SARS-CoV-2 has mutated during the global pandemic leading to viral adaptation to medications and vaccinations. Here we describe an engineered human virus receptor, ACE2, by mutagenesis and screening ...for binding to the receptor binding domain (RBD). Three cycles of random mutagenesis and cell sorting achieved sub-nanomolar affinity to RBD. Our structural data show that the enhanced affinity comes from better hydrophobic packing and hydrogen-bonding geometry at the interface. Additional disulfide mutations caused the fixing of a closed ACE2 conformation to avoid off-target effects of protease activity, and also improved structural stability. Our engineered ACE2 neutralized SARS-CoV-2 at a 100-fold lower concentration than wild type; we also report that no escape mutants emerged in the co-incubation after 15 passages. Therapeutic administration of engineered ACE2 protected hamsters from SARS-CoV-2 infection, decreased lung virus titers and pathology. Our results provide evidence of a therapeutic potential of engineered ACE2.
Electric Circuit Induced by Quantum Walk Higuchi, Yusuke; Sabri, Mohamed; Segawa, Etsuo
Journal of statistical physics,
10/2020, Letnik:
181, Številka:
2
Journal Article
Recenzirano
We consider the Szegedy walk on graphs adding infinite length tails to a finite internal graph. We assume that on these tails, the dynamics is given by the free quantum walk. We set the
ℓ
∞
-category ...initial state so that the internal graph receives time independent input from the tails, say
α
in
, at every time step. We show that the response of the Szegedy walk to the input, which is the output, say
β
out
, from the internal graph to the tails in the long time limit, is drastically changed depending on the reversibility of the underlying random walk. If the underlying random walk is reversible, we have
β
out
=
Sz
(
m
δ
E
)
α
in
, where the unitary matrix
Sz
(
m
δ
E
)
is the reflection matrix to the unit vector
m
δ
E
which is determined by the boundary of the internal graph
δ
E
. Then the global dynamics so that the internal graph is regarded as one vertex recovers the local dynamics of the Szegedy walk in the long time limit. Moreover if the underlying random walk of the Szegedy walk is reversible, then we obtain that the stationary state is expressed by a linear combination of the reversible measure and the electric current on the electric circuit determined by the internal graph and the random walk’s reversible measure. On the other hand, if the underlying random walk is not reversible, then the unitary matrix is just a phase flip; that is,
β
out
=
-
α
in
, and the stationary state is similar to the current flow but satisfies a different type of the Kirchhoff laws.
We consider the Grover walk on infinite trees from the viewpoint of spectral analysis. From the previous work, infinite regular trees provide localization. In this paper, we give the complete ...characterization of the eigenspace of this Grover walk, which involves localization of its behavior and recovers the previous work. Our result suggests that the Grover walk on infinite trees may be regarded as a limit of the quantum walk induced by the isotropic random walk with the Dirichlet boundary condition at the n-th depth rather than one with the Neumann boundary condition.
Circuit Equation of Grover Walk Higuchi, Yusuke; Segawa, Etsuo
Annales Henri Poincaré,
2024/8, Letnik:
25, Številka:
8
Journal Article
Recenzirano
We consider the Grover walk on the infinite graph in which an internal finite subgraph receives the inflow from the outside with some frequency and also radiates the outflow to the outside. To ...characterize the stationary state of this system, which is represented by a function on the arcs of the graph, we introduce a kind of discrete gradient operator twisted by the frequency. Then, we obtain a circuit equation which shows that (i) the stationary state is described by the twisted gradient of a potential function which is a function on the vertices; (ii) the potential function satisfies the Poisson equation with respect to a generalized Laplacian matrix. Consequently, we characterize the scattering on the surface of the internal graph and the energy penetrating inside it. Moreover, for the complete graph as the internal graph, we illustrate the relationship of the scattering and the internal energy to the frequency and the number of tails.
We propose a twisted Szegedy walk for estimating the limit behavior of a discrete-time quantum walk on a crystal lattice, an infinite abelian covering graph, whose notion was introduced by 14. First, ...we show that the spectrum of the twisted Szegedy walk on the quotient graph can be expressed by mapping the spectrum of a twisted random walk onto the unit circle. Secondly, we show that the spatial Fourier transform of the twisted Szegedy walk on a finite graph with appropriate parameters becomes the Grover walk on its infinite abelian covering graph. Finally, as an application, we show that if the Betti number of the quotient graph is strictly greater than one, then localization is ensured with some appropriated initial state. We also compute the limit density function for the Grover walk on Zd with flip flop shift, which implies the coexistence of linear spreading and localization. We partially obtain the abstractive shape of the limit density function: the support is within the d-dimensional sphere of radius 1/d, and 2d singular points reside on the sphere's surface.
