemic has placed epidemic modeling at the forefront of worldwide public policy making. Nonetheless, modeling and forecasting the spread of COVID-19 remains ...a challenge. Here, we detail three regionalscale models for forecasting and assessing the course of the pandemic. This work demonstrates the utility of parsimonious models for early-time data and provides an accessible framework for generating policy-relevant insights into its course. We show how these models can be connected to each other and to time series data for a particular region. Capable of measuring and forecasting the impacts of social distancing, these models highlight the dangers of relaxing nonpharmaceutical public health interventions in the absence of a vaccine or antiviral therapies.
The coronavirus SARS-CoV-2 is the cause of the ongoing COVID-19 pandemic. Therapeutic neutralizing antibodies constitute a key short-to-medium term approach to tackle COVID-19. However, traditional ...antibody production is hampered by long development times and costly production. Here, we report the rapid isolation and characterization of nanobodies from a synthetic library, known as sybodies (Sb), that target the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. Several binders with low nanomolar affinities and efficient neutralization activity were identified of which Sb23 displayed high affinity and neutralized pseudovirus with an IC
of 0.6 µg/ml. A cryo-EM structure of the spike bound to Sb23 showed that Sb23 binds competitively in the ACE2 binding site. Furthermore, the cryo-EM reconstruction revealed an unusual conformation of the spike where two RBDs are in the 'up' ACE2-binding conformation. The combined approach represents an alternative, fast workflow to select binders with neutralizing activity against newly emerging viruses.
We present a comprehensive and up-to-date review of the concept of quantum non-Markovianity, a central theme in the theory of open quantum systems. We introduce the concept of a quantum Markovian ...process as a generalization of the classical definition of Markovianity via the so-called divisibility property and relate this notion to the intuitive idea that links non-Markovianity with the persistence of memory effects. A detailed comparison with other definitions presented in the literature is provided. We then discuss several existing proposals to quantify the degree of non-Markovianity of quantum dynamics and to witness non-Markovian behavior, the latter providing sufficient conditions to detect deviations from strict Markovianity. Finally, we conclude by enumerating some timely open problems in the field and provide an outlook on possible research directions.
A new paradigm for cellulose depolymerization by fungi focuses on an oxidative mechanism involving cellobiose dehydrogenases (CDH) and copper-dependent lytic polysaccharide monooxygenases (LPMO); ...however, mechanistic studies have been hampered by the lack of structural information regarding CDH. CDH contains a haem-binding cytochrome (CYT) connected via a flexible linker to a flavin-dependent dehydrogenase (DH). Electrons are generated from cellobiose oxidation catalysed by DH and shuttled via CYT to LPMO. Here we present structural analyses that provide a comprehensive picture of CDH conformers, which govern the electron transfer between redox centres. Using structure-based site-directed mutagenesis, rapid kinetics analysis and molecular docking, we demonstrate that flavin-to-haem interdomain electron transfer (IET) is enabled by a haem propionate group and that rapid IET requires a closed CDH state in which the propionate is tightly enfolded by DH. Following haem reduction, CYT reduces LPMO to initiate oxygen activation at the copper centre and subsequent cellulose depolymerization.
We consider the Rabi Hamiltonian, which exhibits a quantum phase transition (QPT) despite consisting only of a single-mode cavity field and a two-level atom. We prove QPT by deriving an exact ...solution in the limit where the atomic transition frequency in the unit of the cavity frequency tends to infinity. The effect of a finite transition frequency is studied by analytically calculating finite-frequency scaling exponents as well as performing a numerically exact diagonalization. Going beyond this equilibrium QPT setting, we prove that the dynamics under slow quenches in the vicinity of the critical point is universal; that is, the dynamics is completely characterized by critical exponents. Our analysis demonstrates that the Kibble-Zurek mechanism can precisely predict the universal scaling of residual energy for a model without spatial degrees of freedom. Moreover, we find that the onset of the universal dynamics can be observed even with a finite transition frequency.
School-based interventions are thought to be the most universally applicable and effective way to counteract low physical activity (PA) and fitness although there is controversy about the optimal ...strategy to intervene.
The objective of this review was to summarise recent reviews that aimed to increase PA or fitness in youth and carry out a systematic review of new intervention studies.
Relevant systematic reviews and original controlled and randomised controlled school-based trials with a PA or fitness outcome measure, a duration of ≥12 weeks, a sufficient quality and involvement of a healthy population aged 6-18 years that were published from 2007 to 2010 were included. Results In these reviews, 47-65% of trials were found to be effective. The effect was mostly seen in school-related PA while effects outside school were often not observed or assessed.
The school-based application of multicomponent intervention strategies was the most consistent, promising strategy, while controversy existed regarding the effectiveness of family involvement, focus on healthy populations at increased risk or duration and intensity of the intervention. All 20 trials in the review update showed a positive effect on in-school, out-of-school or overall PA, and 6 of 11 studies showed an increase in fitness. Taking into consideration both assessment quality and public health relevance, multicomponent approaches in children including family components showed the highest level of evidence for increasing overall PA. This review confirms the public health potential of high quality, school-based PA interventions for increasing PA and possibly fitness in healthy youth.
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