We treat a quantum walk model with in- and out-flows at every time step from the outside. We show that this quantum walk can find the marked vertex of the complete graph with a high probability in ...the stationary state. In exchange of the stability, the convergence time is estimated by
O
(
N
log
N
)
, where
N
is the number of vertices. However, until the time step
O
(
N
), we show that there is a pulsation with the periodicity
O
(
N
)
. We find the marked vertex with a high relative probability in this pulsation phase. This means that we have two chances to find the marked vertex with a high relative probability; the first chance visits in the pulsation phase at short time step
O
(
N
)
, while the second chance visits in the stable phase after long time step
O
(
N
log
N
)
. The proofs are based on Kato’s perturbation theory.
Nonalcoholic steatohepatitis (NASH) is a progressive disorder with aberrant lipid accumulation and subsequent inflammatory and profibrotic response. Therapeutic efforts at lipid reduction via ...increasing cytoplasmic lipolysis unfortunately worsens hepatitis due to toxicity of liberated fatty acid. An alternative approach could be lipid reduction through autophagic disposal, i.e., lipophagy. We engineered a synthetic adaptor protein to induce lipophagy, combining a lipid droplet-targeting signal with optimized LC3-interacting domain. Activating hepatocyte lipophagy in vivo strongly mitigated both steatosis and hepatitis in a diet-induced mouse NASH model. Mechanistically, activated lipophagy promoted the excretion of lipid from hepatocytes, thereby suppressing harmful intracellular accumulation of nonesterified fatty acid. A high-content compound screen identified alpelisib and digoxin, clinically-approved compounds, as effective activators of lipophagy. Administration of alpelisib or digoxin in vivo strongly inhibited the transition to steatohepatitis. These data thus identify lipophagy as a promising therapeutic approach to prevent NASH progression.
Energy starvation and the shift of energy substrate from fatty acids to glucose is the hallmark of metabolic remodeling during heart failure progression. However, ketone body metabolism in the ...failing heart has not been fully investigated.
Microarray data analysis and mitochondrial isobaric tags for relative and absolute quantification proteomics revealed that the expression of D-β-hydroxybutyrate dehydrogenase I (Bdh1), an enzyme that catalyzes the NAD
/NADH coupled interconversion of acetoacetate and β-hydroxybutyrate, was increased 2.5- and 2.8-fold, respectively, in the heart after transverse aortic constriction. In addition, ketone body oxidation was upregulated 2.2-fold in transverse aortic constriction hearts, as determined by the amount of
CO
released from the metabolism of 1-
C β-hydroxybutyrate in isolated perfused hearts. To investigate the significance of this augmented ketone body oxidation, we generated heart-specific Bdh1-overexpressing transgenic mice to recapitulate the observed increase in basal ketone body oxidation. Bdh1 transgenic mice showed a 1.7-fold increase in ketone body oxidation but did not exhibit any differences in other baseline characteristics. When subjected to transverse aortic constriction, Bdh1 transgenic mice were resistant to fibrosis, contractile dysfunction, and oxidative damage, as determined by the immunochemical detection of carbonylated proteins and histone acetylation. Upregulation of Bdh1 enhanced antioxidant enzyme expression. In our in vitro study, flow cytometry revealed that rotenone-induced reactive oxygen species production was decreased by adenovirus-mediated Bdh1 overexpression. Furthermore, hydrogen peroxide-induced apoptosis was attenuated by Bdh1 overexpression.
We demonstrated that ketone body oxidation increased in failing hearts, and increased ketone body utilization decreased oxidative stress and protected against heart failure.
Staggered quantum walks on graphs are based on the concept of graph tessellation and generalize some well-known discrete-time quantum walk models. In this work, we address the class of 2-tessellable ...quantum walks with the goal of obtaining an eigenbasis of the evolution operator. By interpreting the evolution operator as a quantum Markov chain on an underlying multigraph, we define the concept of quantum detailed balance, which helps to obtain the eigenbasis. A subset of the eigenvectors is obtained from the eigenvectors of the double discriminant matrix of the quantum Markov chain. To obtain the remaining eigenvectors, we have to use the quantum detailed balance conditions. If the quantum Markov chain has a quantum detailed balance, there is an eigenvector for each fundamental cycle of the underlying multigraph. If the quantum Markov chain does not have a quantum detailed balance, we have to use two fundamental cycles linked by a path in order to find the remaining eigenvectors. We exemplify the process of obtaining the eigenbasis of the evolution operator using the kagome lattice (the line graph of the hexagonal lattice), which has symmetry properties that help in the calculation process.
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